Lymphoma Research Foundation Patient Booklets 2010

Understanding Hodgkin Lymphoma A Guide for Patients, Survivors and Loved Ones Third Edition Understanding Hodgkin L...

Author: Editor-in-chief:M. Coleman | MD

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Understanding

Hodgkin Lymphoma A Guide for Patients, Survivors and Loved Ones Third Edition

Understanding

Hodgkin Lymphoma A Guide for Patients, Survivors and Loved Ones Third Edition

Published by: Lymphoma Research Foundation Editorial Board Chairman: Morton Coleman, MD Medical Writer: Jo Cavallo This guide is an educational resource compiled by the Lymphoma Research Foundation providing general information on Hodgkin lymphoma. Publication of this information is not intended to take the place of medical care or the advice of your doctor. Patients are strongly encouraged to talk to their physicians for complete information on how their disease should be diagnosed, treated and followed. Before starting treatment, patients should discuss the potential benefits and side effects of cancer therapy.

National Headquarters 115 Broadway, 13th Floor New York, NY 10006 (212) 349-2910 (212) 349-2886 fax Helpline: (800) 500-9976 [email protected] Website: lymphoma.org Email: [email protected] This patient guide is supported through unrestricted educational grants from:

Presenting Sponsor

Gold Sponsor

Silver Sponsors

Abbott Oncology Lilly Oncology Xencor © 2009 Lymphoma Research Foundation Information contained herein is the property of the Lymphoma Research Foundation (LRF). Any portion may be reprinted or reproduced provided that LRF is acknowledged to be the author.

ACKNOWLEDGMENTS Lymphoma Research Foundation wishes to acknowledge those individuals listed below who have given generously of their time and expertise. We thank them for their contributions, editorial wisdom and advice which have truly enhanced this publication. The chairman and senior advisors guided the content and development of this publication. Without their dedication and efforts this publication would not have been possible. We hope those in the lymphoma community will now be better informed and have a better understanding of their illness because of the gracious efforts of those involved in the planning and execution of this comprehensive disease guide. Editorial Board Chairman

Steering Committee

Morton Coleman, MD, Weill Cornell Medical College-New York Presbyterian Hospital Senior Advisors Ralph Meyer, MD, National Cancer Institute of Canada and Queens University Jennifer Mills, LMSW, MPH, Lymphoma Research Foundation David Straus, MD, Memorial Sloan-Kettering Cancer Center

Review Committee

Carolyn Bell, MSW, Lymphoma Research Foundation Richard Boyajian, RN, MSN, APN, Dana-Farber Cancer Institute Joseph Connors, MD, British Columbia Cancer Agency Henry Fung, MD, Rush University Medical Center Randy Gascoyne, MD, British Columbia Cancer Agency Richard R. Furman, MD, Weill Cornell Medical College Les Gallo-Silver, ACSW, LCSW-R, LaGuardia Community College, CUNY Sandra Horning, MD, Stanford University Medical Center Lisa B. Kenney, MD, MPH, Dana-Farber Cancer Institute Joanna Morales, Esq, Cancer Legal Resource Center Brian Tomlinson, MPA, BSW, Lymphoma Research Foundation Kathleen Wesa, MD, Memorial Sloan-Kettering Cancer Center Teresa Woodruff, PhD, Northwestern University Anas Younes, MD, MD Anderson Cancer Center Bradley Zebrack, PhD, MSW, MPH, University of Michigan School of Social Work

ii Understanding Hodgkin Lymphoma

Table of Contents Part I: Learning the Basics Chapter 1 Overview of Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 Hodgkin Lymphoma Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 The Causes of Hodgkin Lymphoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 Types of Hodgkin Lymphoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 Chapter 2 Signs and Symptoms of Hodgkin Lymphoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11 When to Seek Medical Attention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11 What the Doctor Looks for During a Physical Examination . . . . . . . . . . . . . . . . . 12 Chapter 3 Getting a Diagnosis—What to Expect . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13 Common Tests Used to Make a Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14 Tumor Bulk . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18 Cancer Staging and What It Means . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18 Getting a Second Opinion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19 Choosing an Oncologist and Treatment Center . . . . . . . . . . . . . . . . . . . . . . . . . . 20

Part 2: Treating Hodgkin Lymphoma Chapter 4 What You Should Know Before Starting Treatment . . . . . . . . . . . . . . . . . . . . . . Treatments for Hodgkin Lymphoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Communicating With Your Healthcare Team . . . . . . . . . . . . . . . . . . . . . . . . . . . . How to Be a Self-Advocate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Factors Affecting Treatment Outcome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Terms Describing Possible Outcomes of Treatment . . . . . . . . . . . . . . . . . . . . . . Chapter 5 Types of Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Chemotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Bone Marrow and Stem Cell Transplantation . . . . . . . . . . . . . . . . . . . . . . . . . . . . Biologic Treatments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Radiation Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Vaccines and Cell Therapies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Complementary and Alternative Remedies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Drug Costs: What to Do If Your Insurance Doesn’t Pay . . . . . . . . . . . . . . . . . . . .

23 24 25 27 28 29 31 32 36 39 40 41 41 43

Part 3: Treatment Side Effects Chapter 6 Coping With Common Treatment Side Effects . . . . . . . . . . . . . . . . . . . . . . . . . . 45 The Difference Between Long-Term Effects and Late Effects of Cancer Treatment . . 45 Side Effects Caused by Chemotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46 Side Effects Caused by Radiation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53 Side Effects Caused by Bone Marrow Transplantation . . . . . . . . . . . . . . . . . . . . 56 Side Effects Caused by Steroids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56 When to See Your Doctor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56 Combating Side Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57 Chapter 7 Sexuality . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59 Sexual Function During Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59 When to Use Contraceptives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 60 Understanding Hodgkin Lymphoma iii

Chapter 8 Fertility Risks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61 How to Protect Fertility During Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61 Chapter 9 Hodgkin Lymphoma During Pregnancy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63 Breast-Feeding During Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64

Part 4: Children and Young Adults With Hodgkin Lymphoma Chapter 10 General Information . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65 Short-Term and Late Effects of Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 66 Chapter 11 Special Concerns for Teenagers and Young Adults . . . . . . . . . . . . . . . . . . . . . . Follow-Up Care . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Developing Healthy Habits . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Quality of Life Issues . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

69 69 71 71

Part 5: Living With Hodgkin Lymphoma Chapter 12 Managing Your Life During and After Treatment . . . . . . . . . . . . . . . . . . . . . . . . Coping Strategies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Life in Remission . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Follow-up Care . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

75 75 76 77

Chapter 13 Why Hodgkin Lymphoma Patients Relapse or Become Refractory . . . . . . . . . 78 How Relapsed and Refractory Hodgkin Lymphoma Is Treated . . . . . . . . . . . . . . 79 Treatments Under Investigation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79

Part 6: Clinical Trials Chapter 14 Overview of Clinical Trials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The Basics of Clinical Trials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Use of a Placebo in Phase III Trials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Participating in a Clinical Trial . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Informed Consent . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Cost of Being in a Clinical Trial . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Finding a Clinical Trial . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

81 81 83 84 84 85 86

Chapter 15 Therapies Under Investigation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 87 Glossary of Medical Terms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89 About the Lymphoma Research Foundation . . . . . . . . . . . . . . . . . . . . . . . . . . Resources for Patients, Survivors and Loved Ones . . . . . . . . . . . . . . . . . . . . . . Resources for Children and Young Adults . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . How to Get Involved and Give Back . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Donate Now . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

iv Understanding Hodgkin Lymphoma

101 101 103 105 107

Part

1

Part 1: L earning the Basics

Chapter 1

Overview of Cancer Our bodies consist of millions of cells that grow and divide in an orderly fashion and work in harmony to support thousands of biological functions. The cells divide only when it is necessary to replace worn-out or dying cells to keep the body healthy. Cancer is a group of diseases that develop as the result of the uncontrolled growth and spread of abnormal cells. Cancer cells are different from normal cells because instead of dying, they continue to grow and divide, forming new abnormal cells. Cancer cells develop when there is damage to the DNA, the hereditary material found in every cell, that is caused either by inherited DNA cell abnormalities or exposure to something in the environment, such as smoking, that causes cell damage. Usually the body is able to destroy these damaged cells, but when the body’s natural defense systems do not work, these abnormal cells may grow in an uncontrollable fashion, eventually forming a cancerous tumor. According to the American Cancer Society, nearly 1,479,350 new cases of cancer are projected in 2009.

Understanding Hodgkin Lymphoma 1

Hodgkin Lymphoma Overview Lymphoma comprises more than 67 subtypes of two related cancers that affect the lymphatic system, Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL). There are six primary types of Hodgkin lymphoma and at least 61 types of non-Hodgkin lymphoma. Hodgkin lymphomas are different from non-Hodgkin lymphomas in the way they develop, spread and are treated. Lymphoma is the most common blood cancer in adults and the third most common cancer overall in children. Lymphoma develops when a genetic error, or mutation, occurs in the way a lymphocyte is produced, causing the abnormal cell to duplicate faster than a normal cell or live longer than a normal lymphocyte. Lymphocytes are small white blood cells that play a large role in defending the body against disease. Like normal lymphocytes, cancerous lymphocytes can grow in many parts of the body, including the lymph nodes, spleen, bone marrow, blood or other organs. There are two types of lymphocytes: B lymphocytes, or B-cells, and T lymphocytes, or T-cells. Most cases of Hodgkin lymphoma start in the B-cells. Named after Thomas Hodgkin, a British physician, who first identified the disease in 1832, Hodgkin lymphoma is a rare cancer, accounting for less than one percent of all cases of cancer in the United States. According to the American Cancer Society, approximately 8,500 new cases of Hodgkin lymphoma are projected each year. Although the cancer can occur in both children and adults, it is most commonly diagnosed in young adults between the ages of 15 and 35 and in older adults over age 50. Nearly 10 percent to 15 percent of all Hodgkin lymphomas are diagnosed in children and teenagers. The disease is more common in men than in women, although, according to the American Cancer Society, over the last 30 years incidence rates have decreased in men and slightly increased in women. Hodgkin lymphoma has been studied more than any other type of lymphoma. The result of those studies has led to rapid advances in the diagnosis and treatment of the disease, and well over 80 percent of patients with Hodgkin lymphoma are cured.

2 Understanding Hodgkin Lymphoma

1 Here is how the immune and lymphatic systems function and affect Hodgkin lymphoma:

The Immune System Hodgkin lymphoma is a cancer that starts in and affects the immune system. The immune system consists of a network of cells, tissues and organs that defend the body against “foreign” invaders (such as bacteria or viruses) or abnormal cells before or after they harm the body. Our ability to survive exposure to both external invaders and internal cell mutations largely depends on the immune system. The immune system is the body’s first defense against disease. It is made up of highly specialized cells and a circulatory system separate from blood vessels called lymphatics. They work together to rid the body of foreign invaders or abnormal cells before they can harm the body. These invading organisms and abnormal or cancerous cells are generally detected by the immune system through proteins called antigens that are located on the surface of all cells, whether they are normal or malignant. Special receptors located on the immune cells bind to these antigens. And just as a lock will only close with the right key, an antigen will only lock with a specific cell from the immune system. When an antigen and an immune cell lock together, the immune response begins, and the body acts to destroy, remove or wall off the foreign invaders or abnormal cells.

The Lymphatic System The lymphatic system is one of the most important parts of the immune system and protects the body from disease and infection. The lymphatic system is a circulatory system that is made up of a series of thin tubes called lymph vessels that branch like blood vessels into all tissues of the body (see page 4). Lymph vessels carry lymph, a fluid that contains white blood cells called lymphocytes. Within this vast network of vessels are groups of small, bean-shaped organs called lymph nodes. Thousands of lymph nodes are found in almost all places in the body, including the elbows, neck, under the arms and in the groin. Lymph flows through lymph nodes and specialized lymph tissues such as the spleen, tonsils, bone marrow and thymus gland.


Anatomy of the Immune System

The immune system is the body’s defense against outside invaders.

Tonsils and adenoids Lymph nodes

Thymus Lymph nodes

Lymph nodes (epitrochlear)

Spleen

Appendix

Bone marrow


Peyer’s patches (inside the abdomen)

Lymph nodes Lymphatic vessels

Immune System Invaders

Bacteria

Viruses

Parasites

Fungi

Pollution

Toxins

How Cancer Forms Inside the body

Abnormal Cells Evade the Immune System

Abnormal Cells Multiply (Cancer)

Tumors May Form (Groups of Abnormal Cells)


Lymph nodes filter lymph fluid, removing bacteria, viruses and other foreign substances from the body. If a large number of bacteria are filtered through a node or series of nodes, swelling may occur and the nodes may become tender to the touch. For example, if you have a sore throat, the lymph nodes under your jaw and in your neck may swell. Most swollen nodes are a reaction to infection and are not cancerous.

How Lymphocytes Work Lymphocytes are a type of white blood cell that help the body fight infections. They are made in the bone marrow, spleen and lymph nodes, and circulate in the blood and lymph vessels. Lymphocytes recognize foreign cells and act quickly to destroy them. There are two main types of lymphocytes: B-lymphocytes and T-lymphocytes. B-lymphocytes develop into cells called plasma cells that make specific proteins called antibodies. Antibodies circulate in the blood and react with toxins, bacteria and some cancer cells and act like biologic guided missiles homing in on only that antigen target on the surface of the cell it has been programmed to attack. The body can then identify and remove these unwanted substances. However, some invaders can avoid B-lymphocytes by growing inside the body’s own cells, and that is where T-lymphocytes play a role. They sense when the body’s own cells have become infected and destroy them directly. T-lymphocytes help the body fight viral infections and destroy abnormal or cancerous cells (cellular immunity). After an invader has been destroyed, surviving B-lymphocytes and T-lymphocytes develop into specialized memory cells that remain on watch in the lymph nodes, waiting to be reactivated if and when a particular antigen is encountered again. These memory cells act as guards that are always on the lookout to prevent specific invaders from controlling the body. The body has a complicated system of checks and balances to keep the number of lymphocytes in equilibrium.

The Causes of Hodgkin Lymphoma Although the exact causes of Hodgkin lymphoma are unknown, research shows that certain risk factors may play a role in the development of the disease. For example, people who have been infected with certain viruses, such as the Epstein-Barr virus, which causes mononucleosis, or the human


1 immunodeficiency virus (HIV), may be at higher risk of developing Hodgkin lymphoma. A weakened immune system caused by either an inherited condition or the use of immunosuppressants to prevent organ transplant rejection has also been linked to the development of Hodgkin lymphoma, as has a family history of the disease, especially among first-degree relatives of a person with Hodgkin lymphoma, such as parents and siblings. However, it is important to remember that even if you have one or more of these risk factors, it does not mean that you will get Hodgkin lymphoma. In fact, most people with risk factors never develop the disease, and many who are diagnosed have no known risk factors.

How Hodgkin Lymphoma Develops Hodgkin lymphoma develops when a lymphocyte (usually a B-cell) becomes abnormal (cancerous). These abnormal cells are called ReedSternberg (R-S) cells, named after the two scientists, Dorothy Reed and Carl Sternberg, who discovered the cell. Most people with Hodgkin lymphoma have R-S cells, although other abnormal cell types may be present as well. Reed-Sternberg cells continually divide, making more and more abnormal cells, which do not die when they should. It is the buildup of these extra cells that forms into a mass of tissue called a tumor. However, the presence of R-S cells alone is not conclusive proof that an individual has Hodgkin lymphoma. To confirm a Hodgkin diagnosis, in addition to the R-S cells, the lymphatic tissue sample must also include other cells and features that are characteristic of Hodgkin lymphoma. A pathologist (a doctor specializing in studying disease through microscopic evaluation of tissue and organs) may use immunological tests that look for cell surface markers (antigens) that identify specific cell types to help make the diagnosis. Hodgkin lymphoma usually starts in the lymph nodes and may be first noticed in areas such as the neck, above the collarbone, under the arms or in the groin. And because lymph tissues all over the body are connected, abnormal (cancerous) lymphocytes can circulate in the lymphatic vessels, causing the lymphoma to spread from one lymph node to another


throughout the body. However, Hodgkin lymphoma can also spread to other areas and organs outside the lymph system. Unlike other lymphomas, Hodgkin lymphoma tends to spread more in sequence from one group of lymph nodes to the next, rarely skipping areas of lymph nodes, a pattern more commonly found in non-Hodgkin lymphoma.

Types of Hodgkin Lymphoma Hodgkin lymphoma has been divided into two main classifications, classical Hodgkin lymphoma—which accounts for about 95 percent of all cases of Hodgkin lymphoma—and lymphocyte predominant Hodgkin lymphoma. There are four main subtypes of classical Hodgkin lymphoma and two subtypes of lymphocyte predominant Hodgkin lymphoma, which are determined by tumor type. The type of tumor a patient has may affect treatment choices. In each type of Hodgkin lymphoma, the tumor cells and the R-S cells are mixed with many normal cells. The abnormal cells are usually in the minority.

Classical Hodgkin Lymphoma Nodular Sclerosis This is the most common subtype of Hodgkin lymphoma, accounting for between 60 percent and 80 percent of all cases of the disease. In nodular sclerosis, the involved lymph nodes contain areas composed of R-S cells mixed with normal white blood cells. The lymph nodes often contain prominent scar tissue, hence the name nodular sclerosis (scarring). The disease is more common in women than men, and it usually affects adolescents and adults under 50. The great majority of patients are cured with current treatments.

Mixed Cellularity This type of Hodgkin lymphoma accounts for about 15 percent to 30 percent of all cases of Hodgkin lymphoma and is found more commonly in men than women. The disease is characterized by the involved lymph nodes containing many R-S cells in addition to several other cell types. Scarring is not apparent. The development of mixed cellularity appears to be associated with HIV and the Epstein-Barr virus. Mixed cellularity primarily affects older adults. More extensive disease is usually present by the time this subtype is diagnosed.


1 Lymphocyte Depletion This is the least common form of Hodgkin lymphoma, accounting for fewer than five percent of all cases, and is characterized by few normal lymphocytes but abundant R-S cells. Lymphocyte depletion is aggressive and usually not diagnosed until the disease is widespread.

Lymphocyte-Rich This recently identified form of Hodgkin lymphoma is rare, accounting for less than five percent of all cases. The disease may be diffuse (spread out) or nodular (knotlike) in form and is characterized by the presence of numerous normal lymphocytes and very few abnormal cells and classical R-S cells. It is usually diagnosed at an early stage in adults and has a low relapse rate.

Lymphocyte Predominant Hodgkin Lymphoma Nodular Lymphocyte Predominant This type of Hodgkin lymphoma is rare, accounting for five percent to ten percent of all cases. It primarily affects more men than women and is usually diagnosed in people under 35. In nodular lymphocyte predominant, most of the lymphocytes found in the lymph nodes are normal (not cancerous). Typical R-S cells are usually not found in this subtype, but large, abnormal B cells with multi-lobulated nuclei, sometimes referred to as popcorn cells, can be seen, as well as reactive small B-cells, which may be distributed in a nodular pattern within the tissues. This subtype is usually diagnosed at an early stage and is not very aggressive. In many ways this form of Hodgkin lymphoma resembles low-grade (indolent) B-cell non-Hodgkin lymphoma.

Diffuse Lymphocyte Predominant This type of Hodgkin lymphoma is extremely rare. The existence of this entity has been questioned. Most cases are in fact nodular LPHL (described above) with an ill-defined nodular pattern. Unlike nodular lymphocyte predominant Hodgkin lymphoma, less small benign B-cells are found. The lymphatic tissue is dominated instead by reactive, nonmalignant T-cells. Disease recurrence is common in this subtype of Hodgkin lymphoma.


Please refer to our website for additional and updated information.

lymphoma.org


1 Chapter 2

Signs and Symptoms of Hodgkin Lymphoma A symptom is something a patient notices and states to their healthcare provider. A sign is something a provider detects on physical examination. Because there are no symptoms specific to lymphomas and, in fact, many initial signs of the disease, such as fever, fatigue, coughing and night sweats, are found in many other illnesses, people often first see their doctor because they think they have a cold, the flu or some other lingering respiratory infection. While the majority (75 percent) of people diagnosed with Hodgkin lymphoma have no symptoms, the most common warning sign of disease presence is a swelling of lymph nodes that may or may not be painful, most often occurring in the neck. Some people may also experience a swelling of lymph nodes in other parts of the body, such as the armpits and groin. Other symptoms of Hodgkin lymphoma may include unexplained intermittent fevers, weight loss (usually by more than ten percent of a person’s normal weight), sweating (usually at night) or lack of energy. A less common symptom is persistent and unexplained itching that grows steadily more severe over time and usually affects the trunk, arms and legs, but it can also be more localized. Coughing, shortness of breath or chest discomfort may be signs of Hodgkin lymphoma in the chest. Usually there is no pain involved in Hodgkin lymphoma, especially in the early stages of the disease, although about five percent of patients may experience pain at the tumor site after drinking alcohol. The reason is unknown.

When to Seek Medical Attention Most people who have these nonspecific symptoms do not have Hodgkin lymphoma. However, it is important that anyone who has persistent symptoms be seen by a doctor to make sure that lymphoma is not present. Serious illnesses are persistent. Seek medical attention if any of the above symptoms last longer than two weeks. Understanding Hodgkin Lymphoma 11

What the Doctor Looks for During a Physical Examination There is no one specific test that allows physicians to routinely screen for lymphoma. If you have symptoms suggesting Hodgkin lymphoma, your doctor will take your medical history and perform a complete physical examination, checking for swollen lymph nodes under the chin, in the neck and tonsil area, above the shoulders, on the elbows, in the armpits and in the groin. The doctor will also examine other parts of your body to see whether there is swelling or fluid in your chest or abdomen that could be caused by swollen lymph nodes. Your abdomen will also be examined to see whether any internal organs are enlarged. You will be asked about pain and examined for any weakness or paralysis that could be caused by an enlarged lymph node pressing against nerves or the spinal cord. If the doctor suspects lymphoma after reviewing your symptoms and performing a physical examination, he or she may order other tests to help confirm the diagnosis. These tests should include a biopsy and may also include blood tests, X-rays and other imaging tests, scans and a bone marrow evaluation.


lymphoma.org


1 Chapter 3

Getting a Diagnosis— What to Expect An accurate assessment of Hodgkin lymphoma requires a number of diagnostic tests. First, a pathologist (a doctor who studies tissues and cells to identify diseases) specializing in hematologic malignancies will examine the tumor tissue under the microscope for the characteristic features of R-S cells in the surrounding tissue and then confirm the diagnosis by analyzing the antigens or markers on the surface of the cells. In classical Hodgkin lymphoma, the cell markers (antigens) are CD30 positive and CD15 positive. In nodular lymphocyte predominate Hodgkin lymphoma, the immunophenotype, or diagnostic proteins, are CD30 negative, CD15 negative and CD20 positive (as seen with B-cell lymphomas). Then examinations will be performed to determine how far the disease has spread (staging) and how well the body is functioning. Depending on your situation, your physician may use some or all of the following tests as well as your medical history and the results of your physical examination to assess the course of treatment that has the best chance of rendering either a remission or cure.

• Lymph node biopsy • Blood tests • Bone marrow examination • Imaging tests: Chest X-ray CT (computerized tomography) scan PET (positron emission tomography) scan Gallium scan • Cardiac Function Test • Pulmonary Function Test


Common Tests Used to Make a Diagnosis Biopsies and How They Are Performed A biopsy is a procedure in which a piece of tissue from an area of suspected cancer is removed from the body and examined under a microscope. The information provided by this tissue sample is crucial to diagnosing and treating Hodgkin lymphoma.

Types of Biopsies There are several types of biopsies. One is called a core needle biopsy, in which a needle is inserted into a lymph node suspected of being cancerous and a small tissue sample is removed. This type of biopsy can be done under local anesthesia, and stitches are usually not required. A core biopsy is more often used to confirm a relapse rather than an initial diagnosis because it often does not produce sufficient tissue to establish a true diagnosis. As a result, if a lymph node is readily accessible, many physicians recommend an open biopsy (also called a surgical biopsy), in which an entire swollen lymph node is usually removed. This procedure can often be done under local anesthesia, but a general (whole body) anesthetic is sometimes needed, and some stitches are often required. When the only signs of lymphoma are in the abdomen or the pelvis, core needle biopsies are often performed. Laparoscopy (inserting a tube) or even abdominal surgery may be necessary to obtain a sufficient sample of the tumor for examination. After a tissue sample has been removed, it is examined by a pathologist to determine a diagnosis. Pathologists look at the tissue under a microscope and then provide the oncologist (a doctor specializing in cancer) with a detailed report. Information obtained from a biopsy indicates the type of Hodgkin lymphoma that is present. If the pathologist’s interpretation of the biopsy is uncertain, the report should be reviewed by a hematopathologist, a pathologist who is an expert in lymphoma. A definitive pathological diagnosis is essential, and if there is any doubt, a second biopsy should be obtained.

Blood Tests Blood tests are performed to determine whether different types of blood, including red blood cells, white blood cells and platelets are normal in 14 Understanding Hodgkin Lymphoma

1 number and appearance when viewed under the microscope. Abnormalities in these blood cells may sometimes be the first sign of lymphoma. Certain blood tests can be used to determine whether a tumor is affecting the liver, kidneys or other parts of the body. Blood abnormalities can also help doctors determine potential treatment choices and predict outcomes. If the lymphoma is circulating in the blood, tests can also be used to classify the tumors according to molecular markers (or antigens) on the surface of cancer cells. This process is called immunophenotyping and is also performed on tissue samples removed by biopsy or bone marrow extraction. This information can help distinguish among different types of lymphoma.

Bone Marrow Examination Bone marrow is the spongy, soft material found inside our bones. Bone marrow contains immature cells called stem cells, which develop into three main types of cells found in the body: red blood cells that deliver oxygen to all parts of the body and take away the waste product carbon dioxide; white blood cells, including lymphocytes, that protect the body from infection; and platelets that help blood clot. Hodgkin lymphoma can spread to the bone marrow. To determine whether cancer is present, doctors may examine part of the marrow by first numbing the area around the skin, tissue and surface of the bone with a local anesthetic, inserting a thin needle into the pelvis or another large bone and withdrawing a small tissue sample. The procedure can be painful at the moment when the marrow is withdrawn. Patients who are anxious about the test should talk with their doctor and nurse to see whether taking a calming medication before the procedure would be helpful. In some instances, evaluation of the bone marrow or blood may be sufficient to make a diagnosis.

Imaging Tests and How They Help Evaluate the Cancer Physicians will often order imaging tests that provide pictures of inside the body. Most of these tests are painless and no anesthetic is required. Several types of imaging procedures may be needed to help best evaluate your cancer, including the following:


X-rays X-rays use radiation to take pictures of areas inside the body. Findings on a chest X-ray may indicate whether the disease is bulky (see “Tumor Bulk,” on page 18). The amount of radiation used in most diagnostic tests is so small that it poses little risk to the patient.

CT or CAT (Computerized Axial Tomography) Scan A CT scan takes X-rays from different angles around the body. The pictures obtained are then combined using a computer to give a detailed image. People with Hodgkin lymphoma often have CT scans of the neck, chest, abdomen and pelvis. These tests are useful in determining how many nodes are involved, how large they are and whether internal organs are affected by the disease.

MRI (Magnetic Resonance Imaging) An MRI is similar to a CT scan, but it uses magnets and radio frequency waves instead of X-rays. An MRI can provide important information about tissues and organs, particularly the nervous system, that is not available from other imaging techniques. An MRI may be ordered when the physician wants to get clear images of the bones, brain and spinal cord to see whether the cancer has spread to these areas.

PET (Positron Emission Tomography) Scan PET scans have now generally replaced gallium scans in many cancer centers because the technique is more convenient and more sensitive, particularly when used in the abdomen area. This test evaluates Hodgkin lymphoma activity in different parts of the body. To perform the test, a radioactive glucose (sugar) tracer substance is first injected into the body. A positron camera is then used to detect the radioactivity and produce cross-sectional images of the body. Unlike gallium scans, which are used primarily to detect response to treatment, PET scans are useful for both determining how much disease is present (staging) and how well it is responding to treatment. PET scans have become so accurate in detecting the level of disease present, treatment can be tailored to an individual patient’s needs.


1 Gallium (Radioisotope) Scan Radioactive gallium is a chemical that collects in some tumors. Gallium scans are sometimes used when a patient is diagnosed with Hodgkin lymphoma. Gallium scans are performed by injecting a small amount of radioactive gallium into the body. The small amount of chemical used is not harmful. The body is then scanned from several angles to see whether the gallium has collected in a tumor. If the tumor attracts the chemical, the scan can be repeated after treatment is completed to help determine if the tumor has completely disappeared or become inactive. The test has largely been replaced by the PET scan which is more sensitive.

Heart Function Tests A MUGA scan (multi gated acquisition scan) is an imaging test that assesses how well your heart ventricles are working. MUGA scans may be done when a patient is resting or exercising, depending on what the physician wants to assess. Patients who are going to receive adriamycin (doxorubicin) will most likely be required to have a MUGA scan before starting treatment to be sure that the heart is functioning normally because adriamycin, the “A” in ABVD, is associated with potential cardiac toxicity. A two-dimensional echocardiogram (2-D echo) is sometimes used in instead of the MUGA scan to test heart functioning.

Pulmonary Function Tests Pulmonary function tests are conducted to help physicians assess how well your lungs work. These tests are commonly ordered for patients with Hodgkin lymphoma who are undergoing ABVD treatment since bleomycin (Blenoxane), the “B” in ABVD, has pulmonary toxicity. Your doctor may wish to order pulmonary function tests before you begin treatment and numerous times thereafter during treatment.


Interpreting Diagnostic Reports It is important to be aware that no one test is definitive. Tests can be reported as “normal” even though lymphoma may be present. Tests may also be reported as abnormal even though no lymphoma is present. Other conditions may mimic Hodgkin lymphoma. The interpretation of tests such as imaging scans can be difficult in some situations and needs to be made in the context of the disease and the patient. Oftentimes, follow-up tests are needed to determine the true significance of previous results. In fact, biopsies occasionally are needed to clarify the results. Some patients like to review their written scan reports. When doing so, it is important to carefully review the findings with the physician.

Tumor Bulk While the term “tumor” refers to any swelling or lump—either benign or malignant—that forms in the body, most doctors and patients use the term to refer to a lump formed by a cancer, such as Hodgkin lymphoma. Tumor bulk refers to how much Hodgkin lymphoma is present. A low-bulk tumor, for instance, is a single mass of tumor tissue in the chest below ten centimeters in largest diameter; a single mass of tumor tissue in the chest above ten centimeters is considered a high-bulk or bulky tumor. In general, the smaller the tumor, the better the chances that it will be completely eliminated by treatment, but even large tumors can be cured. Patients with small tumors (called non-bulky disease) generally have a better prognosis than those with large tumors (bulky disease). Often, but not always, radiation is incorporated in the treatment of bulky tumors.

Cancer Staging and What It Means “Stage” is the term used to describe the extent of tumor spread in the body. Hodgkin lymphoma is divided into four stages, depending on how far the disease has spread. Stages I and II are localized, while stages III and IV are considered advanced, widespread or disseminated. Stage is an important piece of information that helps to predict outcome, or prognosis, and determine approaches to treatment. However, it is important to remember that unlike an advanced stage III or IV diagnosis in solid tumor cancers in which the primary cancer has spread to other sites and may be more difficult to treat, advanced stages of Hodgkin lymphoma can be successfully treated and still have a favorable outcome. 18 Understanding Hodgkin Lymphoma

1 The Four Stages of Hodgkin Lymphoma Stage I (early disease): The cancer is found only in a single lymph node or region. Stage II (locally advanced disease): The cancer is found in two or more lymph node regions on one side of the diaphragm (the breathing muscle that separates the abdomen from the chest). Stage III (advanced disease): The disease involves lymph nodes both above and below the diaphragm. Stage IV (widespread disease): The lymphoma is outside the lymph nodes and spleen and has spread to one or more organs such as bone, bone marrow, lung or liver.

The Meaning of the Letters A, B or E After the Stage Each stage of Hodgkin lymphoma is further divided into “A” and “B” categories, depending on the symptoms patients have when they are diagnosed. Some patients have symptoms that affect their entire body (called systemic symptoms). Some examples include fever, night sweats and weight loss. Patients who have these symptoms will have the letter “B” after the stage of their disease. The “A” category is used to designate a person with no systemic symptoms. The category “E” is used when Hodgkin lymphoma spreads locally from a lymph node into the closely surrounding tissue.

Getting a Second Opinion Before you start therapy, you may want to consider getting a second opinion to confirm the diagnosis and treatment plan, particularly if some aspects of your illness seem complicated or uncertain. Some insurance programs require second opinions; others may cover it if a patient or doctor requests it. If you decide to seek a second opinion, remember that it is best to request a complete copy of your medical records and to provide original X-rays, pathology materials, scans and reports requested by the consulting doctor. Make copies of these medical records—one for yourself and one that you deliver to the consulting physician, preferably before your appointment. Understanding Hodgkin Lymphoma 19

A second opinion is not considered adequate unless another pathologist, preferably one well versed in lymphoma, reviews the tumor sample. Your referring doctor or your healthcare plan can often recommend an oncologist you can visit to get a second opinion.

Choosing an Oncologist and Treatment Center Your primary care doctor will probably have referred you to a specialist— likely a medical oncologist, hematologist or hematologic oncologist. Oncologists are physicians who specialize in diagnosing and treating cancer. Hematologists are physicians who specialize in diagnosing and treating disorders of the blood and lymphatic system. Before agreeing to treatment by a doctor or clinic, be certain that your medical and personal needs will be met. Take time to check your doctor’s credentials, the other members of your medical team, as well as the credentials of the hospital or cancer center. Keep in mind that if you are in a managed care program, your choices may be limited. However, if you are not entirely satisfied with your first consultation, you have the right to choose another healthcare team. Ask your primary care doctor for another referral, or ask other patients with lymphoma for their suggestions. It is important that you feel comfortable with your healthcare team and the quality of care you are receiving.


1 Questions to Ask When Choosing a Doctor and Treatment Center Before beginning treatment, ask these basic questions: • How much experience does this doctor (or clinic) have in treating cancer in general and lymphoma in particular? How many patients with lymphoma are being treated here now? • Is the doctor board certified as an oncologist or hematologist? Has he or she passed qualifying examinations by the American Board of Internal Medicine that certify his or her competency in these specialties? • How does the doctor or clinic stay up-to-date on the latest treatments for lymphoma? • Do the oncologists or hematologists in the clinic participate in clinical trials? • Does this center have state-of-the-art surgical facilities and diagnostic equipment? • Is the doctor or clinic professionally affiliated with any major medical centers or medical schools? • What arrangements are made for medical coverage after hours and on weekends in case of an emergency?



lymphoma.org


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Part 2: Treating Hodgkin Lymphoma

Chapter 4

What You Should Know Before Starting Treatment Getting a cancer diagnosis is frightening, and patients are naturally concerned about what their future may hold. Oftentimes, patients will ask their doctor about their outlook, or prognosis—the medical term used to describe how the disease will progress and the likelihood of recovery. To be an educated healthcare consumer, it is important to understand the nature of cancer and what to expect from treatments, including any possible effects on quality of life, such as lifestyle, emotions and financial issues. Prognosis is usually based on information gathered from hundreds or thousands of other patients who have had the same disease. This statistical information provides physicians with a general idea of what to expect when a patient is diagnosed with a specific type of lymphoma and also gives guidance on the kinds of treatments that have been most successful in treating that cancer. However, no two patients are alike and statistics from large groups of people do not necessarily accurately predict what


will happen to a particular patient. The doctor most familiar with your situation is in the best position to help interpret these statistics and determine how they apply to you.

Treatments for Hodgkin Lymphoma Hodgkin lymphoma patients should take comfort in the fact that this type of cancer is highly curable. More than 80 percent of all patients with Hodgkin lymphoma will be cured of their disease—that number rises to more than 90 percent in patients with early-stage disease. Most people with Hodgkin lymphoma will receive combination chemotherapy with or without radiation. Other treatments may include stem cell or bone marrow transplantation. Advances in how chemotherapy and radiation are administered and a reduction in the amount of doses given are expected to result in a decrease in the long-term and late effects of treatment. Currently, there are many major research efforts under way to investigate the effectiveness of new medications and novel combinations of established therapies, as well as efforts to determine the best ways to minimize the short- and long-term toxicities of these treatments. The science of treating Hodgkin lymphoma is advancing very rapidly, and many new treatments are on the horizon. (See “Therapies Under Investigation,” on page 87).

When to Consider a Clinical Trial Contrary to what many cancer patients believe, participating in a clinical trial is not an indication that they have run out of standard treatment options and that it is their last chance for survival. The purpose of a clinical trial is to monitor the effects of new drugs, drug combinations or new techniques to identify the most effective way to treat Hodgkin lymphoma. Participation in a clinical trial is especially crucial for lymphoma patients: Hodgkin lymphoma comprises a group of rare diseases, and it is often difficult to find sufficient numbers of patients to enroll in the studies. Clinical trials are the standard of care in the treatment of children with cancer, and more than 80 percent of children with cancer are enrolled in clinical trials. If you are interested in participating in a clinical study, ask your doctor if there is an appropriate trial for you and what the potential risks and benefits may be. (See “Clinical Trials,” on page 81.)


Communicating With Your Healthcare Team People diagnosed with lymphoma are often anxious to learn all they can about their disease and treatment choices so they can play an active role in decisions about their care. For many people, getting a cancer diagnosis is shocking, and it is normal to feel a lot of physical and emotional stress following diagnosis. Some people are uncertain about how to talk with doctors, and the combination of stress and uncertainty may make it difficult to know what to say or what questions to ask. Patients can ease their anxieties by establishing an open and honest dialogue with their physician and nurse regarding their diagnosis, and learning about the prescribed treatment regimen, how it works, what tests are involved and what side effects and complications may be associated with it. To help you through the course of your illness, a good first step is to write down all of the questions that come to mind, because eventually you, your family and friends are going to want answers. Before meeting with your doctor or nurse, whether for the first time or for follow-up visits, organize and write out your questions. Put the two or three most important questions at the top of your list, since time with your doctors or nurses may be limited. Also, it is helpful to have a member of your family or a close friend accompany you to the doctor’s office or clinic to help you ask questions and understand and remember answers. It can also be helpful to write down the answers to your questions. Some patients bring a tape recorder to record the answers. Check with your doctor first, though, to make sure he or she does not mind if you tape record the conversation. In general, questions about chemotherapy should be directed to the medical oncologist, and questions about radiotherapy should be directed to the radiation oncologist. Most oncology nurses are also very well informed about cancer treatments, and are a wonderful source of information on a wide range of topics relating to your care. Although family members are often very concerned about their loved one and want information concerning his or her care, strengthened confidentiality rules prohibit physicians from giving out information to anyone without the patient’s expressed permission. For efficiency, it is suggested that one Understanding Hodgkin Lymphoma 25

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family member be designated as the family contact to the physician. You, however, must inform your physician who this individual will be.

Writing an Advance Healthcare Directive Tips on Communicating With Your Doctor • Keep a journal of your symptoms to help you remember the details you want to discuss with your doctor during your office visit and then bring a list of your questions to your appointment. • During your office visit, take notes or tape record your conversation to help you accurately review the information afterward. Bringing along a family member or friend for support and to take notes for you is also helpful. • Do not be afraid to ask questions when you do not understand something. Doctors want to know how best to explain information to you. • Before leaving the doctor’s office, make sure you understand the next step in your care and ask if there is written information you can take home.

And Appointing a Healthcare Proxy Writing down your wishes for your critical medical care in an advance healthcare directive is a way to inform your physician, family members and friends about your healthcare preferences and what special treatment you want or do not want at the end of life. Besides stating your medical care instructions, your advance healthcare directive should also include the name of your healthcare proxy, or decision maker—someone you have chosen whom you believe will carry out your wishes if you are unable to do so, including do not resuscitate (DNR) instructions. Before writing an advance healthcare directive, it is important to understand your rights and the laws regarding advance healthcare directives in your state. Consulting an attorney can provide the legal information you need, but you do not have to use an attorney to write an advance directive. Some things to consider when writing an advance healthcare directive: • Specific instructions on your medical care, including the types of special treatment you want or do not want such as cardiopulmonary resuscitation (CPR), artificial respiration, drugs to make your heart function, kidney dialysis, artificial feeding and certain surgical procedures. • Your choice for your healthcare proxy.


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How to Be a Self-Advocate Being a self-advocate and an active participant in your healthcare can be a positive experience and may help restore a sense of control that was lost following your diagnosis. It is important to remember that you are a partner in your treatment plan, and many patients feel better when they actively participate in their care. The first steps in participating in your treatment are to ask questions, learn about your options and work closely with your doctor. You must be comfortable with your physician and the approach that he or she takes. If you are not, openly discuss your concerns. Remember, confidence in your medical team often leads to confidence in your treatment. If it becomes apparent that you and your team are not a good match, ask for a referral. Your questions will likely vary depending on the purpose of your meeting with your oncologist, e.g., the initial visit to discuss your diagnosis as opposed to a routine visit to monitor a remission. Ask about the timing of office visits, treatments and tests. Your doctor can help explain what the tests will look for, define the possible responses and the options for further care, depending on treatment response. Although each person is different and each response to therapy is unique, knowing someone who has been through the same treatment and who may have had similar concerns can be a source of great comfort. If you are interested in talking to and learning from people who have had similar experiences, ask your oncologist, hematologist, oncology nurse or the oncology social worker about support groups in your area. Consider joining the Lymphoma Support Network, a nationwide buddy program that matches patients or caregivers. This program offers the opportunity to share experiences and information and offer support and encouragement. For more information about this program, call (800) 500-9976 or email [email protected]. Before any tests are performed, be sure to check with your healthcare team to determine which costs are covered by your insurance company and which costs you might be required to pay. And do not be afraid to broach nonmedical issues, such as transportation, finances, insurance and childcare, with your healthcare team. Understanding Hodgkin Lymphoma 27

Tips on Self-Advocacy • Do not be afraid to ask your doctor or nurses questions about your care. • Learn more about your lymphoma from reliable websites, such as the Lymphoma Research Foundation at lymphoma.org. Or ask your doctor for information specific to your type of Hodgkin lymphoma. • Take advantage of other services offered at your doctor’s office, cancer center or hospital, such as counseling, support groups, nutritional counseling and fitness classes. • Consider joining the Lymphoma Support Network, a nationwide buddy program that matches patients or caregivers. For more information about the program, call (800) 500-9976 or email [email protected].

Factors Affecting Treatment Outcome In addition to the type of Hodgkin lymphoma a patient has, many other factors affect how an individual patient responds to therapy.

Age Younger people generally have better outcomes than those who are older. Younger patients may be better able to tolerate the effects of therapy because they generally have fewer health problems, such as heart or lung disease that could limit the type or dose of therapy.

Performance Status Performance status is used to describe a person’s ability to follow a typical lifestyle. Those with good performance status (people who are active) tend to respond better than those with poor performance status (people with chronic health problems or those so ill that they are confined to bed), because they can tolerate more intensive therapy. Performance status is ranked on a scale from 0 to 4.

Extranodal Disease (disease outside the lymph nodes) When Hodgkin lymphoma has spread outside the lymph nodes into the lung, liver, bone or bone marrow, it is referred to as extranodal disease. Hodgkin lymphoma patients with extranodal disease tend to have a lower cure rate compared with those whose disease has not spread.


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Stage of Disease Stage refers to the extent of the spread of the lymphoma. Stages I and II are used to describe localized disease found in an area either above or below the diaphragm (the muscle separating the chest from the abdomen), while stages III and IV refer to more widespread or advanced disease involving lymph nodes and other organs on both sides of the diaphragm. Patients with stage III or IV disease may have a lower cure rate than those with stage I or II disease. However, the majority of these patients are also cured.

Tumor Bulk Patients with bulky (large) tumors generally have a lower cure rate than those with non-bulky disease.

Other Factors A patient’s sex, level of albumin (serum proteins) in the blood, hemoglobin level, white blood count and the number of lymphocytes circulating in the bloodstream may also affect prognosis and treatment options.

Terms Describing Possible Outcomes of Treatment Primary Therapy—This is the first therapy that a patient receives. The choice of primary therapies depends on the pathologic characteristics of the disease and the factors described in the previous section. Complete Remission (CR)—This term is used when all signs of the lymphoma have disappeared after treatment. Although this does not mean that the cancer is completely cured, the symptoms have disappeared and the lymphoma cannot be detected using current tests. If this response is maintained for a long period, it is called a durable remission. The longer a patient is in remission the better the prognosis or outcome and the likelihood of cure. However, as with other cancers, it is possible that Hodgkin lymphoma could recur and, as a result, long-term follow-up medical care is necessary. Cure—When there are no signs of the lymphoma reappearing after many years of continuous, complete remission, doctors may cautiously begin using the word “cure” for Hodgkin lymphoma.


Questions to Ask Before Treatment Begins • What is my exact diagnosis? • What is the stage of my Hodgkin lymphoma? • What are my treatment options? Which do you recommend for me? Why? • What are the risks and possible side effects of each treatment? • What side effects should I report to you? • Are there any late- or long-term side effects I should be aware of? • How long will the treatment last? • What are the chances that the treatment will be successful? • How will the treatment affect my normal activities? • Are new treatments being studied? Would a clinical trial be appropriate for me? • What is the treatment likely to cost? Does my insurance cover it?

Disease Progression—If the disease worsens or the tumor grows during therapy, it is called disease progression (this is also referred to as treatment resistance). Partial Remission (PR)—This term is used if the Hodgkin lymphoma is treated and the tumor shrinks to less than one-half of its original size. Improvement—This term is used if the tumor shrinks following therapy but is still more than one-half of its original size. Stable Disease—The disease does not get better or worse following therapy but stays about the same. Refractory Disease—A cancer that is resistant to treatment. Relapse—The disease reappears or grows after a period of remission.


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Chapter 5

Types of Treatment There were two important advances over the last 25 years that have dramatically changed the way Hodgkin lymphoma is treated. One was the elimination of surgical staging laparotomies, in which a patient’s spleen was removed to evaluate the extent of disease. This was replaced with the practice of noninvasive clinical staging, in which imaging technology like computerized tomography (CT) and positron emission tomography (PET) scans are used to capture detailed images of internal organs and spot enlarged lymph nodes. The second advancement was the reduction in both the amount of radiation therapy given to treat Hodgkin lymphoma patients and a reduction in the field of radiation (the amount of body radiated). There is great concern about the late toxicities associated with radiation therapy, and for that reason, more and more patients receive chemotherapy only as their first-line treatment. To reduce the amount of radiation exposure in patients, involved-field radiation is limited to the sites containing cancerous lymph nodes and leaves uninvolved sites alone. Although it is too early to know for certain, researchers suspect that less exposure to radiation may result in fewer late health effects, such as secondary cancers like breast cancer, lung cancer, leukemia and heart disease. However, because it can take many years for late side effects to manifest, it may be decades before there is scientific proof about the long-term health benefits of involved-field radiation. Changes in both the combinations of chemotherapy drugs used and the number of cycles of chemotherapy given are having a positive impact on the quality of life for many Hodgkin lymphoma patients by reducing— or even eliminating—some long-term side effects from the treatment, such as infertility in men and women. Most people treated for Hodgkin lymphoma will receive some form of chemotherapy and sometimes radiation therapy as their frontline treatment. The addition of biologic agents to chemotherapy is also currently under Understanding Hodgkin Lymphoma 31

investigation in clinical trials. Bone marrow or stem cell transplantation is typically used in the relapsed or refractory setting. Surgery may also be an option under special circumstances, but it is used primarily to obtain a biopsy for diagnostic purposes. Since no two patients are exactly alike, treatment is tailored for each patient’s unique situation. Although the cure rate in Hodgkin lymphoma is already high, research continues to look for ways to treat the small minority of patients who are less resistant (refractory) to treatment. For the small number of patients who relapse, alternative therapies, such as stem cell transplantation, may cure the cancer. Ongoing research also continues to find ways to refine currently available treatments both to limit their levels of toxicity and their potential for causing secondary illnesses and improve long-term survival. Better-targeted drugs that do not cause such damaging side effects are also being pursued. Here is a look at current standard therapies to treat Hodgkin lymphoma and what may be available in the future.

Chemotherapy Chemotherapy (“chemo”) is treatment with drugs (as opposed to radiation, for example). Many different medications are used to either kill cancer cells or prevent them from growing. Because of how they work, chemotherapy drugs may also have a similar effect on rapidly dividing normal cells such as hair, nails and the cells in your mouth.

Combining Chemotherapy Drugs Chemotherapy for Hodgkin lymphoma often consists of giving multiple drugs together (combination chemotherapy) in a defined way (schedule), called a treatment regimen. Drug combinations are used because different medications damage or kill cancer cells in different ways, making them more vulnerable to the treatment. Combining chemotherapy drugs provides a more effective way to kill more tumor cells, because using the drugs together greatly augments the impact of the drug over its use individually or additively. Also, drugs added together in lower doses help reduce the likelihood of side effects without reducing the overall amount of effective chemotherapy. For example, the combination regimen ABVD (adriamycin, bleomycin, vinblastine, dacarbazine) is currently considered


Common Drug Regimens Used to Treat Hodgkin Lymphoma (brand names in parentheses)

Regimen Abbreviation

Drugs

ABVD Doxorubicin (Adriamycin, Rubex) Bleomycin (Blenoxane) Vinblastine (Velban, Velsar) Dacarbazine (DTIC)

Stanford V Mechlorethamine (Mustargen) Doxorubicin (Adriamycin, Rubex) Vinblastine (Velban, Velsar) Bleomycin (Blenoxane) Etoposide (VP-16, VePesid) Prednisone (Deltasone) Involved Field radiation

BEACOPP Bleomycin (Blenoxane) Etoposide (VP-16, Vepesid) Doxorubicin (Adriamycin, Rubex) Cyclophosphamide (Cytoxan) Vincristine (Oncovin) Procarbazine (Matulane) Prednisone (Deltasone)

MOPP Mechlorethamine (Mustargen) Vincristine (Oncovin) Procarbazine hydrochloride (Matulane) Prednisone (Deltasone)

standard therapy: It has less toxicity while sustaining a full capacity to destroy Hodgkin lymphoma cells. Another reason for using combination chemotherapy is to prevent drug resistance. A chemotherapy regimen is a combination of anticancer drugs given at a certain dose in specific sequence according to a strict schedule. This schedule should be maintained whenever possible.


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Clinical investigators often use the first initials of the drugs in a particular treatment regimen to communicate among themselves as a shorthand reference to the treatment. Some of the most common regimens used for Hodgkin lymphoma are outlined on the prior page. Many other combinations are being tested in clinical trials.

Chemotherapy Cycles A single dose of chemotherapy kills only a percentage of the cancer cells, therefore, multiple doses are necessary to kill all the cancer cells. Chemotherapy is scheduled as frequently as possible to minimize tumor growth, prevent the development of resistant cancer cells and achieve the best outcome. Chemotherapy is usually given in cycles, meaning each treatment is followed by several weeks of rest and recovery, during which time no treatment is given. The medicines are usually given according to a schedule that includes a defined number of days between each cycle. Clinical trials have determined how often chemotherapy should be given to kill the most tumor cells while minimizing side effects. Chemotherapy for Hodgkin lymphoma may require as few as two or as many as eight or more cycles of treatment, depending on factors such as the type and stage of the disease, the kind of drugs used, the level of response achieved and the nature and severity of the side effects.

How Chemotherapy Is Given Depending on the chemotherapy regimen, you may receive drugs in pill form, as an injection or as an intravenous drip. If you are going to receive intravenous drugs (ones that are given through a vein) for multiple cycles, your doctor may recommend having a catheter inserted. An intravenous catheter is a device that is put into a vein to make it easier to give drugs. Catheters may be left in place temporarily or permanently. There are several types of catheters. One type, called a Hickman-Broviac catheter, consists of one to three tubes inserted through the chest wall into a vein. Six to twelve inches of tubing remain outside the skin. The main advantage of this type of catheter is that blood can be drawn for tests and drugs given without having to pierce the skin. Disadvantages include the


possibility of infection if the catheter is not cared for properly and the fact that the tubes on the outside of the body make it more obvious that a catheter is in place. If you have this type of catheter, your healthcare team will show you what needs to be done each day to care for it and to make sure it stays clean. A second type of intravenous catheter, called an Infusa-Port or Portacath catheter, is placed under the skin and appears only as a bump on the chest. The advantage of this catheter is that it is easier for patient care—it only needs to be maintained by a nurse once a month (called “flushing”). However, it also has disadvantages. Each time this type of device is used, an injection through the skin is required, and it may not always be convenient to draw blood samples. These devices may also occasionally clot. Another type of intravenous catheter is a peripherally inserted central catheter, or PICC line, which uses a thin, soft plastic tube to deliver medicines and fluids through a large vein in the arm. The PICC line can be kept in place for months and is a good option for patients who need to have many short infusions or continuous infusions given in a hospital or at home with a portable pump. If you need a catheter, discuss the pros and cons of the different types with your doctor. Your situation and personal preferences will be considered in making this decision.

The Importance of Maintaining Chemotherapy Dosing and Scheduling “Dose intensity” is a term used to describe giving preplanned doses of chemotherapy over a specific period of time, while maintaining an acceptable level of side effects. This approach has been shown to be very effective in curing some cancers, including some aggressive lymphomas. Studies have suggested that reducing the dose or delaying chemotherapy may decrease both the chance for a cure and long-term survival in some types of lymphomas. Patients should know that changing the regimen to reduce short-term side effects may actually be harmful in the long run. Some side effects may be unpleasant but tolerable (See “Coping With Common Treatment Side Understanding Hodgkin Lymphoma 35

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Effects,” on page 45). Others may be serious but can often be anticipated and prevented. It is very important that chemotherapy doses and schedules be maintained to the greatest extent possible.

Bone Marrow and Stem Cell Transplantation Hodgkin lymphoma patients who fail to achieve complete remission following frontline therapy or who relapse after achieving complete remission are often treated with second-line chemotherapy regimens, followed by a bone marrow or stem cell transplant. (See “Why Hodgkin Lymphoma Patients Relapse or Become Refractory,” on page 78.) Bone marrow, the spongy material found inside our bones, contains immature “stem” cells. Stem cells develop into three types of cellular elements found in the blood: red blood cells, which deliver oxygen to all parts of the body and take away the waste product carbon dioxide; white blood cells, which protect the body from infection; and platelets, which help blood clot. In the past, stem cells were collected directly from the bone marrow, but they are now usually collected from the peripheral (circulating) blood by timing their collection with the use of growth factors and sometimes chemotherapy that increase their production. The peripheral blood is then washed of stem cells by a machine. Because very high doses of chemotherapy or radiation are used to destroy cancer cells, healthy bone marrow cells are also destroyed. Therefore, a transplant of bone marrow or stem cells is needed to restore healthy bone marrow. Since transplants place great strain on the body, it is not a treatment option for everyone. Among the things to consider are age, medical history, cancer stage, response to previous therapy and chances for a successful transplant.

Sources of Bone Marrow or Stem Cells A key to the success of a transplant is the availability of stem cells. There are two main types of stem cell transplants: allogeneic, in which patients receive bone marrow or peripheral stem cells donated by another person, often a sibling; and autologous, in which patients receive their own cells. Autologous bone marrow transplantation is far more common than allogeneic, because it is much less toxic.


2 How Transplants Are Done Bone marrow or peripheral blood stem cell transplants are performed in four steps: Step 1: Harvesting stem cells or bone marrow Stem cells are usually filtered from the blood in a process called apheresis; the other components of the blood are then returned immediately to the patient. Bone marrow (which contains stem cells) is usually harvested from bones in the hip. Step 2: Processing or preserving the stem cells or bone marrow Machines are sometimes used to purge any malignant cells, filter out unwanted substances and freeze and store the pure transplant material, including cells. Step 3: Administering therapy High-dose chemotherapy is then administered, with or without radiation, to eliminate the cancer cells. This high-dose treatment also wipes out healthy blood and immune cells. The type of chemotherapy given will depend on the stage and type of disease, whether it is a recurrence, the condition of the patient and the treatment facility’s preferences and experiences. Step 4: Reinfusing harvested stem cells or bone marrow As the harvested stem cells or marrow are returned to the body (transplanted), they travel through the circulatory system to the bone marrow, where they implant themselves and slowly begin to make healthy new cells. Over time, the bone marrow produces enough healthy cells to completely repopulate the blood and immune systems. In the period before these new cells are created, patients are more susceptible to infection.

Allogeneic Transplantation Finding a compatible donor is important. Your body will reject stem cells if they are too unlike your own, or the new cells may react against your own cells, a condition called graft-versus-host disease (GVHD). Several different blood tests may be used to see if someone is a suitable transplant donor. The best candidates are siblings. One potential advantage of an allogeneic transplant is that the donor’s immune cells may fight against and destroy the lymphoma cells.

Autologous Transplantation In this procedure, a patient’s own stem cells are removed, known as harvesting (see above), and stored before he or she receives high-dose Understanding Hodgkin Lymphoma 37

chemotherapy or radiation treatment. Then the stem cells are reinfused into the patient’s blood. The advantage to this type of transplant is that there is no danger that the body will reject the bone marrow or stem cells, or that the stem cells will react against the body.

Harvesting Stem Cells In this procedure, stem cells are obtained from the bone marrow or blood to repopulate the body’s cells after high-dose chemotherapy. The cells used in autologous transplantation can be obtained either by harvesting bone marrow or stem cells. A bone marrow harvest involves removing bone marrow, which is a thick red liquid, from the hipbone with a needle. This procedure is done in an operating room and requires general anesthesia for comfort. Once the bone marrow is harvested, it is purified and stored until the day of the transplant. Multiple needle insertions are required to harvest enough bone marrow. This procedure is performed less commonly now but was frequently performed in the past. Although the greatest number of stem cells is found in the bone marrow, these cells are also present in the circulating blood, especially when mobilized by chemotherapy or growth factors. Today, the more common way to collect cells for a transplant is by harvesting them from the blood. This method is often preferred over harvesting from bone marrow because it can be done on an outpatient basis. It involves the withdrawal of blood in a process called apheresis (which means to remove or take away). In this case, stem cells are removed, and the rest of the blood is returned to the patient.

Mini-Bone Marrow or Mini-Stem (Non-Myeloablative/Reduced Intensity) Cell Transplant Mini-bone marrow or mini-stem cell transplants are procedures in which bone marrow or stem cells are received from an allogeneic donor. Unlike the usual allogeneic bone marrow or stem cell transplant, in which high-dose chemotherapy is administered, in these procedures the patient receives lower doses of chemotherapy, just enough to allow the body to accept the new cells. This approach is used to take advantage of the graft-versus-disease effect, in which the transplanted cells recognize the tumor as a foreign entity and activate T-cells to destroy the cancer. Patients who experience a graft-versus-disease effect may remain in 38 Understanding Hodgkin Lymphoma

remission for a longer period. Also, because patients receive lower doses of chemotherapy, they may avoid some of the toxicities seen with higherdose chemotherapy. However, graft-versus-host-disease is a frequent and sometimes serious side effect and is a potentially serious complication of allogeneic bone marrow transplantation.

Biologic Treatments Biologic therapies (including immunotherapy) differ from chemotherapy because they use naturally occurring substances found in the body to treat cancer. These therapies can boost, direct or restore the natural defenses against disease. Examples of biologic therapies directed against tumors include monoclonal antibodies, radioimmunotherapies, interferons, vaccines, antiangiogenesis therapies and genes. Other biologic therapies may improve or restore the white or red cell count. At this time, biologic therapies are only in the investigative stage to treat Hodgkin lymphoma.

Monoclonal Antibodies and How They Work Plasma cells, the most mature B-cells in the body, are white blood cells that specialize in making antibodies. Each plasma cell is responsible for one antibody, otherwise known as a monoclonal antibody (MAb). Each MAb acts specifically against a particular antigen, which is like a beacon that attracts antibodies and immune cells (such as lymphocytes). Using new technologies, scientists can now produce large amounts of antibodies that can be directed to a single antigen on the cell’s surface. A MAb is similar to a guided missile that homes in on an antigen on the lymphoma cell and destroys the cell. A number of strategies involving the use of MAbs to treat cancer are being studied, including (a) MAbs that react with specific types of cancer cells, thereby enhancing a patient’s immune response to the cancer; (b) MAbs that are combined with other anticancer drugs, toxins or radioisotopes, allowing the delivery of these drugs directly to the tumor and bypassing toxicity to most normal cells; and (c) MAbs that are used to help purge and destroy cancer cells before a patient’s stem cells are reinfused in autologous bone marrow transplantation.


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Monoclonal Antibodies as Possible Treatment for Hodgkin Lymphoma Rituximab (Rituxan) was the first monoclonal antibody approved for the treatment of CD20 positive, B-cell non-Hodgkin lymphoma and is currently in clinical trials in the treatment of both the classical form of Hodgkin lymphoma and in the rarer type, lymphocyte predominate Hodgkin lymphoma, which has the CD20 antigen. Rituximab (Rituxan) targets the CD20 antigen found on almost all B-cells, killing both cancerous and many of the normal B-cells but sparing all other cells and tissues. Researchers believe that this therapy works in part via the body’s immune system response triggered by the MAb’s attachment to cancer cells. Because the youngest B-cells in the body (precursor cells that will become B-cells) do not yet have the CD20 antigen, they are not affected. As a result, after treatment the body can replenish its B-cell supply from these young cells. Other monoclonal antibodies are also being investigated in the treatment of Hodgkin lymphoma to target CD30, CD40, CD80 and CD52 antigens. A description of these and other biologic therapies as well as vaccine therapies, histone deacetylase inhibitors, mTOR inhibitors and JAK-2 inhibitors that are currently being tested in the treatment of Hodgkin lymphoma can be found in “Therapies Under Investigation,” on page 87.

Radiation Therapy Radiation therapy (also called radiotherapy) uses high-energy X-rays to kill cancer cells and shrink tumors. Radiation may be combined with chemotherapy. The term “radiation field” is used to describe the part of the body selected to receive radiation therapy. Hodgkin lymphoma generally spreads predictably from one lymph node to another. When the lymphoma is confined to a specific area of the body, for example, the neck, involved-field radiation may be given, meaning the therapy is limited to a small area. When radiation therapy is given more broadly to larger common areas, it is called extended-field radiation. To prepare for radiation therapy, the skin is marked with tiny ink dots called “tattoos,” so the exact same area will be treated every time. Before 40 Understanding Hodgkin Lymphoma

the first treatment, the healthcare team devotes a substantial amount of time marking the body to make sure that specific areas receive radiation. Normal tissues around the radiation field are shielded by lead, which blocks the path of stray radiation beams. Patients lie still on a table beneath a large machine that delivers the radiation. Props and supports with plastic forms, pillows and rolled blankets help keep patients in position. Once the preparations have been made, it takes only a few minutes to deliver the prescribed dose. The total dose of radiation is usually divided and given over one to six weeks. In Hodgkin lymphoma, the common areas of the body that are radiated include lymph nodes in the neck, chest and armpit (mantle field); lymph nodes in the abdomen and possibly spleen; lymph nodes in the pelvis and groin; and in certain circumstances, extended-field radiation to both the mantle and upper abdominal fields. Rarely, total body radiation may be recommended.

Vaccines and Cell Therapies Vaccines are not yet available for the treatment of Hodgkin lymphoma. However, evidence suggests that the Epstein-Barr virus (EBV) may contribute to the development of Hodgkin lymphoma in some people, and testing is under way to determine whether targeting EBV in Hodgkin lymphoma tumor cells with specialized immune cells will be effective against this cancer. In clinical trials, the immune cells of patients with EBV are being collected, processed and then reinfused into the patient in an effort to kill the cancer cells.

Complementary and Alternative Remedies The concept of holistic medicine to treat the mind, body and spirit became popular in the 1970s and is commonly known today as complementary and alternative medicine, but the terms have distinctly different meanings. Alternative therapy refers to unproven or disproven treatments that are used instead of standard or proven therapy. Complementary therapy is used in addition to standard medicine to help improve a patient’s quality of life and to relieve the effects of chemotherapy, radiation and surgery. Currently, there are no viable alternative therapies to conventional cancer care, and Hodgkin lymphoma patients should never use alternative remedies in lieu of standard care. Understanding Hodgkin Lymphoma 41

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Complementary, also known as integrative, medicine includes a vast array of mind/body therapies such as meditation, guided imagery, self-hypnosis, tai chi and yoga; touch therapies such as massage, reflexology and Reiki; acupuncture; and nutrition. However, because even some complementary practices, such as ingesting certain herbs or botanicals, may negatively impact cancer treatment, Hodgkin lymphoma patients should consult with their healthcare team before embarking on any integrative medicine plan.

How Integrative Medicine Helps Acupuncture Some studies show that acupuncture can relieve pain, nausea, fatigue, hot flashes and neuropathy (numbness and tingling in the feet and hands) associated with chemotherapy. Using new ultrathin needles applied to specific points on the body, acupuncture is safe and painless. Needles used should be disposable and only used once.

Mind/Body Techniques Meditation, guided imagery and self-hypnosis are all methods used to manage stress. Yoga and tai chi minimize stress and improve balance and flexibility.

Touch Therapies Massage, reflexology (foot massage) and Reiki involve applying therapeutic pressure to the body to restore a sense of harmony, relaxation and well-being. Massage therapy may reduce patients’ pain levels.

Nutrition Eating a healthy, well-balanced diet that contains five to seven servings of fruits and vegetables a day, having fish or poultry and whole grains and limiting red meat and fat intake and reducing daily alcohol consumption are recommended for patients undergoing treatment.

What to Avoid Dietary supplements such as multivitamins; high doses of vitamins like C, E and folic acid; and antioxidant-rich drinks like green tea, cranberry and pomegranate juice can interfere with cancer treatment and may actually increase the growth of cancer cells. Botanicals and herbs, like ginkgo


biloba, may increase bleeding disorders and either increase or reduce the effectiveness of chemotherapy drugs.

Drug Costs: What to Do If Your Insurance Does Not Pay Many cancer patients today face the problem of how to pay for soaring healthcare costs. Cancer organizations like the Patient Advocate Foundation (patientadvocate.org) and CancerCare (cancercare.org) offer limited financial assistance to patients who qualify. And most pharmaceutical and biotech companies have patient-assistance programs in place that provide drugs for free to qualifying patients. If you are in need of financial assistance, talk with your doctor about available options and how to enroll in an appropriate program.


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Part 3: Treatment Side Effects

CHAPTER 6

Coping With Common Treatment Side Effects Hodgkin lymphoma patients may experience a range of side effects, also called toxicity, from the cancer treatment they receive. The various treatments, including chemotherapy, radiation and steroids, cause different side effects. Fortunately, there are many effective ways to make them more tolerable. Ask your healthcare team about possible side effects from your treatment regimen and be sure to tell your doctor if you experience any of them. In many cases, side effects can be lessened with medications or lifestyle changes.

The Difference Between Long-Term Effects and Late Effects of Cancer Treatment Long-term effects are defined as toxicities that happen during cancer treatment and continue for months or several years, such as fatigue, menopausal symptoms and cardiovascular problems. Late effects are side effects of cancer treatment that become apparent only after treatment has


ended and may arise many months, years or even decades after treatment is completed, such as infertility, osteoporosis and secondary cancers. In general, chemotherapy tends to cause more long-term side effects than late effects in Hodgkin lymphoma survivors, and radiation usually causes more late effects. There is evidence, however, that the combination of doxorubicin (Adriamycin) and radiation, especially when the radiation is directed to the chest area, may result in late effects to the heart, causing a decrease in cardiac function and accelerated atherosclerosis, in which plaque builds up on the inside of the arteries (see “Cardiotoxicity,” below).

Some Common Side Effects Caused by Chemotherapy • Cardiotoxicity

• Hair loss

• Pulmonary Toxicity

• Mouth sores

• Changes in taste

• Nausea/vomiting

• Decreased blood cell production

• Sexual dysfunction

• Diarrhea

• Sterility

• Fatigue

Side Effects Caused by Chemotherapy Chemotherapy is generally most effective at killing cells that are dividing rapidly, such as cancer cells. However, chemotherapy drugs are not selective, and they can also kill or damage normal healthy cells, especially cells that are fast growing, such as hair cells and those in the mouth, the gastrointestinal tract and the bone marrow. Some chemotherapy drugs may also damage heart cells. Side effects of chemotherapy can vary widely depending on the types of drugs that are given and an individual patient’s response. Side effects can be mild or serious. Some of the most common side effects caused by chemotherapy include the following:

Cardiotoxicity Cardiotoxicity (the occurrence of heart muscle damage) from the use of a class of chemotherapy drugs called anthracyclines, including doxorubicin (Adriamycin), in the treatment of both non-Hodgkin and Hodgkin


lymphomas is well documented. Anthracyclines can weaken the heart muscle, causing it to work harder to pump blood. If the damage becomes severe, it can lead to congestive heart failure. Lifestyle choices can also impact a patient’s risk for cardiotoxicity. For example, smoking, obesity, lack of exercise, high cholesterol and high blood pressure may all contribute to chemotherapy-related cardiotoxicity. Careful monitoring by your healthcare team can reduce your chances for developing cardiotoxicity. Most doctors will prescribe a MUGA (multiple gated acquisition) scan, which measures cardiac function, before chemotherapy begins to ensure that chemotherapy is safe.

Pulmonary Toxicity A serious side effect of ABVD may be pulmonary toxicity. It is important to report any change in lung function, such as cough, chest pain or shortness of breath to your doctor. Your doctor may wish to follow your lung status by performing serial or intermittent pulmonary function studies.

Changes in Taste Some patients will experience a change in the way foods or beverages taste. Familiar foods sometimes taste differently (called dysgeusia) or the flavors of foods are not as strong (called hypogeusia). Some patients may also feel that foods have a metallic taste. These side effects are temporary and typically disappear after chemotherapy is completed.

Decreased Blood Cell Production Red blood cells, white blood cells and platelets are constantly being produced in the bone marrow. Chemotherapy treatment may temporarily interfere with the ability of the bone marrow to produce adequate numbers of blood cells. When this occurs it is called myelosuppression. Anemia is the term used when myelosuppression causes a reduction in the number of red blood cells and hemoglobin (contained in the red blood cells). Anemia can cause people to feel very tired. Mild or moderate anemia is common with many chemotherapy regimens, and treatment for the anemia may be necessary.


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Neutropenia is the term used when myelosuppression causes a decrease in neutrophils—the primary type of white blood cells found in the blood. Because neutrophils play a very important role in fighting infection, a low count may cause patients to develop serious or even life-threatening infections that require hospitalization or antibiotic therapy. Also, if the absolute neutrophil count is too low, your doctor may have to reduce your chemotherapy dosage or delay treatment rather than risk infection. Infection is often accompanied by fever. Other symptoms of infection may include chills and night sweats. To prevent and control neutropenia, your doctor will check your white blood cell and neutrophil counts before and during each chemotherapy cycle. When neutropenia threatens your ability to receive the planned dose of chemotherapy, drugs such as filgrastim (Neupogen), pegfilgrastim (Neulasta) or sargramostim (Leukine) can be given after chemotherapy to reduce the duration and severity of neutropenia. These drugs can sometimes cause bone pain and, if in the chest, may make patients think they are having a heart attack. Nonsteroidals may relieve pain rapidly. By keeping the white blood count from dipping too low, these medications can help keep your chemotherapy doses on schedule. Occasionally, oral antibiotics are given to help prevent infection when neutrophil counts are low. Thrombocytopenia is the term used when myelosuppression depletes the number of platelets in your blood. Platelets help start the clotting process when you bleed; if your platelet count is low, you may bruise easily. A low platelet count may also cause prolonged or excessive bleeding from cuts, nosebleeds, bleeding from the gums or bleeding without a previous injury. A platelet transfusion may also be needed in some cases. Tips for Detecting Infection Due to Low Blood Cell Production Report these symptoms immediately to your healthcare team: • Fever (greater than 100.5°F)

• Diarrhea

• Sore throat

• Redness, swelling or pain around a wound

• Rash

• Cough


Tips for Avoiding Dehydration From Diarrhea or Vomiting • Drink plenty of liquids (eight glasses a day). • Look for signs of dehydration, including dry mouth or skin, decreased urine and dizziness or lightheadedness when you stand up. • Avoid milk products, which can worsen diarrhea. • Avoid hard-to-digest foods, such as those high in fiber, which can worsen diarrhea. • Eat plenty of bananas and other high-potassium foods (check with your physician or dietitian to make sure these foods will not interfere with your chemotherapy or other medications you are taking). • Take the medicines that your doctor recommends to control diarrhea (notify your healthcare team if diarrhea occurs).

Tips for Coping With Fatigue • Keep a diary to help you identify when you have the most energy and what activities make you feel fatigued or give you energy. This can help you plan your activities for the times when you have the most energy. • Ask for help. This may be difficult for many people. Accept help if someone offers to assist you or if you need something you do not have the energy to do for yourself. Many family members or friends are happy to give assistance. • Exercise if your doctor says it is okay to do so. But do not overdo it. Simple stretching, range-of-motion exercises or a short walk may give you more energy and not decrease the energy you have. Begin slowly and build up to the level that is right for you. Your doctor, nurse or physical therapist can help you create a personal exercise plan. • Rest and sleep during therapy are very important, but try not to rest more than necessary, because it may decrease your energy level. Many patients find that taking an afternoon nap leaves them feeling less fatigued for the rest of the day, but others find that napping causes less restful nighttime sleep. If you are having trouble sleeping, talk to your healthcare team to determine the reason and what you can do about it.


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Diarrhea Diarrhea can be a side effect of chemotherapy. While most patients do not experience severe diarrhea, the most important thing to remember is to avoid dehydration (a loss of body fluids). Report any bloody diarrhea or fever with diarrhea to your healthcare team.

Fatigue Fatigue is a common side effect of many types of chemotherapy. Fatigue should go away after treatments are over, but it can take weeks or months until it is completely gone. Extreme fatigue may be a sign of anemia. Certain medications may stimulate red blood cell growth.

Hair Loss For many Hodgkin lymphoma patients, hair loss (also called alopecia) is one of the most distressing side effects of chemotherapy. Thinning or loss of hair can occur at any place on the body, including the scalp, eyebrows, eyelashes, arms, legs and pelvis. The hair loss may be variable. All of your scalp hair may fall out, or you may just notice overall thinning. When hair loss occurs, it often starts about two or three weeks after the first chemotherapy treatment. Remember that hair loss due to chemotherapy is usually temporary, and your hair will probably grow back when the chemotherapy regimen is over. Typically, hair will start to grow back within a few weeks after treatment ends. At first, the new hair growing in may be a slightly different texture or color than it was before treatment, but it usually returns to normal.

Mouth Sores The membranes of your mouth may become red, sore or irritated during chemotherapy, which is referred to as mucositis. Infections of the mouth and throat caused by viruses or fungi may also occur. If your throat is persistently sore, tell your healthcare team. They will need to look at your throat and may recommend a throat swab (called a culture) to check for infection. If an infection is present, several medications are available to treat it. To help reduce the risk of mouth infections, consider seeing a dentist and have a complete checkup and cleaning before receiving chemotherapy.


Tips for Caring for Hair Loss These steps can help alleviate chemotherapy-induced hair loss: • Pat your hair dry rather than rub it with a towel after shampooing. • Use a soft-bristle brush and a wide-tooth comb when grooming your hair. • Avoid curlers and hair dryers. • Avoid coloring your hair or using chemicals on it. • Consider using a wig, scarf, turban or soft cotton hat or head wrap. Some health insurance companies cover the cost of wigs with a prescription from your doctor. Check your policy to see if you are covered. • Use a hat or scarf to protect your scalp when out in the sun.

Tips for Preventing or Caring for Mouth Sores • Keep your mouth clean. Use a soft-bristle toothbrush, nonabrasive toothpaste and lip moisturizer. • Avoid mouthwashes that contain alcohol. Your physician or nurse may recommend a swish-and-swallow mouth rinse. • Avoid citrus fruits and juices. • Avoid spicy foods. • Eat soft foods while you are taking chemotherapy to avoid bruising the membranes in your mouth. • Avoid flossing your teeth if your blood counts are low.

Nausea or Vomiting Chemotherapy can cause nausea or vomiting. Drugs that prevent vomiting (called antiemetics) include aprepitant (Emend), ondansetron (Zofran), granisetron (Kytril), metoclopramide (Reglan) and dolasetron (Anzemet), prochlorperazine (Compazine); and a variety of corticosteroids, such as prednisone (Deltasone). Nausea most frequently occurs on the day you receive chemotherapy, but it can also start one or two days later. Your doctor may prescribe an antiemetic before chemotherapy to prevent nausea. In most cases, antiemetics can partially or completely prevent nausea and vomiting. Understanding Hodgkin Lymphoma 51

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Tips for Controlling or Minimizing Nausea and Vomiting • Consume a liquid diet before chemotherapy such as broth, consommé or water. Avoid milk. • Avoid foods that are too hot or too cold and too sweet or too spicy. • Eat smaller and more frequent meals rather than a few large meals each day. • Avoid strong or offensive odors. Get plenty of fresh air. • Take prescribed antiemetics before chemotherapy to prevent nausea. • If vomiting occurs, be careful to avoid dehydration (loss of body fluids).

Sexual Dysfunction Chemotherapy can cause a drop in libido (sex drive). Usually, a normal libido returns after treatment is finished. (See “Sexuality,” on page 59.)

Sterility Chemotherapy (and radiation) can sometimes cause either temporary or permanent sterility (the ability to have children) in both men and women, because the treatment may damage sperm and egg cells. The specific dose of treatment, whether the patient has received one or several therapies and the patient’s age at the time of treatment are all contributing factors to infertility. Talk with your doctor before starting treatment about what you can do to protect your fertility during treatment. (See “Fertility Risks,” on page 61.)

Other Possible Side Effects Some of the other possible side effects of chemotherapy include cough, a decrease in lung function, skin rashes, an increased risk of secondary cancers and general weakness. Some drugs may also cause damage to the nervous system called peripheral neuropathy. Nerve damage can cause side effects such as constipation or a tingling sensation in the fingers and toes. Patients are sometimes at increased risk for viral infections, particularly shingles (herpes zoster). Be sure to immediately report any painful local rash (which sometimes may be accompanied by blisters) to your doctor.


Other possible side effects include sore throat pain and a loss of balance or coordination. Although many of these effects are temporary, some may last for an extended period of time.

Side Effects Caused by Radiation Radiation therapy (or radiotherapy) uses an invisible ray or beam of high-energy particles aimed at tumor sites to kill cancer cells. Radiation is painless and will not make you radioactive. However, there are side effects associated with radiation therapy. The consequences of radiation therapy depend on the treatment dose, the part of the body being treated (usually side effects occur only in the specific area of the body being radiated) and the age of the patient. Some common side effects caused by radiation: • Dry mouth • Fatigue • Hair loss • Loss of appetite and taste • Nausea • Secondary cancers • Skin reactions • Throat irritation Radiation may also cause a drop in the number of white blood cells, which help protect the body against infection. Your healthcare team will monitor your white blood count during treatment.

Dry Mouth A temporary decrease in the production of saliva during radiation therapy may cause patients to experience dry mouth, a condition known as xerostomia, which may result in difficulty in swallowing foods or thick liquids. Dry mouth may also cause food particles to stick to the teeth and gums. And because saliva helps prevent cavities, patients may be advised to visit the dentist before radiation therapy begins to receive fluoride treatments.


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Fatigue The likelihood that you will experience fatigue depends on your illness, the frequency of radiation treatments and the specifics of your radiation therapy. See page 50 for tips on overcoming fatigue.

Hair Loss Unlike the hair loss that is caused by chemotherapy, hair loss caused by radiation occurs only on the specific area of the body that was treated. The hair loss is usually temporary, but it may be permanent (especially with higher doses of radiation). See page 50 for tips to cope with hair loss.

Loss of Appetite and Taste Foods you once found appealing may no longer be appetizing to you during radiation treatments. The good news is that the loss of appetite and taste are usually short-term problems. Remember that eating well helps your body heal and boosts energy levels. Eating four or five small meals during the day may be more comfortable than eating two or three larger ones. Your healthcare team can provide information to help you maintain good nutrition during treatment.

Nausea Nausea may occur after the first radiation treatment, especially in patients who have radiation to the abdomen. Some people can avoid nausea if they avoid eating (especially sweet, spicy or fatty foods) a few hours before radiation treatment. Patients may also want to schedule radiation visits for the end of the day so they can be home if they start to feel nauseous. If nausea becomes a problem, ask your doctor about taking a medication that prevents nausea (an antiemetic) before each radiation therapy session. See page 51 for additional tips to help you cope with nausea and vomiting.

Secondary Cancers The risk for developing secondary cancers from radiation therapy depends on a number of factors, including the amount of radiation given and the part of the body treated. For example, Hodgkin lymphoma patients treated for limited disease in the chest area are at greater risk for developing breast, lung or thyroid cancer. Patients with more extensive disease in lymph node groups below the diaphragm are at greater risk for developing gastrointestinal


cancers such as colon cancer. Less common secondary cancers include basal cell skin cancer and sarcomas of the bone and soft tissue.

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Skin Reactions Radiation can cause a slight to moderate reddening of the skin and is often accompanied by discomfort, itching and flaking. Moist areas, such as around the mouth, may be more prone to irritation (your doctor may recommend zinc oxide ointment for these areas). These skin changes usually diminish and disappear over a few weeks. Your skin could look and feel as if it were sunburned, and it may eventually peel. During radiation treatment you can take steps to protect your skin: • Avoid exposing areas of the skin that are receiving radiation to the sun. These areas will always need extra protection, well after treatment is completed. • Wear a T-shirt or hat and use plenty of sunscreen (with a high SPF) when out in the sun.

Throat Irritation Receiving radiation to the neck, throat or chest may result in a sore throat, dry mouth, nausea or cough. You may have difficulty eating and swallowing, especially toward the end of your treatment program. Let your doctor know if you have difficulty swallowing. There are treatments that can help with the discomfort. Difficulty in swallowing will usually go away a few weeks after treatment. There are things you can do to ease throat irritation during radiation therapy: • Eat bland foods that are soft and smooth and easily digestible, such as pudding, yogurt and milk shakes, as well as commercial dietary supplements. Patients sometims find these to be too sweet. Mixing them with milk or other liquids are often helpful. • Take small bites and swallow each bite completely before taking another. • Try drinking thicker liquids, such as fruit that has been puréed in a blender; they are easier to swallow than thin liquids, but avoid citrus fruits, especially juices.


Side Effects Caused by Bone Marrow Transplantation Patients receiving high doses of chemotherapy and radiation before undergoing a bone marrow transplant may be at increased risk for developing infection, bleeding and other side effects. In addition, patients receiving bone marrow from a donor are at risk for developing graft-versushost disease (GVHD), in which the donated marrow attacks the patient’s tissues. Graft-versus-host disease can occur at any time after the transplant. Drugs may be given to reduce the risk of developing GVHD or to treat the problem once it develops.

Side Effects Caused by Steroids Steroid drugs such as glucocorticosteroids (cortisone, hydrocortisone, dexamethasone, methylprednisone and prednisone) may cause a variety of side effects, including insomnia (the inability to fall asleep), increased appetite, mood or personality changes such as euphoria (an overwhelming sense of bliss) and anger, high blood pressure and weight gain. Prednisone may also trigger diabetes in patients prone to that disease or make the diabetes worse in patients who already have the disease. Steroids for extended periods of time may also cause osteoporosis in at-risk patients. Patients are advised to alert family and friends that personality changes may occur. Patients should avoid making hasty decisions. If personality changes occur, the doctor should be informed— the dose may need to be reduced. (See “The Difference Between Long-Term Effects and Late Effects of Cancer Treatment,” on page 45.)

When to See Your Doctor Your doctor or a member of your healthcare team will discuss possible treatment side effects with you prior to initiating therapy. If you experience a symptom that is not expected or if your symptoms are prolonged, see your doctor. If you experience a medical problem that cannot wait for a regularly scheduled appointment, such as high fever, shortness of breath, unremitting nausea and vomiting, chest pains and dizziness, call your physician, who will evaluate your situation and decide your next course of action. If you cannot reach your physician or a member of your medical team, go to your hospital emergency room for a medical assessment and place another call to your doctor.


Combating Side Effects Pain Management Hodgkin lymphoma patients may experience pain, which can be caused by the lymphoma tumor itself when it presses on bones, nerves or body organs. Pain may occur as the result of treatment, procedures or tests (such as a bone marrow biopsy). Pain may be acute (sudden and lasting for a short period of time) or chronic (over a long period of time). If pain continues without treatment, it often leads to irritation, depression and a lack of energy. It is important to know that you do not have to live in pain and that your medical team, which may include a specialist in pain control, can help relieve your discomfort. Many medical advances have been made in the treatment of pain, including an improved understanding of how medication works to relieve it. Other techniques such as relaxation, guided imagery and biofeedback may also relieve pain. Keeping a journal of when pain occurs, what it feels like (sharp, throbbing, etc.), how strong it is and how long it lasts will help you and your doctor develop the right plan to treat your pain.

Exercise Regular physical activity helps keep the cardiovascular system strong and body muscles flexible. Exercise can also help alleviate breathing problems, constipation, poor appetite and mild depression. It also helps reduce stress and fatigue. Several types of exercise are particularly helpful: • General physical activity such as swimming, dancing, mowing the lawn • Aerobic activity to improve cardiovascular fitness, including walking, jogging, bicycling • Resistance training to strengthen muscles, protect joints and help remedy osteoporosis by building bone mass, including lifting weights or using resistance-training equipment, push-ups, carrying and lifting • Flexibility practices such as stretching and yoga improve range of motion, balance and stability Before starting any exercise program, talk with your doctor about how much exercise is safe for you, and then gradually increase your physical


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activity level. Do not push yourself beyond your limits. It is not necessary to overdo. There is nothing to prove.

Diet Eating a healthy diet is more important than ever when you are going through cancer treatment and can help you keep up your strength and energy, better tolerate treatment-related side effects, decrease your risk of infection and heal and recover quickly. Aim for a diet high in fruits and vegetables (five to seven servings a day), protein (poultry, fish and eggs) and whole grains. Your healthcare team can help you put together an eating plan that suits you. All your daily nutrients should come from food and not dietary supplements such as multivitamins or individual vitamin supplements, because they may interfere with treatment. See “Complementary and Alternative Remedies,” on page 41 for more tips on coping with Hodgkin lymphoma and treatment side effects.


Chapter 7

Sexuality

3

Sexual Function During Treatment The causes of sexual dysfunction experienced by men and women during and after a cancer diagnosis are varied. Psychological factors, such as fear about your illness, altered body image due to hair loss and depression, and the physical side effects of treatment can all conspire to reduce sexual desire (libido) and function. Besides fatigue, some chemotherapy treatments can interfere with testosterone levels in men, resulting in low libido. In women, decreased estrogen production may cause vaginal dryness, hot flashes and other menopausal symptoms. In women, radiation therapy to the pelvis can cause a narrowing of the vagina, painful intercourse and ovarian failure, resulting in infertility (see “Fertility Risks,” on page 61). Some antidepressants and over-the-counter medications also lower sexual desire, as do certain lifestyle choices such as smoking and drinking. Be assured that the lack of sexual desire and function due to treatment is usually temporary. Although many people are often too embarrassed to raise the issue of sexual function with their physician, it is important to recognize that sexuality is an integral part of life and that there is no reason to be uncomfortable discussing your concerns with your doctor. The doctor may order tests to track hormone levels and make recommendations to see a specialist and/or prescribe medications to restore erectile function in men and hormone therapy to alleviate vaginal dryness and other menopausal symptoms in women.

Questions to Ask Your Doctor About Sexual Function • How will my treatment affect my sexuality? • Will sexual function be restored after my treatment is completed? • How long will it take for sexual function to be restored? • Are there successful treatments for my sexual dysfunction? • What can I do to restore sexual desire and function?


When to Use Contraceptives Lymphoma is not a contagious disease, and it cannot be caused by or transferred through sexual intercourse. Condoms should be used for two reasons. Small quantities of chemotherapy may be found in semen or vaginal fluid of people undergoing treatment. Also, getting pregnant during treatment of either the man or the woman is not advisable. It is also recommended that people who have undergone bone marrow or stem cell transplants use condoms to reduce their risk for contracting cytomegalovirus and other infections due to a compromised immune system. To further reduce your risk of infection, avoid sexual intercourse if your blood counts (hemoglobin, white blood cells and platelets) are low. Low blood counts could also cause bleeding. Ask your doctor when it is safe for you to resume sexual intimacy.


Chapter 8

Fertility Risks

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Treatment for Hodgkin lymphoma, such as certain types of chemotherapy, especially alkylating agents, and radiation therapy, can interfere with fertility in several ways. In addition to killing cancer cells, these treatments can also affect healthy cells and reproductive organs like the ovaries and testes, which produce the eggs and sperm crucial to fertility. Whether the infertility is temporary or permanent depends on a number of factors, including the patient’s sex, age at the time of treatment, the specific type and dose of radiation therapy and/or chemotherapy used and treatment duration. Although the chemotherapy regimen ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) commonly used to treat Hodgkin lymphoma contains the alkylating agent decarbazine, it does not appear to affect fertility as much as other regimens containing alkylating agents such as MOPP. If you are considering having children in the future, it is very important to talk to your doctor before treatment begins about how your treatment may affect your fertility. Your doctor will be able to recommend a counselor or fertility specialist who can discuss your individual options.

How to Protect Fertility During Treatment Men Infertility occurs in men when the testes stop producing normal sperm cells. Currently, preserving fertility in men is much easier and more effective than preserving fertility in women. It involves collecting semen and then freezing and storing it in a process known as sperm banking. The sperm can later be thawed and used for intrauterine insemination or in vitro fertilization. For men with low sperm counts, a procedure called testicular sperm extraction (TESE) can be performed in which testicular tissue is removed and the tissue and/or the sperm extracted can then be frozen and stored for later use. Some men who lose fertility immediately following treatment may regain fertility in the future, although the chance of recovering fertility depends on several factors, such as age (younger people are more likely to get their fertility back than older people), the presence of fevers and the amount and duration of radiation and chemotherapy treatments. Understanding Hodgkin Lymphoma 61

Women Cancer treatment may cause women to enter early menopause or may result in other damage that does not allow for a successful pregnancy. Although preserving fertility in women is more difficult than it is in men, the emerging field of oncofertility—a melding of two medical specialties, oncology and assisted reproduction—is providing new hope for lymphoma survivors concerned about their ability to conceive following treatment. To date, the most widely available and successful way of preserving fertility before cancer treatment begins is by removing eggs, fertilizing them in vitro with the sperm of a spouse or donor and then freezing and storing the embryos for future use (embryo banking). Eggs may also be stored unfertilized (egg banking). Banking and using unfertilized eggs is more difficult, but is a technique that has been recently developed. Because both of these techniques require a number of weeks of treatment to complete, they may not be advisable for women needing immediate treatment of their lymphoma. Fertility preservation method under investigation is ovarian tissue cryopreservation (OTC), in which an ovarian tisuse is removed laparoscopically and frozen. Eggs from the tissue follicles are then fertilized and implanted. Giving injections of the drug leuprolid (Lupron) to halt production of hormonal function before chemotherapy begins may limit ovarian exposure to the treatment, thereby protecting the quality of the eggs, although the drug’s use is highly controversial. Before treatment begins, all women of childbearing age should talk to their doctor and a fertility preservation expert about the options available to them. These websites are good resources to find the latest information on fertility preservation techniques: • Fertile Hope (fertilehope.org) • Institute for Fertility Preservation (fertilitypreservation.org) • Myoncofertility.org


Chapter 9

Hodgkin Lymphoma During Pregnancy

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Hodgkin lymphoma diagnosed in women who are pregnant is the same disease found in nonpregnant women of childbearing age, although treatment for pregnant women is different. The tests used to diagnose Hodgkin lymphoma during pregnancy may include the following: • Physical exam and personal and family history • Complete blood count • Blood chemistry studies to measure the amounts of certain substances released into the blood by organs and tissues in the body • Lymph node biopsy • Immunophenotyping to determine whether malignant cells began from the B lymphocytes or the T lymphocytes Following a diagnosis of Hodgkin lymphoma, staging of the disease is done to determine whether cancer cells are limited to the lymph system or have spread to other parts of the body (see “Cancer Staging and What it Means” on page 18). To protect the fetus from the harm of radiation, tests that do not use radiation are performed, including MRI and ultrasound, which uses high-energy sound waves to detect enlarged lymph nodes or organs such as the liver or spleen. Once the staging is completed, treatment will be chosen based on the woman’s wishes, the stage of her Hodgkin lymphoma, how fast the cancer is growing and the age of the fetus. While lymphoma diagnosed during pregnancy is problematic, often treatment can be prescribed that is less likely to harm the fetus. Treatments used during the first trimester of pregnancy may include the following: • Watchful waiting, if the cancer is above the diaphragm and slow growing • Radiation therapy, if the lymphoma is above the diaphragm, with the fetus shielded • Systemic chemotherapy using drugs least harmful to the fetus Understanding Hodgkin Lymphoma 63

Most Hodgkin lymphoma patients diagnosed during the second half of pregnancy, can delay treatment until after the baby is born. Treatment at this time may include the following: • Watchful waiting, with plans to induce delivery when the fetus is 32 to 36 weeks old • Systemic chemotherapy • Steroid therapy • Radiation therapy to relieve breathing problems caused by a large chest tumor

Breast-Feeding During Treatment Breast-feeding is generally not recommended when a woman is undergoing treatment for lymphoma because of the possibility that the chemotherapy drugs may be passed to the child through the mother’s milk. Women of childbearing age should discuss these issues and all possible options with their doctor.


4 Part 4: C hildren and Young Adults With Hodgkin Lymphoma

Chapter 10

General Information Hodgkin lymphoma most commonly affects three age groups: children 14 years old and younger; young adults ages 15 to 34; and older adults ages 55 to 74. Although Hodgkin lymphoma accounts for nearly 4 percent of all cancers in children from birth to age 14 in the United States, it is the most common cancer among teens ages 15 to 19. With modern treatment, Hodgkin lymphoma in children and young adults has a cure rate of about 95 percent. Childhood Hodgkin lymphoma can start in nearly any part of the body and spread to other organs. Some symptoms of Hodgkin lymphoma in children include the following: • Painless swelling of the lymph nodes in the neck, underarm or groin that does not go away in a few weeks • Unexplained fever • Weight loss

• Weakness and fatigue • Coughing, trouble breathing or chest pain • Itchy skin • Drenching night sweats


Although most children with these complaints do not have lymphoma, those with persistent symptoms should see their doctor to make certain that Hodgkin disease is not present. The same tests and procedures performed on adults suspected of having Hodgkin lymphoma are given to children and may include a physical exam, biopsy, chest X-ray and CT or PET scan. While the causes of Hodgkin lymphoma are unknown, the following may increase the risk of childhood or adolescent Hodgkin lymphoma: • Family history (especially siblings of a person diagnosed with lymphoma, although no firm hereditary pattern has been established) • Autoimmune disease • Immunodeficiency • Receipt of an organ transplant • Exposure to chemicals such as pesticides, fertilizers or solvents • Infection with viruses such as Epstein-Barr • Infection with the human immunodeficiency virus (HIV)

Short-Term and Late Effects of Treatment Although children and young adults with Hodgkin lymphoma are treated with lower doses of chemotherapy and radiation therapies than adults with the disease, they still have a significant risk of developing both short-term (temporary), long-term (begin during treatment and continue for months or years after) and late (begin after treatment ends) effects. In fact, according to a report in the New England Journal of Medicine, as many as two-thirds of childhood cancer survivors experience at least one late health effect of treatment. Some factors that impact an individual’s risk for short- and long-term health consequences include gender, type and duration of treatment, age at the time of treatment and overall health. During chemotherapy and radiation treatments, children and adolescents, like adults, may experience these effects: • Anemia (low red blood cell count)

• Fatigue

• Bleeding and easy bruising

• Hair loss

• Decreased white blood cell production (resulting in infections)

• Loss of appetite

• Diarrhea

• Nausea and vomiting


• Low platelet count

Because the brains and bodies of children and young adults are still developing when they receive treatment, the potential for late health effects, which may develop months, years or even decades after treatment is completed, is increased. For example, alkylating chemotherapy agents, such as cyclophosphamide and dacarbazine, have been linked with secondary cancers, including acute myeloid leukemia, thyroid disease (hypothyroid, hyperthyroid, thyroid nodules) and pulmonary toxicity. Steroids, such as prednisone, can cause osteonecrosis, which is the death of bone tissue, due to lack of blood supply, resulting in tiny breaks in the bone. Radiation therapy can lead to thyroid dysfunction, lung cancer and breast cancer in women. The National Cancer Institute and the Children’s Oncology Group is studying whether radiation therapy can be eliminated in children with Hodgkin lymphoma who respond rapidly to chemotherapy alone, thus avoiding putting girls at an increased risk for breast cancer. Other potential late effects from chemotherapy, alone or in combination with radiation therapy, include the following: • Gonadal (testicular) dysfunction, which may result in delayed or arrested puberty • Hypogonadism, in which the testes in boys and the ovaries in girls fail to produce hormones and eggs or sperm • Infertility, the inability to have children (See “Fertility Risks,” on page 61.) • Premature menopause • Cardiotoxicity • Dental abnormalities, including missing teeth and the thinning of root and tooth enamel Short-term and late effects of treatment are not limited to physical problems. Psychological, emotional or social problems, including social withdrawal, depression and anxiety may also develop. These problems can strain relationships with friends, family members and romantic partners. Supportive counseling with a medical professional (psychiatrist, social worker, psychologist, counselor or clergy) and/or medication can help alleviate the symptoms of these disorders. Getting involved in a support group of other teens or young adults with cancer can also help.


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Your medical team can suggest hospital-sponsored support groups. Many young adults find online support communities such as GroupLoop (grouploop.com) for teenagers or Planet Cancer (planetcancer.org) for young adults very beneficial.

QUESTIONS TO ASK ABOUT TREATMENT • Is the treatment you are recommending for my child/adolescent designed for this age group rather than for adult patients? • What are the short- and long-term side effects of the treatment? • Are there other treatment regimens that are as effective with fewer risks? • When should sperm banking be considered? • Can fertility be preserved in girls undergoing pelvic radiation therapy?


lymphoma.org


Chapter 11

Special Concerns for Teenagers and Young Adults The potentially emotionally debilitating side effects of Hodgkin lymphoma treatment, such as hair loss, may make it difficult for teenagers and young adults to adhere to treatment protocols, but the possibility for long-term disease remission and even cure makes it imperative that they do so. Adherence to follow-up medical care is also important for long-term cancer survivorship in order to identify changes in health and to help in the prevention and early detection of secondary cancers, to address the late effects of treatment and to spot other physical or psychosocial problems that may develop months or years after treatment is completed.

Follow-up Care How frequently to schedule follow-up medical visits depends on the type of Hodgkin lymphoma, the treatment received and the state of overall health. Generally, people see their doctor every three to four months for two to three years following treatment and afterward every six months to a year. Because children and young adult Hodgkin lymphoma survivors will have to have regular follow-up medical care for the rest of their lives, it is important that survivors keep a detailed record of their tests and treatments, so that doctors caring for them over their lifetime will have a complete history of their medical care. Many cancer centers now have childhood survivor specialty clinics that provide a comprehensive evaluation of late health effects and recommended screening guidelines. Data show that young adult cancer survivors who have ongoing follow-up care by both oncologists and primary care physicians have the highest rate of adherence to health screening recommendations. Ask your medical team if your cancer center has a childhood survivor clinic.


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At your follow-up appointment, be sure to tell your doctor about • Any symptoms you are experiencing that may signal a cancer recurrence • Pain • Physical problems that interfere with daily life, such as fatigue • Cognitive concerns, such as memory changes or difficulty concentrating • Feelings of sadness, depression or anxiety that will not go away • Sleep problems • Weight gain or loss Depending on medical problems you may be having and your general health, your doctor may recommend tests to check for Hodgkin lymphoma recurrence or screen for secondary cancers. Based on the type of treatment you received, your doctor may also suggest that certain health screenings, such as mammography, begin at an earlier age than what is recommended for the general population. According to the American Cancer Society and Children’s Oncology Group guidelines, women who received radiation to the chest between the ages of 10 and 30 should have yearly mammogram and MRI screenings beginning at age 25 or eight years after completion of radiation therapy, whichever occurs first. Ask your doctor, as you age, what other early health screenings you should have, such as Pap tests, colorectal screenings, prostate exams and bone density tests, and when to schedule them. QUESTIONS TO ASK YOUR DOCTOR ABOUT FOLLOW-UP CARE • What treatments and drugs have I had? • What are some common long-term and late effects of the treatment I received? • What symptoms should I watch for? • How often should I schedule routine visits? • What follow-up tests should I have? • What health screenings should I have and when? • What should I do to maximize my health and well-being? • Will I have trouble getting health insurance because of my cancer?


Developing Healthy Habits Eliminating risky behaviors like smoking or excessive alcohol consumption and maintaining a healthy lifestyle throughout your life can lower your risk for developing secondary illnesses as you age. Ask your doctor if he has any specific dietary and exercise recommendations to help reduce your risks for disease. TIPS FOR HEALTHY LIVING • Do not smoke or use any form of smokeless tobacco. • Eat a balanced diet that includes five or more servings of fruit and vegetables each day; protein (poultry, fish and eggs); and whole grains. • Maintain a regular exercise program that includes at least 30 minutes of some form of aerobic exercise (walking, bicycling or swimming) several days a week. Check with your doctor about a specific exercise plan for you. • Use sunscreen.

Quality of Life Issues Anxiety and Depression Although most children and adolescents treated for cancer adjust well to the emotional upheaval brought on by the diagnosis, a small number of young cancer patients will develop psychological problems, including depression, anxiety, insomnia and relationship difficulties. The signs of depression in children are different than those found in adults. Talk to your healthcare team about having your child assessed for depression if he or she exhibits one or more of the following symptoms for longer than two weeks: • Aggressive behavior

• Feelings of sadness or hopelessness

• Inactivity

• Refusal to go to school

• Changes in appetite

• Learning problems

• Crying

• Fatigue

• Hyperactivity

• Inability to concentrate

• Fear of death

• Constant thoughts of death or suicide

Treatment for childhood depression may include group or individual psychological counseling and/or a prescription for an antidepressant or other medications. Understanding Hodgkin Lymphoma 71

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Dating and New Relationships The experience of learning you have Hodgkin lymphoma and going through treatment can impact how you feel physically and emotionally and may alter your approach to dating and other personal relationships. Some Hodgkin survivors find dating after a diagnosis more difficult because they feel unattractive or worry about how potential partners may react to their diagnosis, while others find dating easier because they feel stronger having survived cancer and they have a greater appreciation of the importance of cultivating personal relationships. Deciding when to tell a potential romantic partner that you are a cancer survivor is an individual choice and should be done when you feel comfortable discussing your personal history with another person. If you are having difficulty dating or discussing your cancer with a romantic partner, talking to a therapist or counselor may help. Websites such as Planet Cancer (planetcancer.org) and I’m Too Young For This (i2Y.com) can also provide a helpful forum to discuss these concerns with other young cancer survivors.

Employment Many young Hodgkin lymphoma patients worry that their cancer diagnosis may sideline their career or put their employment in jeopardy. But employment experts say that decisions about how much to reveal to employers about your lymphoma and when and who to tell should be based more on your comfort level, workplace environment and what you may require in terms of time off for treatment rather than on fear of losing your job. However, before telling anyone at your workplace about your diagnosis, including coworkers, an immediate supervisor or someone in the human resources department, learn what your rights are by reading your employee manual regarding sick time, medical leave and disability benefits. It may also be helpful to familiarize yourself with the laws and agencies that protect against workplace discrimination and allow for medical leave, including the Americans With Disabilities Act (ada.gov); the Family and Medical Leave Act (dol.gov/esa/whd/fmla); and the Equal Employment Opportunity Commission (eeoc.gov). When you are ready 72 Understanding Hodgkin Lymphoma

to talk to your employer about your diagnosis, be sure to have on hand the information from your doctor regarding your treatment plan and how it may affect your work schedule. Before meeting with your supervisor or human resources manager, prepare a list of questions to discuss, including the following: • What is the company’s policy on medical leave? • How can my workload be adjusted to accommodate the time off I may need for treatment? • How much of the cost of my treatment is covered by my health insurance and how much will I be responsible for covering?

Health Insurance Medical costs, including health insurance, are of paramount concern to patients coping with cancer, and although health insurance premiums do tend to go up after a cancer diagnosis, the increase is usually absorbed by the employer if there is a group health plan. If not, the increase may be passed to the individual policyholder. There are also laws, such as the Consolidated Omnibus Budget Reconciliation Act (COBRA) and the Health Insurance Portability and Accountability Act (HIPAA), to protect you from losing your health care coverage if you change or lose your job. To learn more about HIPAA provisions, visit the U.S. Department of Labor website at dol.gov/dol/topic/health-plans/portability.htm. Other resources like the Cancer Legal Resource Center (cancerlegalresource center.org; (866) 843-2572) can provide information on a variety of legal issues, including health insurance coverage and employment discrimination.


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lymphoma.org


Part 5: L iving With Hodgkin Lymphoma

Chapter 12

Managing Your Life During and After Treatment Coping Strategies Each person’s experience with cancer is different, and how you cope with the physical and emotional impact of having Hodgkin lymphoma is unique. However, there are some general issues, such a the ones below, that many patients encounter.

Talking About Your Fears It is important to communicate your fears and concerns about having Hodgkin lymphoma with your loved ones, friends, doctors or counselors. Writing down your fears in a journal may also help.

Overcoming Depression It is not unusual for people living with cancer to feel sad or depressed. Being diagnosed with Hodgkin lymphoma and undergoing treatment can be challenging both physically and emotionally. Signs of sadness or


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depression include sleeping more or less than usual, lack of energy, crying and an inability to concentrate. In addition to challenging life circumstances, depression may also be caused by certain medications. If you are feeling depressed, be assured that help is available. Tell your doctor or members of your healthcare team about your feelings. They will be able to refer you to a professional individual (psychiatrist, social worker, psychologist or counselor) who will help you overcome sad feelings through talk therapy, medication or both. Support groups may also provide you with the comfort of being with others who have had similar experiences.

Dealing With Physical Changes Hair loss and other changes in appearance caused by treatment may make many people feel unattractive. Ask your doctor what changes you can expect, and plan ahead to buy a wig or head coverings if hair loss is a possibility. Getting advice from a makeup artist may also be beneficial in improving your appearance. Also, ask your healthcare team for advice on how to manage temporary changes such as dry skin, brittle nails and a blotchy complexion.

Maintaining a Healthy Lifestyle Eating a healthy diet, engaging in regular physical exercise and getting sufficient rest can help combat the stress and fatigue of Hodgkin lymphoma and its treatment (see “Combating Side Effects,” on page 57).

Life in Remission Although finishing cancer treatment and becoming a cancer survivor is a time to celebrate, it is normal to experience lingering feelings of anxiety and worry about a relapse. This is also a time when many people find it useful to take stock of their life and review goals and priorities, perhaps even making career and lifestyle changes. Adjusting to the “new” normal routines of life after cancer may take a few weeks or months. Developing a wellness plan in conjunction with advice from your medical team that includes ways you can take better care of your physical, emotional, social and spiritual needs can help you regain a sense of control and well-being.


Some changes to consider making: • Quit smoking and reduce alcohol consumption • Exercise (walking, biking, swimming) for about 30 minutes on most days can reduce anxiety, depression and fatigue and improve mood • Eat a healthy diet that includes fruits, vegetables, protein and whole grains (see “Combating Side Effects,” on page 57)

Follow-up Care At your first visit with your doctor following the completion of your treatment, ask him or her about your follow-up care schedule, which is different for each Hodgkin lymphoma survivor based on his or her disease type, age and general health. Although Hodgkin lymphoma is highly curable—between 80 percent and 90 percent of patients are cured of their disease—it is still very important to adhere to your follow-up healthcare plan to determine whether the lymphoma has recurred and to detect health problems resulting from treatment. During these visits your doctor will ask about any medical changes since the last appointment; give you a physical examination; and may prescribe imaging, blood, molecular diagnostic or other laboratory tests. To stay proactive in your healthcare, be sure to get the following information from your healthcare team: • Copies of your medical records and a written summary of your treatment in case you switch oncologists or need to see a primary care physician for routine medical care • A list of signs of disease recurrence and late effects from treatment At your follow-up care appointments, be sure to tell your doctor about: • Any new symptoms • Pain • Physical problems that disrupt your daily life such as fatigue, insomnia, sexual dysfunction, weight gain or loss • Any new problems such as heart disease, diabetes, high blood pressure • Any new medications or vitamins you are be taking • Emotional problems such as anxiety or depression Understanding Hodgkin Lymphoma 77

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Chapter 13

Why Hodgkin Lymphoma Patients Relapse or Become Refractory Hodgkin lymphoma has been studied more than any other type of lymphoma. These studies have contributed to rapid advances in the diagnosis and treatment of the disease. The vast majority of Hodgkin lymphoma patients—over 80 percent—will be cured of their cancer with first-line treatment. And even for those patients who relapse (the lymphoma returns following a remission) or become refractory (the lymphoma is resistant to primary treatment), secondary therapies are often successful in providing another remission and may even cure the Hodgkin lymphoma. For classical Hodgkin lymphoma, most relapses typically occur within the first three years following diagnosis, although some relapses occur much later. Exactly why an individual patient relapses is not known, although there are a number of clinical and laboratory factors that are associated with an increased risk of relapse. The International Prognostic Score includes seven factors that predict which Hodgkin lymphoma patients are at high risk for relapse. They include: • Late stage disease • Age • Sex (men are at greater risk for relapse) • Hemoglobin level • Albumin level • White cell count • Lymphocyte level These additional prognostic markers are used to predict early-stage disease patients at high risk for relapse: • Advanced age • Bulky-mass tumors • Multiple nodal sites 78 Understanding Hodgkin Lymphoma

• Serologic markers, such as elevations of Interluken 10 and Interluken 6 and soluble CD30

How Relapsed and Refractory Hodgkin Lymphoma Is Treated There are a number of treatment options available for patients with relapsed or refractory Hodgkin lymphoma. It is important to remember that secondary therapies are often successful in providing a second remission and may even be curative. Exactly what type of treatment is prescribed for individual patients depends on several factors, including when the relapse occurs, the patient’s age, the extent of disease, overall health and previous therapies received. The usual secondary treatment for the majority of patients consists of a chemotherapy regimen that is different from the initial therapy. An autologous stem cell transplant (using a patient’s own stem cells) usually follows. There are a number of secondary treatments available for patients with relapsed or refractory Hodgkin lymphoma. These treatment options are designed for use prior to transplant or to be used in patients who are not eligible for transplant and include: • ESHAP (etoposide, methylprednisone, cisplatin, cytarabine) • DHAP (dexamethasone, cisplatin, cytosine arabinoside) • DICE (dexamethasone, ifosfamide, cisplatin, etoposide) •GND (gemcitabine, vinorelbine, liposomal doxorubicin) • ICE (ifosfamide, carboplatin, etoposide) • IGEV (ifosfamide, gemcitabine, vinblastine)

Treatments Under Investigation In addition to conventional chemotherapies, there are a number of new agents to treat relapsed or refractory patients. For example, bendamustine (Treanda), a novel alkylating agent, which is already approved for relapsed chronic lymphocytic leukemia and relapsed follicular lymphoma, is being studied for relapsed and refractory Hodgkin lymphoma in clinical trials. There are also monoclonal antibodies for CD30-positive relapsed/ refractory Hodgkin lymphoma, other biologoc therapies, and also immunomodulatory drugs (IMiD). See page 87 for a complete listing. Understanding Hodgkin Lymphoma 79

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The monoclonal antibody rituximab (Rituxan) may also have a role in the treatment of relapsed/refractory Hodgkin lymphoma. Although rituximab (Rituxan) targets the CD20 antigen, which is not usually expressed on R-S cells, it is expressed in nearly all cases of lymphocyte predominate Hodgkin lymphoma and may also be present on classical Hodgkin lymphoma lymphocytes. Clinical trials are underway to study the effectiveness of rituximab (Rituxan) in combination with ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) in the treatment of classical Hodgkin lymphoma.


lymphoma.org


Part 6: C linical Trials

Chapter 14

Overview of Clinical Trials A clinical trial is a research study designed to answer basic questions about a new treatment or a new way of using an old treatment. There are hundreds of lymphoma clinical trials now under way in hospitals, cancer centers and doctors’ offices around the country. The government, pharmaceutical and biotech companies, universities and physician groups often sponsor clinical trials. The Food and Drug Administration (FDA) and the review board of participating hospitals must approve each phase in a clinical trial.

The Basics of Clinical Trials Clinical trials are done to study new drugs and treatment strategies. Examples of what clinical trials might investigate include the following: • A novel drug that is not approved by the FDA nor proven effective as treatment • A new indication (use) for a drug already approved by the FDA as a treatment for a different disease


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• Comparison of a new treatment with a standard treatment to determine which one is more effective or has fewer side effects • Determining how lifestyle changes can help cancer patients • Looking for ways to prevent cancer from occurring New drugs must pass through a rigorous approval process governed by the FDA before becoming a therapy for use in hospitals and clinics. The trials used to assess these drugs are typically divided into three types, called phases, each of which is designed to determine certain information. Phase I tries to determine the tolerability of a potential treatment; phase II tests the drug’s effectiveness in a small group of patients; and phase III tests the drug’s effectiveness compared to standard therapies or other available treatments in a large, varied group of patients with a specific cancer. Patients may be eligible to take part in different stages depending on their condition, type and stage of Hodgkin lymphoma and the type of treatment, if any, previously given.

Phase I This often involves the “first in human” studies. Phase I studies are designed to determine the dose of the drug that will be subsequently studied and the drug’s toxicities. The drugs are first tested in laboratory animals to determine an approximate dose for use in humans and what toxicities might be seen. Once ready for human testing, a much lower dose than what was used in the laboratory animals is selected as the starting dose for the phase I study. This first dose level of a drug is then tested in a few patients, typically three to six, to make sure that the drug is tolerated at that dose. These patients are treated one at a time to minimize the number of patients exposed to a potentially harmful drug should unexpected toxicities arise. If none of the patients at the first dose level experience any toxicities, then a higher dose is tried. The dose is slowly escalated in this manner until toxicities develop or the desired treatment effect is achieved.

Phase II Once the therapy dose is determined and shown to be safe in a phase I trial, it is then ready to be tested in a phase II study. Phase II studies aim to establish whether the therapies have any evidence of effectiveness. In a typical phase II study, 20 to 40 patients with similar or the same disease 82 Understanding Hodgkin Lymphoma

are all treated in the same manner. The investigators determine a response rate for the drug in the disease. Based upon the response rate obtained, the decision is made as to whether the drug should be further developed for the disease. Phase II studies might be used to generate preliminary data on a drug or to confirm data to obtain FDA approval. Phase II studies are also done to investigate whether a therapy already approved for one type of disease is an effective treatment for another.

Phase III Phase III trials are performed to determine whether the treatments developed in phase I and II studies are better than what is currently considered the “standard of care.” Phase III studies often require a large number of patients. Once a patient elects to enroll in a phase III study, he or she is assigned to one of two groups in a process called “randomization.” In randomization, a computer assigns the treatment the patient is to receive. One group receives the standard therapy and the other group receives the experimental treatment. It is important to remember that this randomization process is done so that each treatment arm will have patients with similar characteristics and be free of bias. Additionally, no one knows which of the treatments being studied is better or if there is even a difference. This is why the study is being done, to learn if there is a difference. Besides testing for drug effectiveness and safety, phase III studies also try to determine if the new treatment extends life or provides patients with a better quality of life.

Use of a Placebo in Phase III Trials A placebo, or sugar pill, is an inactive ingredient that is used is some types of clinical trials to ensure that the test results are unbiased. It is important to note that clinical trial participants will never receive a placebo in phase III trials if, as with Hodgkin lymphoma, standard therapy exists. Patients would only potentially receive a placebo if there were no standard therapies for comparison. Placebo-controlled trials are never done in a manner to deny patients an effective therapy. They are often done to add a new therapy to what might be the standard therapy.


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Clinical trials are closely monitored. If it is determined that one arm (group) of patients are statistically doing better than the other, the treatment may be stopped. Trial participants may be placed on the superior treatment.

Participating in a Clinical Trial Clinical trials should not be considered a “last resort” by patients. Hodgkin lymphoma patients can often benefit from participation in clinical trials in both the frontline treatment setting and in the relapsed treatment setting. Clinical trials offer patients therapies that are not otherwise available to all patients and are monitored very closely. However, as explained above, being part of some trials might mean that you receive the standard therapy. If you receive the new treatment, it may or may not be more effective than the standard one, and it may or may not be more hazardous. Generally, patients benefit from participating in clinical trials because they are monitored closely. The healthcare team studying the new treatment will explain to you all of the possible risks and benefits of a specific trial.

Informed Consent Informed consent is the process in which you learn about all of the expected risks and benefits of a clinical trial. After the healthcare team has answered all your questions, you will be given an informed consent form to sign. The form lists, in writing, everything known about the risks and benefits of the study. Once you sign the consent form, you will be enrolled in the trial. However, you can leave a clinical trial at any time. If you decide to leave, your doctor will discuss other treatment options available to you.


Cost of Being in a Clinical Trial Clinical trials are very expensive undertakings for the study sponsor. Patient costs vary depending on the study, who is sponsoring the trial and what portion of the trial-related expenses the sponsor will cover. Some health insurance and managed healthcare providers will pay for the basic medical procedures associated with the trial, such as lab tests, scans and hospitalization when required, while others may define clinical trials as “experimental” or “investigational” and not cover some of the routine costs such as doctor visits, tests or treatments. The costs vary depending on the study and the health plan. Medicare provides coverage for patient care associated with government-sponsored clinical trials. If a patient is taking part in a National Cancer Institute (NCI) trial being conducted at the National Institutes of Health (NIH) campus, located in Bethesda, Maryland, the NCI will pay for the study drug and the costs related to the study. A stipend to assist with travel, food and lodging expenses is also provided. Some cancer centers or hospitals provide financial assistance or discounted rates for room and board facilities and have special research units that will pay for study-related costs. (See “Drug Costs: What to Do If Your Insurance Does Not Pay,” on page 43.)

QUESTIONS TO ASK YOUR DOCTOR • What is the purpose of this clinical trial? • Who is sponsoring the trial (National Cancer Institute, a cancer center, a pharmaceutical company)? • How long does the study last? • What are the risks involved? • Will I be in any discomfort or pain? • What kinds of tests, procedures or treatments will be performed; how many and how often? • Will I be able to see my own doctor during the trial? • What costs will I be responsible for?


6

Finding a Clinical Trial Ask your doctor if you could benefit from participation in a clinical trial and if there is one available locally. Here are some additional ways to find clinical trials: • Contact the Lymphoma Helpline at the Lymphoma Research Foundation at (800) 500-9976 to request a clinical trial search. • Cancer centers in your area may also have information about clinical trials for your type of lymphoma. • The NIH websites Cancer.gov and Clinicaltrials.gov are good online resources and have clinical study listing services for patients.


lymphoma.org


Chapter 15

Therapies Under Investigation There are many therapies being investigated through clinical trials in the treatment of Hodgkin lymphoma. Many of these therapies incorporate standard treatments described on the previous pages. The chart below includes many of these therapies, although it is not meant to be an entirely comprehensive list of all the drugs being tested. Check with your physician for additional information. Monoclonal Antibodies

Predominant Target Mechanism of Action

Comments

Rituximab (Rituxan)

CD20

Adult Hodgkin lymphoma

Alemtuzumab (Campath)

CD52


SGN-30 and SGN-35

CD30

Childhood and adult Hodgkin lymphoma

MDX-060

CD30


XmAb-2513

CD30


Other Biologic Therapies EBV-specific cytotoxic T lymphocytes

adoptive immunotherapy


New Agents Lenalidomide (Revlimid)

Bortezomib (Velcade)

IMiDs (immunomodulatory derivative) proteasome inhibitor



Panobinostat (LBH589)

histone deacetylase inhibitor


MGCD-0103



Vorinostat (Zolinza)



SNDX-275 (Entinostat)



SB101518

JAK2 inhibitor


RAD001 (Everolimus)

mTOR inhibitor


Alkylating agent


Alkylators Bendamustine (Treanda)


6


lymphoma.org


GLOSSARY OF MEDICAL TERMS Absolute neutrophil count (ANC): A measurement of the number of mature neutrophils (a type of white blood cell) that are available for fighting infection. A low ANC increases the risk for infection.

Advanced disease: Disease that has spread to multiple locations. Aggressive lymphomas: Lymphomas that are fast growing and generally need to be treated immediately. Also called intermediate-grade or high-grade lymphomas.

Allogeneic transplant: A procedure in which a patient receives bone marrow or stem cells donated by another person. Alopecia: Hair loss. Alopecia from chemotherapy is almost always temporary; hair grows back when therapy is finished.

Anemia: A shortage of red blood cells, causing weakness and fatigue. Angiogenesis: The process of developing new blood vessels. Antiangiogenesis therapies: Drugs that prevent tumors from developing new blood vessels, thereby stopping or limiting tumor growth. Antibody: A substance made by B lymphocytes that reacts with antigens (particularly identifying proteins) on toxins, bacteria and some cancer cells and either kills or marks them for removal. Antiemetic: A drug that reduces or prevents nausea and vomiting. Antigen: Identifying proteins located on the surface of all cells. The immune system uses antigens to determine whether cells are a necessary part of the body or need to be destroyed.

Apheresis: The part of the stem cell transplantation procedure in which stem cells are removed from the blood.

Autologous transplant: A type of bone marrow or stem cell transplantation in which a patient receives his or her own cells. Understanding Hodgkin Lymphoma 89

Beta (2) microglobulin (B2M): A protein found in the blood. Higher levels of B2M suggest that the lymphoma may be more aggressive.

Biologic therapy: Treatment that uses or stimulates the immune system or other body systems to fight infection and disease.

Biopsy: Removal of a small piece of tissue for evaluation under a microscope. Bone marrow: Spongy material found inside the bones containing stem cells that develop into three types of cells: red blood cells that deliver oxygen to the body and take away carbon dioxide; white blood cells that protect the body from infection; and platelets that help the blood to clot. Cancer: Abnormal cell growth that cannot be controlled by the body’s natural defenses. Cancerous cells can grow and eventually form tumors.

Catheter (intravenous access): A device that is temporarily or permanently put into a vein that makes it easier to give medications.

Cerebrospinal fluid: Fluid that is present around the spine and brain. It may be examined to determine if Hodgkin lymphoma has spread to these parts of the body. Chemotherapy: Treatment with drugs to stop the growth of rapidly dividing cancer cells, including lymphoma cells.

Chemotherapy cycle: Term used to describe the process in which chemotherapy is given, followed by a period of rest in which the body is allowed to recover.

Chemotherapy regimen: Combinations of anticancer drugs given at a certain dose in a specific sequence according to a strict schedule. Clinical trial: A research study in which a new treatment is given to patients to determine whether it is safe, more effective or less toxic than current therapies.


Complete remission (CR): Term used when all signs of the disease have disappeared after treatment.

CT or CAT (computerized axial tomography) scan: This imaging test provides a series of detailed pictures of inside the body using an X-ray machine linked to a computer. Cure: The disease is gone. There are no signs or symptoms of lymphoma, and a significant period of time has passed during which there have been no relapses. Decreased blood cell production: A decrease in the production of red blood cells, white blood cells and platelets that may occur as a side effect of cancer or cancer therapies. Also called myelosuppression.

Diaphragm: The muscle below the lungs and heart that separates the abdomen from the chest. Disease progression: The term used if the disease worsens despite treatment (also called treatment failure). DNA: Abbreviation for deoxyribonucleic acid, an essential component of genes.

Dose intensity: A term used to describe giving the highest possible doses of drugs over a specific period of time with acceptable side effects. Durable remission: When a complete response lasts for years. Dysgeusia: When familiar foods taste differently. Echocardiogram: Use of ultrasound to examine the heart. It is ordered when potential cardiotoxic chemotherapy is used. Etiology: The study of the causes of a disease. The cause of Hodgkin lymphoma is unknown.


Extranodal disease: Hodgkin lymphoma that has spread outside the lymphatic system.

Fatigue: A decreased capacity for activity that is often accompanied by feelings of weariness, sleepiness or irritability. Gallium (radioisotope) scan: When injected into the body, radioactive gallium is a chemical that collects in some tumors. The body is then scanned to see whether the gallium has collected in a tumor.

Generalized disease: A cancer that has spread throughout the body. Gene: The basic building block of heredity that are present in all cells. Genes are composed of DNA and other materials.

Gene therapy: Therapy approaches that alter the genetic structure, making tumor cells more susceptible to either the immune system or chemotherapy drugs.

Grade: A method of classifying a tumor on the basis of how aggressively it is growing. Graft-versus-host disease (GVHD): Occurs when a donor’s bone marrow (graft) recognizes the recipient of the marrow (the host) as foreign. In response, the immune cells in the donor marrow attack the foreign cells in the host. Harvesting: A procedure in which stem cells are obtained from the blood or bone marrow for use in repopulating the body’s cells after high-dose chemotherapy.

Hematologist: A doctor who specializes in treating diseases of the blood and blood-forming tissues.

Histology: The study of tissue characteristics that may lead to identifying a specific type of tumor.


Hodgkin lymphoma: One of the two major types of lymphomas that begin in the lymph nodes and tissues of the lymphatic system. All other lymphomas are classified as non-Hodgkin lymphomas.

Hypogeusia: When the flavors of foods are not as strong as normal. Hypothyroidism: A condition in which there is lower than normal production of thyroid hormone. Low thyroid levels can lead to a variety of effects, including mild weight gain, dry skin, fatigue and sleepiness.

Idiotype: A unique “fingerprint” portion of an antibody present on the surface of B-cells. Idiotype vaccine: A lymphoma vaccine that is custom-made to attack an individual patient’s lymphoma and contains idiotype (unique) tumor material and an immune stimulant.

Immune system: One of the body’s defense mechanisms. All lymphomas are diseases of the immune system.

Immunological test: Blood test that detects the presence of diagnostic proteins or antigens on a tumor. Immunotherapy: See biologic therapy. Improvement: This term is used if a tumor shrinks following therapy but is still more than one-half of its original size.

Indolent lymphoma: Lymphoma that is slow growing and has few symptoms. Also called low-grade lymphoma. Laparoscopy: Passing a tube through the abdominal wall to obtain a small sample of tissue for examination under the microscope.

Leukemia: Disease generally characterized by the overproduction of abnormal or immature white blood cells that circulate or are present in the blood.


Leukopenia: A shortage of white blood cells, resulting in the inability to fight infecting organisms such as bacteria, fungi and viruses.

Localized disease: A cancer that is only present in a limited part of the body, for example, the neck or armpits. Local therapy: A therapy that only affects a small area. Lymph: The watery fluid in the lymph system that contains white blood cells (lymphocytes). Lymph nodes: Small bean-shaped glands located in the small vessels of the lymphatic system. There are thousands of lymph nodes located throughout the body, with clusters of them in the neck, under the arms, the chest, abdomen and groin. Lymph nodes filter lymph fluid, trapping and destroying potentially harmful bacteria and viruses. Lymphatics: Lymph channels and vessels that transport lymph fluid. They are similar to blood vessels but smaller.

Lymphatic system: The channels, tissues and organs that store and carry lymphocytes that fight infection and other diseases. Lymphocyte: A type of white blood cell. Lymphocytes, carried along by the lymph fluid, are part of the immune system and fight infection.

Lymphoma: A malignant disease that begins in the lymph nodes, organs and tissues of the lymphatic system (immune system). Hodgkin lymphoma is one type of lymphoma; the other major type is called non-Hodgkin lymphoma.

Malignant: Cancerous—a malignant tumor is a cancerous tumor. Medical oncologist: A doctor who specializes in the use of chemotherapy, hormone therapy and many other types of biologic therapies to treat cancer. Memory cells: Types of B lymphocytes and T lymphocytes. After a foreign invader or unwanted cell has been destroyed, surviving B and T


lymphocytes develop into specialized memory cells that remain on watch and can provide protection if the invader is encountered in the future.

Metastasize: To spread to other organs of the body. Cancer may spread from its primary site to other sites or organs.

Monoclonal antibodies: Biologic therapies that act specifically against a particular antigen. Scientists can produce large amounts of antibody that can be directed to a single target (or antigen) on the cell’s surface. Monoclonal antibodies have been developed to help combat specific cancers, including some forms of Hodgkin lymphoma. MRI (magnetic resonance imaging): This test uses magnets and radio frequency waves to produce images of inside the body. MRIs can provide information about tissues and organs that is not available from other imaging techniques.

Mucositis: Inflammation of the lining of tissues and organs. In the mouth, it is characterized by sores or inflammation.

Myelosuppression: A reduction in the bone marrow’s ability to make red blood cells, white blood cells and platelets. Neutropenia: An abnormally low level of neutrophils (the white blood cells responsible for fighting bacterial infections).

Neutrophils: The primary type of white blood cells found in the blood that fight bacteria, etc. Non-bulky tumor: A small tumor. Non-Hodgkin lymphoma (NHL): A group of several closely related cancers that arise from the lymphatic system. Although the different types of NHL have some things in common, they differ in what the cancer cell looks like under a microscope, how the cells grow and how the tumor affects the body.


Oncologist: A doctor who specializes in treating cancer. Some specialize in chemotherapy (medical oncologists), radiotherapy (radiation oncologists) or surgery (surgical oncologists).

Palliation: Treatment that is given to remove or relieve symptoms. Para-aortic: The area close to the aorta. The aorta is the largest vessel in the body and rises from the heart.

Partial remission: The term used when a cancer has shrunk in size by at least half but has not totally disappeared. The cancer can still be detected, and other treatments may be recommended. Pathologist: A doctor who specializes in studying disease through microscopic evaluation of body tissues and organs. Any tissue suspected of being cancerous must first be examined by a pathologist to confirm the diagnosis.

PCR (Polymerase chain reaction): A molecular test that can identify small amounts of genetic material.

Performance status: A method used to describe a person’s ability to follow a typical lifestyle.

Peripheral neuropathy: Damage to the nerves. This condition can be caused by some drugs and is usually characterized by tingling and weakness or numbness in the extremities.

PET (positron emission tomography) scan: A type of test that may be used instead of a gallium scan to identify areas in the body that are affected by Hodgkin lymphoma. This test evaluates metabolic activity in different parts of the body using a radioisotope.

Plasma cell: A mature B-cell that makes antibodies—these antibodies help the body destroy or remove toxins, bacteria and some cancer cells.

Primary therapy: The first therapy given after a diagnosis of cancer.


Prognosis: The likely outcome of a disease, including the chance of recovery.

Pulmonary function test: A procedure for determining the capacity of the lungs to exchange oxygen and carbon dioxide efficiently.

Radiation field: The part of the body that receives radiation therapy. Radiation oncologist: A doctor who specializes in treating cancer with radiation.

Radiation therapy: The use of radiation beams (X-rays) to treat a cancer. High doses of high-energy radiation beams, carefully focused on a tumor, will kill cancer cells. Radiation therapy (with or without chemotherapy) is used to treat certain lymphomas, including Hodgkin lymphoma. Radioimmunotherapy: A therapy that is prepared by attaching a radioactive isotope to a monoclonal antibody.

Radionuclide tests: Tests that use radioactive substances to help evaluate the function of tissues.

Refractory disease: A cancer that is resistant to treatment. Regimen: A specific combination of drugs (chemotherapy), their doses and their schedules of administration. A regimen may also include radiotherapy.

Relapse: The return of cancer after treatment. Lymphoma may recur in the area where it first started, or it may occur in another place. Remission: The absence of disease. A patient is considered in remission when the lymphoma has been treated and tumors have diminished by at least 50 percent (partial) or have totally disappeared (complete). Remission does not necessarily mean cure.


Risk factor: A factor that may increase the chance that a person will develop Hodgkin lymphoma. It is important to note that most people with risk factors never develop lymphoma, and many who are diagnosed have no identifiable risk factors.

Salvage therapy: Therapy that is given if the primary therapy is not successful or if the disease disappears and then comes back.

Spleen: An organ on the left side of the upper abdomen, near the stomach. A key component of the lymphatic system, the spleen produces and stores lymphocytes and releases them when required as part of the body’s response to infections and other stimuli. The spleen may store blood and remove old blood cells from circulation. Stable disease: Disease that does not get better or worse following therapy. Stage: The extent of cancer in the body, including whether the disease has spread from the original site to other body parts.

Standard therapy: The most widely used primary therapy. Synergism: The term used when two or more drugs given together provide a better anticancer effect than expected from the additive effects of the medications alone. Systemic symptoms: Symptoms that affect the entire body. Examples of these include fever, night sweats and weight loss.

Thrombocytopenia: A shortage of platelets in the blood, which reduces the ability of the blood to clot.

Thymus gland: A gland located behind the sternum (breastbone) that enhances the reproduction and development of lymphocytes. T lymphocytes are processed in the thymus.

Toxicities: The unwanted side effects of cancer therapies, such as a decrease in blood cells, nausea and vomiting, and hair loss.


Tumor: An abnormal mass or swelling of tissue. Tumors may occur anywhere in the body. A tumor may be benign (harmless) or malignant (cancerous).

Vaccine: A substance or group of substances meant to cause the immune system to respond. A vaccine can help the body recognize and destroy cancer cells. Lymphoma vaccines often combine cancer antigens with a substance to stimulate the patient’s own natural defenses to fight the disease. These vaccines are custom-made for each patient, using a sample of tumor obtained from the patient’s lymph nodes.

VEGF (vascular endothelial growth factor): One of a number of substances that stimulate blood vessel formation, angiogenesis—a process necessary for tumor growth.

Watchful waiting: An approach in which no immediate medical, surgical or radiation therapy is given. Patients are followed closely to make sure the cancer does not progress.

Xerostomia: A temporary reduction in the production of saliva. X-ray: Radiation that is used in low doses to provide images of the inside of the body and in high doses to treat cancer.



lymphoma.org


About the Lymphoma Research Foundation The Lymphoma Research Foundation (LRF) is the nation’s largest lymphomafocused nonprofit health organization devoted exclusively to funding lymphoma research and providing patients and healthcare professionals with the most current information on the disease. The Foundation’s mission is to eradicate lymphoma and serve those touched by this disease. The Lymphoma Research Foundation was formed in 2001 with the merger of the Cure For Lymphoma Foundation (CFL) and the Lymphoma Research Foundation of America (LRFA). Both organizations were founded by lymphoma advocates who wanted to turn a life-altering diagnosis into a positive experience for others with the disease. Ellen Glesby Cohen founded LRFA in Los Angeles in 1991. Until her death in 2000, Ellen was a tireless champion for patients and their families who created new education and support programs and served as a staunch advocate for improved government legislation. Jerry and Barbara Freundlich founded CFL in 1994 in New York City. Jerry is a long-term survivor of non-Hodgkin lymphoma.

Resources for Patients, Survivors and Loved Ones Receiving a diagnosis of lymphoma can be challenging. Whether you or someone you love is newly diagnosed or a long-term survivor, understanding the latest medical information and accessing appropriate support services may help. LRF offers a wide array of programs and support services to assist you from the point of diagnosis through long-term survivorship.

Patient Services and Support Lymphoma Helpline and Clinical Trials Information Service Through this phone and email service, trained staff members are available to answer your questions and provide individual support to you and your loved ones. Services are available in any language.


Lymphoma Support Network (LSN) This national one-to-one peer support program matches lymphoma patients or caregivers with volunteers who have had similar lymphomarelated experiences.

Lymphoma Newsline Lymphoma-related news can be distributed to you directly through this free electronic news services. Sign up by clicking on the “register” icon on LRF’s homepage at lymphoma.org.

In-Person Patient Education Programs North American Educational Forum on Lymphoma This two-day national forum is held annually and provides critical information about the latest in lymphoma research, making the best decisions about treatment options and patient support issues.

Lymphoma Workshop: Understanding Lymphoma Basics and Current Treatment Options These regional, full-day educational programs provide the latest information about lymphoma, current treatment options and patient support issues.

Multimedia Programs Because LRF understands that information about lymphoma continually changes throughout the year, the ongoing production of webcasts, podcasts and teleconferences enable you to access the latest information on specific topics anywhere, anytime.

Webcasts Webcast programs offer you the opportunity to navigate through a synchronized audio and slide presentation.

Podcasts Podcasts (video format) can be viewed on LRF’s website.


Teleconferences Teleconferences are hour-long interactive telephone programs that provide an opportunity to learn more about lymphoma, treatments and promising research from leading lymphoma experts. These are conducted live, and the archived version is available after the program.

Publications Patient Guides In addition to this publication, LRF also produces Understanding Non-Hodgkin Lymphoma: A Guide for Patients, Survivors and Loved Ones and Understanding Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL): A Guide for Patients, Survivors and Loved Ones.

Fact Sheets Fact sheets with the latest disease- and treatment-specific information are available in either hard copy or in PDF on LRF’s website. New topics are added on a regular basis; check to see if the topic you are looking for is available.

Newsletters To keep you abreast of LRF research and news in the wider lymphoma community, you can sign up to receive any of LRF’s regular newsletters either electronically or via mail. Any of LRF’s publications may be ordered by visiting lymphoma.org. Individual and bulk copies are available free of charge.

Resources for Children and Young Adults Lymphoma in Your Teens, 20s and 30s LRF offers a wide array of webcasts and podcasts for individuals affected by lymphoma as teens or young adults, including topics specifically designed to help friends and family. Visit lymphoma.org/youngadults to access these programs.


LIVESTRONG Young Adult Alliance The Lance Armstrong Foundation’s LIVESTRONG Young Adult Alliance is a coalition of organizations with the goal to improve the survival rates and quality of life for young adults with cancer between the ages of 15 and 40. By visiting livestrong.org/yaa you can access the websites of all member organizations that specifically provide services for young adults with cancer.

Planet Cancer Planet Cancer is a peer support community for young adults going through the tremendously isolating experience of cancer between the ages of 18 and 40. On Planet Cancer, young adult patients and survivors connect 24 hours a day, 7 days a week through a dynamic and irreverent social networking website and face-to-face retreats. Planet Cancer also provides advocacy programs to build awareness about the unique medical and psychosocial needs of this often-overlooked age group. Visit planetcancer.org to access these services. Ulman Cancer Fund for Young Adults This organization focuses on how cancer affects young adults and offers scholarships, community grants, advocacy services and a guidebook. Visit ulmanfund.org for more information.

How to Access Programs and Services Many of the aforementioned programs are available on LRF’s website at lymphoma.org. For additional information about these resources, call (800) 500-9976 or email us at [email protected]. If you would like to order additional copies of Understanding Hodgkin Lymphoma: A Guide for Patients, Survivors and Loved Ones, please call (800) 500-9976 or visit lymphoma.org.


How to Get Involved and Give BACK Take Action to Make a Difference The LRF Advocacy Program is a network of people and programs dedicated to increasing awareness and support for the lymphoma community. The Advocacy Program focuses on taking action on laws, policies and positions that affect every lymphoma patient and survivor. By contacting elected officials via phone calls, email and letters in support of these priorities, local advocates help LRF to make lymphoma a national health priority. To become involved, visit lymphoma.org/advocacy.

Start or Join a Local Chapter Chapter volunteers work tirelessly to educate people about lymphoma, conduct outreach, raise funds for research and participate in public policy and advocacy initiatives. To learn more about a chapter in your area or how to start one, please visit lymphoma.org/chapters or call (800) 235-6848.

Raise Funds and Awareness Raise funds and awareness by participating in a variety of events being held across the country such as Lymphomathon walks, bike rides, golf tournaments, galas, lunches, young professional social events and much more! Visit lymphoma.org/events for more information.

Join Team LRF Team LRF is a program through which people across the country raise much-needed funds and awareness for lymphoma research through sporting events such as marathons, half marathons, triathlons, hiking adventures, bowling tournaments, soccer matches, bike rides, lacrosse tournaments, paddling events, dance-a-thons, spin-a-thons, yoga-a-thons and much more. Join Team LRF in an existing LRF-partnered event in your area, or join Team LRF Teammates Across the Country if you wish to raise funds by starting your own event or by participating in an event in which LRF does not have official charity entries. Visit lymphoma.org/ teamlrf for more information.


Notes _____________________________________________________________


Donate Now The Lymphoma Research Foundation (LRF) is a nonprofit health organization with 501(c)(3) status. If you would like to support LRF, your generous gift will help us move closer to finding a cure, while helping those affected by the disease.

Three easy ways to give: Website: lymphoma.org/donatenow Call: (800) 235-6848 M ail: Cut out this form and mail it to Lymphoma Research Foundation, 115 Broadway, 13th Floor, New York, New York 10006 or FAX Fax: (212) 349-2886

Amount of donation $ Make checks payable to the Lymphoma Research Foundation. Charge my n Amex

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Understanding Non-Hodgkin Lymphoma 109

This patient guide is supported through unrestricted educational grants from: Presenting Sponsor

Gold Sponsor

Understanding

Non-Hodgkin Lymphoma A Guide for Patients, Survivors and Loved Ones Third Edition

Understanding

Non-Hodgkin Lymphoma A Guide for Patients, Survivors and Loved Ones 3rd Edition

This guide is an educational resource compiled by the Lymphoma Research Foundation providing general information on non-Hodgkin lymphoma. Publication of this information is not intended to take the place of medical care or the advice of your doctor. Patients are strongly encouraged to talk to their physicians for complete information on how their disease should be diagnosed, treated and followed. Before starting treatment, patients should discuss the potential benefits and side effects of cancer therapy.

National Headquarters 115 Broadway, 13th Floor New York, NY 10006 (212) 349-2910 phone (212) 349-2886 fax Helpline: (800) 500-9976 [email protected] Website: lymphoma.org Email: [email protected] This patient guide is supported through unrestricted educational grants from:

Presenting Sponsor

Gold Sponsor

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Abbott Oncology Lilly Oncology © 2010 Lymphoma Research Foundation Information contained herein is the property of the Lymphoma Research Foundation (LRF). Any portion may be reprinted or reproduced provided that LRF is acknowleged to be the source.

ACKNOWLEDGMENTS The Lymphoma Research Foundation wishes to acknowledge those individuals listed below who have given generously of their time and expertise. We thank them for their contributions, editorial wisdom and advice, which have truly enhanced this publication. The chairman and senior advisors guided the content and development of this publication. Without their dedication and efforts this publication would not have been possible. We hope those in the lymphoma community will now be better informed and have a better understanding of their illness because of the gracious efforts of those involved in the planning and execution of this comprehensive disease guide. Editorial Board

Steering Committee

Chairman Morton Coleman, MD, Weill Cornell Medical College–New York Presbyterian Hospital Senior Advisors Stephanie A. Gregory, MD, Rush University Medical Center Jennifer Mills, LMSW, MPH, Lymphoma Research Foundation Owen A. O’Connor, MD, PhD, New York University Cancer Institute

Review Committee

Carolyn Bell, MSW, Santa Monica–UCLA Medical Center Richard Boyajian, RN, MSN, APN, Dana-Farber Cancer Institute Jennifer Brown, MD, PhD, Dana-Farber Cancer Institute Bruce D. Cheson, MD, Georgetown University Hospital Joseph Connors, MD, British Columbia Cancer Agency Richard I. Fisher, MD, University of Rochester Medical Center, James P. Wilmot Cancer Center Anna Franklin, MD, MD Anderson Cancer Center Jonathan Friedberg, MD, University of Rochester Medical Center Richard R. Furman, MD, Weill Cornell Medical College–New York Presbyterian Hospital Les Gallo-Silver, ACSW, LCSW-R, LaGuardia Community College, CUNY Randy Gascoyne, MD, British Columbia Cancer Agency Irene Ghobrial, MD, Dana-Farber Cancer Institute

ii Understanding Non-Hodgkin Lymphoma

Review Committee (continued)

Leo I. Gordon, MD, Northwestern University Andre Goy, MD, Hackensack University Medical Center Thomas M. Habermann, MD, Mayo Clinic College of Medicine John Hainsworth, MD, Sarah Cannon Research Institute Steven Horwitz, MD, Memorial Sloan-Kettering Cancer Center Elaine Jaffee, MD, National Cancer Institute Rebecca H. Johnson, MD, Seattle Children’s Judy Jones, LPC, Cutaneous Lymphoma Foundation John P. Leonard, MD, Weill Cornell Medical College–New York Presbyterian Hospital Craig Lustig, MPA, Children’s Cause for Cancer Advocacy Ralph Meyer, MD, National Cancer Institute of Canada and Queens University Thomas P. Miller, MD, University of Arizona, Arizona Cancer Center Joanna Morales, Esq, Cancer Legal Resource Center John M. Pagel, MD, PhD, Fred Hutchinson Cancer Research Center Lauren Pinter-Brown, MD, UCLA Medical Center Oliver W. Press, MD, PhD, Fred Hutchinson Cancer Research Center Kanti Rai, MD, Long Island Jewish Medical Center Andrei Shustov, MD, Fred Hutchinson Cancer Research Center Sonali Smith, MD, The University of Chicago David Straus, MD, Memorial Sloan-Kettering Cancer Center James Testaverde, BS, Lymphoma Research Foundation Brian Tomlinson, MPA, BSW, Lymphoma Research Foundation Julie Vose, MD, University of Nebraska Medical Center Tim Walker, MA, National Marrow Donor Program Kathleen Wesa, MD, Memorial Sloan-Kettering Cancer Center Michael Williams, MD, University of Virginia School of Medicine Teresa Woodruff, PhD, Northwestern University Anas Younes, MD, MD Anderson Cancer Center Bradley Zebrack, PhD, MSW, MPH, University of Michigan School of Social Work Andrew Zelenetz, MD, PhD, Memorial Sloan-Kettering Cancer Center Contributing Medical Writer: Jo Cavallo

Understanding Non-Hodgkin Lymphoma iii

Table of Contents Part I: Learning the Basics Chapter 1 Overview of Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Non-Hodgkin Lymphoma Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The Causes of Non-Hodgkin Lymphoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Common Types of Non-Hodgkin Lymphoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1 2 6 7

Chapter 2 Signs and Symptoms of Non-Hodgkin Lymphoma . . . . . . . . . . . . . . . . . . . . . . . 17 When to Seek Medical Attention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17 What the Doctor Looks For. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17 Chapter 3 Getting a Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Common Diagnositic Tests . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Grading and Staging Non-Hodgkin Lymphoma . . . . . . . . . . . . . . . . . . . . . . . . . . Getting a Second Opinion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Choosing an Oncologist and Treatment Center . . . . . . . . . . . . . . . . . . . . . . . . . .

19 19 25 26 27

Part 2: Treating Non-Hodgkin Lymphoma Chapter 4 What You Should Know Before Starting Treatment . . . . . . . . . . . . . . . . . . . . . . Communicating With Your Healthcare Team . . . . . . . . . . . . . . . . . . . . . . . . . . . . How to Be a Self-Advocate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Factors Affecting Treatment Outcome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

29 30 32 33

Chapter 5 Types of Treatment for Non-Hodgkin Lymphoma . . . . . . . . . . . . . . . . . . . . . . . . Watchful Waiting . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conventional Chemotherapy Approaches . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Radiation Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Stem Cell Transplantation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Novel Targeted Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . New Versions of Established Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Interferon . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Complementary and Alternative Remedies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Drug Costs: What to Do If Your Insurance Does Not Pay . . . . . . . . . . . . . . . . . . . When to Consider a Clinical Trial . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

37 37 38 44 46 50 56 57 58 60 60

iv Understanding Non-Hodgkin Lymphoma

Part 3: Treatment Side Effects Chapter 6 Coping With Common Treatment Side Effects . . . . . . . . . . . . . . . . . . . . . . . . . . Side Effects Caused By: Chemotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Radiation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Steroids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Rituximab and Other Biological Therapies . . . . . . . . . . . . . . . . . . . . . . . . . . . Bone Marrow or Stem Cell Transplantation . . . . . . . . . . . . . . . . . . . . . . . . . . Surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Combating Side Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The Difference Between Long-Term Effects and Late Effects . . . . . . . . . . . . . . .

61 69 70 70 71 71 71 73

Chapter 7 Sexuality . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Sexual Function During Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . When to Use Contraceptives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pregnancy and Breast-Feeding During Treatment . . . . . . . . . . . . . . . . . . . . . . . .

75 75 75 76

61

Chapter 8 Fertility Risks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77 How to Protect Fertility in Men . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77 How to Protect Fertility in Women . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 78

Part 4: Children and Young Adults With Non-Hodgkin Lymphoma Chapter 9 General Information . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Survival . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Detection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Treatment Options . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Coping . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Important Considerations for Childhood Lymphoma Survivors . . . . . . . . . . . . .

79 80 80 81 81 81

Chapter 10 Special Concerns for Teenagers and Young Adults . . . . . . . . . . . . . . . . . . . . . . Specific Treatment Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Important Considerations for Long-Term Young Adult Survivors . . . . . . . . . . . Emotional and Practical Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

83 83 84 84

Understanding Non-Hodgkin Lymphoma v

Part 5: Living With Non-Hodgkin Lymphoma Chapter 11 Regaining Your Life During and After Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . Coping . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Life After Remission . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Follow-Up Care . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

87 87 88 88

Chapter 12 Relapsed or Refractory NHL . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91

Part 6: Clinical Trials Chapter 13 Overview of Clinical Trials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 93 Basics of Clinical Trials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 93 Participating in a Clinical Trial . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95 Chapter 14 New Agents or Applications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97 Drugs Affecting Protein Disposal . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97 Drugs Affecting How Cancer Cells Divide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 98 Teaching Cancer Cells How to Die . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 99 Agents Affecting Immunologic Targets . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 101 Drugs Selectively Targeting Cancer Cell Gene Expression . . . . . . . . . . . . . . . . 105 Drugs Targeting Essential Lymphoma Biology . . . . . . . . . . . . . . . . . . . . . . . . . . 107 New Derivatives of Old Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109 Glossary of Medical Terms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 111 About the Lymphoma Research Foundation . . . . . . . . . . . . . . . . . . . . . . . . . . 123 Resources for Patients, Survivors and Loved Ones . . . . . . . . . . . . . . . . . . . . . 123 Resources for Children and Young Adults . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 126 How to Get Involved and Give Back . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 127 Donate Now . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 129

vi Understanding Non-Hodgkin Lymphoma

Part

1


Chapter 1

Overview of Cancer Our bodies consist of millions of cells that grow and divide in an orderly fashion and work in harmony to support thousands of biological functions. The cells divide only when it is necessary to replace worn-out or dying cells. Cancer is a group of diseases that develop as the result of the uncontrolled growth and spread of abnormal cells. Cancer cells are different from normal cells because instead of dying in an orderly fashion, they continue to grow and divide, forming new abnormal cells. Cancer cells develop when there is damage to the DNA, the hereditary material found in every cell, that is caused either by inherited DNA cell abnormalities and/or exposure to something in the environment, such as smoking. Usually the body is able to destroy these damaged cells, but when the body’s natural defense systems do not work sufficiently, these abnormal cells may grow in an uncontrollable fashion, eventually forming a cancerous tumor.

Learning the Basics 1

Non-Hodgkin Lymphoma Overview Lymphoma comprises about 67 subtypes of two related cancers that affect the lymphatic system, Hodgkin lymphoma and non-Hodgkin lymphoma (NHL). There are six types of Hodgkin lymphoma and at least 61 types of non-Hodgkin lymphoma. Hodgkin lymphomas are somewhat different from non-Hodgkin lymphomas in the way they develop, spread and are treated. Lymphoma is the most common blood cancer and the third most common cancer among children. Lymphoma usually develops when a genetic error, or mutation, occurs within a lymphocyte, causing the abnormal cell to duplicate faster than a normal cell or live longer than a normal lymphocyte. Lymphocytes are small white blood cells that play a large role in the immune system, which defends the body against foreign invaders, such as bacteria or viruses. Like normal lymphocytes, cancerous lymphocytes can travel in the blood and grow in many parts of the body, including the lymph nodes, spleen, bone marrow, blood or other organs. As a result, while some NHLs are localized in one area of the body, most are present throughout the body by the time of diagnosis. Although the various types of NHL have some things in common, such as their lymphatic origin, they differ in their appearance under the microscope, their molecular features, their growth patterns, their impact on the body and how they are treated. Non-Hodgkin lymphoma is divided into two major groups: B-cell lymphomas and T-cell lymphomas. B-cell lymphomas develop from abnormal B-lymphocytes (“B” because B-lymphocytes come from the bone marrow) and account for 85 percent of all NHLs. T-cell lymphomas develop from abnormal T-lymphocytes (“T” because normally T-lymphocytes spend part of their lifespan in the thymus gland, a small organ in the chest) and account for the remaining 15 percent of NHLs. Non-Hodgkin lymphoma has grown from being a relatively uncommon disease to being the fifth most common cancer in the United States, nearly doubling in incidence since the early1970s, and increasing among women since 1991. According to the American Cancer Society, over 65,000 new cases of NHL are diagnosed annually. 2 Understanding Non-Hodgkin Lymphoma

1 The Immune System Non-Hodgkin lymphoma is a cancer of the lymphocytes, which play a vital role in the immune system. The immune system is one of the body’s major defenses against disease. It is made up of highly specialized cells and a circulatory system separate from blood vessels, called the lymph system. The cells of the immune system work together to rid the body of foreign invaders, such as bacteria and viruses, before they can harm the body. These invading organisms are generally detected by the immune system through proteins called antigens that are located on the surface of all cells, including both normal and germ cells. Special receptors located on the immune cells lock onto these antigens. And just as a lock will only close with the right key, an immune cell can only lock onto an antigen if it has a specific receptor on its cell surface. When an antigen and an immune cell lock together, the immune response begins, and the body acts to destroy, remove or wall off the foreign invaders or affected cells.

The Lymphatic System The lymphatic system is one of the most important parts of the immune system and protects the body from disease and infection. The lymphatic system is a circulatory system that is made up of a series of thin tubes called lymph vessels that branch out like blood vessels into all tissues of the body (see page 4). Lymph vessels carry lymph, a fluid that contains white blood cells called lymphocytes. Within this vast network of vessels are groups of small, bean-shaped organs called lymph nodes. Thousands of lymph nodes are found throughout the body, including the elbows, neck, armpits and groin. Lymph fluid flows through lymph nodes and specialized lymph tissues such as the spleen, tonsils, bone marrow and thymus gland. Lymph nodes filter lymph fluid, removing bacteria, viruses and other foreign substances from the body. If a large number of foreign substances are filtered through a node or series of nodes, swelling may occur and the nodes may become tender to the touch. Most swollen nodes are a reaction to infection and are not cancerous.

How Lymphocytes Work Lymphocytes are a type of white blood cell that helps the body fight infections. They are made in the bone marrow, spleen and lymph nodes, and circulate in the blood and lymph vessels. Lymphocytes recognize Learning the Basics 3




Thymus Lymph nodes


Spleen

Peyer’s patches Appendix

Bone marrow

4 Understanding Non-Hodgkin Lymphoma



Bacteria

Viruses

Parasites

Fungi

Pollution

Toxins






foreign cells and act quickly to destroy them. There are two main types of lymphocytes: B-lymphocytes and T-lymphocytes. B-lymphocytes develop into cells called plasma cells, which make specific proteins called antibodies. Antibodies recognize and lock onto specific antigens. They circulate in the blood and react with toxins, bacteria and some cancer cells and act like biologic guided missiles homing in on only those antigen targets they have been programmed to attack on the surface of the cell. The body can then identify and remove these unwanted substances. However, some invaders can avoid B-lymphocytes by growing inside the body’s cells and that is where T-lymphocytes play a role. They sense when the body’s own cells have become infected and destroy them directly. T-lymphocytes help the body fight viral infections, tuberculosis and fungal infections and may play a role in destroying abnormal or cancerous cells. After an invader has been destroyed, surviving B-lymphocytes and T-lymphocytes develop into specialized memory cells that remain on watch in the lymph nodes, waiting to be reactivated if and when a particular antigen is encountered again. These memory cells act as “guards” that are always on the lookout to prevent specific invaders from spreading in the body. The body has a complicated system of checks and balances to keep the number of lymphocytes in balance.

The Causes of Non-Hodgkin Lymphoma Although the exact causes of non-Hodgkin lymphoma (NHL) remain unknown, some common factors appear to have an impact on risk. For example, NHL incidence increases with age. Approximately 70 percent of people diagnosed with NHL are 50 years old or more; they are more likely to be men than women; and they are more likely to be Caucasian than African-American. The disease is also more common among people with depressed immune systems and those exposed to environmental carcinogens, pesticides, herbicides, viruses and certain bacteria. Risk for developing lymphoma may be higher in individuals who: • have a family history of NHL • are affected with an autoimmune disease • have received an organ transplant • have been exposed to chemicals such as pesticides, fertilizers or organic solvents for a long period 6 Understanding Non-Hodgkin Lymphoma

1 • have been infected with viruses such as Epstein-Barr (which causes mononucleosis), human T-lymphotropic virus type 1 (HTLV-1), HIV/AIDS, hepatitis C or certain bacteria such as H.pylori However, it is important to note that having one or more of these risk factors does not mean you will develop NHL. In fact, most people with risk factors never develop the disease, and most of those diagnosed with lymphoma have never been exposed to clearly identifiable risk factors. While they do not know why NHL develops, they do know that it cannot be caused by injury or caught from someone who has the disease.

Where Non-Hodgkin Lymphoma Develops Tumors may be present in a single lymph node or in several at once. Although some NHLs are localized in one area, most are found in multiple parts of the body by the time the diagnosis is confirmed. Some lymphomas can occur outside the lymphatic system and are identified by their tissue of origin, such as the mucosa (lining of organs) or skin.

Common Types of Non-Hodgkin Lymphoma Classifying the type of NHL a patient has is determined through a tumor tissue biopsy. Since the two main types of lymphocytes are B-lymphocytes and T-lymphocytes, most lymphomas are designated as either B-cell or T-cell. Because there are so many types of NHL (at least 61), and new subtypes are continually being identified, classifying lymphoma is complicated and has evolved over the years. Most recently, the World Health Organization (WHO) adopted a lymphoma classification system that combines updated information on the appearance, growth pattern, immunologic and genetic features of the cells, as well as how the disease acts in the body. The WHO classification recognizes several new types of NHL and represents an advance in the ability to distinguish specific lymphomas. This new classification system has helped to facilitate cooperation and communication among doctors around the world. The WHO classification system is a modification of the Revised European American Lymphoma (REAL) classification, upon which it was based.


The Difference Between Indolent and Aggressive Lymphomas Because there are so many different forms of NHL, they are often grouped according to their clinical behavior and whether they are indolent (slowgrowing or low grade) or aggressive (intermediate or high grade). Indolent lymphomas are usually chronic but not curable. Aggressive lymphomas, while potentially life threatening, can often be cured. (See “Grading and Staging Non-Hodgkin Lymphoma,” on page 25.)

Types of Indolent Non-Hodgkin Lymphoma

Follicular Lymphoma Follicular lymphoma is a relatively common lymphoma, making up between 20 percent and 30 percent of all NHLs, and typically occurs in middle-aged and older adults, but it can affect younger people in their 30s and 40s. Follicular lymphoma is typically slow-growing and arises from B-lymphocytes, making it one of the B-cell lymphomas. Follicular lymphoma usually appears in lymph nodes throughout the body. They arise in the germinal center or follicle of the lymph node. Often, the first sign of follicular lymphoma is a painless swelling in the neck, armpit or groin caused by enlarged lymph nodes. Because follicular lymphoma is a common indolent lymphoma, it is often used as a model for the treatment of other slow-growing lymphomas. Follicular lymphoma may eventually transform into a more aggressive form of the disease, often referred to as histologic transformation. As with most indolent lymphomas, people with follicular NHL usually will present with disease in many parts of the body, including the bone marrow.

Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma According to the American Cancer Society, approximately 15,000 new cases of CLL and 3,600 new cases of SLL are diagnosed annually. This form of cancer is usually diagnosed in older adults over the age of 50—more than half of the people with CLL are over age 70. Chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) are considered B-cell malignancies and are essentially the same disease with slightly different manifestations. The same kind of cell,


1 known as a lymphocyte, is involved in both CLL and SLL. The only difference between the two diseases is where the cancer primarily occurs. When the cancer cells are located mostly in the lymph nodes, the disease is called SLL. When most of the cancer cells are located in the bloodstream and the bone marrow, the disease is referred to as CLL, although the lymph nodes and spleen are often involved as well. Thinking of CLL/SLL as a lymphoma and not a form of leukemia is important because CLL has a clinical course and treatment regimen that is similar to other indolent lymphomas. Chronic lymphocytic leukemia tends to be a slow-growing cancer. However, over time, it can progress to a more aggressive type of lymphoma. The staging system for CLL is different from the staging system applied to other NHLs. For a more detailed description of CLL, visit cllinfogroup. org or request a copy of the Lymphoma Research Foundation’s publication entitled Understanding CLL/SLL: A Guide for Patients, Survivors and Loved Ones.

Marginal Zone Lymphoma Marginal zone B-cell lymphomas, a group of indolent lymphomas whose cells come from B-lymphocytes normally found in the marginal zone of the secondary lymphoid follicles in the spleen and lymph nodes, accounts for approximately seven percent of all NHLs. The median age for diagnosis of this type of lymphoma is 65. Marginal zone lymphomas encompass three basic types: (1) extranodal or mucosa-associated lymphoid tissue (MALT), occurring outside the lymph nodes, (2) nodal, occurring within the lymph nodes, and (3) splenic, occurring mostly in the spleen and blood. Skin-associated lymphoid-tissue-related B-cell lymphoma (SALT) is also considered a form of MALT lymphoma. Marginal zone and MALT lymphomas vary from other types of B-cell NHLs in a number of ways: • their natural history is different • many people who develop MALT lymphoma have a history of inflammation or autoimmune disorders Learning the Basics 9

• chronic inflammation is associated with Helicobacter pylori (H. pylori), a microbial pathogen linked to chronic gastritis • sometimes, MALT lymphomas can be treated with antibiotics Different infections have also been implicated in other forms of MALT lymphoma. Hepatitis C has been associated with splenic marginal zone lymphoma. Nodal marginal zone B-cell lymphomas are uncommon and are sometimes called monocytoid B-cell lymphomas.

Waldenstrom’s Macroglobulinemia Waldenstrom’s macroglobulinemia (also known as lymphoplasmacytic lymphoma or immunocytoma) is a rare B-cell lymphoma that occurs in less than two percent of people with NHL. There are about 1,500 new cases of Waldenstrom’s each year. The disease usually affects older adults and is primarily found in the bone marrow, although lymph nodes may sometimes be involved. Waldenstrom’s is characterized by a high level of a protein called immunoglobulin M (IgM) in the blood. These high levels of IgM can cause a thickening of the blood, resulting in symptoms such as nosebleeds, headaches, dizziness and blurring or loss of vision. For more information, visit the International Waldenstrom’s Macroglobulinemia Foundation (iwmf.com).

Cutaneous T-Cell Lymphoma Cutaneous lymphomas arise in the skin and account for approximately two percent to three percent of all NHL cases. Cutaneous lymphomas include both B-cell and T-cell lymphomas, though T-cells are more common. The age of presentation is, on average, between 50-60 years, though younger people are also diagnosed with cutaneous T-cell lymphoma (CTCL). The most common form of CTCL is mycosis fungoides, which is often indolent and appears as reddish skin patches, plaques or scales. An advanced, or variant, form of mycosis fungoides is called Sézary syndrome, which is often characterized by redness and scaling of the skin, enlarged lymph nodes and malignant T-cells circulating in the blood. Depending on the symptoms or stage of disease, treatments are directed at the skin (e.g., ultraviolet light, topical steroids, topical chemotherapies, topical retinoids and electron beam radiation therapy) or the entire body (e.g., oral retinoids, photopheresis,


1 fusion proteins, interferon, systemic chemotherapy and histone deacetylase inhibitors). A common topical retinoid used to treat cutaneous lymphomas is bexarotene (Targretin). Denileukin diftitox (Ontak) is a commonly used fusion protein. Within recent years, new treatment options have emerged specifically for T-cell lymphomas, including romidepsin (Istodax) and vorinostat (Zolinza). Numerous other agents are being investigated in clinical trials, as well as more effective ways to deliver current treatments. Patients with cutaneous lymphoma may be treated by dermatologists, radiation oncologists, medical oncologists or a combination. For more detailed information on cutaneous lymphoma disease-specific biology and treatment options, please contact the Cutaneous Lymphoma Foundation (clfoundation.org).

Types of Aggressive Non-Hodgkin B-cell Lymphoma

Diffuse Large B-Cell Lymphoma Diffuse large B-cell lymphoma (DLBCL) is the most common form of NHL, accounting for up to one-third of newly diagnosed cases. Although most frequently seen in adults—the median age at diagnosis is 57—the disease may also be seen in young people. The disease is an aggressive, or fast-growing, lymphoma and can arise in the lymph nodes or outside of the lymphatic system. It may be localized or generalized (spread throughout the body). Despite being an aggressive lymphoma, DLBCL is potentially curable. The first sign of DLBCL is usually rapid swelling in the neck, armpit or groin caused by enlarged lymph nodes. Other symptoms include night sweats, chills, unexplained fevers and weight loss.

Mantle Cell Lymphoma Mantle cell lymphoma is a B-cell lymphoma that affects approximately six percent of all NHL patients. Mantle cell lymphoma usually affects men over 50. Frequently, patients with mantle cell lymphoma have many lymph nodes, one or more organs and bone marrow involved. The gastrointestinal tract is a very common extra-nodal site of involvement. Mantle cell


lymphoma may initially follow an indolent, or slow-growing, course but may transform early into an aggressive disease and is, therefore, often treated as an aggressive lymphoma. In general, it is currently incurable with standard approved therapies.

Burkitt’s Lymphoma, Burkitt-like Lymphoma (Small Non-Cleaved Cell Lymphoma) Burkitt’s lymphoma is an aggressive B-cell form of NHL that occurs most often in children and young adults. There are three main types of Burkitt’s lymphoma: sporadic, endemic and immunodeficiency-related disease. While sporadic Burkitt’s lymphoma occurs throughout most of the world, endemic Burkitt’s lymphoma is found mostly in Africa and is often associated with the Epstein-Barr virus (EBV). Immunodeficiency-related Burkitt’s lymphoma is diagnosed most often in people infected with HIV/AIDS. The disease may affect the jaw, central nervous system, bone marrow, bowel, kidneys, ovaries or other organs. Burkitt’s lymphoma has a specific chromosomal abnormality called the t(8;14) translocation and behaves aggressively. Burkitt’s lymphoma is potentially curable.

Types of Aggressive Non-Hodgkin T-Cell Lymphoma

Peripheral T-Cell Lymphomas Peripheral T-cell lymphomas refer to a large number of different T-cell lymphomas that together comprise between 10 percent and 15 percent of all cases of NHL and can occur anytime during adulthood. The term “peripheral T-cell lymphoma” is based on the fact that these tumors are composed of T-cells (not B-cells) and that the cells are mature. Most peripheral T-cell lymphomas are aggressive, with the exception of mycosis fungoides (see “Cutaneous T-cell Lymphoma,” on page 10). Some varieties of peripheral T-cell lymphoma are quite rare in the United States but can more commonly be found in Asia, notably Japan, where an infection with a virus called HTLV-1 is prevalent. Its presence makes it more likely for an individual to develop a specific type of peripheral T-cell lymphoma. It has also been found in individuals coming from Caribbean countries.


1 Anaplastic Large-Cell Lymphoma Anaplastic large-cell lymphoma (ALCL) is a rare type of aggressive T-cell lymphoma comprising about 3 percent of all lymphomas in adults and between 10 percent and 30 percent of all lymphomas in children. It can present either systemically (meaning in organs throughout the body) or cutaneously (on the surface of the skin). Systemic anaplastic large-cell lymphoma may respond well to chemotherapy treatment and is potentially curable. When ALCL is confined to the skin, it follows a less aggressive course and is associated with a rare condition called lymphomatoid papulosis (LyP), which, though not classified as a lymphoma, is often a precursor to development of cutaneous anaplastic large-cell lymphoma. Patients with systemic ALCL are divided into two groups, depending on the expression of a protein called anaplastic lymphoma kinase (ALK). The prognosis for ALCL depends on whether a patient is ALK positive (expresses the protein) or ALK negative (does not express the protein). ALK positive disease responds well to chemotherapy, putting most patients in long-term remission or cure. A majority of ALK negative patients will relapse within five years and are treated more aggressively, often with transplant.

Angioimmunoblastic Lymphoma Angioimmunoblastic lymphoma (AILD) is a fast-growing T-cell lymphoma that accounts for between one percent and two percent of all cases of NHL in the United States. Symptoms include high fever, night sweats, skin rash and some types of autoimmune disorders, such as autoimmune hemolytic anemia (AIHA) and immune thrombocytopenic purpura (ITP), in which the body does not recognize its own cells. As a result, the body makes antibodies against and destroys its own cells or tissues, such as platelets (ITP) and red blood cells (AIHA). Angioimmunoblastic lymphoma may be treated first with steroids, although it often progresses and requires chemotherapy and other medications. In advanced cases, transplantation may be used.


Blastic NK-Cell Lymphoma Blastic NK-cell lymphoma is a very rare T-cell lymphoma, affecting only a few people (usually adults) each year. This lymphoma is very fast growing, is difficult to treat and can arise anywhere in the body. Since this disease is so rare, patients should consult with their medical team to find promising therapies or clinical trials.

Nasal T-Cell Lymphoma Although this fast-growing lymphoma is very rare in the United States, it is relatively common in Asia and parts of Latin America, leading researchers to suspect that some ethnic groups may be more prone to this cancer, which affects both children and adults. This type of lymphoma is associated with the Epstein-Barr virus. As with other rare cancers, patients should consult with their medical team for treatment options and the availability of clinical trials.

Other Lymphomas

AIDS-Related Lymphomas Lymphomas occurring in HIV-positive patients are usually aggressive. It is estimated that as many as ten percent of people who are HIV-positive will ultimately develop lymphoma. Although both Hodgkin and non-Hodgkin lymphomas may occur in AIDS patients, non-Hodgkin lymphomas are more common and include diffuse large B-cell, Burkitt’s/Burkitt-like and primary central nervous system lymphoma.

Primary Central Nervous System Lymphoma Primary central nervous system lymphoma (PCNSL) is a type of cancer that is limited to the brain or spinal cord but may also be found in tissues around the eye. An increasing occurrence of this disease has been seen in patients with AIDS and others whose immune system has been compromised. Median age of diagnosis for patients with PCNSL is 55 years for patients with a normal immune system and 31 years for AIDS patients. Although in the past the outlook for patients with this cancer has been poor, today the survival rate has greatly improved.


1 Pediatric Lymphoma Childhood NHL comprises about five percent of all NHL cases diagnosed in the United States. The most common types are lymphoblastic lymphoma, Burkitt’s lymphoma, diffuse large B-cell lymphoma and anaplastic large-cell lymphoma. Lymphoblastic lymphoma is closely related to childhood acute lymphoblastic leukemia. The number of children with NHL continues to increase. (See “Children and Young Adults With Non-Hodgkin Lymphoma,” beginning on page 79.)

Treatment-Related T-Cell Lymphomas Treatment-related T-cell lymphomas sometimes appear after solid organ or bone marrow transplantation. The immune system suppression that is required for transplant patients can put them at risk for developing post-transplant lymphoproliferative disorders, certain unusual forms of peripheral T-cell lymphoma and other types of non-Hodgkin lymphoma. Treatment-related T-cell lymphomas may require therapy that differs from the standard treatments normally used to treat these conditions.

Enteropathy-Type T-Cell Lymphoma Enteropathy-type T-cell lymphoma is an extremely rare subtype of T-cell lymphoma that appears in the intestines and is strongly associated with celiac disease. As with other rare cancers, patients should discuss treatment options with their medical team.

Hepatosplenic Gamma-Delta T-Cell Lymphoma Hepatosplenic gamma-delta T-cell lymphoma is an extremely rare and aggressive disease that starts in the liver or spleen. This lymphoma may occur in young males with Crohn’s disease who are immunosuppressed. As with other rare cancers, patients should discuss treatment options with their medical team.

Lymphoblastic Lymphoma Lymphoblastic lymphoma can appear in both B-cells and T-cells but is much more common in T-cells, comprising 80 percent of all lymphoblastic lymphomas. This lymphoma is most often diagnosed in children. With


intensive chemotherapy the complete remission rate can be very high. The disease is often treated similarly to acute lymphoblastic leukemia.

Rare Immune System Cancers Rare immune system cancers include a group of rare diseases that are neither B-cell nor T-cell lymphomas, but instead are cancerous forms of other types of white blood cells and include histiocytic and dendritic cell neoplasms. Patients diagnosed with these cancers should seek advice from their medical team about clinical trials that might be recruiting patients.

T-Cell Leukemias T-cell leukemias are also derived from T-cells and can act like T-cell lymphoma. These cancers include T-cell promyelocytic leukemia, T-cell granular lymphocytic leukemia, aggressive NK-cell leukemia and adult T-cell lymphoma/leukemia.


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1 Chapter 2

Signs and Symptoms of Non-Hodgkin Lymphoma A sign is something a provider detects on physical examination. A symptom is something a patient notices and states to their healthcare provider. Signs are actual findings found on evaluation by the healthcare provider. Symptoms are the patient’s reported physical experiences that may indicate the presence of disease. Some patients may not experience any symptoms and their lymphoma may be detected initially upon routine physical examination. Others may experience one or more of the following symptoms: chills, fever, sweating (most often at night), unexplained weight loss, headaches, lack of energy, itching, swollen lymph nodes or symptoms produced by enlarged lymph nodes, such as pain.

When to Seek Medical Attention It is important that anyone who has persistent symptoms be seen by a doctor to make sure that lymphoma is not present. Serious illnesses are persistent. Seek medical attention if any of the above symptoms last longer than two weeks. Many of these symptoms can arise from different causes and need not be cancer.

What the Doctor Looks For There is no one particular test that allows physicians to routinely screen for lymphoma. Anyone with symptoms suggesting NHL, should see their doctor who will take a medical history and perform a complete physical examination, checking for swollen lymph nodes under the chin, in the neck and tonsil area, above the shoulders, on the elbows, in the armpits and in the groin. The doctor may examine other parts of the body to see whether there is swelling or fluid in the chest or abdomen that could be caused by swollen lymph nodes. The abdomen will also be examined to


see whether any internal organs are enlarged. Patients will be asked about pain and examined for any weakness or paralysis that could be caused by an enlarged lymph node pressing against nerves or the spinal cord. If the doctor suspects lymphoma after reviewing the signs and symptoms, he or she may order other tests to help confirm the diagnosis. These tests should include a biopsy and may also include blood tests, X-rays and other imaging tests, scans and a bone marrow evaluation.


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1 Chapter 3

Getting a Diagnosis An accurate assessment of NHL requires a number of diagnostic tests. First, a hematopathologist (a doctor specializing in the identification of hematologic malignancies) will examine the tumor tissue under a microscope and confirm the diagnosis. Examinations will then be performed to determine how far the disease has spread (staging) and how well the body is functioning.

Common Diagnostic Tests Physicians may use some or all of the following tests as well as the patient’s medical history and the results of the physical examination to assess the best course of treatment or treatments that have the best chance of rendering either a remission or cure. Common Tests Used to Evaluate NHL • Biopsy • Blood tests • Bone marrow examination • Cerebrospinal fluid examination • Imaging tests: X-ray CT (computerized tomography) scan MRI (magnetic resonance imaging) PET (positron emission tomography) scan Gallium (radioisotope) scan (rarely used any longer) • Molecular diagnostic tests

Biopsies A biopsy is a procedure in which a piece of tissue from an area of suspected disease is removed from the body and examined under a microscope. The information provided by this tissue sample is crucial to diagnosing and treating NHL. Learning the Basics 19

Excisional Biopsy The preferred type of biopsy to establish an initial diagnosis of lymphoma is called an open “excisional” biopsy in which an entire lymph node or a generous wedge of tissue is surgically removed. Because there are many types of lymphoma, the precise subtype of lymphoma must be exactly determined to select the best therapy. This generally requires a microscopic review of the lymph node tissue extracted, preferably from a generous sample. Trying to make a diagnosis from a small tissue specimen can lead to errors in diagnosis and suboptimal therapy. Laparoscopy (inserting a tube into the abdomen) or abdominal surgery may be necessary to obtain a sufficient sample of the tumor for examination.

Needle Biopsy When lymph nodes are in locations that are difficult to biopsy, for example, deep in the chest or abdomen, a more limited “needle” biopsy may suffice, especially if a bore needle is used to perform a “core” biopsy. In this type of biopsy, a needle is inserted into a lymph node suspected of being cancerous and a small tissue sample is removed. A core biopsy can be done under local anesthesia and stitches are usually not required.

Fine Needle Aspirate An even more limited type of biopsy is called a fine needle aspirate (FNA), which is performed using a very small gauge needle. This technique yields mostly scattered cells, and intact lymph node architecture is not preserved. Such needle biopsies are more often used to confirm a relapse rather than an initial diagnosis because they often do not produce sufficient tissue to establish a precise diagnosis. After a tissue sample has been removed it is examined by a pathologist (a doctor who studies tissues and cells to identify diseases) who develops a report. To confirm a diagnosis, the oncologist uses this report along with the results of immunologic studies. If the pathologist’s interpretation of the biopsy is uncertain, the report should be reviewed by a hematopathologist, since a pathological diagnosis of lymphoma can sometimes be difficult to make.


1 Blood Tests Blood tests are performed to determine whether different types of blood cells, including red blood cells, white blood cells and platelets, are normal in number and appearance when viewed under the microscope. Abnormalities in these blood cells may sometimes be the first sign of lymphoma. Certain blood tests can be used to determine whether lymphoma is affecting the liver, kidneys or other parts of the body. Blood abnormalities can also help doctors determine potential treatment choices and predict outcomes. For example, in patients with NHL, levels of the enzyme lactate dehydrogenase (LDH) and/or the protein beta (2) microglobulin (B2M) are commonly measured because higher levels of either or both suggest that the lymphoma may be more aggressive and that more intensive treatment may be needed. If the lymphoma is circulating in the blood, tests can also be used to classify the tumors according to molecular markers (or antigens) on the surface of cancer cells. This process is called immunophenotyping and is also performed on tissue samples removed by biopsy or bone marrow extraction. This information can help distinguish different types of lymphoma.

Bone Marrow Examination Bone marrow is the spongy, soft material found inside our bones. Bone marrow contains immature cells called stem cells, which develop into three main types of cells found in the body: red blood cells that deliver oxygen to all parts of the body and take away the waste product carbon dioxide; white blood cells, primarily neutrophils and lymphocytes, which protect the body from infection; and platelets, which help blood clot. Non-Hodgkin lymphoma can spread to the bone marrow or start in the bone marrow. To determine whether lymphoma is present, doctors may examine part of the marrow by first numbing the area around the skin, tissue and surface of the bone with a local anesthetic and then inserting a thin needle usually into an area of the pelvic bone and extracting a small tissue sample. The procedure can be painful at the moment the marrow is withdrawn. Patients who are anxious about the test should talk with their doctor and nurse to see whether taking a calming medication before the procedure would be helpful.


Cerebrospinal Fluid Examination In a small number of patients, NHL can spread to the nervous system. When this happens, the fluid present around the spinal cord and the brain (cerebrospinal fluid) may be abnormal and contain cancer cells. To determine whether this has occurred, the physician may recommend a test called a spinal tap or a lumbar puncture, in which a thin needle is inserted into the lower back under local anesthetic. A small sample of fluid is then removed, and the cerebrospinal fluid is examined for chemical content and abnormal cells.

Imaging Tests Physicians will often order imaging tests that provide pictures of the inside of the body. Most of these tests are painless, and no anesthetic is required. Several types of imaging procedures may be needed to help best evaluate lymphoma, including the following:

X-rays X-rays use radiation to take pictures of areas inside the body. The amount of radiation used in most diagnostic tests is so small that it poses little risk to the patient.

CT (computerized axial tomography) Scan A CT scan takes X-rays from different angles around the body. The pictures obtained are then combined using a computer to give a detailed image. People with NHL often have CT scans of the neck, chest, abdomen and pelvis. These tests are useful in determining how many lymph nodes are involved, how large they are and whether internal organs are affected by the disease.

MRI (magnetic resonance imaging) An MRI is similar to a CT scan but uses magnets and radiofrequency waves instead of X-rays. An MRI can provide important information about tissues and organs, particularly the nervous system, that is not available from other imaging techniques. Because this testing technique works well to get clear images of the bones, brain and spinal cord, an MRI may be ordered when the physician wants to see whether the lymphoma has spread in these areas.


1 PET (positron emission tomography) Scan PET scans have largely replaced gallium scans (in which radioactive gallium was injected into the body) in many cancer centers, because the technique is more convenient and more sensitive. This test evaluates NHL activity in all parts of the body. To perform the test, a radioactive glucose (sugar) tracer substance is first injected into the body. A positron camera is then used to detect the radioactivity and produce cross-sectional images of the body. Unlike gallium scans, which are used primarily to detect response to treatment, PET scans are useful for both determining how much disease is present (staging) and how well it is responding to treatment. While CT scans show the size of a lymph node, gallium and PET scans show if the lymph node is active (still has disease). Today, CT and PET scans are often being combined into one test (CT/PET).

Molecular Diagnostic Tests Over the past decade, scientists have gained a deeper understanding of how lymphoma works at the molecular level. This understanding has led to powerful new diagnostic tools and treatments. These tools include polymerase chain reaction (PCR) and fluorescence in situ hybridization (FISH), which can detect small amounts of genetic material, and a variety

Questions to Ask Your Doctor Before Having a Procedure • Why is this procedure necessary? • What will the procedure tell us about my condition? • Can the same information be obtained in any other way? • What is involved in doing this procedure? • What are the possible risks, complications and side effects? • How long will the procedure take? • Will I feel pain? • When will I know the results? • When will we talk about the results? • What will my out-of-pocket costs be? • Should anyone else be present when I have the procedure? • Will I need someone to take me home afterward?


of immunological techniques that detect the expression of specific proteins (antigens) on the surface of tumor cells. Using these tests, doctors can sometimes detect cancer earlier, and they can more accurately classify tumor types. This information may help the physician choose the most appropriate treatment for the disease. Immunologic and genetic tests can find evidence of cancer unseen by a pathologist’s microscope. An advantage of molecular diagnostic tests is that they are usually very sensitive and require only tiny amounts of tissue obtained from biopsies, fine-needle aspirates or sometimes blood. Researchers are currently developing ways to measure the activity of genes within the cells of a lymphoma sample. This technique is called microarray analysis, which may lead to even more accurate diagnoses based on a tumor’s individual genetic characteristics and behavior. Because it is too complex to be performed routinely, the method is currently being used in an experimental setting for assessing NHL tumors. Interpreting Diagnostic Reports It is important to be aware that no one test is definitive. Tests can be reported as “normal” even though lymphoma may be present. Tests may also be reported as abnormal even though no lymphoma is present. Other conditions may mimic lymphoma. The interpretation of tests, such as imaging scans, can be difficult in some situations and needs to be made in the context of the disease and the patient. Oftentimes, follow-up tests are needed to determine the true significance of previous results. In fact, biopsies occasionally are needed to clarify the results. Some patients like to review their written scan reports. When doing so, it is important to review the findings with the physician.

Other Tests In addition to these tests, doctors may also order tests to evaluate the health of organs that could be affected by treatments. Examples of some tests include echocardiograms or radionuclide tests to evaluate the heart and pulmonary function tests to evaluate the lungs.


1 Grading and Staging Non-Hodgkin Lymphoma Although people often confuse the terms grade and stage in a lymphoma diagnosis, their meanings are very different.

Grading Non-Hodgkin Lymphoma Grading lymphoma tumors is important because it helps to define the usual growth pattern and aggressiveness of the lymphoma cells and helps the physician determine the kind of treatment to be prescribed. Lymphomas classified as low-grade, or indolent, tend to grow very slowly and may need treatment less urgently. Indolent lymphomas, although usually extremely responsive to therapy, are rarely cured with conventional therapy and are usually widespread at the time of diagnosis. Nevertheless, patients often live for a long time with a good quality of life. Some indolent lymphomas can transform over time into more aggressive types requiring more intensive treatment. Intermediate- and high-grade NHLs are often classified as aggressive because these tumors generally grow rapidly and may require treatment soon after diagnosis. Although people with more aggressive lymphomas often need more immediate intensive treatment, their cancers are potentially curable.

Staging Non-Hodgkin Lymphoma Non-Hodgkin lymphoma is divided into four stages, based on how far the disease has spread. Stages I and II are considered localized, while stages III and IV are considered advanced, widespread or disseminated. However, it is important to remember that being diagnosed with NHL at an advanced stage III or IV is common, and—unlike a stage IV diagnosis in solid tumor cancers in which the primary cancer has spread to other sites—advanced stages for NHL can be successfully treated and may still be cured. Staging the disease helps doctors to predict outcome or prognosis and determine treatment approaches.

The Meaning of the Letters A, B or E After the Stage Each stage of NHL is further divided into “A,” “B” and “E” categories, depending on the symptoms patients have when they are diagnosed. Learning the Basics 25

The A category is used to designate a person with no symptoms. The B category is used to designate a person with symptoms that affect their entire body (called systemic symptoms). Examples of these include fever, night sweats and weight loss. The E category is used when the disease spreads directly from a lymph node into an organ. Category E can also be used when the disease involves a single organ outside the lymphatic system with no other local lymphatic involvement. The Four Stages of Non-Hodgkin Lymphoma Stage I (early disease): The cancer is found only in a single lymph node region OR in one organ or area outside the lymph node. Stage II (locally advanced disease): The cancer is found in two or more lymph node regions on one side of the diaphragm (the breathing muscle that separates the abdomen from the chest). Stage III (advanced disease): The disease involves lymph nodes both above and below the diaphragm. Stage IV (widespread disease): The lymphoma cells are found in several parts of one or more organs or tissues (in addition to the lymph nodes). Or, it is in the liver, blood, or bone marrow.

Getting a Second Opinion Before starting therapy, patients may want to consider getting a second opinion to confirm the diagnosis and treatment plan, particularly if some aspects of the NHL are complicated or uncertain. Some insurance programs require second opinions; others may cover it if a patient or physician requests it. Sometimes, second opinions are obtained at academic medical centers. The hematologists/oncologists specializing in lymphoma may provide a consultation and establish a collaborative relationship with a local oncologist for treatment and follow-up care. When seeking a second opinion, patients should remember that it is best to request a complete copy of all medical records and provide original X-rays, pathology materials, scans and reports that are requested by the consulting physician. It may be useful to keep a copy of the medical


1 records. A second opinion is not considered adequate unless another pathologist, preferably one well versed in lymphoma, reviews the tissue and blood samples. A patient’s physician or healthcare team can often recommend an oncologist for a second opinion.

Choosing an Oncologist and Treatment Center Before agreeing to treatment by a physician or clinic, a patient should be certain that all of their medical and personal needs will be met. Take time to check: (1) the credentials of the physician, the other members of the medical team and the hospital or cancer center, (2) the portion of time the physician spends researching or treating NHL and (3) the patient resources within the cancer center. Patients should keep in mind that if in a managed care program, choices may be limited. However, if a patient is not entirely satisfied with their first consultation, they have the right to choose another healthcare team. Referrals may be obtained by speaking with other NHL patients or asking their primary physician. It is important that patients feel comfortable with their healthcare team and the quality of care they are receiving. Questions to Ask When Choosing a Doctor and Treatment Center Before beginning treatment, ask these basic questions: • How much experience does this doctor (treatment center) have in treating cancer in general, and lymphoma in particular? How many patients with lymphoma are being treated here now? • Is the doctor board certified as an oncologist or hematologist? Has he or she passed qualifying examinations by the American Board of Internal Medicine that certify his or her competency in these specialties? • Do the oncologists, hematologists or center participate in clinical trials? • Does the clinic or center have state-of-the-art surgical facilities and diagnostic equipment? • Is the doctor or clinic affiliated with any major medical center or medical school? • What arrangements are made for medical coverage after hours and on weekends, in case of an emergency? • Is my health insurance accepted at this center? Will the office file claims for reimbursement and process the paperwork? • How may I learn more about my type of lymphoma?



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Part 2: Treating Non-Hodgkin Lymphoma

Chapter 4

What You Should Know Before Starting Treatment Getting a lymphoma diagnosis is frightening, and patients are naturally concerned about what their future may hold. Oftentimes, patients will ask their doctor about their outlook, or prognosis, the medical term used to describe how the disease will progress and the likelihood for recovery. To be an educated healthcare consumer, it is important to understand the nature of NHL and what to expect from treatments, including any possible effects on quality of life, such as lifestyle, emotions and financial issues. Prognosis is usually based on information gathered from hundreds or thousands of other patients who have had the same disease. This statistical information provides physicians with a general idea of what to expect when a patient is diagnosed with a specific type of NHL and also gives guidance on the kinds of treatments that have been most successful in treating that cancer. However, it is important to remember that no two patients are alike and that statistics from large groups of people do not

Treating Non-Hodgkin Lymphoma 29

always accurately predict what will happen to a particular patient. The doctor most familiar with your situation is in the best position to help interpret these statistics and determine how they apply to you.

Communicating With Your Healthcare Team People who are diagnosed with NHL are often anxious to learn all they can about their disease and treatment choices so they can play an active role in decisions about their care. For many people, getting an NHL diagnosis is shocking and it is normal to feel a lot of physical and emotional stress following diagnosis. Some people are uncertain about how to talk with physicians, and the combination of stress and uncertainty may make it difficult to know what to say or what questions to ask. Patients can ease their anxieties by establishing an open and honest dialogue with their physician and nurse regarding their diagnosis, and learning about what the prescribed treatment regimen is, how it works, what tests are involved and what side effects and complications may be associated with it. A good first step is to write down all of the questions that come to mind. Before meeting with a physician or nurse, whether for the first time or for follow-up visits, organize and write out all questions. Put the two or three most important questions at the top of the list, since time with physicians or nurses may be limited. But make sure that a member of the medical team reads all of the questions, because they may see some that are more important than the patient realizes. Also, it is helpful for patients to have a member of their family or a close friend accompany them to the physician’s office or clinic to help ask questions and understand and remember answers. It can also be helpful to write down the answers to the questions. Some patients bring a recording device to record the answers. Patients should check with their physician before recording any conversations. Most oncology nurses are also very well informed about cancer treatments and are a good source of information on a wide range of topics. Oncology social workers are also available to assist with practical and emotional needs from the point of diagnosis onward.


Although family members are often very concerned about their loved one and want information concerning his or her care, growing confidentiality rules prohibit physicians from giving out information to anyone without the patient’s expressed permission. For efficiency, it is suggested that one family member be designated as the family contact to the physician. However, the patient must inform their physician who this individual will be in advance.

Tips on Communicating With Your Doctor • Keep a journal of your symptoms to help you remember the details you want to discuss with your doctor during your office visit and bring a list of your questions to your appointment. • During your office visit, take notes or tape record your conversation to help you accurately review the information afterward. Bringing along a family member or friend for support and to take notes for you is also helpful. • Do not be afraid to ask questions when you do not understand something. Doctors want to know when you are uncertain or confused and will try to explain information to you. • Before leaving the doctor’s office, make sure you understand the next step in your care and ask if there is written information you can take home.

Writing an Advance Healthcare Directive and Appointing a Healthcare Proxy Writing down wishes for critical medical care in an advance healthcare directive is a way that patients can inform their physician, family members and friends about their healthcare preferences and what special treatment they want or do not want at the end of life. Besides stating medical care instructions, the advance healthcare directive should also include the name of the patient’s healthcare proxy, or decision maker. This person should be someone the patient believes will carry out their wishes if they are unable to do so, including do not resuscitate (DNR) instructions. Before writing an advance healthcare directive, it is important that patients understand their rights and the laws regarding advance healthcare directives in their state. Consulting an attorney can provide the legal information, but patients do not have to use an attorney to write an advance directive. Some things a patient should consider when writing an advance healthcare directive include: Treating Non-Hodgkin Lymphoma 31

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• Specific instructions on the medical care, including the types of special treatment a patient wants or does not want, such as cardiopulmonary resuscitation (CPR), artificial respiration, drugs to make the heart function, kidney dialysis, artificial feeding and certain surgical procedures. • A patient’s choice of healthcare proxy.

How to Be a Self-Advocate Being a self-advocate and an active participant in healthcare can be a positive experience and may help restore a sense of control that was lost following diagnosis. It is important for patients to remember that they are a partner in their treatment plan and many patients feel better when they actively participate in their care. The first steps in participating in treatment are to ask questions, learn about options and work closely with the physician. Patients must be comfortable with their physician and the approach that they take. If not, patients should openly discuss their concerns. Confidence in the medical team often leads to confidence in treatment. If the patient does not feel that the team is a good match, they should ask for a referral. Questions will likely vary depending on the purpose of the meeting with the oncologist (e.g., the initial visit to discuss the diagnosis as opposed to a routine visit to monitor a remission). Ask for the timing of office visits, treatments and tests. The physician can help explain what the tests will look for and define the possible responses and the options for further care depending on treatment response. Although each person is different and each response to therapy is unique, knowing someone who has been through the same treatment and who may have had similar concerns can be a source of great comfort for patients. If a patient is interested in talking to and learning from people who have had similar experiences, they should ask their oncologist, hematologist, oncology nurse or the oncology social worker about any support groups in their area. The Lymphoma Support Network, a nationwide buddy program that matches patients or caregivers, offers the opportunity to share experiences and information, and offers support and encouragement. For more information about this program, call (800) 500-9976 or e-mail [email protected]. 32 Understanding Non-Hodgkin Lymphoma

2 Tips on Self-Advocacy • Do not be afraid to ask your doctor or nurses questions about your care. • Learn more about your lymphoma from reliable websites, such as the Lymphoma Research Foundation at lymphoma.org. Or ask your doctor for information specific to your type of lymphoma. • Take advantage of other services offered at your doctor’s office, cancer center or hospital, such as counseling, support groups, nutritional counseling and fitness classes. • Consider joining the Lymphoma Support Network, a nationwide buddy program that matches patients and/or caregivers. For more information about the program, call (800) 500-9976 or e-mail [email protected].

Before any tests are performed, a patient should check with their healthcare team to determine which costs are covered by insurance and which are not. A patient should not be afraid to broach nonmedical issues, such as transportation, finances, insurance and childcare, with the healthcare team.

Factors Affecting Treatment Outcome Before treatment, patients often wonder how they will respond to a specific regimen. This depends on the type of lymphoma as well as other factors, which may be remembered by the acronym APPLES.

Age People under the age of 60 generally have better treatment outcomes than those who are older. Younger patients may be better able to tolerate the effects of therapy because they generally have fewer health problems, such as heart or lung disease, that could limit the type or dose of therapy.

Prior Therapy The greater the number of prior therapies, the less likely treatment will be successful, which is why it is important to attack the tumor initially with the most effective therapy available.


Performance Status Performance status is used to describe a person’s ability to follow a typical lifestyle. Those with good performance status (people who are active) tend to respond better than those with poor performance status (people with chronic health problems or those so ill that they are confined to bed) because they can tolerate more intensive therapy. Performance status is ranked on a scale from 0 to 4, with a number of 2, 3 or 4 indicating progressively sicker patients.

Levels of Blood Proteins Lactate dehydrogenase (LDH) and beta (2) microglobulin (B2M) are proteins found in the blood. Higher levels of LDH or B2M suggest that the lymphoma may be more aggressive. People who have normal levels of these proteins appear to have better outcomes than those with higher levels of these proteins.

Extranodal Disease (disease outside the lymph nodes) Patients with NHL that has spread outside the lymph nodes to other areas, such as the bone marrow or nervous system, tend to have a lower cure rate compared with those whose disease has not spread.

Stage of Disease Stages I and II are used to describe localized disease, and stages III and IV refer to more widespread or advanced disease. Patients with stage III or IV disease may have a lower cure rate compared with individuals with stage I or II disease. Based on many of these and other factors, physicians have developed indices, such as the International Prognostic Indicator (IPI) or FLIPI (for follicular lymphoma), to predict the success of the therapy. By referring to these indices, physicians will make treatment choices as to how to approach an individual’s particular lymphoma.


2 Questions to Ask Before Treatment Begins • What is my exact diagnosis? • What is the stage and grade of my disease? • What are my treatment choices? Which do you recommend for me? Why? • What are the risks and possible side effects of each treatment? • What side effects should I report to you? • Are there any late- or long-term side effects I should be aware of? • How long will the treatment last? • What are the chances that the treatment will be successful? • How will the treatment affect my normal activities? • Are new treatments being studied? Would a clinical trial be appropriate for me? • What is the treatment likely to cost? Does my insurance cover it?



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Chapter 5

Types of Treatment for Non-Hodgkin Lymphoma Many effective treatment options exist for NHL patients. The type of treatment chosen depends on the type of lymphoma and its stage, as well as other prognostic factors. (See “Factors Affecting Treatment Outcome” on page 33.) This chapter includes a description of types of standard and approved therapies, including: (1) watchful waiting, (2) conventional chemotherapy approaches, (3) radiation therapy, (4) stem cell transplantation, (5) novel targeted agents, (6) newer versions of established agents and (7) interferon. For each section, a description of the mechanism of action will be presented, along with the therapies approved by the United States Food and Drug Administration (FDA) at the time of print. It is important to remember that new therapies may have been approved since this book went to print and that additional indications for the therapies discussed in this chapter may be granted as clinical trials reveal new uses. Refer to Chapter 14 for therapies under investigation. For the most up-to-date resources, visit lymphoma.org or fda.gov.

Watchful Waiting Understanding Watchful Waiting “Watchful waiting” or “watch-and-wait” refers to an approach wherein the patient has regular visits and follow-up evaluation procedures, such as laboratory and imaging tests, but no specific anti-lymphoma treatment is given. The patient pursues a normal life as long as symptoms of NHL are not present and the disease is clinically stable. Watchful waiting may be appropriate either at the time of initial diagnosis or following treatment for selected indolent lymphoma patients. When the patient begins to develop lymphoma-related symptoms, or when there are signs that the disease is progressing, watchful waiting will be abandoned in favor of active treatment. Watchful waiting is not a treatment option for aggressive lymphomas, as treatment is almost always needed shortly following diagnosis.


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Current Perspectives on Watchful Waiting The standard of care for advanced-stage, asymptomatic follicular lymphoma is often the watch-and-wait approach. However, ongoing clinical studies are testing whether giving the monoclonal antibody rituximab (Rituxan)- either alone or in combination with chemotherapy- may prolong survival. This technique is sparking debate among physicians about whether to abandon the watchful waiting approach in some patients. However, watchful waiting is still appropriate for patients with a very low risk of disease progression based on prognostic data, and indicated after protracted courses of rituximab (Rituxan). As more drugs with high efficacy and very favorable toxicity profiles emerge, it is likely that these treatment opportunities will replace watchful waiting in selected patients.

Conventional Chemotherapy Approaches Chemotherapy (“chemo”) is treatment with drugs (as opposed to radiation, for example).

Combining Chemotherapy Drugs Chemotherapy for NHL often consists of giving several drugs together (combination chemotherapy) in a defined way (schedule), called a treatment regimen. Drug combinations are used because different medications damage or kill cancer cells in different ways making them more vulnerable to the treatment. Combining chemotherapy drugs together provides a more effective way to kill more tumor cells, because using the drugs together greatly augments the impact of each drug (called synergism). In addition, when some drugs are added together in lower doses it helps reduce the likelihood of side effects without reducing the overall amount of effective chemotherapy. For example, the combination of four drugs (cyclophosphamide, doxorubicin or hydroxydaunorubicin, vincristine and prednisone), referred to as CHOP chemotherapy, represents the standard therapy for diffuse large B-cell lymphoma (DLBCL). This combination uses drugs that are given in somewhat less toxic amounts while sustaining a full or augmented (synergistic) capacity to destroy NHL. Another reason for combination chemotherapy is to prevent the emergence of drug resistance.


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Common Chemotherapy Drugs DNA-Altering Drugs These drugs damage DNA, the building blocks of genes, to prevent cell growth. Chemical Name

Brand or Other Name

Examples of Use in Combination Chemotherapy

Bendamustine

Treanda

Bendamustine-Rituximab

(Rituxan) (referred to as

B-R)

Carboplatin

Paraplatin

ICE

Carmustine

BCNU BiCNU

Stem cell transplantation

Chlorambucil

Leukeran

Single agent

Cisplatin

Platinol CDDP

DHAP

Cyclophosphamide Cytoxan CTX

CHOP, EPOCH, CEEP HyperCVAD

Dacarbazine

DTIC

ABVD

Ifosfamide

Ifex

ICE

Mechlorethamine

Nitrogen mustard Mustargen

MOPP

Melphalan

Alkeran L-PAM

Stem cell transplantation

Procarbazine

Matulane

MOPP

Antitumor Antibiotics (Anthracyclines) hese drugs interact with DNA and decrease cell survival. They come from T natural sources, such as plants or microorganisms. Chemical Name

Brand or Other Name


Bleomycin

Blenoxane

ABVD

Doxorubicin

Adriamycin Doxil (pegylated form) Hydroxydaunorubicin Rubex

CHOP, ABVD, HyperCVAD, EPOCH


Synthetic Drugs That Act Like Doxorubicin (Anthracenediones) Chemical Name

Brand or Other Name


Mitoxantrone

Novantrone

FND, GNP

Antimetabolites These drugs interfere with normal cell growth by inhibiting synthesis of DNA. Chemical Name

Brand or Other Name

Chlorodeoxyadenosine Cladribine Leustatin 2-CdA Cytarabine


Single Agent

Cytosine arabinoside DHAP Ara-C Cytosar DepoCyt

Fludarabine phosphate Fludara

FCR, FND-R, R-Flu

Methotrexate

Rheumatrex Trexall

HyperCVAD, Single agent

Pentostatin

Nipent

PCR

Etoposide

VP-16 Etopophos Toposar VePesid

ICE, CHOEP, LPOCH

Gemcitabine

Gemzar

GNP

Pralatrexate

Folotyn

Single agent


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Hormones These drugs also affect cell growth.

Chemical Name

Brand or Other Name

Topical steroid creams

Diprolene Temovate Lidex

Decadron Deltasone

Dexamethasone Prednisone

Drugs That Prevent Cells From Dividing by Blocking Cell Duplication (Mitosis)

Chemical Name

Brand or Other Name

Vinblastine

Velban

Vincristine

Oncovin Vincasar

Navelbine

Vinorelbine

Chemotherapy Cycles Chemotherapy is usually given in cycles in which each treatment is followed by a period of rest and recovery. Together, each period of treatment and non-treatment is called a “chemotherapy cycle.” Clinical trials have determined how often chemotherapy should be given to kill the most tumor cells while minimizing side effects. However, timing may vary depending on the specific treatment. For NHL, a chemotherapy cycle is typically given every one, two, three or four weeks. Chemotherapy for NHL may require as few as three or as many as eight or more cycles of treatment, depending on factors such as the stage of the disease, the type of lymphoma, the kind of drugs used, the level of response achieved and the nature and severity of the side effects.


Common Chemotherapy Regimens Used to Treat Non-Hodgkin Lymphoma (common brand names are in parenthesis) Note: Many of these regimens can also include the monoclonal antibody rituximab (Rituxan), which is often noted as an “R.”

Regimen Abbreviation Drugs CP

Chlorambucil (Leukeran) Prednisone (Deltasone)

CVP (COP)

Cyclophosphamide (Cytoxan) Vincristine (Oncovin) Prednisone (Deltasone)

CHOP-R

Cyclophosphamide (Cytoxan) Doxorubicin or Hydroxydaunorubicin (Adriamycin, Rubex) Vincristine (Oncovin) Prednisone (Deltasone)

EPOCH

Etoposide (VP-16, VePesid) Prednisone (Deltasone) Vincristine (Oncovin) Cyclophosphamide (Cytoxan) Doxorubicin or Hydroxydaunorubicin (Adriamycin, Rubex)

FND

Fludarabine (Fludara) Mitoxantrone (Novantrone) Dexamethasone (Decadron, Dexasone)

HyperCVAD/MTX-Ara-C

Cyclophosphamide (Cytoxan) Vincristine (Oncovin) Doxorubicin (Andriamycin) Dexamethasone (Decadron) Methotrexate (Rheumatrex) Cytarabine (Ara-C, Cytosar)


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Regimen Abbreviation Drugs ICE

Ifosfamide (Ifex) Carboplatin (Paraplatin) Etoposide (VP-16, VePesid)

DHAP

Dexamethasone (Decadron) Cisplatin (Platinol, CDDP) Cytarabine (Ara-C, Cytosar)

ESHAP

Dexamethasone (Decadron) Cisplatin (Platinol, CDDP) Cytarabine (Ara-C, Cytosar) Etoposide (VP-16, VePesid)

How Chemotherapy Is Given Depending on the regimen, chemotherapy may be administered in pill form, as an injection or as an intravenous drip. For patients receiving intravenous drugs (ones that are given through a vein) for multiple cycles, an intravenous catheter may be inserted to make it easier to give drugs. Catheters may be left in place temporarily or permanently. There are several types of catheters. One type, called a Hickman-Broviac catheter, consists of one to three tubes inserted through the chest wall into a vein. Six to twelve inches of tubing remain outside the skin. The main advantage of this type of catheter is that blood tests can be drawn and drugs given without having to pierce the skin. Disadvantages include: (1) the possibility of infection if the catheter is not cared for properly and (2) the tubes on the outside of the body make it more obvious that a catheter is in place. Patients who have this type of catheter will receive specific instructions from their healthcare team regarding proper care and cleaning. A second type of intravenous catheter, called an Infusa-Port or Portacath catheter, is placed under the skin and appears only as a bump on the chest. The advantage of this catheter is that it is easier for patient care because it only needs to be maintained by a nurse once a month (called


“flushing”). However, it also has disadvantages. Each time this type of device is used, an injection through the skin is required, and it may not always be convenient to draw blood samples. These devices may also occasionally clot. Another type of intravenous catheter is a peripherally inserted central catheter or PICC line, which uses a thin, soft plastic tube to deliver medicines and fluids through a large vein in the arm. While the PICC line is a more temporary device, it can be kept in place for a number of months, and is a good option for patients who need to have many short infusions or continuous infusions given in a hospital or at home with a portable pump. Patients in need of a catheter should discuss the pros and cons of the different types with their physician.

The Importance of Maintaining Chemotherapy Dosing and Scheduling “Dose intensity” is a term used to describe giving the highest possible doses of chemotherapy over a specific period of time, while maintaining an acceptable level of side effects. This approach has been shown to be very effective in curing some cancers, including some aggressive lymphomas. Studies have suggested that reducing the dose or delaying chemotherapy may decrease both the chance for a cure and long-term survival in some types of lymphomas. Patients should know that changing the regimen to reduce short-term side effects may actually be harmful in the long run. Some side effects may be unpleasant but tolerable. (See “Coping With Common Treatment Side Effects” on page 61.) Others may be serious but can often be anticipated and prevented. It is very important that chemotherapy schedules be maintained to the greatest extent possible.

Radiation Therapy Radiation therapy (also called radiotherapy) uses high-energy x-rays to kill cancer cells and shrink tumors. Radiation is a most often localized, which means it only affects cancer cells in the treated area. The term “radiation field” is used to describe the part of the body selected to receive radiation therapy. Radiation is generally confined to lymph nodes, the areas immediately surrounding lymphoma nodes or the area


of origin if the lymphoma arose from an extranodal site. These fields are determined on a case-by-case basis and depend on the type of tumor and the extent of disease. Radiation may be given to a limited or involved field (a small area) or may be given more broadly to larger common areas (extended field). To prepare for radiation therapy, the skin is marked with tiny ink dots (called tattoos) so the exact area will be treated every time. Before the first treatment, the healthcare team devotes a substantial amount of time marking the body to make sure that only the targeted areas receive radiation. Normal tissues around the radiation field are shielded by lead, which blocks the path of stray radiation beams. Patients lie still on a table beneath a large machine that delivers the radiation painlessly. Props and supports with plastic forms, pillows and rolled blankets help keep patients in the proper position. Once the preparations have been made, it takes only a few minutes to deliver the prescribed dose. The total dose of radiation is usually divided and given over one to six weeks. The site must carefully be guarded from the sun during and after radiation therapy.There are many different types of radiation as well as different ways to deliver radiation. Some of the more common types of radiation and delivery methods used in the treatment of NHL include:

Electron Beam (EB) Radiation Electron beam (EB) radiation is a form of external radiation therapy whereby a machine outside the body is used to send electrons, or negatively charged particles, directly to the area where the lymphoma is found and, potentially, to nearby lymph nodes.

Radioimmunotherapy Radioimmunotherapy is a form of “liquid radiation” whereby a radioactive molecule is attached to a monoclonal antibody to target specific cancer cells. (See “Radioimmunotherapy,” on page 53.)

Intensity-modulated Radiation Therapy (IMRT) Intensity-modulated Radiation Therapy (IMRT) is a form of external radiation therapy whereby different doses of radiation are directed toward the cancer site using radiation beams of varying intensities.


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First, a three-dimensional image of the tumor is collected using CT, MRI or PET scans. A special computer program is then used to analyze the three-dimensional image and design radiation beams that conform to the specific shape of the tumor. This technique allows physicians to target the tumor with radiation, while sparing the healthy tissue surrounding it.

Total Skin Electron Beam Radiation Therapy (TSEBT) Total Skin Electron Beam Radiation Therapy (TSEBT) is often used for the treatment of cutaneous T-cell lymphoma (CTCL). TSEBT directs radiation to the entire surface of the body. However, the radiation only penetrates the outer layers of the skin, sparing deeper layers and other tissues from radiation exposure. For more information on this type of therapy and its use, visit the Cutaneous Lymphoma Foundation’s website at clfoundation.org.

Photopheresis or Extracorporeal Photochemotherapy When using photopheresis, a fraction of a patient’s blood is removed and treated with an agent that makes lymphocytes more susceptible to cell death when exposed to ultraviolet A light. The blood is then exposed to ultraviolet A light and re-infused back into the patient. This form of therapy has been approved by the US Food and Drug Administration for the treatment of cutaneous T-cell lymphoma. It may also be effective in the treatment of graft versus host disease (GVHD), a common complication following allogeneic stem cell transplantation. For more information on this type of therapy and its use, visit the Cutaneous Lymphoma Foundation’s website at clfoundation.org.

Stem Cell Transplantation Bone marrow transplants are now called stem cell transplants because they use three types of blood-forming stem cells: • Bone marrow • Peripheral (circulating) blood (also called peripheral blood stem cells or PBSC) • Cells collected from an umbilical cord after a baby is born


A transplant using any one of these cells can replace a patient’s damaged marrow with healthy blood-forming cells, resulting in a new blood and immune system. With these new cells working in the patient’s bone marrow (the spongy material found inside our bones) the marrow can once again form healthy: • Red blood cells, which carry oxygen to all parts of the body • White blood cells, which fight infections • Platelets, which control bleeding by helping blood to clot To get the patient’s body ready for a transplant, he/she will receive chemotherapy and/or radiation. This will destroy or suppress the immune system. Physicians call this a preparative regimen, or conditioning. The new stem cells grow in the body, and take over the blood-forming machinery in the marrow. Because a transplant places great strain on a patient’s body, it is not an option for everyone. Among the things to consider are age, medical history, cancer stage and response to previous therapy. In some patients, a reduced-intensity conditioning regimen can be used, which lowers the strain on the body (see below). There are two types of stem cell transplants: allogeneic, in which patients receive stem cells from another person, and autologous, in which patients receive their own cells.

Autologous Transplantation In this procedure, a patient’s own stem cells are removed—preferably while the patient is in remission—and frozen. When it is time for the transplant, the patient will receive very high-dose chemotherapy and/or radiation, after which the thawed stem cells are re-infused back into the patient’s body. The cells go into the bloodstream, where they make their way to the bone marrow where they belong. The advantage to this type of transplant is that the patient’s body cannot reject the stem cells, and there is no risk of graft versus host disease (GVHD), which may occur with allogeneic transplantation. A disadvantage is that autologous transplantation has a higher risk of relapse than allogeneic transplantation. Autologous transplants use primarily marrow or PBSCs; cord blood has only been used in rare instances.


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Allogeneic Transplantation In allogeneic transplantation, a donor’s stem cells are used. Finding a compatible donor is important because the body will reject stem cells if they are too unlike the patient’s own cells. The new cells may also react against the patient’s body, a condition called graft-versus-host disease (GVHD). However, allogeneic transplants also have one important potential advantage: the donor’s immune cells can destroy any lymphoma cells in the body not killed by the conditioning regimen. Very sensitive tests are used to see if someone is a suitable transplant donor. The best candidates are siblings, but there is only a one in four chance that a sibling will be a close enough match for a transplant. If no family members are a match, a search for an unrelated donor (or a cord blood unit) in a large registry of volunteers can be initiated.

Reduced-intensity Transplants (Mini-Allogeneic Transplants) Reduced-intensity transplants (also called non-myeloablative or minitransplants) use less-intense conditioning to prepare patients for allogeneic transplantation. These transplants use just enough chemotherapy and/or radiation to allow the patient’s body to accept the new cells. This approach takes advantage of the graft-versus-disease effect, in which the transplanted cells (the “graft”) recognize the cancerous cells in the patient’s body as foreign and destroy them. Patients receiving reducedintensity transplants may avoid some of the side effects seen with higher-dose chemotherapy.

How Transplants Are Done Transplants are performed in four steps: Step 1: Collecting stem cells Stem cells are collected (harvested) in one of three ways: • Bone Marrow - To harvest bone marrow, physicians use a hollow needle inserted into the hip bone. This is done in an operating room and the donor receives general or local anesthesia. Once the marrow is harvested, it is either quickly transported to the waiting patient (in an allogeneic transplant) or frozen until needed for an autologous transplant.


• Peripheral Blood Stem Cells (PBSC) - The second, and now more common way to collect stem cells from an adult, is by harvesting PBSCs from the blood. In this case, the donor takes a drug called a growth factor that causes the stem cells in the marrow to move into the peripheral blood. The stem cells are then removed from the donor’s blood using a process called apheresis. Blood is taken from a vein in one of the donor’s arms and passes through an apheresis machine, which separates out the stem cells. The rest of the blood, minus the stem cells, is returned to the donor through a different vein. • Cord Blood - Cord blood is collected at birth from a newborn’s umbilical cord. After the delivery is complete, trained technicians pierce the base of the cord with a sterile needle and drain the blood into a collection bag. The cord blood cells are then processed, tested and frozen until needed for a patient. Step 2: Processing or preserving stem cells In autologous transplants, marrow and PBSC collections are frozen for later re-infusion. In allogeneic transplants, cells undergo minimal processing and are given to the waiting patient as soon as possible. Cord blood cells (almost exclusively used in allogeneic transplants) are shipped frozen to the patient’s hospital, where they are kept until the patient is conditioned and ready to receive them. Step 3: Pre-transplant conditioning Before receiving the cells, patients are conditioned with chemotherapy and/or radiation. High-dose conditioning is always used in autologous transplants. In allogeneic transplants, the type and dose of the conditioning depends on the stage and type of disease, whether it is a recurrence and the condition of the patient. Step 4: Infusing the stem cells When the patient is ready, the stem cells are infused into the patient’s bloodstream through a needle inserted into a vein in one arm. The infused cells travel through the bloodstream, pass through the bones and implant themselves in the marrow. There, they slowly begin to make healthy new cells. Over time, the marrow produces enough healthy cells to completely


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restore the patient’s blood and immune system. Until these new cells are created, patients are more susceptible to infections. For more information on transplantation, please visit the National Marrow Donor Program’s website at marrow.org.

Novel Targeted Agents Monoclonal Antibodies Plasma cells, the most mature B-cells in the body, are white blood cells that specialize in making antibodies. Each plasma cell is responsible for one antibody, otherwise known as a monoclonal antibody (MAb). Each MAb acts specifically against a particular antigen, which is like a beacon that attracts antibodies and immune cells. Scientists can now produce large amounts of antibodies that can be directed to a specific antigen on the cell’s surface. A MAb is similar to a guided missile that homes in on a target (an antigen) on the lymphoma cell and destroys the cell. A number of strategies involving the use of MAbs to treat cancer are being studied, including (a) MAbs that react with specific types of cancer cells, thereby enhancing a patient’s immune response to the cancer; (b) MAbs that are combined with other anticancer toxins or radioisotopes, allowing the delivery of radiation therapy, toxins or radiation directly to the tumor and bypassing toxicity to most normal cells; and (c) MAbs that are used to help purge and destroy cancer cells before a patient’s stem cells are reinfused in autologous bone marrow transplantation.

Rituximab (Rituxan) Rituximab (Rituxan) was the first monoclonal antibody approved for cancer therapy by the US Food and Drug Administration (FDA) as a single agent in the treatment of relapsed or refractory lymphoma patients with CD20 positive, B-cell non-Hodgkin lymphoma. This drug targets the CD20 antigen found on the surface of almost all B-cells. Rituximab (Rituxan) is now FDA approved for the treatment of patients with the following:


• relapsed or refractory, low-grade or follicular, CD20-positive, B-cell NHL as a single agent • previously untreated follicular, CD20-positive, B-cell NHL in combination with CVP chemotherapy • non-progressing (including stable disease), low-grade, CD20-positive, B-cell NHL, as a single agent, after first-line CVP chemotherapy • previously untreated diffuse large B-cell, CD20-positive NHL in combination with CHOP or other anthracycline-based chemotherapy regimens Rituximab (Rituxan) is currently approved in Europe for the frontline treatment of CLL. However, the US FDA approval to use rituximab (Rituxan) in CLL is pending review. Ongoing research is exploring the effectiveness of using rituximab (Rituxan) in combination with chemotherapeutic agents, such as fludarabine (Fludara), in the treatment of CLL. Because rituximab (Rituxan) has been found to have a very favorable toxicity profile, it has been found to not enhance the toxicity of existing chemotherapy regimens. For this reason, rituximab (Rituxan) is now being integrated into virtually every chemotherapy regimen and new drug for the treatment of B-cell malignancies. For example, the addition of rituximab (Rituxan) to CHOP chemotherapy was found to markedly enhance the overall cure rate of CHOP chemo in patients with diffuse large B-cell lymphoma. Similarly, the addition of rituximab (Rituxan) to fludarabine (Fludara) has been found to markedly improve the effectiveness of fludarabine (Fludara) alone in indolent lymphomas, such as follicular lymphoma and CLL. As additional new drugs are approved by the FDA, one common strategy to improve these new found therapies is to evaluate them over time in combination with r to improve the efficacy of these new agents (e.g., bendamustine-rituxan). Ongoing clinical trials will continue to evaluate the safety profile of adding rituximab (Rituxan) to both FDA approved as well new agents yet to be approved by the FDA.


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Alemtuzumab (Campath) Alemtuzumab (Campath), which targets the antigen CD52, was the first US Food and Drug Administration (FDA) specifically approved for the treatment of chronic lymphocytic leukemia (CLL). It works very well in patients in whom the CLL cells are confined to blood and bone marrow. It does not appear to work alone very well in patients with bulky lymph nodes or spleen. However, in these situations, it has been used successfully in combination with other MAbs like rituximab (Rituxan) or with chemotherapy. Alemtuzumab (Campath) may increase susceptibility to certain viral (e.g., cytomegalovirus reactivation; CMV), fungal and bacterial infections, and it is mandatory to use medications to prevent these infections while on this drug. Alemtuzumab (Campath) is also being tested in T-cell lymphoma.

Ofatumumab (Arzerra) Ofatumumab (Arzerra) is another monoclonal antibody that targets the CD20 antigen, which is found on the surface of chronic lymphocytic leukemia (CLL) cells. The Food and Drug Administration (FDA) granted the accelerated approval of ofatumumab (Arzerra) for the treatment of patients with CLL whose disease is refractory to fludarabine (Fludara) and alemtuzumab (Campath) in fall 2009. Unlike other monoclonal antibodies, ofatumumab (Arzerra) binds to a specific part of the CD20 protein on the surface of cells called the small loop epitope. This drug kills cells by recruiting proteins called “complement,” that lead to tumor cell death. It also induces antibody dependent cellular cytoxicity (ADCC) by recruiting the body’s immune system to kill the CLL cells. This drug is presently being studied in patients with other B-cell malignancies.

Immunoconjugates The ability to link potentially toxic drugs or radioactive agent to MAbs offers a unique opportunity to target an otherwise toxic agent specifically to tumor cells. This strategy involves the development of immonoconjugates which have the added benefit of sparing normal tissues from exposure to these otherwise very toxic therapeutic agents. To date, a variety of immunoconjugates have been developed, including


radioimmunoconjugates, which involve the linking of a radioisotope to the backbone of a MAb (i.e., Bexxar and Zevalin) and immunotoxin conjugates that conjugate specific proteins or other small molecules to a MAb which bring the toxic drug in close proximity to the tumor cell and allow for high efficiency killing of the tumor without the significant toxicity that would be seen if the small molecule was given by itself.. Examples include denileukin diftitox (Ontak) and inotuzumab ozogamicin (CMC-544).

Radioimmunotherapy Radioimmunotherapy involves the attachment of a radioactive molecule to a monoclonal antibody. This therapy delivers radiation directly to lymphoma cells that express the CD20 antigen on their surface. Currently, two radioimmunotherapy drugs are commercially available and continue to be further examined in clinical trials. These include ibritumomab tiuxetan (Zevalin) and tositumomab (Bexxar). Researchers agree these therapies have high activity in patients with indolent and some transformed lymphomas, including those with relapsed disease. Ongoing studies are examining the effectiveness of using combination chemotherapy with a monoclonal antibody versus a radioimmunotherapy agent. There are also other agents (which are directed against targets other than CD20) in clinical trials. The two currently available therapies are more similar than different. Both therapies require specific imaging tests and the administration of a “dosimetric dose” before giving the therapeutic dose that actually treats the lymphoma. Treatment for both drugs is completed in approximately one week. While some scheduling and side effect differences exist between the two products, the basic premise of this treatment includes imaging tests, two injections of the radioimmunotherapy agent and a close monitoring of blood counts for some time thereafter. Patients receiving radioimmunotherapy should speak with their physician about the specific safety precautions associated with this treatment. Because small amounts of radiation may be present in body fluids, such as blood and urine, it may be recommended that for a few days after treatment patients slightly modify their activities with respect to contact with others.


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• Ibritumomab tiuxetan (Zevalin): Ibritumomab tiuxetan (Zevalin) combines the cell targeting ability of the monoclonal antibody rituximab (Rituxan) with the additional killing ability of the radioisotope yttrium-90. This drug was originally approved in 2002 by the US Food and Drug Administration for the treatment of patients with relapsed (disease returns after treatment) or refractory (disease does not respond to treatment), low-grade or follicular B-cell non-Hodgkin lymphoma. In fall 2009, ibritumomab tiuxetan (Zevalin) received expanded label approval from the FDA for the treatment of patients with previously untreated follicular non-Hodgkin lymphoma (NHL), who achieve a partial or complete response to first-line chemotherapy. •T ositumomab (Bexxar): Tositumomab (Bexxar) uses a radioisotope called Iodine-131 attached to a monoclonal antibody called tositumomab. This drug is FDA approved for the treatment of patients with relapsed or refractory, low-grade or follicular B-cell non-Hodgkin lymphoma.

Denileukin Diftitox (Ontak) Denileukin Diftitox (Ontak) is a targeted therapy referred to as a “fusion toxin.” This molecule combines the interleukin-2 receptor with a diphtheria toxin. When this drug targets and binds to the interleukin-2 receptor on the surface of a cell, it releases the toxin. This toxin then interrupts protein synthesis within the cell and leads to cell death. Dinileukin diftitox (Ontak) is approved by the FDA for the treatment of cutaneous lymphomas and is currently under investigation in other forms of NHL, including CLL.

Proteasome Inhibitors Nearly all cells in the body continually break down their own protein components to remove improperly made or damaged proteins and to control cell growth and other vital processes. The “cellular disposal” system which handles these proteins is called the “proteasome.” In this form of cellular housekeeping, the proteasome cuts up protein molecules that are no longer needed by the cell. Recently, physicians and scientists have learned that certain cancer cells are particularly vulnerable to a new class of molecules called proteasome inhibitors.


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Bortezomib (Velcade) Bortezomib (Velcade), a therapy first approved for a type of blood cancer called multiple myeloma, was the first drug of this type approved to treat cancer. Bortezomib is a relatively selective and reversible inhibitor of the proteasome, which means that exposure to the drug is necessary for its activity. This drug has been approved for relapsed mantle cell lymphoma and is currently being tested as a therapy for follicular lymphoma. The major side effect of the drug that limits its use in many patients is neurotoxicity. (For a listing of other proteasome inhibitors currently under investigation, see page 98.)Recent studies with bortezomib (Velcade) have also demonstrated that inhibiting the proteasome appears to complement many conventional chemotherapy agents to treat lymphoma in a synergistic fashion. These data have now led to the development of novel chemotherapy platforms (e.g., R-CHOP-Velcade, RC-Velade-P; RCHVelcade-P) for the treatment of both aggressive and indolent lymphomas. Presently available data seems to suggest that the integration of bortezomib (Velcade) into these combination chemotherapy regimens may be very active in patients whose disease has become resistant to otherwise conventional chemotherapy agents. Clearly the future use of proteasome inhibitors, including bortezomib (Velcade) and other agents with more favorable toxicity profiles, will be dependent upon their activity in combination with other conventional chemotherapy active drugs.

Histon Deacetylase Inhibitors (HDAC) Histone deacetylase inhibitors, referred to as HDAC inhibitors, are a new kind of drug that interferes with a process within cells known as acetylation and deacetylation. These reactions (acetylation and deacetylation) are known to influence the activation or inactivation of many genes inside tumor cells. Some of these genes, as well as proteins affected by acetylation and deacetylation, can influence the growth and survival of lymphoma and other cancer cells. Some HDAC inhibitors have been found to affect genes and proteins involved in the cell cycle arrest and cell death of lymphoma cells. Targeting these pathways in the treatment of cancer is an important new strategy. Although the understanding of how these drugs work in specific cancers cells is still early, learning how to best modulate those genes and proteins involved in the development of cancer is a focus of current research and many new treatment approaches. Treating Non-Hodgkin Lymphoma 55

Vorinostat (Zolinza) Vorinostat (Zolinza) is the first treatment in this category to be approved for lymphoma. Vorinostat (Zolinza) was approved for the treatment of cutaneous T-cell lymphoma and is now being investigated in many other forms of NHL. Some recent exciting developments with vorinostat (Velcade) have shown that it potently synergizes with proteasome inhibitors, such as bortezomib (Velcade), and is now being studied in large international randomized studies with patients with multiple myeloma, mantle cell lymphoma and the T-cell lymphomas.

Romidepsin (Istodax) Romidepsin (Istodax) was approved in the fall of 2009 for the treatment of cutaneous T-cell lymphoma in patients who have received at least one prior systemic therapy. Romidepsin (Istodax) is now under review for the treatment of peripheral T-cell lymphoma. Like vorinostat (Zolinza), romidepsin (Istodax) has also been found to synergize with proteasome inhibitors and combination chemotherapy regimens and is now being studied in many phase I and phase II settings in combination with other drugs known to be active in the treatment of lymphoma.

Newer Versions of Established Agents Scientists continuously examine new uses for established agents and also explore how to create newer versions of existing therapies to make them more effective and less toxic. The two drugs below represent therapies recently approved in the United States.

Bendamustine (Treanda) Bendamustine (Treanda) is a novel alkylating agent that damages the DNA in tumor cells, thereby disrupting the cell cycle and causing cell death. Approved originally for clinical use in Germany for cancer, the US FDA approved bendamustine (Treanda) in 2008 for the treatment of indolent B-cell NHL that has progressed during or within six months of receiving rituximab (Rituxan) or a rituximab-containing regimen. It has also been approved to treat chronic lymphocytic leukemia (CLL), both in front-line as well as for previously treated patients. Data from randomized controlled trials in Europe suggest that a combination of rituximab


(Rituxan) and bendamustine (Treanda) may have a more favorable toxicity profile and equivalent or better efficacy in patients with indolent and mantle cell lymphoma who have been treated with other combination chemotherapy regimens such as R-CVP and R-CHOP. The implications of this data indicate that this two drug combination regimen may find a solid place among the available choices for treatment of NHL and CLL. Future clinical trials will continue to study bendamustine (Treanda) in combination with many of the new exciting drugs as discussed in Chapter 14.

Pralatrexate (Folotyn) In fall 2009, the US Food and Drug Administration approved pralatrexate (Folotyn) for the treatment of patients with relapsed (disease returns after treatment) or refractory (disease does not respond to treatment) peripheral T-cell lymphoma. Pralatrexate (Folotyn) belongs to a class of chemotherapy drugs called anti-folates. It is different than other anti-folates, like methotrexate, in that pralatrexate (Folotyn) selectively accumulates in certain tumor cells. Given that this is the first drug approved for peripheral T-cell lymphomas, there is a lot of interest in combining pralatrexate (Folotyn) with other drugs to treat people with various types of lymphoma. Studies that are ongoing or planned include combinations with gemcitabine (Gemzar), HDAC inhibitors and proteasome inhibitors.

Interferon Interferon alfa (Intron A, Roferon-A) is a protein produced naturally by the body to help fight infection and cancer cells. Interferon alfa (Intron A, Roferon-A) and is approved for the treatment of certain forms of NHL. Scientists and physicians believe that interferon alfa (Intron A, Roferon-A) probably kills tumor cells directly and may also stimulate the normal host immune system to eradicate malignant cells. Some oncologists recommend administration of interferon alfa (Intron A, Roferon-A) as maintenance therapy for patients who are in remission after treatment with chemotherapy and for patients with cutaneous T-cell lymphoma. Most studies to date show some improvement in the length of remission with minimal improvement in survival. The most common side effects of interferon alfa (Intron A, Roferon-A) therapy are flu-like symptoms, including fever,


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weakness, tiredness and muscle and joint aches. These side effects have limited the drugs use by physicians in the United States. To reduce the impact of these flu-like symptoms, physicians may recommend injecting interferon alfa (Intron A, Roferon-A) shortly before bed, drinking a lot of nonalcoholic and non-caffeinated fluids to stay well hydrated and, if your physician recommends, taking nonprescription pain relievers such as acetaminophen or ibuprofen. Interferon alfa (Intron A, Roferon-A) can sometimes cause depression, which may be severe. Patients should speak with their physician if they become depressed while taking interferon alfa (Intron A, Roferon-A). Uncommon side effects include a diminished appetite, an aversion to food (anorexia) or a decrease in thyroid function. Questions to Ask Before Undergoing Radiation Therapy • What is the goal of my radiation? • How will radiation be given? • When will treatments begin? • When will treatments end? • How will I feel during therapy? • What can I do to take care of myself during and after therapy? • How will we know whether the radiation is working? • How will radiation treatment affect my normal activities? • What are the side effects of radiation?

Complementary and Alternative Remedies The concept of holistic medicine to treat the mind, body and spirit became popular in the 1970s and is commonly known today as complementary and alternative medicine, but the terms have distinctly different meanings. Alternative therapy refers to unproven or disproven treatments that are used instead of standard or proven therapy. Currently, there are no viable alternative therapies to conventional cancer care, and NHL patients should never use alternative remedies in lieu of standard care. Complementary therapy may be considered in addition to standard medicine to help improve a patient’s quality of life and to relieve the effects of chemotherapy, radiation and surgery.


Complementary therapy, also known as integrative medicine, includes a vast array of mind/body therapies, such as meditation, guided imagery, self-hypnosis, tai chi and yoga; touch therapies such as massage, reflexology and Reiki; acupuncture; and nutrition. However, because even some complementary practices, such as ingesting certain herbs or botanicals, may negatively impact cancer treatment, NHL patients should consult with their healthcare team before embarking on any integrative medicine plan.

How Integrative Medicine Helps • Acupuncture—Some studies show that acupuncture may relieve pain, nausea, fatigue, hot flushes and neuropathy (numbness and tingling in the feet and hands) associated with chemotherapy and may help decrease mild depression. Using ultra-thin needles applied to specific points on the body, acupuncture is safe and painless. Needles used should be disposed of and only used once. • Mind/Body techniques—Meditation, guided imagery and self-hypnosis are all methods used to manage stress. Yoga and Tai chi minimize stress and improve balance and flexibility. • Touch therapies—Massage, reflexology (foot massage) and Reiki involve applying therapeutic pressure to the body to restore a sense of harmony, relaxation and well-being. Studies suggest that massage may lessen pain. • Nutrition—For patients undergoing treatment, it is recommended that they eat a healthy, well-balanced diet that contains five to seven servings of fruits and vegetables a day, fish or poultry and whole grains. Adding nutritional supplements to the diet may also be beneficial.

What to Avoid Dietary supplements such as multivitamins; high doses of vitamins like C, E and folic acid; and antioxidant-rich drinks like green tea, cranberry and pomegranate juice can interfere with cancer treatment and may actually increase the growth of cancer cells in some patients. Botanicals and herbs like ginkgo biloba may in some instances increase bleeding disorders and either increase or reduce the effectiveness of chemotherapy drugs.


Questions to Ask Your Doctor • Am I a candidate for integrative medicine? • What types of integrative medicine would be most beneficial for me? • How much physical activity should I have each day? • What food and drinks should I avoid?

Drug Costs: What to Do if Your Insurance Does Not Pay Many cancer patients today face the problem of how to pay for soaring healthcare costs. Cancer organizations like the Lymphoma Research Foundation (lymphoma.org) and CancerCare (cancercare.org) offer limited financial assistance to patients who qualify. Most pharmaceutical companies have patient assistance programs in place that provide drugs for free to qualifying patients. If you are in need of financial assistance, talk with your doctor about available options and how to enroll in an appropriate program. Before undergoing a medical procedure, check with your insurance carrier to ensure that it is covered. If there is a dispute about coverage or if coverage is denied, ask your insurance carrier about its appeals process. If you are unsuccessful, contact your state’s department of insurance to file an appeal.

When to Consider a Clinical Trial Contrary to what many cancer patients may believe, participating in a clinical trial is not an indication that they have run out of standard treatment options, that it is their last chance for survival or that they are “guinea pigs.” The purpose of a clinical trial is to safely monitor the effects of a new drug on patients over time and to identify more effective therapies for specific diseases. In fact, development of new therapies is solely dependent on the clinical trial process. Participation in a clinical trial is especially crucial for lymphoma patients, because NHL comprises a group of rare diseases, and it is often difficult to find enough patients to enroll in the studies. If you are interested in participating in a clinical study, ask your doctor if there is an appropriate trial for you and what the potential risks and benefits may be. (See Chapter 13.)


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Part 3: Treatment Side Effects

Chapter 6

Coping With Common Treatment Side Effects Non-Hodgkin lymphoma patients may experience a range of side effects, also called toxicity, from the cancer treatment they receive. The various treatments, including chemotherapy, radiation, steroids and surgery, cause different side effects. Fortunately, there are many effective ways to make them more tolerable. Patients should ask their healthcare team about possible treatment side effects and inform the physician if they experience any. In many cases, side effects can be lessened with medications or lifestyle changes.

Side Effects Caused by Chemotherapy Chemotherapy is generally most effective at killing cells that are dividing rapidly, such as cancer cells. However, chemotherapy drugs are not selective. Therefore, they can also affect normal healthy cells, especially cells that are fast-growing, such as hair cells and those in the mouth, the

Treatment Side Effects 61

gastrointestinal tract and the bone marrow. Some chemotherapy drugs may also damage heart cells. Side effects of chemotherapy can vary widely depending on the types of drugs that are given and an individual patient’s response. Side effects can be mild or serious. Some of the most common side effects caused by chemotherapy include the following: Some Common Side Effects Caused by Chemotherapy • Cardiotoxicity

• Hair loss

• Changes in taste

• Mouth sores


• Nausea/vomiting

• Risk of infections


• Diarrhea

• Sterility

• Fatigue

Cardiotoxicity Cardiotoxicity (damage to the heart or heart muscle) from standard chemotherapy drugs has been well documented in the treatment of solid tumor cancers. However, less is known about the late effects of chemotherapy on non-Hodgkin lymphoma patients because there are so many different subtypes of the disease and treatment cycles are not the same. For example, the majority of patients with diffuse large B-cell lymphoma may only need to be treated with chemotherapy once, therefore, their risk for developing chemotherapy-related cardiovascular disease is small. Conversely, NHL patients with indolent, or slow-growing, lymphoma may need multiple treatments over the course of many years, raising their risk for developing cardiotoxicity. In general, cardiac drugs used in NHL regimens are kept within the safe or “acceptable” range, where cardiac toxicity is usually not encountered. Lifestyle can also impact a patient’s risk for cardiotoxicity. For example, previous heart disease, smoking, obesity, lack of exercise, high cholesterol and high blood pressure may all contribute to chemotherapy-related or radiation-related cardiotoxicity. Careful monitoring by your healthcare team can reduce your chances for developing cardiotoxicity. Most doctors will prescribe either an 62 Understanding Non-Hodgkin Lymphoma

echocardiogram or a MUGA (multiple gated acquisition) scan, which measures cardiac function, before cardiac toxic chemotherapy begins. This will ensure that the chemotherapy dose is well within the range considered heart safe.


Decreased Blood Cell Production Red blood cells, white blood cells and platelets are constantly being produced in the bone marrow. Both chemotherapy and chemoimmunotherapy treatment may temporarily interfere with the ability of the bone marrow to produce adequate numbers of blood cells. When this occurs, it is called myelosuppression. Anemia is the term used when myelosuppression causes a reduction in the number of red blood cells. Anemia can cause people to feel very tired and have shortness of breath. Mild or moderate anemia is common with many chemotherapy regimens, and treatment for the anemia may be necessary. Neutropenia is the term used when myelosuppression causes a decrease in neutrophils—the primary type of white blood cells found in the blood. Because neutrophils play a very important role in fighting infection, a low count may cause patients to develop serious or even life-threatening infections that require hospitalization or antibiotic therapy. Also, if the absolute neutrophil count (ANC) is too low, the chemotherapy dosage may need to be reduced or treatment delayed rather than risk infection. Infection is often accompanied by fever. Other symptoms of infection may include chills and night sweats. To prevent and control neutropenia, physicians will check patients’ white blood cell and neutrophil counts before and during each chemotherapy


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cycle. When neutropenia threatens a patient’s ability to receive the planned dose of chemotherapy, drugs such as filgrastim (Neupogen), pegfilgrastim (Neulasta) or sargramostim (Leukine) can be given after chemotherapy to reduce the duration and severity of neutropenia. These drugs can sometimes cause bone pain and, if in the chest, may make patients think they are having a heart attack. Nonsteroids may relieve this pain rapidly. By keeping the white blood count from dipping too low, these medications can help keep chemotherapy doses on schedule. Occasionally, oral antibiotics are given to help prevent infection when neutrophil counts are low. Thrombocytopenia is the term used when myelosuppression depletes the number of platelets in the blood. Platelets help start the clotting process when bleeding occurs. If platelet counts are low, patients may bruise easily. A low platelet count may also cause prolonged or excessive bleeding from cuts, nose bleeds, bleeding from the gums or bleeding without a previous injury. A platelet transfusion may be needed in some cases.

Risk of Infections A normal white blood cell count ranges from 4,000 to 10,000. Physicians regularly monitor the absolute neurtophil count (ANC), the number of neutrophils in the peripheral blood. When the ANC drops below 1,500, patients are at high risk for contracting infections. If a fever of 100.5°F or greater develops, patients should immediately contact their physician or go to the emergency room.

Tips for Detecting Infection Due to Low Blood Cell Production • Fever (greater than 100.5°F)

• Diarrhea

• Sore Throat


• Rash

• Cough


Diarrhea Diarrhea can be a side effect of chemotherapy. While most patients do not experience severe diarrhea, the most important thing to remember is to avoid dehydration (a loss of body fluids). Patients should report bloody diarrhea or fever with diarrhea to their healthcare team.

Fatigue Fatigue is a common side effect of many types of chemotherapy. Fatigue should go away after treatments are over, but it can take weeks or months until it is completely gone.

Hair Loss One side effect of chemotherapy is hair loss (also called alopecia). Thinning or loss of hair can occur at any place on the body, including the scalp, eyebrows, eyelashes, arms, legs and pelvis. The hair loss may be variable. It is important to note that hair loss does not occur with all drugs. Remember that hair loss due to chemotherapy is usually temporary. At first, the new hair growing in may be a slightly different texture or color than it was before treatment, but it oftens returns to normal. Tips for Avoiding Dehydration From Diarrhea or Vomiting • Drink plenty of liquids (eight glasses a day) of not just water, but electrolyte replacement drinks as well (e.g., Gatorade, Powerade). • Look for signs of dehydration, including dry mouth or skin, decreased urine and dizziness or lightheadedness when you stand up. • Avoid milk products, which can worsen diarrhea. • Avoid hard-to-digest foods, such as those with high fiber, which can worsen diarrhea. • Eat plenty of bananas and other high-potassium foods (check with your physician or dietitian to make sure these foods will not interfere with your chemotherapy or other medications you are taking). • Take the medicines that your doctor recommends to control diarrhea (notify your healthcare team if diarrhea occurs).


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Mouth Sores The membranes of the mouth may become red, sore or irritated during chemotherapy, which is referred to as mucositis. Infections of the mouth and throat caused by viruses or fungi may also occur. If throat soreness

Tips for Coping With Fatigue • Keep a diary to help you keep track of when you have the most energy and which activities make you feel fatigued or give you energy. This can help you plan your activities for the times when you have the most energy. • Ask for help. This may be difficult for many people. Accept help if someone offers to assist you or if you need something you do not have the energy to do for yourself. Many family members or friends are happy to give assistance. • Exercise if your doctor says it is okay to do so, but do not overdo it. Simple stretching, range-of-motion exercises or a short walk may give you more energy and not decrease the energy you have. Begin slowly and build up to the level that is right for you. Your doctor, nurse or physical therapist can help you create a personal exercise plan. • Rest and sleep during therapy are very important, but try not to rest more than necessary because it may decrease your energy level. Many patients find that taking an afternoon nap leaves them feeling less fatigued for the rest of the day, but others find that napping causes less restful nighttime sleep. If you are having trouble sleeping, talk to your healthcare team to determine the reason and what you can do about it.

Tips for Caring for Hair Loss These steps can help alleviate chemotherapy-induced hair loss: • Pat your hair dry rather than rubbing it with a towel after shampooing. • Use a soft-bristle brush and a wide-tooth comb when fixing your hair. • Avoid curlers and hair dryers. • Avoid coloring your hair or using chemicals on it. • Some patients use a wig, scarf, turban or soft cotton hat or head wrap. Some health insurance companies cover the cost of wigs with a prescription from your doctor. Check your policy to see if you are covered. • Use a hat or scarf to protect your scalp when out in the sun.


occurs, the healthcare team will examine the throat and may do a swab (called a culture) to check for infection, particularly herpes, fungus and bacterial infections. If an infection is present, several medications are available to treat it. To help reduce the risk of mouth infections, a physician may request a complete dental checkup and cleaning before receiving chemotherapy.

Nausea or Vomiting Chemotherapy can cause nausea or vomiting. Drugs that prevent vomiting (called antiemetics) include aprepitant (Emend), ondansetron (Zofran), granisetron (Kytril), metoclopramide (Reglan), prochlorperazine (Compazine) and dolasetron (Anzemet), and a variety of


Tips for Controlling or Minimizing Nausea and Vomiting • Consume a liquid diet before chemotherapy such as broth, consommé or water. Avoid milk. • Avoid foods that are too hot or too cold and too sweet or too spicy. • Eat smaller and more frequent meals rather than a few large meals each day. • Avoid strong or offensive odors. Get plenty of fresh air. • Take prescribed antiemetics before chemotherapy to prevent nausea. • If vomiting occurs, be careful to avoid dehydration (loss of body fluids).


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corticosteroids, such as Deltasone (prednisone). Nausea most frequently occurs on the day chemotherapy is administered, but it can also start several days later. Physicians may prescribe an antiemetic before chemotherapy to prevent nausea. In most cases, antiemetics can partially or completely prevent nausea and vomiting.

Sexual Dysfunction Chemotherapy can cause a drop in libido (sex drive). Usually, a normal libido returns after treatment is finished. (See Chapter 7.)

Sterility Chemotherapy (and radiation) can sometimes cause either temporary or permanent sterility (the ability to have children) in both men and women, because the treatment may damage sperm and egg cells. The specific dose of treatment, whether the patient has received one or several therapies and the patient’s age at the time of treatment are all contributing factors to infertility side effects. Patients should speak with their physicians about fertility presevation before starting treatment. (See Chapter 8.)

Other Possible Side Effects Some of the other possible side effects of chemotherapy include cough, a decrease in lung function, skin rashes and general weakness. Some drugs may also cause damage to the nervous system called peripheral neuropathy. Nerve damage can cause side effects such as constipation or a tingling sensation in the fingers and toes. Patients should immediately report any painful local rash (which sometimes may be accompanied by blisters) to their physician. Other possible side effects include a sore throat and a loss of balance or coordination. Although many of these effects are temporary, some may last for an extended period.


Side Effects Caused by Radiation In NHL, radiation therapy (or radiotherapy) is sometimes used to shrink an enlarged spleen or swollen lymph nodes, eliminating symptoms stemming from those growths. Radiation therapy uses an invisible radioactive ray or beam of high-energy particles aimed at specific sites to kill cancer cells. While radiotherapy is painless, there are side effects associated with the treatment. The consequences of radiation therapy depend on the treatment dose, the part of the body being treated (usually side effects occur only in the specific area of the body being radiated) and the age of the patient, among other factors. Some common side effects caused by radiation therapy in NHL patients include: • Fatigue • Nausea • Skin reactions • Long-term and late effects Radiation may also cause a drop in the number of white blood cells, which help protect the body against infection. Therefore, white blood cells will be monitored during treatment.

Fatigue The likelihood that patients will experience fatigue depends on their disease and the specific radiation plan. (See page 66 for tips on overcoming fatigue.)

Nausea Nausea may occur after radiation treatment, especially in patients who have radiation to the abdomen. Some people can avoid nausea if they eliminate eating (especially sweet, spicy or fatty foods) a few hours before radiation treatment. Taking a medication that prevents nausea (an antiemetic) before each radiation therapy session may be recommended. (See page 67 for additional tips regarding coping with nausea and vomiting.)


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Skin Reactions Radiation can cause a slight to moderate reddening of the skin and is often accompanied by discomfort, itching and flaking. These skin changes usually diminish and disappear over a few weeks. During radiation treatment, patients can protect their skin by: • Avoiding exposing areas of the skin that are receiving radiation to the sun. These areas will always need extra protection, even after treatment is completed. • Wearing a T-shirt and using plenty of sunscreen (with a high SPF) when out in the sun.

Side Effects Caused by Steroids Steroid drugs, such as cortisone, dexamethasone and prednisone, may cause a variety of side effects, including insomnia (the inability to fall asleep), increased appetite, mood or personality changes, high blood pressure and weight gain. Prednisone may also trigger diabetes in patients prone to that disease or make the diabetes worse in patients who already have the disease. High-doses of steroids may also cause osteoporosis in at-risk patients. Patients are advised to alert family and friends that personality changes may occur. Patients should avoid making hasty decisions. If personality changes occur, the physician should be informed— the dose may need to be reduced.

Side Effects Caused by Rituximab and Other Biological Therapies Although side effects caused by biological therapies vary according to the specific type of treatment, they usually occur during treatment administration and may include flu-like symptoms such as chills, fever, muscle aches, weakness, loss of appetite, nausea, vomiting and diarrhea. Rituximab (Rituxan) reduces immunoglobulin levels, particularly when given as maintenance. As a result, some patients may experience an increase in infection, particularly sinusitis and upper respiratory infections, which may prove more difficult to treat and sometimes require gammaglobulin.


Side Effects Caused by Bone Marrow or Stem Cell Transplantation Patients receiving high doses of chemotherapy and radiation before undergoing a stem cell transplant may be at increased risk for developing infection, bleeding and other side effects. In addition, patients receiving stem cells from a donor are at risk of developing graft versus host disease (GVHD), a condition where the donated marrow attacks the patient’s tissues. Graft versus host disease can occur at any time after the transplant. Drugs may be given to reduce the risk of developing GVHD or to treat the problem once it develops.

Side Effects Caused by Surgery Although surgery is used primarily to make a diagnosis, there are instances when surgery is used to treat NHL. Side effects caused by surgery depend on several factors, such as the location of the tumor, the type of operation and the patient’s general health. Pain is a common side effect after surgery but is easily controlled with medication. It is also common to feel tired or weak following surgery. How long it takes to recover from surgery varies from patient to patient.

Combating Side Effects Pain Management Pain may result from treatment. For example, pegfilgrastim (Neulasta), given to stimulate white blood cells, may cause bone pain. Pain may also occur as a result of procedures or tests (such as bone marrow biopsy). Pain may be acute (comes on quickly) or chronic (lasts over a long period of time). Living with pain can have a negative effect on overall quality of life. However, many medical advances have been made in the treatment of pain, including an improved understanding of how medication works to relieve it. Many healthcare teams now include pain specialists. Several techniques, such as relaxation, guided imagery and biofeedback, may also relieve pain. Keeping a journal of when pain occurs, what it feels like


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when to call or see your physician Your physician or a member of your healthcare team will discuss possible treatment side effects with you prior to initiating therapy. If you experience a side effect that is not expected or if your complications are prolonged, see your physician. If you experience a medical problem that cannot wait for a regularly scheduled appointment, such as high fever, shortness of breath, unremitting nausea and vomiting, chest pains and dizziness, call your physician, who will evaluate your situation and decide your next course of action. If you cannot reach your physician or a member of your medical team, go to your hospital emergency room for a medical assessment and place another call to your physician.

(sharp, throbbing, etc.), how strong it is and how long it lasts will help physicians develop the most appropriate pain management plan. For more information on managing pain, visit the American Pain Foundation’s website at painfoundation.org.

Exercise Regular physical activity helps keep the cardiovascular system strong and body muscles flexible. Exercise can also help alleviate breathing problems, constipation, poor appetite and mild depression. It also helps reduce stress and fatigue. Several types of exercise are particularly helpful: • General physical activity, such as swimming, dancing, mowing the lawn • Aerobic activity to improve cardiovascular fitness, such as walking, jogging, bicycling • Resistance training to strengthen muscles, protect joints and help remedy osteoporosis by building bone mass, such as lifting weights or using resistance-training equipment, push-ups, carrying and lifting • Flexibility practices to improve range of motion, balance and stability, such as stretching and yoga Patients should consult their physician before starting an exercise program.


Diet Eating a healthy diet is important during NHL treatment. Nutritionists specializing in oncology care can be helpful in developing individualized nutrition plans. Patients should consult their physician before taking dietary supplements such as multivitamins or individual vitamin supplements because they may interfere with treatments.

The Difference Between Long-Term Effects And Late Effects Long-term effects are defined as toxicities that happen during cancer treatment and continue for months or several years, such as fatigue, menopausal symptoms and cardiovascular problems. Late effects are side effects of cancer treatment that become apparent only after treatment has ended and may arise many months, years or even decades after treatment is completed, such as infertility, osteoporosis and secondary cancers, such as lung cancer. In general, chemotherapy tends to cause more long-term side effects than late effects in NHL survivors, and radiation usually causes more late effects. There is evidence, however, that the combination of doxorubicin (Adriamycin) and radiation, especially when the radiation is directed to the chest area, may result in late effects to the heart, causing a decrease in cardiac function and accelerated atherosclerosis in which plaque builds up on the inside of the arteries. (See “Cardiotoxicity”, page 62).


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lymphoma.org


Chapter 7

Sexuality

3

Sexual Function During Treatment The causes of sexual dysfunction experienced by men and women during and after a cancer diagnosis are varied. Psychological factors, such as fear about illness, altered body image due to hair loss and depression, and the physical side effects of treatment, can all conspire to reduce sexual desire (libido) and function. Besides fatigue, some chemotherapy treatments can interfere with testosterone levels in men, resulting in low libido. In women, decreased estrogen production may cause vaginal dryness, hot flashes and other menopausal symptoms. In women, radiation therapy to the pelvis can cause a narrowing of the vagina, painful intercourse and ovarian failure, resulting in infertility. (See “Fertility Risks,” on page 77.) Some antidepressants and over-the-counter medications also lower sexual desire, as do certain lifestyle choices, such as smoking and drinking. Be assured that the lack of sexual desire and function due to treatment is usually temporary. Although many people are often too embarrassed to raise the issue of sexual function with their physician, it is important to recognize that sexuality is an integral part of life and patients should discuss this with their physician. Physicians may order tests to track hormone levels and make recommendations to see a specialist and/or prescribe medications to restore erectile function in men and hormone therapy to alleviate vaginal dryness and other menopausal symptoms in women.

When to Use Contraceptives Lymphoma is not a contagious disease, and it cannot be caused by or transferred through sexual intercourse. However, because small quantities of chemotherapy may be found in semen or vaginal fluid of people undergoing treatment, using condoms is recommended during sexual intercourse. It is especially important for men to use condoms and women to use birth control if they are getting chemotherapy and should be mandatory when taking immunomodulatory drugs, such as thalidomide Treatment Side Effects 75

Questions to Ask Your Doctor About Sexual Function • How will my treatment affect my sexuality? • Will sexual function be restored after my treatment is completed? • How long will it take for sexual function to be restored? • Are there successful treatments for my sexual dysfunction? • What can I do to restore sexual desire and function?

(Thalomid) and lenalidomide (Revlimid), a derivative of thalidomide, which may cause birth defects in developing fetuses. Avoiding pregnancy while on chemotherapy is necessary since chemotherapy drugs may affect the fetus. Women should alert their physician if they suspect they have become pregnant. It is also recommended that people who have undergone stem cell transplants use condoms to reduce their risk for contracting cytomegalovirus and other infections, due to a compromised immune system. To further reduce risk of infection, patients should avoid sexual intercourse if their blood counts (hemoglobin, white blood cells and platelets) are low. Patients should ask their physician when it is safe to engage in sexual intimacy.

Pregnancy and Breast-Feeding During Treatment Women who are undergoing diagnostic procedures or receiving treatments for lymphoma should inform their doctor if there is any possibility that they may be pregnant. Lymphoma diagnosed during pregnancy is problematic, but treatment can often be prescribed that is less likely to harm the fetus. In some types of lymphoma, particularly slow-growing ones, such as follicular lymphoma, it may be possible to wait to treat the disease until the baby is born. Breast-feeding is generally not recommended when a woman is undergoing chemotherapy for lymphoma because of the possibility that the drugs are passed to the child through the mother’s milk. Women of childbearing age should discuss these issues and all possible options with their doctor.


Chapter 8

Fertility Risks

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Treatment for NHL, such as certain types of chemotherapy, especially alkylating agents, and radiation therapy to the pelvic area, can interfere with fertility in several ways. In addition to killing cancer cells, these treatments can also affect healthy cells and reproductive organs like the ovaries and testes, which produce the eggs and sperm crucial to fertility. Whether the infertility is temporary or permanent depends on a number of factors, including the patient’s sex, age at the time of treatment, the specific type and dose of radiation therapy and/or chemotherapy and treatment duration. Patients considering having children in the future should consult their physician before treatment begins. A fertility specialist may also be consulted. The doctor will be able to recommend a counselor or fertility specialist.

How to Protect Fertility in Men Infertility occurs in men when the testes stop producing normal sperm cells. Preserving fertility in men is much easier and more effective than preserving fertility in women. It involves collecting semen and then freezing and storing it in a process known as sperm banking. The sperm can later be thawed and used for intrauterine insemination or in vitro fertilization. For men with low sperm counts, a procedure called testicular sperm extraction (TESE) can be performed in which testicular tissue is removed and the tissue and/or the sperm extracted can then be frozen and stored for later use. Some men who lose fertility immediately following treatment may regain fertility in the future, although the chance of recovering fertility depends on several factors such as age (younger people are more likely to get their fertility back than older people), the amount and duration of radiation to pelvic areas and types of chemotherapy treatments.


How to Protect Fertility in Women Cancer treatment may cause women to enter early menopause or may result in damage that does not allow for a successful pregnancy. Although preserving fertility in women is more difficult than in men, there are several options available to women. The most widely available and successful way of preserving fertility before cancer treatment is by removing eggs, fertilizing them in vitro with the sperm of a spouse or donor and then freezing and storing the embryos for future use (embryo banking). Eggs may also be stored unfertilized (egg banking), although that process is more difficult. Banking and using unfertilized eggs is more difficult, but it is a technique that has been recently developed. Both of these techniques require several weeks of treatment to complete, therefore, they may not be advisable for women needing immediate treatment of their lymphoma. Another fertility preservation method under investigation is ovarian tissue cryopreservation (OTC). Giving injections of the drug leuprolid (Lupron) to halt production of hormonal function before chemotherapy begins may limit ovarian exposure to the treatment, thereby protecting the quality of the eggs, although the drug’s use is highly controversial. Before treatment begins, all women of childbearing age should talk to their doctor and a fertility preservation expert about the options available to them. The following websites are good resources for finding the latest information on fertility preservation techniques: Fertile Hope (Fertilehope.org); Institute for Fertility Preservation (Fertilitypreservation.org); and Myoncofertility.org.


4 Part 4: C hildren and Young Adults With Non-Hodgkin Lymphoma

Chapter 9

General Information Despite the rarity of childhood cancers, scientific investigators have made tremendous advances in its treatment. In 2009, nearly 11,000 new cases of cancer were expected to occur in children between the ages of 0 and 14 years. According to the International Classification of Childhood Cancer, NHL makes up only 4.3 percent of all childhood cancers. The most common types of childhood lymphoma include: • Hodgkin lymphoma • Burkitt’s and Burkitt-like lymphoma • Diffuse large B-cell lymphoma • Lymphoblastic lymphoma • Anaplastic lymphoma While the causes of NHL are unknown, the following may increase the risk of childhood or adolescent NHL: • Family history (although no hereditary pattern has been established) • Autoimmune disease • Receipt of an organ transplant Children and Young Adults With Non-Hodgkin Lymphoma 79

• Exposure to chemicals, such as pesticides, fertilizers or solvents • Infection with viruses, such as Epstein-Barr virus, human T-lymphotropic virus type 1, HIV, hepatitis C or certain bacteria (e.g., H. pylori)

Survival The past three decades have seen a tremendous improvement in the survival rates of childhood cancers, including lymphoma. This upward trend is due to the continuous development of new and improved treatments resulting from successful clinical trial investigations. According to the most recent statistics, the five-year survival rate for children diagnosed with NHL is 86 percent.

Detection The symptoms of NHL are often nonspecific and may mimic the symptoms of other common illnesses. Therefore, parents should ensure that children receive regular medical check ups and report any unusual or persistent symptoms to their child’s physician. Some symptoms of NHL in children include: • Shortness of breath • Trouble breathing • Wheezing • Swelling of the head or neck • Trouble swallowing • Painless swelling of the lymph nodes in the neck, armpit, stomach or groin • Fever for no apparent reason • Weight loss • Night sweats Children suspected of having NHL will undergo similar tests and procedures as adults, which may include a physical exam, blood work, biopsy, X-ray, and CT or PET scan.


Treatment Options Because childhood cancers are so rare, oncologists specializing in these diseases are often located at academic medical centers and affiliated with clinical trials. The majority of children with cancer are treated in clinical trials. High clinical trial enrollment has led to rapid increases in the survival rates of children and teens with cancer over the past several decades. Therefore, patients that are eligible should consider participating in a clinical trial. Common treatment options include chemotherapy, radiation and stem cell transplant. However, compared to adults, children with NHL are often treated with different therapeutic regimens as well as lower doses of chemotherapy. The treatment that is selected depends largely on the type of NHL and the stage of disease.

Coping Getting an NHL diagnosis can be difficult for the child as well as the family. Psychosocial problems, such as social withdrawal, depression and anxiety, may develop, straining relationships with friends and family. Many resources exist to help children, siblings and family members cope with the diagnosis. Some helpful resources include: • National Children’s Cancer Society (nationalchildrenscancersociety.com) • Candlelighter’s Childhood Cancer Foundation (candlelighters.org) • SuperSibs! (supersibs.org)

Important Considerations for Childhood Lymphoma Survivors Childhood lymphoma survivors may be at risk for developing late effects from their NHL treatment. For example, some treatments have been linked to cardiotoxicity, secondary cancers and infertility later in life. Therefore, it is important to review the potential long-term health implications of all treatments being considered with the physician prior to their administration. It is also important for childhood lymphoma survivors to adhere to an appropriate follow-up care plan so that any late effects resulting from their previous NHL treatment can be diagnosed and treated as early as possible.

Children and Young Adults With Non-Hodgkin Lymphoma 81

4

The Children’s Oncology Group (COG) has developed guidelines for screening and managing the late effects of cancer treatment in childhood cancer survivors. To view the guidelines, please visit survivorshipguidelines.org. Patients should discuss these guidelines with their physician to create an individualized care plan based on their personal disease and treatment history.


lymphoma.org


Chapter 10

Special Concerns for Teenagers And Young Adults 4 Individuals diagnosed with NHL as teenagers or young adults may have unique needs, as compared to younger or older individuals. Awareness is growing and a new movement in cancer care has begun. In 2006, the National Cancer Institute and the Lance Armstrong Foundation convened a group of experts and published Closing the Gap: Research and Care Imperatives for Adolescents and Young Adults with Cancer: Report of the Adolescent and Young Adult Oncology Progress Review Group which defined adolescents and young adults (AYAs), those diagnosed between the ages of 15-39, as an “orphaned group” in cancer care and outlined research and practice areas of need. While an individual’s risk of developing lymphoma increases with age, the disease affects people of all ages, including teenagers and young adults. Lymphomas are among the top five most common cancers diagnosed among those 15-39.

Specific Treatment Considerations Because AYAs span a large age range, treatment options do not fit neatly into the two medical categories within oncology, “pediatric” or “adult,” which have different treatment protocols and approaches to care. Therefore, patients diagnosed in their late teens and early twenties may be treated by either pediatric or adult oncologists. The treatment options for young adults diagnosed with lymphoma may vary based on whether they are treated with adult (see Chapters 5 and 14) or pediatric (see Chapter 9) protocols or standards of care. Treatment options include chemotherapy, radiation, transplantation, immunologic agents and novel therapeutic agents. Recent research also suggests the need to more fully understand how common treatment regimens work or do not work in AYA patients. Dosing, in particular, may be unique for this population. Adolescents and young adults may be able to tolerate different dosing regimens better than


,,,

those diagnosed in older adulthood, because of better functioning of their liver, kidneys and blood systems. Further research is exploring the unique biology of young adults with cancer to determine specific care considerations for this age group.

Important Considerations for Long-Term Young Adult Lymphoma Survivors People in their twenties and thirties often change jobs and geographic locations frequently, take more risks and are the highest uninsured age range. All of these factors combined may make follow-up care logistically challenging. However, follow-up care is critical to detecting and treating long-term and late effects of NHL treatment. Follow-up care plans may vary based on the type of treatment used, other existing health conditions and age, among other factors. Most often, young adults will be encouraged to live a balanced, healthy lifestyle (e.g., not smoking, eating a balanced diet and exercising regularly), visit a general practitioner (and an OB-GYN for women) and receive regular follow-up care. Patients should ask their doctor what early health screenings they should have, such as mammograms, colorectal screenings, prostate exams and thyroid, cardiac and bone density tests, and when to schedule them. Some of these tests may be suggested at an earlier age for cancer survivors than the general population. Survivorship recommendations may vary for those diagnosed under or over the age of 18. People diagnosed with lymphoma at any age should speak with their physician about how specific follow-up guidelines translate into plans for their individual care. It is ideal to begin this dialogue as primary (first) therapy is being completed.

Emotional and Practical Considerations Intimate relationships, careers and finding one’s place in the world are just beginning to evolve for people in their twenties and thirties. Therefore, a lymphoma diagnosis during this stage of life may be very different emotionally than at other points in life. Newly diagnosed young adults may wish to consider joining on-line communities to meet other young adults with lymphoma. Planet Cancer, a program of the Livestrong Foundation) offers a peer community specifically for young adults. The Ulman Fund for Young Adults with Cancer (ulmanfund.org) also provides


resources for young adults diagnosed with cancer. For a complete listing of young adult cancer organizations, visit livestrong.org/yaa. Young adults diagnosed with NHL should also be aware of their employment and career rights, such as what to disclose, insurance issues and more. The Cancer Legal Resource Center (cancerlegalresourcecenter.org) provides free and confidential information and resources on cancer-related legal issues to cancer survivors, their families, friends, employers, health care professionals, and others coping with cancer. Cancer and Careers (cancerandcareers.org) provides support and resources to those living with a cancer diagnosis who work.

Tips for Healthy Living • Do not smoke or use any form of smokeless tobacco. • Eat a balanced diet that includes five or more servings of fruit and vegetables each day, protein (poultry, fish and eggs) and whole grains. • Maintain a regular exercise program that includes at least 30 minutes of some form of aerobic exercise (walking, bicycling or swimming) several days a week. Check with your doctor about a specific exercise plan for you.



lymphoma.org


Part 5: L iving With Non-Hodgkin Lymphoma

Chapter 11

Regaining Your Life During And After Cancer Coping with NHL varies among individuals. Some common coping strategies are highlighted below.

Coping Communicating It is important that patients communicate their fears and concerns about having NHL with their loved ones, friends, physicians, nurses or social workers. Writing down their fears in a journal may also help.

Overcoming Depression It is not unusual for people living with cancer to feel sad or depressed. Being diagnosed with NHL and undergoing treatment can be challenging both physically and emotionally. Signs of sadness or depression include sleeping more or less than usual, lack of energy, crying and an inability to concentrate. In addition to challenging life circumstances, depression may Living With Non-Hodgkin Lymphoma 87

5

also be caused by certain medications. Patients who experience any symptoms of depression that last longer than two weeks should contact a psychiatrist, social worker, psychologist or counselor.

Coping with Physical Changes Hair loss, weight loss/gain and changes in physical appearance may occur as a result of treatment. To cope with these changes, patients should speak with their healthcare team, get ideas from other NHL survivors and use techniques most comfortable to them.

Maintaining a Healthy Lifestyle Eating a healthy diet, engaging in regular physical exercise and getting sufficient rest can help combat the stress and fatigue of NHL and its treatment. (See “Combating Side Effects,” on page 71.)

Life After Remission Although finishing NHL treatment can be significant, it is normal to experience ongoing feelings of anxiety and worry about a relapse. Adjusting to the “new” normal routines of life during and after cancer may take a few weeks or months to complete. Developing a wellness plan with guidance from the healthcare team may lead to a better sense of overall well-being. Some changes to consider making: • Quit smoking • Reduce alcohol consumption • Exercise (walking, biking, swimming) • Eat a healthy diet

Follow-Up Care Most people with NHL will have a favorable response to initial treatment, enabling them to achieve either a complete remission or a partial remission. However, regardless of the type of remission achieved, it is important that each patient adhere to a schedule of regular follow-up office visits established by his or her physician. Follow-up visits can range in frequency from every few months to once a year depending on the patient’s disease progression, age, general health and time from last treatment.


Upong completing treatment, the healthcare team will develop a follow-up care schedule. This will include appointments with the hematologist/ oncologist as well as regular visits with the general practitioner, OB-Gyns, etc. The hematologist/oncologist will monitor the status of the NHL through physical examination and various tests (e.g., blood, imaging, etc.).

stay proactive To stay proactive in your healthcare, be sure to get the following information from your medical team: • Copies of your medical records and a written summary of your treatment in case you switch oncologists or need to see a primary care physician for routine medical care • A list of signs of disease recurrence and late side effects from treatment At your follow-up care appointments, be sure to tell your doctor about: • Any new symptoms • Pain • Physical problems that disrupt your daily life, such as fatigue, insomnia, sexual dysfunction, weight gain or loss • Any new health problems, such as heart disease, diabetes or high blood pressure • Any new medications or vitamins you are taking • Emotional problems, such as anxiety or depression

Living With Non-Hodgkin Lymphoma 89

5


lymphoma.org


Chapter 12

Relapsed or Refractory NHL A “relapse” (sometimes called a recurrence) is when an individual’s disease returns after treatment. An individual’s disease is considered “refractory” when it does not respond to treatment. Numerous treatment options exist for patients with relapsed or refractory NHL, which are often referred to as secondary therapies. Chemotherapy regimens used for relapsed or refractory lymphoma are usually different from the initial therapy (see chart included in this chapter). Rituximab (Rituxan) may be used in combination with many of these chemotherapy regimens. Radioimmunotherapy agents ibritumomab tiuxetan (Zevalin) and tositumomab (Bexxar) are also used in the relapsed setting. Many centers will consider using autologous or allogeneic transplantation for patients with relapsed or refractory NHL. Sequential transplantations are possible if the disease continues to return or does not fully respond. Exactly what type of treatment is optimal for individual patients with relapsed or refractory NHL depends on several factors, including type of lymphoma, age, extent of disease, overall health and previous therapies received. It is important to remember that while relapses may occur for patients with either indolent or aggressive NHLs, the specific treatment options may vary. Patients who do not go into complete remission following treatment or who do not respond to treatment should not lose hope. Complete remission may be achieved following a diagnosis of relapsed or refractory disease. Many of the novel therapeutic agents that have been approved by the FDA (e.g., bortezomib, pralatrexate) and those being investigated in clinical trials focus specifically on those who have relapsed or refractory disease. It is important to remember that patients may seek second opinions at any point from diagnosis onward and often chose to do so if their disease relapses or is considered refractory.

Living With Non-Hodgkin Lymphoma 91

5

Detailed below are common chemotherapy regimens used once patients relapse. Lymphoma research continually evolves as physicians and scientists discover new therapies and more effective ways of giving existing treatments. Chapter 14 describes some of the options currently under investigation.

Chemotherapy Regimens Used for Relapsed Non-Hodgkin Lymphoma (common brand names are in parenthesis) Note: Many of these regimens can also include the monoclonal antibody rituximab (Rituxan), which would be noted by the letter “R.”


Drugs

DHAP

Dexamethasone (Decadron) Cytarabine (Ara-C, Cytosar) Cisplatin (Platinol)

DICE

Dexamethasone (Decadron) Ifosfamide (Ifex) Cisplatin (Platinol) Etoposide (VP-l6, VePesid)

ESHAP Etoposide (VP- 16, VePesid) Cisplatin (Platinol) Cytarabine (Ara-C, Cytosar) Methylprednisolone (Medrol) ICE

Ifosfamide (Ifex) Carboplatin (Paraplatin) Etoposide (VP- 16, VePesid)

Mini-BEAM

Carmustine (BCNU) Etoposide (VP- 16, VePesid) Cytarabine (Ara-C, Cytosar) Meiphalan (Alkeran) Methotrexate (Rheumatrex)

PEP-C (oral)

Prednisone (Deltasone) Etoposide (VP- 16, VePesid) Procarbazine (Matulane) Cyclophosphamide (Cytoxan)



6

Chapter 13

Overview of Clinical Trials A clinical trial is a research study designed to answer basic questions about a new treatment or a new way of using an old treatment. There are hundreds of NHL clinical trials now underway in hospitals, cancer centers and physicians’ offices around the country. The government, pharmaceutical and biotechnology companies, universities and physician groups often sponsor clinical trials. The Food and Drug Administration (FDA) and the institutional review board of participating hospitals or institutions must approve each phase in a clinical trial.

Basics of Clinical Trials Clinical trials are performed to study new drugs and treatment strategies. Clinical trial investigations may study the following: • A novel drug • A new indication (use) for a drug already approved by the FDA as a treatment for a different disease • Compare a new treatment with a standard treatment to determine which one is more effective or has fewer side effects Clinical Trials 93

New drugs must pass through a rigorous approval process governed by the Food and Drug Administration (FDA) before it becomes a standard therapy for use in hospitals and clinics. The trials used to assess these drugs are typically divided into three types, called phases, each of which is designed to answer certain questions. Phase I tries to determine whether a potential treatment is well tolerated; phase II tests the drug’s effectiveness in a small group of patients; and phase III tests the drug’s effectiveness compared to standard therapies or other available treatments in a large, varied group of patients with a specific cancer. Patients may be eligible to take part in different stages depending on their condition, type and stage of lymphoma and the type of treatment, if any, previously given.

Phase I Phase I studies (first in human studies) are designed to assess the maximum tolerated dose (MTD), frequency of treatment and overall safety of the drug in a small number of patients.

Phase II Once the therapy dose is determined and shown to be safe in a phase I trial, it is then ready to be tested in a phase II study. Phase II studies aim to establish whether the therapies have any evidence of effectiveness in a larger group of patients with a particular type of cancer (e.g., follicular lymphoma). Phase II studies might be used to generate preliminary data on a drug or to confirm data to obtain FDA approval. Phase II studies also investigate whether a therapy already approved for one type of disease is effective treatment for another.

Phase III Phase III trials are performed to determine whether the treatments developed in phase I and II studies are better than what is currently considered the “standard of care” for a specific disease. Phase III studies often require a large number of patients. Once a patient elects to enroll in a phase III study, he or she is assigned to one of two groups in a process called “randomization.” In randomization, a computer assigns the treatment the patient is to receive. One group receives the standard therapy and the 94 Understanding Non-Hodgkin Lymphoma

other group receives the experimental treatment. It is important to remember that this randomization process is done so that each treatment arm will have patients with similar characteristics and be free of bias. The randomization in phase III trials allows researchers to determine whether or not the new treatment is any more effective or less toxic than the standard of care.

Use of a Placebo in Phase III Trials A placebo, or sugar pill, is an inactive ingredient that is used is some types of clinical trials to ensure that the test results are unbiased. It is important to note that clinical trial participants will never receive a placebo in phase III trials if standard therapy exists. Patients would only potentially receive a placebo if there were no standard therapies to test against. Placebo-controlled trials are never done in a manner to deny patients an effective therapy.

Participating in a Clinical Trial Clinical trials should not be considered a “last resort” by patients. Non-Hodgkin lymphoma patients can often benefit from participation in clinical trials both in the frontline treatment setting and in the relapsed treatment setting. Clinical trials offer patients therapies that are not otherwise available to all patients and are monitored very closely.

Informed Consent During the informed consent process, the healthcare team will review the design of the study, possible risks and benefits and what will be expected of the participant. The healthcare team will answer any questions and ask the patient to sign a consent form, indicating their desire to particpate in the study.

The Cost of Being in a Clinical Trial Clinical trials are very expensive undertakings for the study sponsor. Patient costs vary depending on the study, who is sponsoring the trial, what portion of the trial-related expenses the sponsor will cover and the patient’s health insurance coverage. Some health insurance and managed healthcare providers will pay for the basic medical procedures associated with the trial, such as lab tests, scans and hospitalization when required, Clinical Trials 95

6

while others may define clinical trials as “experimental” or “investigational” and not cover some of the routine costs, such as physician visits, tests or treatments. The costs vary depending on the study and the health plan. Medicare provides coverage for patient care associated with governmentsponsored clinical trials. If a patient is taking part in a National Cancer Institute (NCI) trial being conducted at the National Institutes of Health (NIH) in Bethesda, Maryland, the NCI will pay for the study drug and the costs related to the study. A stipend for travel, food and lodging is also provided. Some cancer centers provide financial assistance or discounted rates for room and board and have special research units that will pay for study-related costs. Some organizations, including the Lymphoma Research Foundation, provide financial assistance for treatment-related expenses. (See “Drug Costs: What to Do If Your Insurance Does Not Pay,” on page 60.) Patients should ask their physician what clinical trials may be most appropriate for them. Here are some additional ways to find information: • Contact the Lymphoma Helpline at the Lymphoma Research Foundation at (800) 500-9976 to request a clinical trial search. • Cancer centers in your area may also have information about trials. • Coalition of Cancer Cooperative Groups (CancerTrialsHelp.org). • NIH websites (Cancer.gov and Clinicaltrials.gov). Questions to Ask Your Doctor • What is the purpose of this clinical trial? • Who is sponsoring the trial (National Cancer Institute, a cancer center, a pharmaceutical company)? • How long does the study last? • What are the risks involved? • Will I be in any discomfort or pain? • What kinds of tests, procedures or treatments will be performed; how many and how often? • Will I be able to see my own doctor during the trial? • What costs will I be responsible for?


Chapter 14

New Agents or Applications Many drugs are approved by the United States Food and Drug Administration (FDA) for very specific and often restricted indications. This chapter will focus exclusively on those drugs that are not currently FDA approved for lymphoma and may represent major advances in our efforts to cure or manage cancer better. Therefore, patients may find that these drugs are only available in clinical trial. This chapter will forego detailed discussions about presently approved agents in lymphoma and efforts to expand their indications in specific subtypes of the disease. Refer to Chapter 5 for more detailed description of already approved agents in lymphoma. It is critical to remember that today’s science is moving very fast. Therefore, the charts in this chapter may not be entirely comprehensive or accurate depending on when this information is being read. Please check with the Lymphoma Research Foundation or your physician for additional information and recent updates.

Drugs Affecting Protein Disposal In an effort to improve on the therapeutic efficacy of bortezomib (Velcade), scientists have focused on trying to develop new proteasome inhibitors with similar biochemical properties. Bortezomib (Velcade), while very active in patients with multiple myeloma and mantle cell lymphoma, is also associated with a sometimes significant neurotoxicity that may leave patients with numbness in their fingers and toes. Also, bortezomib (Velcade) is thought to be a “reversible proteasome inhibitor.” The reversibility of the drug effect implies a need to repeatedly administer the drug to obtain optimal inhibition of the proteasome. New versions of proteasome inhibitors have focused on trying to accomplish the following: (1) to develop proteasome inhibitors with markedly less neurotoxicity; (2) develop potentially “irreversible inhibitors of the proteasome” that require less frequent dosing of the drug; (3) to develop proteasome inhibitors with very selective abilities to inhibit the complex proteasome; and (4) to develop orally available proteasome inhibitors.

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To date, a variety of new proteasome inhibitors which meet some of these criteria have been successfully developed. One of these agents, carfilzomib, is being studied in randomized clinical trials against bortezomib (Velcade) in patients with multiple myeloma. To date, carfilzomib has not been associated with significant neurotoxicity while appearing to produce marked activity in patients with multiple myeloma who have relapsed following bortezomib (Velcade) treatment. Many of the developments in regard to new versions of proteasome inhibitors are oriented toward improving efficacy, decreasing toxicity and improving the convenience of administration. Other proteasome inhibitors in development with improved features include MLN-9708, which is an orally available proteasome inhibitor. This drug affords patients more convenient dosing and allows patients to take the drug at home. Agent

Predominant Mechanism of Action

Comments

Carfilzomib (PR-171)

Proteasome inhibitor Similar to bortezomib; known to be an irreversible proteasome inhibitor; no neurotoxicity

NPI-0052

Proteasome inhibitor Relapsed or refractory lymphoma

MLN-9708

Proteasome inhibitor

NHL and HL; orally available

Drugs Affecting How Cancer Cells Divide The intrinsic features of every cancer cell revolve around the ability of the tumor cell to divide when it should not, and their ability to resist cell death when it should die. One very exciting area of new drug discovery and development is focused on targeting those proteins directly involved in stimulating cancer cells to grow. The intrinsic control of any cancer cell’s growth, just as in a car, involves an “accelerator” and “brake system.” Clearly, two strategies to intervene would involve turning off the accelerator and turning on the brakes in cell division. An exciting number of new drugs have emerged which appear to selectively turn off the accelerator in tumor cells and to selectively turn on the brakes. One class of drugs with this property


are known as CDK inhibitors and include drugs such as flavopiridol. Flavopiridol has been discovered to be potently active in patients with CLL and other slow-growing versions of leukemia and lymphoma. In addition to those drugs targeting the specific proteins involved in cell cycle regulation and control are a host of new drugs that are targeting other aspects of this biology, including those involved in the growth and mitosis (cell separation process that results in two identical cells) of tumor cells. Among these are drugs targeting aurora kinase (e.g., MLN-8237) purine nucleoside phosphorylases (e.g., BCX-1777) and novel approaches affecting tubulin biology (e.g., ixabepilone; kinesin spindle protein inhibitors). Agent


Comments

Flavopiridol CDK Inhibitor

Activity seen in CLL and mantle cell lymphoma

MLN-8237

Aurora A kinase inhibitor

Relapsed NHL

AT-9283

Aurora A kinase and aurora B kinase inhibitor

NHL

Forodesine hydrochloride (BCX-1777)

Purine nucleoside phosphorylase inhibitor

Cutaneous T-cell lymphoma

Ixabepilone Tubulin polymerization

Approved in breast cancer; under investigation in NHL

Liposomal vincristine (Marquibo)

Tubulin polymerization

Aggressive NHL

SB-921

Kinesin spindle protein inhibitor

HL

Teaching Cancer Cells How to Die Perhaps one of the most exciting new areas in cancer drug discovery over the last decade has revolved around the discovery and development of new small molecules which appear to “teach” cancer cells how to die. As noted above, one intrinsic feature of every tumor cell is its ability to divide when it should not and to resist dying when it should die. This “cell death thermostat” is established by the expression of a variety of proteins in the cell known as pro- and anti-apoptotic modulators. Pro-apoptotic proteins

Clinical Trials 99

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induce cell death while anti-apoptotic proteins resist cell death. Clearly, tumor cells contain an overabundance of those anti-apoptotic proteins which help the tumor cells survive even despite very toxic environments, including those imposed by chemotherapy. One of the first of these drugs is oblimersen (Genasense). Since the development of oblimersen (Genasense), a variety of new small molecules, many of which are orally available, have been developed. These drugs appear to inhibit the anti-apoptotic influence of many different proteins within the tumor cell, thereby increasing the sensitivity of the tumor cell to the induction of cell death by chemotherapy. Though these agents are now in very early development, they have so far demonstrated very promising activity in early phase clinical trials across a whole range of lymphomas. The future development of these agents will be oriented toward studying them in combination and lowering the threshold required to induce cell death. These agents have the value that they target biology that is selectively overrepresented in tumor cells and therefore are not associated with the same toxicity seen with combination chemotherapy. To date, these agents have been found to be very tolerable in early phase I and II clinical trials in patients with lymphoma. Agent


Oblimersen (Genasense) Bcl-2 only ABT-263

Comments Being studied in melanoma and CLL

Bcl-2, Bcl-XL Active in CLL; may make chemotherapy more effective; broad applicability

AT-101 Bcl-2, Bcl-XL, Bcl-W

Similar to ABT-263 above; orally available; being combined now with chemotherapy

Obatoclax mesylate (GX15-070) Bcl-2 Being studied in solid tumors and blood cancers, including follicular NHL, CLL and other forms of lymphoma YM-155

Survin inhibitor

NHL and other solid tumors

AMG-655

TRAIL

Relapsed HL and NHL


Agents Affecting Immunologic Targets Monoclonal Antibodies Because lymphomas are derived from cells known to play a critical role in the immune system, scientists and physicians have been trying to find ways to manipulate the immune system in order to treat various lymphomas. The success of rituximab (Rituxan) represents one significant breakthrough that has established proof of principle. Targeting proteins expressed solely on the surface of B-cells with a monoclonal antibody (MAb) can lead to significant improvements in long-term survival of patients with B-cell malignancies. Given the success of rituximab (Rituxan) and other MAbs in lymphoma, there is now a significant national and international effort to identify new engineered MAbs with unique properties to broaden their activity and improve their efficacy across these different diseases. Examples of new MAbs include lumiliximab, GA101, veltuzumab and others listed in the table below, some of which are designed to target unique antigens other than CD20 on the surface of B-cell malignancies. Agent


Comments

GA-101

CD20

NHL

Ocrelizumab

CD20

NHL

AME-133v

CD20

NHL

Veltuzumab

CD20

NHL

Epratuzumab (LymphoCide)

CD22

NHL

Inotuzumab ozogamicin (CMC544)

CD22

NHL

SAR3419

CD19

Relapsed B-cell NHL

Lumiliximab

CD23

CLL

Alemtuzumab (Campath) CD52

FDA indication in B-cell CLL

XmAb2513

CD30

Relapsed HL

SGN-40 (Dacetuzumab)

CD40

NHL, including CLL continued

Clinical Trials 101

Agent


Comments

TRU-016

CD37

CLL and other lymphomas

HCD122

CD40

Relapsed HL and B-cell NHL

Galiximab

CD80

Follicular lymphoma

Anti-CTLA-4 CD152

Follicular and mantle cell lymphoma

Immunoconjugates Other new versions of MAbs include various immonoconjugates that link an immunotoxin to the MAb scaffold in order to enhance the internalization and localization of the toxin conjugate. One example of this strategy that has proven very efficacious in anaplastic large cell lymphoma (ALCL) and Hodgkin lymphoma (HL) is SGN-35. This molecule takes advantage of a MAb directed against the CD30 antigen on the surface of some cells, which is conjugated to a toxin called monomethyl auristatin E (MMAE). Monomethyl auristatin E (MMAE) is a highly potent chemical that cannot be given by itself, because of its toxicity. However, when it is conjugated to the CD30 MAb it is delivered precisely to the tumor cells without any unnecessary toxicity. This drug development platform represents a major advance in the treatment of challenging diseases such as ALCL and relapsed HL. Agent


SGN-35 CD30

Comments Anaplastic large cell lymphoma and Hodgkin lymphoma

Immunomodulatory Drugs In addition to MAbs and immunoconjugates, there are a host of new immunomodulatory drugs modeled after thalidomide (Thalomid), including new agents such as lenalidomide (Revlimid) and pomalidomide (Actimid). These agents are known to activate the patient’s own immune system to mount an immune response against the cancer cells inside the patient’s body. While the exact mechanisms by which these drugs kill tumor cells are only now being slowly understood, it is clear that these drugs are having dramatic activity across many hematologic malignancies, including 102 Understanding Non-Hodgkin Lymphoma

myelodysplastic syndrome (MDS), multiple myeloma, T-cell lymphomas, follicular lymphoma and mantle cell lymphoma. The future development of these drugs is likely to be linked to their ability to treat small volumes of tumor, or minimal residual disease, in patients following primary therapy. Therefore, they are being studied as oral maintenance therapies in those lymphomas inclined to relapse following primary therapy. Agent


Lenalidomide (Revlimid) Immunomodulatory Thalidomide (Thalomid)

FDA approved in myeloma and disease of bone marrow failure; now being investigated in many forms of NHL

Immunomodulatory FDA approved in myeloma; preceded approval of lenalidomide above

Pomalidomide (Actimid) Immunomodulatory Aldesleukin (Proleukin)

Comments

Being investigated in solid tumors and blood disorders

Immunomodulatory FDA approved in other types of cancer; under investigation in NHL

Interleukin-12 Immunomodulatory

Cutaneous T-cell lymphoma; AIDS-related lymphoma

Therapies Interfering with the B-Cell Receptor Finally, another drug class that has recently emerged with significant promise includes those therapies directed toward interfering with the B-cell receptor. The B-cell receptor plays an important role on B-cells by regulating the growth and proliferation. The B-cell receptor mediates B-cell interactions with other proteins or cells in the body, which can cause lymphoma cells to divide and grow continuously. New drugs designed to interfere with the B-cell receptor, including Syk inhibitors, have shown promising activity in patients with very heavily pretreated B-cell malignancies. BTK inhibitors are drugs that interfere with signaling molecules within the B-cell referred to as Bruton’s tyrosine kinase (BTK). Inhibiting the production of BTK may also stop the overproduction of malignant B-cells. Continued research into the understanding of the underlying biology of B- and T-cell lymphomas will lead to the identification of new disease-specific targets that will eventually contribute to the development of new drugs targeting this biology in a very selective way. Clinical Trials 103

Agent


Comments

R788 (Fostamatinib disodium) Syk inhibitor

Several types of B-cell and T-cell NHL

PCYC-04753

BTK inhibitor

Relapsed B-cell NHL

PCI-32765

BTK inhibitor

Relapsed B-cell NHL

Vaccines Unlike monoclonal antibody therapy, which is a form of “passive immunity,” vaccines are considered a form of active immunity. In passive immunity, antibody generated outside the body in a special laboratory tags the lymphoma cells, which are then removed by the spleen. There is no memory of the exposure, and the effect is over once the antibody is cleared from the body. In active immunity, the vaccine is designed to stimulate the patient’s own immune system to recognize and respond only to those cells carrying the specific antigen, or tumor-specific idiotype, against which the vaccine was made. Vaccines are not yet available as standard treatments, but various vaccines are being evaluated in clinical trials. Lymphoma vaccines are designed to enhance the patient’s own immune defense system to fight his or her disease. These vaccines, often referred to as idiotype (e.g., patient specific) are custom-made, using a tumor sample from the patient’s lymph node. In order to create an individual vaccine, a patient’s lymphoma must be accessible for biopsy. It is not yet known how effective these vaccines will be, but the results from large randomized phase III trials are currently being evaluated. So far, two of these large clinical trials have failed to show sufficient benefit compared to standard treatment. The results of one other trial have produced positive results in selected patients. Agent BiovaxID

Predominant Mechanism of Action Idiotype


Comments Follicular lymphoma

Drugs Selectively Targeting Cancer Cell Gene Expression One of the more exciting areas of drug development over the last decade has emerged from our understanding of how tumor cells turn on and turn off specific genes that contribute to their ability to proliferate (multiply) and resist cell death. This process is governed by a balance of expression of two sets of enzymes known as HATs (histone acetyltransferases) and HDACs (histone deacetylases). The acetylation of specific proteins in DNA can open DNA and turn on a number of different genes involved in growth and survival. The removal of those “acetyl groups” from the proteins of the DNA leads to silencing of those genes. The recent discovery that certain drugs could inhibit the deacetylation process, specifically the HDACs, allows the DNA to be maintained in an open and “transcriptionally active state.” By using small molecules, physicians and scientists are now able to potentially turn on a host of genes within the tumor cell, which may help reverse the malignant process. The first of this class of drugs that has been approved for the treatment of cancer was vorinostat (Zolinza) for cutaneous T-cell lymphoma (CTCL). For reasons that are not entirely clear, this class of drugs seems to have activity across all different types of T-cell lymphomas and appears to complement the activity of many conventional and other investigational drugs now being studied for the treatment of cancer. Following the approval of vorinostat (Zolinza) for the treatment of CTCL, another HDAC inhibitor, known as romidepsin (Istodax) was recently approved in November 2009 for CTCL. Romidepsin (Istodax) is an intravenously administered HDAC inhibitor that appears to be associated with a very good overall response rate and durable remissions in patients with CTCL resistant to vorinostat (Zolinza) and other conventional drugs used for this disease. In addition to these drugs, and with our ever-growing knowledge around this biology, there are now a number of new HDAC inhibitors that have exhibited very promising activity in a variety of different forms of lymphoma. One of those drugs, known as belinostat, is administered as an intravenous preparation and has been shown to have significant activity in patients with peripheral T-cell lymphoma (PTCL). Belinostat

Clinical Trials 105

is now under study in a large international phase II trial in patients with PTCL resistant to conventional chemotherapy. New orally available forms of belinostat are now in development and appear to be associated with a very favorable toxicity profile, ease of administration and promising activity in various subtypes of NHL. Another HDAC inhibitor being developed is panobinostat. Panobinostat, like vorinostat (Zolinza), is an orally available HDAC inhibitor that is chemically very similar to vorinostat (Zolinza). But unlike vorinostat (Zolinza), panobinostat has demonstrated marked activity in patients with Hodgkin lymphoma resistant to conventional chemotherapy. Panobinostat is now being studied across a variety of NHLs, including a FDA directed study for patients with relapsed or refractory Hodgkin lymphoma. This means, that should this trial demonstrate sufficient activity, it could become approved by the FDA for all patients with Hodgkin lymphoma. As this field continues to emerge, it is becoming increasingly more apparent that HDAC inhibitors will complement a whole host of other drugs, including proteasome inhibitors, Bcl-2 directed therapies, MAbs like rituximab (Rituxan) and other agents also known to affect gene expression, such as the hypomethylating agents. This latter class consists of two drugs now approved by the US FDA for the treatment of myelodysplastic syndrome: 5-azacytidine (Vidaza) and 5-aza-2-deoxycytidine. New evidence from a variety of different laboratories and clinical settings has begun to demonstrate that this two arm attack on gene transcription using both HDAC inhibitors and hypomethylating agents is a very promising strategy for the treatment of acute myeloid leukemia and possibly some forms of lymphoma. Future efforts will be directed toward understanding which genes are modulated following exposure to these drugs in an effort to identify certain biomarkers of response in specific patients with different types of lymphoma. Agent


Comments

Panobinostat HDAC-inhibitor

Under investigation in relapsed HL, PTCL, other NHL

Belinostat

PTCL, other NHL

HDAC-inhibitor


Drugs Targeting Essential Lymphoma Biology One of the major challenges in cancer research over the last several decades has been trying to understand the specific biologic differences between normal B- and T-lymphocytes and malignant B- and T-cell lymphomas. Intensive investigation into these biological differences has begun to reveal a number of unique targets that appear to be overrepresented in malignant B- and T-cell lymphomas, compared to their normal, benign (non-cancerous) B- and T-cell lymphocyte counterparts. For example, it has been recently discovered that an important pathway controlling the translation of genetic information from DNA to protein, the PI3Kinase- AKT-mTor pathway is markedly overexpressed in a whole variety of different lymphoproliferative malignancies. Over the last decade, a number of new drugs have been developed which specifically target this pathway including mTor inhibitors such as rapamycin, temsirolimus (Torisel) and everolimus, which seem to inhibit an important protein in this pathway known as the “mammalian target of rapamycin.” Inhibition of this protein effects genes involved in the development of lymphoma, including but not limited to cyclin-D1, Bcl-2 and NFkB, all of which play an important role in stimulating the growth and inhibiting the death of malignant cells. Other drugs that appear to target this pathway selectively include those drugs targeting PI3 kinase (PI3K) directly, such as CAL101, which appears to have very promising activity in patients with mantle cell lymphoma in very early clinical trials. Other drugs targeting this pathway include agents capable of inhibiting the AKT pathway (e.g., perifosine), which also has effects on tumor cells similar to that seen with the mTor inhibitors. The recent elucidation of this important pathway on which many B- and T-cell lymphomas have been found to be “addicted,” represents a unique opportunity to target the biology of the lymphomas. Future studies of these agents will be directed toward the combined inhibition of the pathway and the merits of combining these drugs with conventional drugs known to be effective in treating lymphomas.

Clinical Trials 107

Another target that has emerged as essential and perhaps unique in the development of B-cell lymphoma is a protein known as protein kinase C-beta (PKC-beta). The identification that PKC-beta was an important target among patients with relatively poor prognosis diffuse large B-cell lymphoma (DLBCL) represented a unique opportunity to target this biology with drugs capable of inhibiting PKC-beta. One such drug that had been studied in rheumatologic disorders and inhibited PKC-beta was enzastaurin. To date, enzastaurin has been studied in a variety of phase I and phase II clinical trials in patients with DLBCL. While the drug appears to be modest in terms of its ability to shrink tumor, it has been found to produce very prolonged stabilization of disease in patients with otherwise very aggressive forms of lymphoma. Enzastaurin is now being studied in a large randomized controlled trial to determine whether administration of oral enzastaurin after primary chemotherapy for patients with poor risk DLBCL represents a maintenance type approach to enhance the survival of patients with otherwise aggressive forms of lymphoma. Agent


Comments

Perifosine AKT inhibitor

Active in many blood cancers. New class of drugs with broad applicability

RAD001 (Everolimus) mTor inhibitor

NHL, under study in mantle cell lymphoma

Temsirolimus (Torisel) mTor inhibitor

Approved for renal cell carcinoma. Being studied in many types of lymphoma, including mantle cell lymphoma

CAL-101 PI3K inhibitor

Relapsed or refractory hematologic malignancies

Enzastaurin HCl PKC-b

Under study in diffuse large-B cell lymphoma

Bevacizumab (Avastin)

Relapsed aggressive lymphoma

VEGF

Other therapeutic strategies directed against both the tumor cell proper as well as the stromal microenvironment (i.e., the normal cellular milieu within which the tumor cell resides) include drugs capable of affecting angiogenesis (the growth of blood vessels that sustain growth of tumors). While drugs affecting angiogenesis have found an important niche in the 108 Understanding Non-Hodgkin Lymphoma

treatment of patients with solid tumor malignancies, like breast cancer, colon cancer and glioblastoma multiforme, the activity in patients with hematologic malignancies is less clear. Bevacizumab (Avastin) is a MAb that targets VEGF (vascular endothelial growth factor). VEGF and other angiogenic proteins are known to play an important role in stimulating lymphoma cells to divide by binding to proteins on their cell surface. They are also known to play an important role in regulating the stromal microenvironment of the lymph node in which the lymphoma cell resides. Precisely how drugs targeting VEGF work in hematologic malignancies remains uncertain. However, early data has suggested that while these drugs do not appear to exhibit marked activity in their ability to shrink tumor, they too, like enzastaurin, appear to be able to sustain protracted and prolonged durations of response compared to other conventional therapies. The role of these proteins and other angiogenesis inhibitors in lymphoma is still an area of active research.

New Derivatives of Old Drugs While there are some examples where scientists are trying to improve existing drugs, the bulk of the effort has been focused on the discovery of new agents that selectively target the unique biology of the lymphoma. Other examples of new versions of older drugs are provided in the following table. Agent


Comments

Pixantrone Anthracycline-like

Under US FDA review for relapsed/refractory aggressive NHL

Temozolomide (Temodar) Alkylating agent

Approved for brain cancer; being investigated in lymphomas of the central nervous system (CNS)

Liposomal doxorubicin (Doxil) Anthracycline

Less cardiotoxic version of doxorubicin; active in NHL

Epirubicin hydrochloride Anthracycline (Epirubicin)

Many types of NHL and HL; related to doxorubicin

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lymphoma.org


GLOSSARY OF MEDICAL TERMS Absolute neutrophil count (ANC): A measurement of the number of mature neutrophils (a type of white blood cell) that are available for fighting infection. A low ANC increases the risk for infection.

Advanced disease: Disease that has spread to multiple locations. Aggressive lymphomas: Lymphomas that are fast growing and generally need to be treated immediately. Also called intermediate-grade or high-grade lymphomas. Allogeneic transplant: A procedure in which a patient receives bone marrow or stem cells donated by another person. Alopecia: Hair loss. Alopecia from chemotherapy is almost always temporary; hair grows back when therapy is finished.

Anemia: A shortage of red blood cells, causing weakness and fatigue. Angiogenesis: The process of developing new blood vessels. Antiangiogenesis therapies: Drugs that prevent tumors from developing new blood vessels, thereby stopping or limiting tumor growth. Antibody: A substance made by B-lymphocytes that reacts with antigens on toxins, bacteria and some cancer cells and either kills or marks them for removal.

Antiemetic: A drug that reduces or prevents nausea and vomiting. Antigen: Identifying proteins located on the surface of all cells. The immune system uses antigens to determine whether cells are a necessary part of the body or need to be destroyed.


Autologous transplant: A type of bone marrow or stem cell transplantation in which a patient receives his or her own cells. Beta (2) microglobulin (B2M): A protein found in the blood. Higher levels of B2M suggest that the lymphoma may be more aggressive. 111 Understanding Non-Hodgkin Lymphoma

UnderstandingGlossary Non-Hodgkin of Medical Lymphoma Terms 111


Biopsy: Removal of a small piece of tissue for evaluation under a microscope.

Bone marrow: Spongy material found inside the bones containing stem cells that develop into three types of cells: red blood cells that deliver oxygen to the body and take away carbon dioxide; white blood cells that protect the body from infection; and platelets that help the blood to clot.

Bulky tumor: A large tumor, usually greater than five, seven or ten centimeters. Cancer: Abnormal cell growth that cannot be controlled by the body’s natural defenses. Cancerous cells can grow and eventually form tumors.


Cerebrospinal fluid: Fluid that is present around the spine and brain. It may be examined to determine if NHL has spread to these parts of the body. Chemotherapy: Treatment with drugs to stop the growth of rapidly dividing cancer cells, including lymphoma cells.


Chemotherapy regimen: Combinations of anticancer drugs given at a certain dose in a specific sequence according to a strict schedule. Clinical trial: A research study in which a new treatment is given to patients to determine whether it is safe, more effective or less toxic than current therapies.

Combination Chemotherapy: Several drugs given together to increase response rate of certain tumors.

112 Understanding UnderstandingNon-Hodgkin Non-HodgkinLymphoma Lymphoma

Glossary of Medical Terms 112


CT or CAT (computerized axial tomography) scan: This imaging test provides a series of detailed pictures of inside the body using an X-ray machine linked to a computer.

Cure: There are no signs or symptoms of lymphoma, and a significant period of time (usually defined by years) has passed during which there are no relapses. Decreased blood cell production: A decrease in the production of red blood cells, white blood cells and platelets that may occur as a side effect of cancer or cancer therapies. Also called myelosuppression.

Diaphragm: The muscle below the lungs and heart that separates the abdomen from the chest. Disease progression: The term used if the disease worsens despite treatment (also called treatment failure).

DNA: Abbreviation for deoxyribonucleic acid, an essential component of genes.

Dose intensity: A term used to describe giving the highest possible doses of drugs over a specific period of time with acceptable side effects.

Durable remission: When a complete response lasts for years. Dysgeusia: When familiar foods taste differently. Echocardiogram: Use of ultrasound to examine the heart. It is ordered when potential cardiotoxic chemotherapy is used. Etiology: The study of the causes of a disease. Extranodal disease: NHL that has spread outside the lymphatic system. Fatigue: A decreased capacity for activity that is often accompanied by feelings of weariness, sleepiness or irritability. UnderstandingGlossary Non-Hodgkin of Medical Lymphoma Terms 113

Gallium (radioisotope) scan: When injected into the body, radioactive gallium is a chemical that collects in some tumors. The body is then scanned to see whether the gallium has collected in a tumor.

Generalized disease: A cancer that has spread throughout the body. Genes: The basic building blocks of heredity that are present in all cells. Genes are comprised of DNA and other materials.

Gene therapy: Therapy approaches that alter the genetic structure of tumor cells, making them more susceptible to either the immune system or chemotherapy drugs.

Grade: A method of classifying a tumor on the basis of how aggressively it is growing. Graft versus host disease (GVHD): Occurs when a donor’s bone marrow (graft) recognizes the recipient of the marrow (the host) as foreign. In response, the immune cells in the donor marrow attack the foreign cells in the host. Harvesting: A procedure in which stem cells are obtained from the blood or bone marrow for use in repopulating the body’s cells after high-dose chemotherapy.

Hematologist: A physician who specializes in treating diseases of the blood and blood-forming tissues.


Hodgkin lymphoma: One of the two major types of lymphoma that begin in the lymph nodes and tissues of the lymphatic system. All other lymphomas are classified as non-Hodgkin lymphomas. Hodgkin lymphoma has a characteristic cell, the Reed-Sternberg cell, seen by the pathologist under the microscope when looking at the tissue from the biopsy.

Hypogeusia: When the flavors of foods are not as strong as normal. 114 Understanding UnderstandingNon-Hodgkin Non-HodgkinLymphoma Lymphoma


Hypothyroidism: A condition in which there is lower than normal production of thyroid hormone. Low thyroid levels can lead to a variety of effects, including mild weight gain, dry skin, fatigue and sleepiness.


Immune system: One of the body’s defense mechanisms. All lymphomas are diseases of the immune system. Immunological tests: Blood tests that detect the presence of diagnostic proteins or antigens on a tumor. Immunotherapy: See biologic therapy. Improvement: This term is used if a tumor shrinks following therapy but is still more than one-half of its original size.

Indolent lymphoma: Lymphoma that is slow growing and has few symptoms. Also called low-grade lymphoma. Lactate dehydrogenase (LDH): An enzyme found in the blood. Higher levels of LDH suggest that the lymphoma may be more aggressive.

Laparoscopy: Passing a tube through the abdominal wall to obtain a small sample of tissue for examination under the microscope.

Leukemia: Disease generally characterized by the overproduction of abnormal or immature white blood cells that circulate or are present in the blood. Leukopenia: A shortage of white blood cells, resulting in the inability to fight infecting organisms such as bacteria, fungi and viruses. Localized disease: A cancer that is only present in a limited part of the body, for example, the neck or armpits. 115 Understanding Non-Hodgkins Lymphoma


Local therapy: A therapy that only affects a small area. Low-grade lymphoma: Lymphoma that grows slowly and has few symptoms. Also called indolent lymphoma. Lymph: The watery fluid in the lymph system that contains white blood cells (lymphocytes). Lymph nodes: Small bean-shaped glands located in the small vessels of the lymphatic system. There are thousands of lymph nodes located throughout the body, with clusters of them in the neck, under the arms, the chest, abdomen and groin. Lymph nodes filter lymph fluid, trapping and destroying potentially harmful bacteria and viruses. Lymphatic system: The channels, tissues and organs that store and carry lymphocytes that fight infection and other diseases. Lymphocyte: A type of white blood cell. Lymphocytes, carried along by the lymph fluid, are part of the immune system and fight infection.

Lymphoma: A malignant disease that begins in the lymph nodes, organs and tissues of the lymphatic system (immune system). Hodgkin lymphoma is one type of lymphoma; the other major type is called non-Hodgkin lymphoma. There are approximately 61 types of nonHodgkin lymphoma.

Malignant: Cancerous—a malignant tumor is a cancerous tumor. Medical oncologist: A physician who specializes in the use of chemotherapy, hormone therapy and many other types of biologic therapies to treat cancer.

Memory cells: Memory cells are types of B-lymphocytes and T-lymphocytes. After a foreign invader or unwanted cell has been destroyed, surviving B- and T-lymphocytes develop into specialized memory cells that remain on watch and can provide protection if the invader is encountered in the future.

116 Understanding UnderstandingNon-Hodgkin Non-HodgkinLymphoma Lymphoma

UnderstandingGlossary Non-Hodgkin Lymphoma 116 of Medical Terms 116


Monoclonal antibodies: Biologic therapies that act specifically against a particular antigen. Scientists can produce large amounts of antibody that can be directed to a single target (or antigen) on the cell’s surface. Monoclonal antibodies have been developed to help combat specific cancers, including some forms of non-Hodgkin lymphoma.

MRI (magnetic resonance imaging): MRI uses magnets and radio frequency waves to produce images of inside the body. MRIs can provide information about tissues and organs that is not available from other imaging techniques.


Myelosuppresion: A reduction in the bone marrow’s ability to make red blood cells, white blood cells and platelets. Neutropenia: An abnormally low level of neutrophils (the white blood cells responsible for fighting bacterial infections).

Neutrophils: The primary type of white blood cells found in the blood that fight bacteria, etc. Non-bulky tumor: A small tumor, usually less than five centimeters (approximately two inches) Non-Hodgkin lymphoma (NHL): A group of several closely related cancers that arise from the lymphatic system. Although the different types of NHL have some things in common, they differ in what the cancer cell looks like under a microscope, how the cells grow and how the tumor affects the body. Oncologist: A physician who specializes in treating cancer. Some specialize in chemotherapy (medical oncologists), radiotherapy (radiation oncologists) or surgery (surgical oncologists).

117 Understanding Non-Hodgkins Non-Hodgkin Lymphoma Lymphoma



Partial remission (PR): The term used when a cancer has shrunk in size by at least half but has not totally disappeared. The cancer can still be detected, and other treatments may be recommended.

Pathologist: A physician who specializes in studying disease through microscopic evaluation of body tissues and organs. Any tissue suspected of being cancerous must first be examined by a pathologist to confirm the diagnosis.

PCR (Polymerase chain reaction): A molecular test that can identify small amounts of genetic material. This test is done if looking for minimal residual disease.

Performance status: A term used to describe a person’s ability to follow a typical lifestyle.


PET (positron emission tomography) scan: A type of test that may be used instead of gallium scans to identify areas in the body that are affected by non-Hodgkin lymphoma. This test evaluates metabolic activity in different parts of the body using a radioisotope.


Primary therapy: The first therapy given after a diagnosis of cancer. Prognosis: The likely outcome of a disease, including the chance of recovery.



Radiation field: The part of the body that receives radiation therapy. Radiation oncologist: A physician who specializes in treating cancer with radiation.

Radiation therapy: The use of radiation beams (X-rays) to treat a cancer. High doses of high-energy radiation beams carefully focused on a tumor will kill cancer cells. Radiation therapy (with or without chemotherapy) is used to treat certain lymphomas. Radioimmunotherapy: A therapy that is prepared by attaching a radioactive isotope to a monoclonal antibody. Radionuclide tests: Tests that use radioactive substances to help evaluate the function of tissues.


Relapse: The return of cancer after treatment. Lymphoma may recur in the area where it first started, or it may occur in another place.

Remission: The absence of disease. A patient is considered in remission when the lymphoma has been treated and tumors have diminished by at least 50 percent (partial) or have totally disappeared (complete). Remission does not necessarily mean cure. Patients with intermediate or aggressive lymphomas must achieve a complete remission and maintain it for a period of time, usually five or more years, before there is consideration of cure. Patients with low-grade tumors are usually not considered cured because the disease can reappear even with a long remission of many years. Patients may have a complete or partial remission.


Risk factors: Factors that may increase the chance that a person will develop NHL. It is important to note that most people with risk factors never develop lymphoma, and many who are diagnosed have no identifiable risk factors.


Spleen: An organ on the left side of the upper abdomen, near the stomach. A key component of the lymphatic system, the spleen produces and stores lymphocytes and releases them when required as part of the body’s response to infections and other stimuli. The spleen may store blood and remove old blood cells from circulation.

Stable disease: The disease does not get better or worse following therapy. Stage: The extent of cancer in the body, including whether the disease has spread from the original site to other body parts.

Standard therapy: The most widely used primary therapy. Synergism: The term used when two or more drugs given together provide a better anti-cancer effect than expected from the additive effects from the medications alone.

Systemic symptoms: Symptoms that affect the entire body. Examples of these include fever, night sweats and weight loss.


Thymus gland: A gland located behind the sternum (breastbone) that enhances the reproduction and development of lymphocytes. T-lymphocytes are processed in the thymus.



Tumor: An abnormal mass or swelling of tissue. Tumors may occur anywhere in the body. A tumor may be benign (non-cancerous) or malignant (cancerous).

Vaccine: A substance or group of substances meant to cause the immune system to respond. A vaccine can help the body recognize and destroy cancer cells. Lymphoma vaccines often combine cancer antigens with a substance to stimulate the patient’s own natural defenses to fight the disease. These vaccines in lymphoma are custom-made for each patient, using a sample of tumor obtained from the patient’s lymph nodes.

VEGF (Vascular Endothelial Growth Factor): One of a number of substances that stimulate angiogenesis, blood vessel formation—a process necessary for tumor growth.

Watchful waiting: An approach in which no immediate medical, surgical or radiation therapy is given. Patients are followed closely to make sure the cancer does not progress. Watchful waiting is an appropriate option for some patients with indolent (slow-growing) non-Hodgkin lymphoma.

Xerostomia: A temporary reduction in the production of saliva or “dry mouth.”

X-ray: Radiation that is used in low doses to provide images of the inside of the body and in high doses to treat cancer.



lymphoma.org


About The Lymphoma Research Foundation The Lymphoma Research Foundation (LRF) is the nation’s largest lymphomafocused nonprofit health organization devoted exclusively to funding lymphoma research and providing patients and healthcare professionals with the most current information on the disease. The Foundation’s mission is to eradicate lymphoma and serve those touched by this disease. The Lymphoma Research Foundation was formed in 2001 with the merger of the Cure For Lymphoma Foundation (CFL) and the Lymphoma Research Foundation of America (LRFA). Both organizations were founded by lymphoma advocates who wanted to turn a life-altering diagnosis into a positive experience for others with the disease. Ellen Glesby Cohen founded LRFA in Los Angeles in 1991. Until her death in 2000, Ellen was a tireless champion for patients and their families who created new education and support programs and served as a staunch advocate for improved government legislation. Jerry and Barbara Freundlich founded CFL in 1994 in New York City. Jerry is a long-term survivor of non-Hodgkin lymphoma.

Resources for Patients, Survivors and Loved Ones Receiving a diagnosis of lymphoma can be challenging. Whether you or someone you love is newly diagnosed or a long-term survivor, understanding the latest medical information and accessing appropriate support services may help. LRF offers a wide array of programs and support services to assist you from the point of diagnosis through long-term survivorship.

Patient Services and Support Lymphoma Helpline and Clinical Trials Information Service Through this phone and e-mail service, trained staff members are available to answer your questions and provide individual support to you and your loved ones. Services are available in any language.

The Lymphoma Research Foundation 123


Lymphoma Newsline Lymphoma-related news can be distributed to you directly through this free electronic news services. Sign-up is required by clicking on the “register” icon on LRF’s homepage at lymphoma.org.

In-Person Patient Education Programs North American Educational Forum on Lymphoma This two-day forum is held annually and provides critical information about making the best decisions on treatment options, patient support issues and the latest in lymphoma research.

Lymphoma Workshop: Understanding Lymphoma Basics & Current Treatment Options These regional, full-day educational programs provide the latest information about lymphoma, current treatment options and patient support issues.

Multi-Media Programs Because LRF understands that lymphoma information continually changes throughout the year, the on-going production of webcasts, podcasts and teleconferences enable you to access the latest information on specific topics anywhere, anytime.


Podcasts Podcast (MP3) programs are presented in audio format only and can be downloaded to your portable MP3 player.


Teleconferences Teleconferences are hour-long interactive telephone programs that provide an opportunity to learn more about lymphoma, treatments and promising research from leading lymphoma experts. These are conducted live and the archived version is available after the program.

Publications Booklets In addition to this publication, LRF also produces Understanding Hodgkin Lymphoma: A Guide for Patients, Survivors and Loved Ones and Understanding Chronic Lymphocytic Leukemia (CLL): A Guide for Patients, Survivors and Loved Ones.

Fact Sheets Fact sheets are available to provide you with the latest disease- and treatment-specific information and are available in either hard copy or in PDF on LRF’s website. New topics are added on a regular basis, so be sure to check to see if the topic you are looking for is available.

Newsletters To keep you abreast of LRF research and news in the wider lymphoma community, you can sign-up to receive any of LRF’s regular newsletters either electronically or via mail. Any of LRF’s publications may be ordered by visiting lymphoma.org. Individual and bulk copies are available free of charge.


Resources for Children and Young Adults Lymphoma in Your Teens, 20s and 30s LRF offers a wide array of webcasts and podcasts for individuals affected by lymphoma in their teens, 20s and 30s, including topics specifically designed to help friends and family. Visit lymphoma.org/youngadults to access these programs. Lance Armstrong Foundation’s LIVESTRONG Young Adult Alliance The LIVESTRONG Young Adult Alliance is a coalition of organizations with the goal to improve the survival rates and quality of life for young adults with cancer between the ages of 15 and 40. By visiting livestrong.org/ yaa you can access the websites of all member organizations that specifically provide services for young adults with cancer.

Planet Cancer Planet Cancer (a program of the Lance Armstrong Foundation) is a peer support community for Young Adults going through the tremendously isolating experience of cancer between the ages of 18 and 40. On Planet Cancer, young adult patients and survivors connect 24 hours a day, 7 days a week through a dynamic and irreverent social networking website and face-to-face retreats. Planet Cancer also provides advocacy programs to build awareness about the unique medical and psychosocial needs of this often-overlooked age group. Visit planetcancer.org to access these services. Ulman Cancer Fund for Young Adults This organization focuses on how cancer affects young adults and offers scholarships, community grants, advocacy services and a guidebook; ulmanfund.org.

How to Access Programs and Services Many of the aforementioned programs are available on LRF’s website at lymphoma.org. For additional information about these resources, call (800) 500-9976; e-mail us at [email protected]. If you would like to order additional copies of Understanding NonHodgkin Lymphoma: A Guide for Patients, Survivors and Loved Ones, please call (800) 500-9976 or go to lymphoma.org. 126 Understanding Non-Hodgkin Lymphoma

How to Get Involved and Give Back Take Action to Make a Difference The LRF Advocacy Program is a network of people and programs dedicated to increasing awareness and support for the lymphoma community. The Advocacy Program focuses on taking action on laws, policies and positions that affect every lymphoma patient and survivor. By contacting elected officials via phone calls, email and letters in support of these priorities, local advocates help LRF to make lymphoma a national health priority. To become involved, visit lymphoma.org/advocacy.

Start or Join a Local Chapter LRF meets the needs of the lymphoma community through our nationwide chapter network. Chapter volunteers work tirelessly to educate people about lymphoma, conduct outreach, raise funds for research and participate in public policy and advocacy initiatives. To learn more about a chapter in your area or how to start one, please visit lymphoma.org/chapters or call (800) 235-6848.

Raise Funds and Awareness Raise funds and awareness by participating in a variety of events being held across the country such as Lymphomathon walks, bike rides, golf tournaments, galas, lunches, young professional social events and much more. Visit lymphoma.org/events for more information.

Join Team LRF Team LRF is a program through which people across the country raise much-needed funds and awareness for lymphoma research through sporting events such as marathons, half marathons, triathlons, hiking adventures, bowling tournaments, soccer matches, bike rides, lacrosse tournaments, paddling events, dance-a-thons, spin-a-thons, yoga-a-thons and much more. Join Team LRF in an existing LRF-partnered event in your area, or join Team LRF Teammates Across the Country if you wish to raise funds by starting your own event or by participating in an event in which LRF does not have official charity entries. Visit lymphoma.org/ teamlrf for more information.


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Chronic Lymphocytic Leukemia/ Small Lymphocytic Lymphoma

A Guide for Patients, Survivors and Loved Ones First Edition

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A Guide for Patients, Survivors and Loved Ones First Edition

Published by: Lymphoma Research Foundation, in collaboration with CLL Information Group Editorial Board Chairman: Morton Coleman, MD

This guide is an educational resource compiled by the Lymphoma Research Foundation providing general information on chronic lymphocytic leukemia/ small lymphocytic lymphoma.Publication of this information is not intended to take the place of medical care or the advice of your physician. Patients are strongly encouraged to talk to their physicians for complete information on how their disease should be diagnosed, treated and followed. Before starting treatment, patients should discuss the potential benefits and side effects of cancer therapy.

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© 2010 Lymphoma Research Foundation Information contained herein is the property of the Lymphoma Research Foundation (LRF). Any portion may be reprinted or reproduced provided that LRF is acknowledged to be the author.

ACKNOWLEDGMENTS Lymphoma Research Foundation wishes to acknowledge those individuals listed below who have given generously of their time and expertise. We thank them for their contributions, editorial wisdom and advice, which have truly enhanced this publication. Editorial Board Steering Committee Chairman Morton Coleman, MD, Weill Medical College of Cornell University–New York Presbyterian Hospital Senior Advisors Bruce D. Cheson, MD, FACP, Georgetown University Hospital, Lombardi Comprehensive Cancer Center Jennifer M. Mills, LMSW, MPH, Lymphoma Research Foundation Kanti Rai, MD, Long Island Jewish Medical Center Review Committee John Balan, MS, CLL Information Group Carolyn Bell, MSW, Santa Monica–UCLA Medical Center Richard Boyajian, RN, MSN, APN, Dana-Farber Cancer Institute Jennifer Brown, MD, PhD, Dana-Farber Cancer Institute John Byrd, MD, Ohio State Medical Center Asher Chanan-Khan, MD, Roswell Park Cancer Institute Richard I. Fisher, MD, University of Rochester Medical Center, James P. Wilmot Cancer Center David Frank, MD, PhD, Dana-Farber Cancer Institute Richard Furman, MD, Weill Medical College of Cornell University Les Gallo-Silver, ACSW, LCSW-R, LaGuardia Community College Neil E. Kay, MD, Mayo Clinic Michael J. Keating, MB, BS, MD Anderson Cancer Center Lisa B. Kenney, MD, MPH, Dana-Farber Cancer Institute Thomas J. Kipps, MD, PhD, UCSD Cancer Center John P. Leonard, MD, Weill Medical College of Cornell University Joanna Morales, Esq., Cancer Legal Resource Center Owen A. O’Connor, MD, PhD, New York University Cancer Institute John M. Pagel, MD, PhD, Fred Hutchinson Cancer Research Center Oliver W. Press, MD, PhD, Fred Hutchinson Cancer Research Center David J. Straus, MD, Memorial Sloan-Kettering Cancer Center James Testaverde, BS, Lymphoma Research Foundation Brian Tomlinson, MPA, BSW, Lymphoma Research Foundation Parameswaran Venugopal, MD, Rush University Medical Center Julie M. Vose, MD, University of Nebraska Medical Center Kathleen M. Wesa, MD, Memorial Sloan-Kettering Cancer Center Teresa K. Woodruff, PhD, Northwestern University Bradley J. Zebrack, PhD, MPH, MSW, University of Michigan School of Social Work Clive Zent, MD, Mayo Clinic Contributing Medical Writer: Jo Cavallo ii Understanding CLL/SLL

Table of Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 Part I: Learning the Basics Chapter 1 Cancer Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 Cancer Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 Overview of Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma . . . 4 Causes of CLL . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 Risk Factors for CLL . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 How the Immune System Works . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 How the Lymphatic System Works . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 Chapter 2 Signs and Symptoms of Chronic Lymphocytic Leukemia . . . . . . . . . . . . . . . . . . 11 When to Seek Medical Attention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12 What the Physician Looks for During a Physical Examination . . . . . . . . . . . . . . 12 Chapter 3 Getting a Diagnosis—What to Expect . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15 Laboratory Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15 Biopsies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18 Imaging Tests . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19 Staging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21 Getting a Second Opinion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22 Choosing an Oncologist and Treatment Center . . . . . . . . . . . . . . . . . . . . . . . . . . 22

Part 2: Treating Chronic Lymphocytic Leukemia Chapter 4 What You Should Know Before Starting Treatment . . . . . . . . . . . . . . . . . . . . . . Prognostic Factors Affecting Treatment Outcome . . . . . . . . . . . . . . . . . . . . . . . . Communicating With Your Healthcare Team . . . . . . . . . . . . . . . . . . . . . . . . . . . . Writing an Advance Healthcare Directive and Appointing a Healthcare Proxy . . How to Be a Self-Advocate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Chapter 5 Types of Treatment Currently Available . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Watchful Waiting . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Chemotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Newer Versions of Established Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Monoclonal Antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Stem Cell Transplantation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Radiation Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Splenectomy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Complementary and Alternative Remedies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Drug Costs: What to Do If Your Insurance Does Not Pay . . . . . . . . . . . . . . . . . . .

25 26 28 29 30 33 34 34 38 38 41 42 43 43 44

Part 3: Disease and Treatment Side Effects Chapter 6 Transformations, Complications and Side Effects . . . . . . . . . . . . . . . . . . . . . . . 45 Transformations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45 Complications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46 Side Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47 Long-Term Effects and Late Effects of CLL . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55 Combating Side Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56 Understanding CLL/SLL iii

Chapter 7 Sexuality . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59 Sexual Function During Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59 When to Use Contraceptives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59 Chapter 8 Fertility Risks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61 How to Protect Fertility in Men . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61 How to Protect Fertility in Women . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62 Chapter 9 If You Relapse or Do Not Respond to Treatment . . . . . . . . . . . . . . . . . . . . . . . . . 63

Part 4: Living With Chronic Lymphocytic Leukemia Chapter 10 Regaining Your Life After Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65 Coping . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65 Life After Remission and Follow-Up Care . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 66

Part 5: Clinical Trials Chapter 11 Clinical Trials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69 Basics of Clinical Trials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69 Participating in a Clinical Trial . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71 Chapter 12 Therapies Under Investigation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73 Glossary of Medical Terms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79 About CLL (Chronic Lymphocytic Leukemia) Information Group . . . . . . . . . . Website . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Internet Discussion Group . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Contact Information . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

91 91 91 91

About the Lymphoma Research Foundation . . . . . . . . . . . . . . . . . . . . . . . . . . . Resources for Patients, Survivors and Loved Ones . . . . . . . . . . . . . . . . . . . . . . . Resources for Children and Young Adults . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . How to Get Involved and Give Back . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Donate Now . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

93 93 95 97 99

iv Understanding CLL/SLL

Introduction The Lymphoma Research Foundation (LRF) has previously produced, and now updated, guide books for non-Hodgkin lymphoma (NHL) and Hodgkin lymphoma (HL) patients. Non-Hodgkin lymphoma, however, was treated broadly, covering the multiple subtypes of the disease. In collaboration with the CLL Information Group (CIG), LRF has now prepared the first disease-specific lymphoma information book, focusing on chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL). These two entities are essentially the same disease, presenting in two different locations—either the blood (CLL) or the lymph (SLL). Although the two information books developed by LRF are invaluable in providing much general information to lymphoma patients, this booklet, a first in a series, focuses on one specific disease subtype, CLL.

Understanding CLL/SLL 1

For more information, visit

lymphoma.org cllinfogroup.org

2 Understanding CLL/SLL

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Chapter 1

Cancer Overview Cancer Overview Cancer is a group of diseases that develop as the result of uncontrolled growth and spread of abnormal cells. Our bodies consist of millions of cells that grow and divide in an orderly fashion and work in harmony to support thousands of biological functions. These cells divide only when it is necessary to replace worn-out or dying cells to keep the body healthy. Cancer cells are different from normal cells because, instead of dying, they continue to grow and divide, forming new, abnormal cells. Cancer cells develop when there is damage to the DNA (the building blocks of genetic material found in every cell) that is caused either by inherited DNA cell damage or exposure to something in the environment, such as smoking. Oncogenes are packets of DNA that enable normal cells to turn cancerous. Usually the body is able to destroy these damaged cells, but when the body’s natural defense systems do not work, these abnormal cells may grow in an uncontrollable fashion, eventually forming a cancerous tumor. Understanding CLL/SLL 3

Overview of Chronic Lymphocytic Leukemia/ Small Lymphocytic Lymphoma Chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) are considered B-cell malignancies, generally thought of as a non-Hodgkin lymphoma, and are essentially the same disease with slightly different manifestations. The same kind of cell, known as a lymphocyte (a type of white blood cell), is involved in both CLL and SLL. The only difference between the two diseases is where the cancer primarily occurs. When the cancer cells are located mostly in the lymph nodes (small, bean-shaped organs of the lymphatic system found in nearly every part of the body, including the elbows, neck, under the arms and groin), the disease is called SLL. When most of the cancer cells are located in the bloodstream and the bone marrow (the spongy tissue inside bones where blood cells are made), the disease is referred to as CLL, although the lymph nodes and spleen are often involved as well. Thinking of CLL/SLL as a lymphoma and not a form of leukemia is important because CLL has a clinical course and treatment regimen that is similar to other indolent lymphomas. Chronic lymphocytic leukemia tends to be a slow-growing cancer. However, over time, it can progress to a more aggressive type of lymphoma. According to the American Cancer Society, approximately 15,000 new cases of CLL and 3,600 new cases of SLL are diagnosed annually. This form of cancer is usually diagnosed in older adults over the age of 50—more than half of the people with CLL are over age 70.

Causes of CLL Normally, bone marrow produces blood stem cells (immature cells) that develop into mature blood cells and become either a myeloid (blood forming) stem cell or a lymphoid (a type of white blood cell) stem cell. The myeloid stem cell develops into one of three types of mature blood cells: • Red blood cells, which carry oxygen and other materials to tissues in the body


1 • Neutrophils (white blood cells), which fight infection and disease • Platelets, which help prevent bleeding by causing blood clots to form The lymphoid stem cell develops into a lymphoblast cell (a lymphocyte that has become larger after being stimulated by an antigen) and then into one of three types of lymphocytes: • B-lymphocytes (B-cells), which make antibodies to fight infection • T-lymphocytes (T-cells), which help B-lymphocytes make antibodies to fight infection • Natural killer (NK) cells, which attack cancer cells and viruses When these cells grow old, they die naturally and are continuously replaced by new cells. Chronic lymphocytic leukemia occurs when there is damage to the deoxyribonucleic acid (DNA) of developing cells in the bone marrow. DNA acts as a blueprint for cells, instructing them how and when to grow and divide. Certain genes (packets of DNA), called oncogenes, cause cells to divide, while other genes, called tumor suppressor genes, slow down the process of cell division and cause cells to die normally (apoptosis) at the appropriate time. In CLL, something occurs to disrupt the process of cell death such that the cells do not die as planned. Instead, the cells accumulate in the lymph nodes, bone marrow, blood stream and other organs. The increasing number of lymphocytes in the blood and bone marrow crowd out healthy white blood cells, red blood cells and platelets, which may result in infection, anemia and easy bleeding. Although the exact mechanism that causes CLL is unknown, many people with the disease have chromosome abnormalities in their cells. Normal human cells have 23 pairs of chromosomes. Some people with CLL have an extra chromosome or some other abnormality.


Risk Factors for CLL Anything that increases a person’s risk for contracting a disease is called a risk factor. Unlike other forms of cancer, CLL has few known risk factors. Some studies suggest that certain environmental factors might play a role, including exposure to herbicides and insecticides used in farming or the defoliant Agent Orange used during the Vietnam War. It is important to remember that the presence of one or more risk factors does not mean that CLL will develop. In fact, most people with risk factors never develop the disease and many who are diagnosed have no known risk factors.

How the Immune System Works The immune system consists of a network of cells, tissues and organs that defend the body against “foreign” invaders (such as bacteria or viruses) or abnormal cells. Our ability to survive exposure to both external invaders and internal cell mutations (abnormalities) largely depends on the immune system. The immune system is the body’s first defense against disease. It is made up of highly specialized cells and a circulatory system separate from blood vessels called the lymphatic system. The specialized cells and the lymphatic system work together to rid the body of foreign invaders or abnormal cells before they can harm the body. These invading organisms and abnormal or cancerous cells are generally detected by the immune system through antigens (proteins that are located on the surface of all cells). Special receptors located on the immune cells lock on to these antigens. And just as a lock will only close with the right key, an antigen will only lock with a specific cell from the immune system. When an antigen and an immune cell lock together, the immune response begins, and the body acts to destroy, remove or wall-off the foreign invaders or abnormal cells. In CLL, the risk of infection is heightened due to a compromised immune system from the cancer and/or its treatment. About 75 percent of CLL patients will have hypogammaglobulinemia, a condition in which the level of immunoglobulins (antibodies) in the blood is low (hypo). This condition increases the risk for infection, despite the fact that CLL patients have the


1 normal amount of infection-fighting B-cells. One reason may be that the body’s T-cells, which help the B-cells make antibodies to fight off infection, are not working properly. CLL patients also have defective activation of a group of blood proteins called the complement system, which help fight common bacteria to which these patients are susceptible. To ward off infections, it is best to stay up-to-date on vaccines for pneumonia and influenza, although they may not work as well because of the impaired immune system resulting from CLL. Chronic lymphocytic leukemia patients should also avoid live vaccines (e.g., chicken pox vaccine). In addition, T-cell dysfunction may also be responsible for altering the immune system, causing it to attack healthy red blood cells (autoimmune hemolytic anemia) and platelets (thrombocytopenia). This can result in fatigue, shortness of breath and bleeding disorders. (See “Signs and Symptoms of Chronic Lymphocytic Leukemia,” on page 11.)

How the Lymphatic System Works The lymphatic system is one of the most important parts of the immune system because it protects the body from disease and infection. The lymphatic system is a circulatory system made up of a series of thin tubes called lymph vessels that branch like blood vessels into all tissues of the body (see page 8). Lymph vessels carry lymph, a transparent fluid that contains white blood cells called lymphocytes. Within this vast network of vessels are groups of small, bean-shaped organs called lymph nodes. Thousands of lymph nodes are found throughout the body, including the elbows, neck, under the arms and groin. Lymph flows through lymph nodes and specialized lymph tissues such as the spleen, tonsils, bone marrow and thymus gland. Lymph nodes filter lymph fluid, removing bacteria, viruses and other foreign substances from the body. If a large number of bacteria are filtered through a node or series of nodes, they may swell and become tender to the touch. For example, if a person has a sore throat, the lymph nodes under their jaw and in their neck may swell. Most swollen nodes are a reaction to infection and are not cancerous.





Thymus Lymph nodes


Spleen

Appendix

Bone marrow





Many of these invaders come from outside the body. The immune system is the body’s defense. It acts like a shield to detect and defeat these invaders.

Bacteria

Viruses

Parasites

Fungi

Pollution

Toxins


Sometimes the threat comes from within the body. Cancer occurs when abnormal cells cannot be controlled and continue to grow and multiply.








1 Chapter 2

Signs and Symptoms of Chronic Lymphocytic Leukemia A symptom is anything out of the ordinary a patient is experiencing that could be caused by a disease. A sign is any abnormality that a healthcare professional discovers upon examination of a patient. Oftentimes, people with CLL have no obvious symptoms of the disease at diagnosis. In fact, the cancer is usually discovered during a routine medical examination. According to experts, about one-third of all CLL patients will live for years—and even decades—without symptoms or serious ramifications of having the disease. Another one-third of patients will require therapy immediately or will be symptomatic within three to five years, requiring treatment. Another one-third will experience intermediate disease progression in which the cancer is dormant and then becomes active, but will respond to treatment. It is important to remember, however, that every person is unique. Symptoms of CLL occur because the malignant B-cells accumulate in certain areas of the body, such as in the blood, bone marrow, lymph nodes and spleen, crowding out healthy cells and causing a range of problems. For example, when malignant cells take up space in the lymph node, the lymph node enlarges (lymphadenopathy). When they take up space in the bone marrow, they may affect the blood cells in the following ways: • Because red blood cells carry oxygen from your lungs to all parts of your body, a shortage of red blood cells (anemia) can cause shortness of breath, fatigue and pale skin. • A shortage of healthy white blood cells (leukopenia) and/or neutrophils (a type of white blood cell), referred to as neutropenia or granulocytopenia, can make the body prone to developing infections. Even though CLL patients frequently have high white blood cell counts, the cells are not functioning properly and do not protect against infection the way normal white blood cells do.


• Blood platelet cells help prevent and control bleeding and promote blood clotting. When there is a shortage of blood platelets (thrombocytopenia), patients may experience easy bleeding, including frequent nosebleeds, bleeding from the gums or tiny red marks caused by minor hemorrhaging in the skin (petechiae). Patients may also bruise more easily. Chronic lymphocytic leukemia can also cause swelling of the liver and spleen and enlargement of the lymph nodes in the neck, underarm, stomach or groin. Other symptoms of CLL include: • Fever and/or chills • Severe weight loss in which ten percent of the baseline body weight is lost within six months • Profuse night sweats • Profound fatigue It is important to acknowledge that it is not clear what causes these symptoms.

When to Seek Medical Attention Although symptoms in the early phases of CLL are often vague and nonspecific, it is important that anyone who has persistent symptoms be seen by a physician to make sure that CLL is not the cause. The onset of CLL symptoms is a signal that the cancer is active and an indication that treatment should be started.

What the Physician Looks for During a Physical Examination Often, CLL does not cause symptoms. The first suspicion that something might be wrong may come from blood tests showing blood cell count abnormalities. However, physical symptoms may also be present and alert physicians of potential disease. Patients should tell their physician if they have been experiencing a general decline in health or have any of the following symptoms:


1 • Painless swelling of the lymph nodes in the neck, underarm, stomach or groin • Fatigue • Pain or fullness below the ribs • Fever and infection of the skin, lungs, kidneys or other sites • Weight loss The physician will take a medical history and perform a complete physical examination, checking for signs of disease, such as swelling of the lymph nodes, spleen and liver, and listening to the heart and lungs. The physician will also measure blood pressure and the pulse and look for any physical signs of infection or any other cancers, especially on the skin. If the physician suspects CLL after reviewing the symptoms and the results from the examination, other tests may be ordered to help confirm the diagnosis. These tests should include a complete blood count (CBC) and may include biopsies from a lymph node and/or the bone marrow and specific laboratory tests.





1 Chapter 3

Getting a Diagnosis— What to Expect Getting an accurate assessment of CLL requires a number of diagnostic tests. First, a hematopathologist (a physician who studies tissues and cells to identify blood diseases) or a hematologist (a physician specializing in blood disorders, including CLL) will examine blood and possibly bone marrow samples under a microscope looking for abnormal cells and changes in the structure or number of chromosomes in the lymphocytes. The hematopathologist or hematologist will also determine whether the lymphocytes are those of CLL or another type of leukemia or lymphoma. Depending on a patient’s situation, a physician may use some or all of the following tests, as well as a medical history and a physical examination, to select the course of treatment with the best chance of controlling the disease.

Laboratory Studies General Blood Chemistry Studies After the blood cells have been removed during blood testing, the fluid portion that remains is analyzed to help determine how well vital organs, such as the liver and kidneys, are performing. An unusual (higher or lower than normal) amount of a substance can be a sign of disease in the organ or tissue that makes it. During treatment, general chemistry tests may also be used to identify liver or kidney damage caused by the therapy regimen or other complications of the disease. Levels of immunoglobulin, a blood protein, may also be evaluated to ensure that there are enough antibodies to fight infections. Immunoglobulin levels are often low in people with CLL. Elevated levels of another blood protein, called beta-2-microglobulin, can indicate a more advanced stage of CLL.


Laboratory Tests Complete Blood Count Blood tests are routinely performed to diagnose CLL and are later used to determine how well treatment is working and whether the cancer is progressing. Information from a complete blood count (CBC) shows the characteristics and amounts of blood cells, including the number of red blood cells, the amount of hemoglobin (a protein found in red blood cells that carries oxygen), the different types of white blood cells (lymphocytes, monocytes, neutrophils, basophils and eosinophils) and platelets, and whether abnormal cells are present. Most people with CLL will have high levels of lymphocytes (lymphocytosis). Sometimes, CLL patients may not have enough red blood cells or have abnormal levels of platelets. Common Tests Used to Evaluate CLL Laboratory tests: • General blood chemistry studies • Flow cytometry • Immunohistochemistry • Polymerase chain reaction (PCR) • Mutational status • Fluorescence in-situ hybridization (FISH) and conventional chromosomal analysis • Other tests Biopsies: • Lymph node biopsy (not usually necessary and may be performed when clinically indicated) • Bone marrow examination and aspiration (not necessarily performed to diagnose CLL but is performed when clinically indicated) Imaging tests: • X-ray • CT (computerized axial tomography) scan (not routinely performed) • PET (positron emission tomography) scan (not routinely performed)


1 Flow Cytometry Flow cytometry is performed using samples of blood treated with light-sensitive chemicals, which are then passed in front of a laser beam. The amount of light given off by the sample identifies the presence of various cellular proteins. This technique measures specific proteins and/or antigens on cells and “clusters of differentiation,” called CDs. Cells carry these markers on their outer surface. The type and strength of expression of these markers help physicians determine whether the disease is CLL. The markers classically characteristic of CLL are CD5, CD20, CD23 and CD52.

Immunohistochemistry Immunohistochemistry is a test in which the cells in a sample of lymph node tissue, blood or bone marrow are examined under a microscope to look for the presence of abnormal cells associated with CLL and to determine whether the malignant lymphocytes originated from B-lymphocytes or T-lymphocytes. The tissue samples are treated with fluorescent chemicals that attach themselves to the malignant cells and are then looked at under a microscope to identify the abnormal cells.

Polymerase Chain Reaction (PCR) Polymerase chain reaction (PCR) is a specialized molecular test performed on either blood or bone marrow samples to identify malignant cells based on the cells’ genetic abnormalities. This test is primarily used following treatment to monitor the patient’s disease.

Mutational Status The mutational status of a gene known as IgVH may predict how quickly CLL might progress. Every B-cell rearranges its genes to make specific antibodies to a particular target (antigen), which, for instance, may be on a bacteria. When CLL is derived from cells that undergo the change to make antibodies (mutated genes), an individual will have a more indolent (slow-growing) course of disease. A person with un-mutated (unchanged) IgVH will likely have a more progressive and/or aggressive disease than those with the mutated gene.


Fluorescence In-Situ Hybridization (FISH) Fluorescence in-situ hybridization (FISH) is a test in which special fluorescent proteins are used to detect changes in the structure or number of chromosomes in the lymphocytes in samples of blood or bone marrow. Identifying these abnormalities helps physicians predict how CLL will progress. In CLL, abnormalities in chromosomes 11, 12, 13 and especially 17 are of particular interest. Chromosome 17 carries the p53 gene, which has an effect on regulating cell death (apoptosis). The normal functioning of the p53 gene is important in the response to chemotherapy. Loss of part of chromosome 17 is associated with particularly aggressive CLL.

Other Tests Other tests may include lactate dehydrogenase (LDH), tests for anemia and other tests the physician deems necessary.

Biopsies A biopsy is a procedure in which a piece of tumor tissue or bone marrow is removed from the body and examined under a microscope to look for abnormal cells.

Lymph Node Biopsy A “core biopsy” is obtained by inserting a needle into a lymph node suspected of being cancerous and removing a small tissue sample. An “excisional biopsy,” in which an entire lymph node or a generous wedge of tissue is surgically removed, is often the preferred method because it provides ample tissue for the pathologist to make an accurate diagnosis. A lymph node biopsy is not always necessary, however, it may be performed when clinically indicated.

Bone Marrow Examination and Aspiration Bone marrow is the spongy, soft material found inside our bones. Bone marrow contains immature cells called stem cells, which develop into three main types of cells found in the body:


1 • red blood cells that deliver oxygen to all parts of the body and take away the waste product carbon dioxide • white blood cells that protect the body from infection • platelets that help blood clot A bone marrow biopsy is obtained using a needle to remove a sampling of tissue most often from the back of the hipbone. During a bone marrow examination, physicians first numb the area around the skin, tissue and surface of the hipbone with a local anesthetic. While a bone marrow biopsy is not required to diagnose CLL, it can sometimes be performed when clinically indicated. The procedure can be painful at the moment when the marrow is withdrawn. Patients who are anxious about the test should talk with their physician and nurse to see whether taking a calming medication before the procedure would be helpful.

Imaging Tests Physicians will often order medical imaging tests to assess the condition of internal organs. These may be done as part of the overall diagnosis, to look for signs of cancer in internal organs, in preparation of treatment or as part of follow-up care. Most of these tests are painless and no anesthetic is required. Several types of imaging procedures may be needed to evaluate the CLL, including:

X-Ray X-rays use radiation to take pictures of areas inside the body. In CLL, an X-ray may be performed to examine the organs and bones. The amount of radiation used in most diagnostic tests is so small that it poses little risk to the patient.

CT (computerized axial tomography) Scan A CT scan takes X-rays from different angles around the body and is used to generate detailed cross-sectional images as well as three-dimensional images of the body’s internal organs. A dye may be injected into a vein or swallowed to help the organs or tissues show up more clearly. The


pictures obtained are then combined using a computer to give a detailed image. People with CLL may have CT scans of the chest, abdomen and pelvis. These tests are useful in determining how many nodes are involved, how large they are and whether internal organs are affected by the disease.

PET (positron emission tomography) Scans PET scans evaluate CLL activity in all parts of the body. To perform the test, a radioactive glucose (sugar) tracer substance is first injected into the body. A positron camera is then used to detect the radioactivity and to produce cross-sectional images of the body. PET scans are not routinely performed in CLL except when transformation to a more aggressive disease is suspected.

Other Tests In addition to these tests, physicians may also order tests to evaluate the health of organs potentially affected by treatments, such as the heart (echocardiograms or radionuclide tests) and lungs (pulmonary function tests).

Questions to Ask Your Physician Before Having a Procedure • Why is this procedure necessary? • What will the procedure tell us about my condition? • What is involved in doing this procedure? • What are the possible risks, complications and side effects? • Will I feel pain? • What will my out-of-pocket costs be? • Will I need someone to take me home afterwards?


1 Staging After a CLL diagnosis is confirmed, the stage of the disease will be determined. The Rai Staging System is used in the United States to determine the amount of disease, or tumor burden, that is present in patients with CLL. The Binet Classification System is more commonly used in Europe. It is important to note that the staging system used for CLL is different from other lymphomas because of the involvement of blood and bone marrow from the outset. The Rai Staging System is divided into five stages as follows: Stage 0 - Low risk. Lymphocytosis (an abnormal increase in the number of lymphocytes, a type of white blood cell, in the blood) is present in the blood or bone marrow only. Stage 1 - Intermediate risk. Lymphocytosis, plus enlarged lymph nodes. Stage 2 - Intermediate risk. Lymphocytosis, plus enlarged spleen and/or enlarged liver, with or without enlarged lymph nodes. Stage 3 - High risk. Lymphocytosis, plus anemia (low red blood cell count), with or without enlarged lymph nodes, spleen or liver. Stage 4 - High risk. Lymphocytosis, plus thrombocytopenia (low platelets), with or without anemia, enlarged lymph nodes, spleen or liver.

When to Begin Treatment A physician uses clinical judgment when deciding when to start treatment, although the Rai Staging System often plays a large role in this decision. The standard of care for stage 0 disease is observation. Only when a patient is participating in a treatment research study would he or she be offered any treatment. Patients with an intermediate risk category (stage 1 or 2) are generally observed. However, patients with poor prognostic markers (such as Zap-70 positive, unmutated IgVH genes, CD38 positive or certain types of chromosomal abnormalities) may be offered therapy early. It should be noted that confirmatory data for this approach are not currently available. Studies are now being performed to help determine whether early intervention for patients with poor prognostic markers is or is not useful. Patients in stage 3 and 4 generally require treatment. Understanding CLL/SLL 21

Getting a Second Opinion Before starting therapy, patients may want to consider getting a second opinion to confirm the diagnosis and treatment plan, particularly if some aspects of the CLL are complicated or uncertain. Some insurance programs require second opinions; others may cover it if a patient or physician requests it. Sometimes second opinions are obtained at academic medical centers. The hematologists/oncologists specializing in lymphoma may provide a consultation and establish a collaborative relationship with a local oncologist for treatment and follow-up care. When seeking a second opinion, patients should remember that it is best to request a complete copy of all medical records and provide original X-rays, pathology materials, scans and reports that are requested by the consulting physician. It may be useful to keep a copy of the medical records. A second opinion is not considered adequate unless another pathologist, preferably one well versed in CLL, reviews the tissue and blood samples. A patient’s physician or healthcare team can often recommend an oncologist for a second opinion.

Choosing an Oncologist and Treatment Center Before agreeing to treatment by a physician or clinic, a patient should be certain that all of their medical and personal needs will be met. Take time to check: (1) the credentials of the physician, the other members of the medical team and the hospital or cancer center, (2) the portion of time the physician spends researching or treating CLL and (3) the patient resources within the cancer center.


1 Patients should keep in mind that if in a managed care program, choices may be limited. However, if a patient is not entirely satisfied with their first consultation, they have the right to choose another healthcare team. Referrals may be obtained by speaking with other CLL patients or asking their primary physician. It is important that patients feel comfortable with their healthcare team and the quality of care they are receiving.

Questions to Ask When Choosing a Physician and Treatment Center Before beginning treatment, ask these basic questions: • How much experience does this physician (or clinic) have in treating cancer in general and lymphoma in particular? How many patients with lymphoma are being treated here now? • Is the physician board certified as an oncologist or hematologist? Has he or she passed qualifying examinations by the American Board of Internal Medicine that certify his or her competency in these specialties? • How does the physician or clinic stay up-to-date on the latest treatments for CLL? • Do the oncologists or hematologists in the clinic participate in clinical trials? • Does this center have state-of-the-art surgical facilities and diagnostic equipment? • Is the physician or clinic professionally affiliated with any major medical centers or medical schools? • What arrangements are made for medical coverage after hours and on weekends in case of an emergency?





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Part 2: T reating Chronic Lymphocytic Leukemia

Chapter 4

What You Should Know Before Starting Treatment Getting a CLL diagnosis is frightening and patients are naturally concerned about what their future may hold. Oftentimes, patients will ask their physician about their outlook or prognosis, the medical term used to describe how the disease will progress and the likelihood of recovery. To be an educated healthcare consumer, it is important to understand the nature of CLL and what to expect from treatments, including any possible effects on quality of life, such as lifestyle, emotions and financial issues. Prognosis is usually based on information gathered from hundreds or thousands of other patients who have had the same disease. This statistical information provides physicians with a general idea of what to expect when a patient is diagnosed with CLL and also gives guidance on the kinds of treatments that have been most successful in treating CLL. However, it is important to remember that no two patients are alike and that statistics from large groups of people do not always accurately


predict what will happen to a particular patient. A physician most familiar with an individual patient’s situation is in the best position to help interpret these statistics and determine their applicability. It is also important to remember that while progress has been made in understanding CLL there are no known prognostic markers physicians can use to determine how CLL will progress in individual patients, when to begin treatment or which treatments will be most effective. The one exception appears to be in CLL patients with a p53 deletion on chromosome 17. In those patients, the purine analogue fludarabine (Fludara), one of the most commonly prescribed chemotherapy drugs in CLL, may not be effective.

Prognostic Factors Affecting Treatment Outcome There are several traditional prognostic markers physicians use to determine when to start therapy and the type of treatment for each patient. They include: • The Rai stage at diagnosis • Lymphocyte doubling time (doubling in less than 3-6 months is associated with an unfavorable prognosis) • Pattern of bone marrow involvement • Age (younger people may tolerate the effects of more aggressive treatment because they generally have fewer health problems, such as heart or lung disease, that could limit the type or dose of therapy) • The presence of beta-2-microglobulin in the plasma (higher levels imply a poorer prognosis) • Number of circulating prolymphocytes (precursor of a lymphocyte) in the blood


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Novel Prognostic Markers Over the last decade, several novel prognostic markers have been identified and may be more accurate in predicting disease outcome. They include: • C D38 antigen expression - CD38 is a protein attached on the outside of leukemia cells. The presence of CD38 suggests a faster disease progression, although scientists still do not completely understand why CD38 plays a role in CLL. In addition, the exact level of expression for a cell to be considered “positive” is under debate. • F luorescent in-situ hybridization (FISH) - This technique is useful in finding common recurring chromosomal abnormalities in CLL, which reflect gene abnormalities. In CLL, chromosomes 11, 12, 13 and 17 are of particular interest. Hematologists pay particular attention to aberrations (variations from the normal) in chromosome 17, where the p53 gene is located, because the normal function of p53 seems to be crucial in how well patients respond to chemotherapy (See page 18 for additional description). • I mmunoglobulin heavy chain variable gene mutation status (IgVH)The mutational status of the IgVH gene helps predict how quickly CLL may progress. Patients with mutated IgVH are more likely to have an indolent (slow-growing) course of CLL. Patients with unmutated IgVH are more likely to have a progressive and/or aggressive disease. • Z AP-70 expression - ZAP-70 is an intracellular molecule involved with cell activation. The exact level of ZAP-70 seems to be crucial in deciding if a patient is positive or not for ZAP-70. The presence of ZAP-70 is associated with faster disease progression. The absence of ZAP-70 is associated with slower disease progression. • C D49d gene expression - CD49d is a surface protein on the outside of the CLL B-cell. Recent studies have shown that CD49d can be reliable in determining overall survival and when to initiate treatment. CD49d is measured by flow cytometry testing and is a potential therapeutic target.


It is very important to recognize that at this time the use of these novel prognostic markers is not fully understood and research is ongoing.

Performance Status Performance status is used to describe a person’s ability to follow a typical lifestyle. Those with good performance status (people who are active) tend to respond better to treatment than those with poor performance status (people with chronic health problems or those so ill that they are confined to bed), because they can tolerate more intensive therapy. Performance status is ranked on a scale from 0 to 5, with 5 having the poorest performance status.

Communicating With Your Healthcare Team People who are diagnosed with CLL are often anxious to learn all they can about their disease and treatment choices so they can play an active role in decisions about their care. For many people, getting a CLL diagnosis is shocking and it is normal to feel a lot of physical and emotional stress following diagnosis. Some people are uncertain about how to talk with physicians, and the combination of stress and uncertainty may make it difficult to know what to say or what questions to ask. Patients can ease their anxieties by establishing an open and honest dialogue with their physician and nurse regarding their diagnosis, and learning about what the prescribed treatment regimen is, how it works, what tests are involved and what side effects and complications may be associated with it. A good first step is to write down all of the questions that come to mind. Before meeting with a physician or nurse, whether for the first time or for follow-up visits, organize and write out all questions. Put the two or three most important questions at the top of the list, since time with physicians or nurses may be limited. But make sure that a member of the medical team reads all of the questions, because they may see some that are more important than the patient realizes. Also, it is helpful for patients to have a member of their family or a close friend accompany them to the physician’s office or clinic to help ask questions and understand and remember answers. It can also be helpful to write down the answers to the questions. Some patients bring a 28 Understanding CLL/SLL

recording device to record the answers. Patients should check with their physician before recording any conversations. Most oncology nurses are also very well informed about cancer treatments and are a good source of information on a wide range of topics. Oncology social workers are also available to assist with practical and emotional needs from the point of diagnosis onward. Although family members are often very concerned about their loved one and want information concerning his or her care, growing confidentiality rules prohibit physicians from giving out information to anyone without the patient’s expressed permission. For efficiency, it is suggested that one family member be designated as the family contact to the physician. However, the patient must inform their physician who this individual will be in advance. Tips on Communicating With Your Physician • Keep a journal of your symptoms to help you remember the details you want to discuss with your physician during your office visit and then bring a list of your questions to your appointment. • During your office visit, take notes or tape record your conversation to help you accurately review the information afterward. Bringing along a family member or friend for support and to take notes for you is also helpful. • Do not be afraid to ask questions when you do not understand something. Physicians want to know how best to explain information to you. • Before leaving the physician’s office, make sure you understand the next step in your care and ask if there is written information you can take home.

Writing an Advance Healthcare Directive and Appointing a Healthcare Proxy Writing down wishes for critical medical care in an advance healthcare directive is a way that patients can inform their physician, family members and friends about their healthcare preferences and what special treatment they want or do not want at the end of life. Besides stating medical care instructions, the advance healthcare directive should also include the name of the patient’s healthcare proxy, or decision maker. This person should be someone the patient believes will carry out their wishes if they are unable to do so, including do not resuscitate (DNR) Understanding CLL/SLL 29

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instructions. Before writing an advance healthcare directive, it is important that patients understand their rights and the laws regarding advance healthcare directives in their state. Consulting an attorney can provide the legal information, but patients do not have to use an attorney to write an advance directive. Some things a patient should consider when writing an advance healthcare directive include: • Specific instructions on the medical care, including the types of special treatment a patient wants or does not want, such as cardiopulmonary resuscitation (CPR), artificial respiration, drugs to make the heart function, kidney dialysis, artificial feeding and certain surgical procedures. • A patient’s choice of healthcare proxy.

How to Be a Self-Advocate Being a self-advocate and an active participant in healthcare can be a positive experience and may help restore a sense of control that was lost following diagnosis. It is important for patients to remember that they are a partner in their treatment plan and many patients feel better when they actively participate in their care. The first steps in participating in treatment are to ask questions, learn about options and work closely with the physician. Patients must be comfortable with their physician and the approach that they take. If not, patients should openly discuss their concerns. Confidence in the medical team often leads to confidence in treatment. If the patient does not feel that the team is a good match, they should ask for a referral. Questions will likely vary depending on the purpose of the meeting with the oncologist (e.g., the initial visit to discuss the diagnosis as opposed to a routine visit to monitor a remission). Ask for the timing of office visits, treatments and tests. The physician can help explain what the tests will look for and define the possible responses and the options for further care depending on treatment response. Although each person is different and each response to therapy is unique, knowing someone who has been through the same treatment and who may have had similar concerns can be a source of great comfort for patients. If a patient is interested in talking to and learning from people


who have had similar experiences, they should ask their oncologist, hematologist, oncology nurse or the oncology social worker about any support groups in their area. Patients should consider joining the Chronic Lymphocytic Leukemia Information Group (CIG) at cllinfogroup.org and signing up for CLL-specific discussion groups (See page 91 for instructions). The Lymphoma Support Network, a nationwide buddy program that matches patients or caregivers, offers the opportunity to share experiences and information, and offers support and encouragement. For more information about this program, call (800) 500-9976 or e-mail [email protected]. Before any tests are performed, a patient should check with their healthcare team to determine which costs are covered by insurance and which are not. A patient should not be afraid to broach nonmedical issues, such as transportation, finances, insurance and childcare, with the healthcare team.

Tips on Self-Advocacy • Do not be afraid to ask your physician or nurse questions about your care. • Learn more about your CLL from reliable websites, such as the Chronic Lymphocytic Leukemia Information Group (cllinfogroup.org) or the Lymphoma Research Foundation (lymphoma.org). Or ask your physician for information specific to CLL. • Take advantage of other services offered at your physician’s office, cancer center or hospital, such as counseling, support groups, nutritional counseling and fitness classes. • Consider joining the Chronic Lymphocytic Leukemia Information Group (CIG) at cllinfogroup.org • Sign up for one of several discussion groups ([email protected] or [email protected]) • Contact the Lymphoma Support Network, a nationwide buddy program that matches patients or caregivers. For more information about the program, call (800) 500-9976 or e-mail: [email protected].


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Questions to Ask Before Treatment Begins • What is my exact diagnosis? • What is the stage of my CLL? • What are my treatment options? Which do you recommend for me? Why? • What are the risks and possible side effects of each treatment? • What side effects should I report to you? • Are there any late- or long-term side effects I should be aware of with the treatment? • How long will the treatment last? • What are the chances that the treatment will be successful? • How will the treatment affect my normal activities? • Are new treatments being studied? Would a clinical trial be appropriate for me? • What is the treatment likely to cost? Does my insurance cover it?




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Chapter 5

Types of Treatment Currently Available Fifty years ago, the only therapies available for people with CLL were the alkylating agents chlorambucil (Leukeran) and cyclophosphamide (Cytoxan). Today, there are numerous effective treatment options available to physicians and patients including those recently approved (e.g., bendamustine), although a cure for the disease remains elusive. Generally, CLL manifests as either an indolent (slow-growing), asymptomatic disease that requires no initial treatment or a more aggressive form that requires immediate treatment. The last decade has seen dramatic advancements made in both better prognostic tests and novel therapies for CLL. A better understanding of the biology of CLL and the microenvironment around the tumor cells is resulting in more effective, less toxic treatments. While the ultimate goal for researchers remains finding a cure for CLL, the goal that appears closer at hand is the ability to turn the disease into a long-term, chronic illness in which patients will be able to experience a high quality of life. This chapter includes a description of standard and approved therapies, including: (1) watchful waiting, (2) conventional chemotherapy approaches, (3) newer versions of established agents, (4) monoclonal antibodies, (5) stem cell transplantation, (6) radiation therapy, (7) splenectomy and (8) complementary and alternative remedies. For each section, a description of the mechanism of action will be presented, along with the therapies approved by the United States Food and Drug Administration (FDA) at the time of print. It is important to remember that new therapies may have been approved since this book went to print and that additional indications for the therapies discussed in this chapter may be granted as clinical trials reveal new uses. Refer to Chapter 12 for therapies under investigation. For the most up-to-date resources, visit lymphoma.org or fda.gov. Understanding CLL/SLL 33

Watchful Waiting Watch and wait has been the standard approach to care in asymptomatic CLL patients. However, the long-standing approach is coming under closer scrutiny as better targeted, less toxic drugs are making their way to the clinic. Early results from clinical studies are showing that there may be a benefit in treating patients at the time of diagnosis, even some in early stage, when they are healthier and better able to tolerate therapy. There are also some indications that early treatment may give cancer cells less time to develop resistance to the therapy. Studies are underway now in the United States in CLL patients with high-risk prognostic factors as determined, for example, by the presence of an unmutated immunoglobulin heavy chain variable gene, to determine whether they would benefit from immediate therapy with the purine analogue fludarabine (Fludara) and the monoclonal antibody rituximab (Rituxan). A similar study in Europe looks at early therapy of asymptomatic patients with this gene mutation as a well as other poor prognostic factors to see if such intervention with fludarabine (Fludara), cyclophosphamide (Cytoxan) and rituximab (Rituxan) could improve their outcome compared to treatment only at disease progression. However, these studies are ongoing and no conclusions can be drawn at this time. Results from these studies will not be known for years. In the meantime, CLL patients with so-called high-risk prognostic factors in early stage disease may want to discuss with their hematologists/oncologists the advantages and disadvantages of early treatment and whether to participate in a clinical trial. It is important to keep in mind, however, that prognostic markers predict how well a population of patients will do, but not how one individual patient will do. They are not generally used to determine when to initiate therapy. However, based on recent studies, it appears that the knowledge of these prognostic factors is likely to influence the selection of the most appropriate therapy when it is indicated.

Chemotherapy Chemotherapy (“chemo”) is a cancer treatment with drugs (as opposed to radiation, for example). Many different medications are used to either kill cancer cells or prevent them from growing. Because of how they


work, chemotherapy drugs may also have a similar effect on rapidly dividing normal cells such as hair, nails and the cells in your mouth. People with advanced or symptomatic CLL are generally treated first with chemotherapy in combination with monoclonal antibodies (proteins that bind specifically to the tumor cells and kill them, sparing normal tissues). Chemotherapy regimens in CLL are generally well tolerated.

Combining Chemotherapy Drugs Chemotherapy for lymphoma often consists of giving several drugs together (combination chemotherapy) in a defined way (schedule), called a treatment regimen. Drug combinations are used because different medications damage or kill cancer cells in different ways, making them more vulnerable to the treatment. Combining chemotherapy drugs provides a more effective way to kill more tumor cells because using the drugs together greatly augments the impact each drug would have if used individually or additively. This is called synergism. In addition, when some drugs are added together in lower doses, it helps reduce the likelihood of side effects without reducing the overall amount of effective chemotherapy.

Chemotherapy Cycles Chemotherapy is usually given in cycles in which each treatment is followed by several weeks of rest and recovery. Together, each period of treatment and nontreatment is called a chemotherapy cycle. A chemotherapy cycle is typically given every one, two, three or four weeks. The medicines are usually given according to a schedule, with a defined number of days passing between each time the drugs are given. Clinical trials have determined how often chemotherapy should be given to kill the most tumor cells while minimizing side effects. A typical chemotherapy regimen and cycle for CLL may include fludarabine (Fludara) and rituximab (Rituxan) or fludarabine (Fludara), cyclophosphamide (Cytoxan) and rituximab (Rituxan) given every day for three to five days, followed by no treatment for three to four weeks. Usually up to six cycles of the treatment are given, unless the regimen is ineffective or intolerable side effects develop necessitating the therapy be stopped. Also, fewer cycles are given if additional chemotherapy is thought to be less curative than harmful.


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How Chemotherapy Is Given Depending on the chemotherapy regimen, the type of drugs and the number of cycles, a patient may receive drugs in pill form, as an injection or as an intravenous push or drip. If patients are going to receive intravenous drugs (ones that are given through a vein) for multiple cycles, their physician may recommend having a catheter inserted. An intravenous catheter is a device that is put into a vein to make it easier to give drugs. Catheters may be left in place temporarily or permanently. There are several types of catheters. One type, called a Hickman-Broviac catheter, consists of one to three tubes inserted through the chest wall into a vein. Six to twelve inches of tubing remains outside the skin. The main advantage of this type of catheter is that blood tests can be drawn and drugs given without having to pierce the skin. Disadvantages include: (1) the possibility of infection, particularly if the catheter is not cared for properly, and (2) the tubes on the outside of the body make it more obvious that a catheter is in place. If patients have this type of catheter, the healthcare team will show them what needs to be done each day to care for it and to make sure it stays clean. A second type of intravenous catheter, called an Infusa-Port or Portacath catheter, is placed under the skin and appears only as a bump on the chest. The advantage of this catheter is that it is easier for patient care because it only needs to be maintained by a nurse once a month (called “flushing”). However, it also has disadvantages. Each time this type of device is used, an injection through the skin is required, and it may not always be convenient to draw blood samples. These devices may also occasionally clot. Another type of intravenous catheter is a peripherally inserted central catheter or PICC line, which uses a thin, soft plastic tube to deliver medicines and fluids through a large vein in the arm. The PICC line can be kept in place for months. It is a good option for patients who need to have many short infusions or continuous infusions given in a hospital or at home with a portable pump for a defined, shorter time. Patients should discuss the pros and cons of the different types of catheters with their physician. A patient’s situation and personal preferences will be considered in making this decision. 36 Understanding CLL/SLL

2 Common Types of Drugs Currently Available for THE Treatment of CLL Combination Chemotherapy HOP C • Cyclophosphamide (Cytoxan) • Doxorubicin or Hydrodoxydaunorubicin (Adriamycin, Rubex) • Vincristine (Oncovin) • Prednisone (Deltasone) CHOP-R • Cyclophosphamide (Cytoxan) • Doxorubicin or Hydrodoxydaunorubicin (Adriamycin, Rubex) • Vincristine (Oncovin) • Prednisone (Deltasone) • Rituximab (Rituxan) Monoclonal Antibodies Alemtuzumab (Campath) Ofatumumab (Arzerra) Rituximab (Rituxan) Immunomodulatory Drugs (Imids) Lenalidomide Alkylating Agents Bendamustine (Treanda) Chlorambucil (Leukeran) Cyclophosphamide (Cytoxan, Neosar) Oxaliplatin (Eloxatin) Purine Nucleoside Analogues Cladribine (Leustatin, 2-Cda) Fludarabine (Fludara) Pentostatin (Nipent) Steroids Prednisone, dexamethasone (Decadron, Dexasone) Methlyprednisolone (Solu-Medrol) Hydrocortisone Note: Rituximab (Rituxan) is not currently approved by the US FDA for the treatment of CLL. It is however approved for other types of lymphoma. Despite the pending approval of rituximab (Rituxan), most centers in the US are currently using the drug in combination with other treatments.


Newer Versions of Established Agents Scientists continuously examine new uses for established agents and also explore how to create newer versions of existing therapies to make them more effective and less toxic. The drug below represents a therapy recently approved in the United States for CLL.

Bendamustine (Treanda) Bendamustine (Treanda) is a novel alkylating agent that damages the DNA in tumor cells, thereby disrupting the cell cycle and causing cell death. Approved originally for clinical use in Germany for cancer, the US FDA approved bendamustine in 2008 for the treatment of indolent B-cell NHL that has progressed during or within six months of receiving rituximab (Rituxan) or a rituximab-containing regimen. It has also been approved to treat CLL. Data based on randomized controlled trials in Europe have now begun to suggest that rituximab (Rituxan) and bendamustine (Treanda) may have a more favorable toxicity profile and equivalent or better efficacy in patients with indolent lymphoma who have been treated with other combination chemotherapy regimens such as R-CVP and R-CHOP. The implications of this data have begun to suggest that this two drug combination regimen may spare patients exposure to multiple chemotherapy drugs and toxicity from these agents without comprising efficacy. Future clinical trials will continue to validate these observations and will begin to study bendamustine (Treanda) in combination with numerous novel therapeutic agents in CLL and other forms of lymphoma.

Monoclonal Antibodies Plasma cells, the most mature B-lymphocytes in the body, are blood cells that specialize in making antibodies. Each plasma cell is responsible for one antibody, otherwise known as a monoclonal antibody (MAb). Each MAb acts specifically against a particular antigen, which is sort of like a beacon that attracts antibodies produced by immune cells. Using new technologies, scientists can now produce large amounts of monoclonal antibodies that can be directed to a single antigen on the cell’s surface. A MAb is similar to a guided missile that homes in on an antigen target on the lymphoma cell and destroys the cell. 38 Understanding CLL/SLL

A number of strategies involving the use of MAbs to treat cancer are being studied, including: (1) MAbs that react or bind with specific types of cancer cells, thereby enhancing a patient’s immune response to the cancer, (2) MAbs that are attached to other anticancer drugs, toxins or radioisotopes, allowing the delivery of these drugs directly to the tumor and bypassing toxicity to most normal cells, and (3) MAbs that are used to help purge and destroy cancer cells remaining in stem cell preparations before the latter is infused in autologous bone marrow transplantation.

Alemtuzumab (Campath) Alemtuzumab (Campath) was the first Food and Drug Administration (FDA)-approved monoclonal antibody specifically for the treatment of CLL and targets the antigen called CD52. It works very well in patients whose CLL cells are confined to blood and bone marrow. It does not appear to work alone very well in patients with very large lymph nodes or spleen. However, in these situations, it has been used successfully in combination with other MAbs like rituximab (Rituxan) or with chemotherapy. Alemtuzumab (Campath) may increase susceptibility to certain viral, fungal and bacterial infections, and it is mandatory to use medications to prevent these infections while on this drug.

Ofatumumab (Arzerra) Ofatumumab (Arzerra) is another monoclonal antibody that targets the CD20 antigen, which is found on the surface of CLL cells. The FDA granted the accelerated approval of ofatumumab (Arzerra) for the treatment of patients with CLL whose disease is refractory to fludarabine (Fludara) and alemtuzumab (Campath) in fall 2009. Unlike other monoclonal antibodies, ofatumumab (Arzerra) binds to a specific part of the CD20 protein on the surface of cells called the small loop epitope. This drug kills cells by recruiting proteins called “complement,” that lead to cell death. It also induces antibody dependent cellular cytoxicity by recruiting the body’s natural killing cells to kill CLL cells. As this drug was just recently approved by the FDA, future editions of this book will provide more detail.

Rituximab (Rituxan) Rituximab (Rituxan) was the first monoclonal antibody approved for the treatment of lymphoma. It targets the protein antigen called CD20, which Understanding CLL/SLL 39

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Common Combination Drug Regimens Used to Treat CLL (brand names in parentheses) R=rituximab (Rituxan) is not currently approved by the US FDA for the treatment of CLL. It is however approved for other types of lymphoma. Despite the pending approval of rituximab (Rituxan), most centers in the US are currently using the drug in combination with other treatments.


Drugs

CHOP CHOP-R FR FCR PCR OFAR CFAR BR BCR HDMP + Rituximab

Cyclophosphamide (Cytoxan) Doxorubicin or Hydrodoxydaunorubicin (Adriamycin, Rubex) Vincristine (Oncovin) Prednisone (Deltasone) Cyclophosphamide (Cytoxan) Doxorubicin or Hydrodoxydaunorubicin (Adriamycin, Rubex) Vincristine (oncovin) Prednisone (Deltasone) Rituximab (Rituxan) Fludarabine (Fludara) Rituximab (Rituxan) Fludarabine (Fludara) Cyclophosphmide (Cytoxan, Neosar) Rituximab (Rituxan) Pentostatin (Nipent) Cyclophosphmide (Cytoxan, Neosar) Rituximab (Rituxan) Oxaliplatin (Eloxatin) Fludarabine (Fludara) Cytarabine Rituximab (Rituxan) Cyclophosphmide (Cytoxan, Neosar) Fludarabine (Fludara) Alemtuzumab (Campath) Rituximab (Rituxan) Bendamustine (Treanda) Rituximab (Rituxan) Bendamustine (Treanda) Cyclophosphmide (Cytoxan, Neosar) Rituximab (Rituxan) High-Dose Methylprednisolone (Solu-Medrol) Rituximab (Rituxan)


is found on the surface of most CLL cells. Rituximab (Rituxan) is currently approved in Europe for the frontline treatment of CLL. However, Food and Drug Administration (FDA) approval is pending for its use in CLL in the United States. Despite the pending approval of rituximab (Rituxan), most centers in the US are currently using the drug in combination with other treatments. Ongoing research is exploring the effectiveness of using rituximab (Rituxan) in combination with chemotherapeutic agents, such as fludarabine (Fludara), in the treatment of CLL.

Stem Cell Transplantation Stem cell transplantation is often divided into two types: (1) autologous, where the patient’s own hematopoietic stem cells are collected and transfused into the patient following some chemotherapy or radiotherapy (i.e., myeloablative therapy) and (2) allogeneic, when hematopoietic stem cells are collected from a related or unrelated donor and transfused into the patient. Typically, the sources of stem cells used in transplant include bone marrow, peripheral (circulating) blood and cells collected from the umbilical cord after a baby is born. Depending on the type of transplant (autologous versus allogeneic) and the extent of disease, the type of myeloablative therapy used will vary. Typically, autologous stem cell transplants rely on high doses of chemotherapy to eradicate residual lymphoma. In contrast, allogeneic and umbilical cord transplants rely on an immunologically mediated anti-tumor effect (i.e., graft versus lymphoma) mediated by the donor stem cells. In CLL, the patient’s own hematopoietic stem cells are rarely used because they are often contaminated with the CLL. Usually in CLL, cells from a donor are used, most commonly in a reduced intensity allogeneic transplant. The utility of “reduced intensity” allogeneic transplantation (sometimes referred to as “mini-allogeneic transplantation”) in patients with CLL is well established and found to be better tolerated than the fully myeloablative transplants. In reduced intensity transplants, the patient receives low doses of chemotherapy or radiation, usually just enough to allow the body to accept the new cells from a donor. This approach is used to take advantage of the graft versus CLL effect, in which the transplanted donor cells recognize the tumor as a foreign entity


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and activate T-cells to destroy the cancer. Patients who experience a graft versus CLL effect may remain in remission for a longer period. Also, because patients receive lower doses of chemotherapy, they may avoid some of the toxicities seen with higher dose chemotherapy. In CLL, transplantation is a treatment option typically reserved for patients whose CLL does not respond to standard therapies, although for those with high risk features, transplant is being investigated earlier in the disease course. Those patients whose disease has transformed into a more aggressive form of lymphoma, called Richter’s syndrome, could potentially benefit from a stem cell transplant. For more detailed information about stem cell transplantation, please visit the National Marrow Donor Program’s website at marrow.org.

Radiation Therapy Radiation therapy (also called radiotherapy) uses high-energy X-rays to kill cancer cells and shrink tumors. Radiation is a local therapy, which means it only affects cancer cells in the treated area. While radiation therapy is not commonly prescribed in the treatment of CLL, it is sometimes used in patients with limited disease to relieve symptoms associated with bulky lymph nodes that develop as CLL cells accumulate. Radiation therapy used for localized CLL is called involved-field radiation in which the X-ray beam is directed only at the affected tissues. To prepare for radiation therapy, the skin is marked with tiny ink dots called “tattoos” so the exact same area will be treated every time. Before the first treatment, the healthcare team devotes a substantial amount of time marking the body to make sure that specific areas receive radiation. Normal tissues around the radiation field are shielded by lead, which blocks the path of stray radiation beams. Patients lie still on a table beneath a large machine that delivers the radiation. Props and supports with plastic forms, pillows and rolled blankets help keep patients in position. Once the preparations have been made, it takes only a few minutes to deliver the prescribed dose. Generally, treatment is given five days a week for five to six weeks.


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Splenectomy Some patients with CLL will develop a very large spleen due to an accumulation of CLL cells, which can cause discomfort or pressure. While radiation or chemotherapy are effective in relieving symptoms, removing the spleen usually provides longer lasting benefits, including increases in red blood cells and platelet counts. Patients who have their spleen removed are more vulnerable to certain infections, which, if not treated, could be life threatening. It is important for patients who have their spleen removed to start antibiotics early (almost immediately) if they develop a fever. Patients should be given the pneumonia vaccine prior to splenectomy even though the immune response by patients with CLL is less than optimal.

Complementary and Alternative Remedies The concept of holistic medicine to treat the mind, body and spirit became popular in the 1970s and is commonly known today as complementary and alternative medicine, but the terms have distinctly different meanings. Alternative therapy refers to unproven or disproven treatments that are used instead of standard or proven therapy. Complementary therapy is used in addition to standard medicine to help improve a patient’s quality of life and to relieve the effects of chemotherapy, radiation and surgery. Currently, there are no viable alternative therapies to conventional cancer care, and CLL patients should never use alternative remedies in lieu of standard care. Complementary medicine, also known as integrative medicine, includes a vast array of mind/body therapies such as meditation, guided imagery, self-hypnosis, tai chi and yoga; touch therapies, such as massage, reflexology and Reiki; acupuncture; and nutrition. However, because some complementary practices, such as ingesting certain herbs or botanicals, may negatively impact cancer treatment, CLL patients should consult with their healthcare team before embarking on any integrative medicine plan.


How Integrative Medicine Helps • Acupuncture—Acupuncture may relieve pain, nausea, fatigue, hot flashes and neuropathy (numbness and tingling in the feet and hands) associated with chemotherapy; and may help decrease mild depression. Done using new ultra-thin needles applied to specific points on the body, acupuncture is safe and painless. • Mind/Body Techniques—Meditation, guided imagery and self-hypnosis may be used to manage stress. Yoga and tai chi minimize stress and improve balance and flexibility. • Touch Therapies—Massage, reflexology (foot massage) and Reiki involve applying therapeutic pressure to the body and restore a sense of harmony, relaxation and well-being. • Nutrition—Eating a healthy, well-balanced diet is recommended for patients undergoing treatment.

What to Avoid Some supplements may increase or reduce the effectiveness of chemotherapy drugs. Patients should speak to their physician about everything they are taking or considering taking, including all over-thecounter medications, vitamins, herbs and other supplements, especially during times of treatment.

Drug Costs: What to Do if Your Insurance Does Not Pay Many cancer patients today face the problem of how to pay for soaring healthcare costs. Cancer organizations like the Lymphoma Research Foundation (lymphoma.org) and CancerCare (cancercare.org) offer limited financial assistance to patients who qualify. Most pharmaceutical and biotechnology companies have patient assistance programs in place that provide drugs for free to qualifying patients. If you are in need of financial assistance, talk with your physician about available options and how to enroll in an appropriate program. Also, drugs are often free in clinical trials.


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Part 3: D isease and Treatment Side Effects

Chapter 6

Transformations, Complications and Side Effects Chronic lymphocytic leukemia patients may experience a range of side effects from the treatment they receive. The various treatments, including chemotherapy, chemoimmunotherapy (a combination of chemotherapy and monoclonal antibodies), radiation and steroids, cause different side effects. Fortunately, there are many effective ways to make them more tolerable. In many cases, side effects can be lessened with medications or lifestyle changes.

Transformations One of the most serious complications of CLL is the progression or transformation to a more aggressive form of non-Hodgkin lymphoma known as diffuse large B-cell lymphoma. Also called Richter’s syndrome, this type of transformation is rare, with a risk of about one percent per year. CLL can also result in other forms of cancer including Hodgkin lymphoma and multiple myeloma. In some cases, a compromised immune Understanding CLL/SLL 45

system and/or the Epstein-Barr virus may be responsible for the transformation. Transformation can be difficult to treat especially in patients who have received prior chemotherapy. Patients with transformation often have fever, night sweats, weight loss, elevated LDH (lactate dehydrogenase) and characteristic changes on the PET scan.

Prolymphocytic Leukemia Prolymphocytic leukemia (PLL) is a relatively rare transformation of CLL. It is a variant of CLL with a more aggressive course of illness.

Myelodysplastic Syndrome and Acute Myeloid Leukemia Myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) are rare complications of CLL treatment. The transformation may be the result of certain combinations of chemotherapy agents, including chlorambucil (Leukeran) and other alkylating agents such as cyclophosphamide (Cytoxan), which damage the DNA of blood-forming cells. These damaged cells can become malignant leading to MDS and AML.

Complications Tumor Lysis Syndrome Tumor lysis syndrome consists of a group of metabolic complications usually occurring at the beginning of therapy when there are a high number of cancerous cells circulating in the body. This syndrome occurs when tumor cells release a number of waste products. Because the kidneys must clear these wastes, the rapid response to therapy can stress the kidneys, sometimes causing renal failure. Tumor lysis syndrome is usually manageable by the administration of fluids and/or slowing down CLL treatment. The drug allopurinol (Zyloprim) is often used prophylactically in patients who may be prone to tumor lysis syndrome. Rasburicase (Elitek) may also be used in high risk cases.

Shingles Shingles is a reactivation of the varicella-zoster virus, the same virus that causes chickenpox. Shingles usually causes a skin rash that blisters and stops abruptly in the midline of the body. This is associated with pain that can be severe. There are effective treatments for shingles, including the antiviral drugs acyclovir (Zovirax) and valcyclovir (Valtrex). However, 46 Understanding CLL/SLL

the best results are only achieved when shingles is treated early after onset. Delays in treatment often cause prolonged and even permanent pain in the involved regions of the body. Although vaccines are available to reduce the risk of shingles, they use live viruses and are not advisable for people with compromised immune systems, such as those with blood cancers. Also, patients receiving a purine analog or combination chemotherapy are placed on prophylactic (preventative) antiviral drugs (e.g., acyclovir or famvir) and/or medications (e.g., bactrim or septra) to prevent certain opportunistic infections, such as pneumocystis pneumonia (PCP).

Side Effects Side Effects Caused by Chemotherapy Chemotherapy is generally most effective at killing cells that are dividing rapidly, such as cancer cells. However, chemotherapy drugs are not selective. Therefore, they can also affect normal healthy cells, especially cells that are fast growing, such as hair cells and those in the mouth, the gastrointestinal tract and the bone marrow. Some chemotherapy drugs may also damage heart cells. Side effects of chemotherapy can vary widely depending on the types of drugs that are given and an individual patient’s response. Side effects can be mild or serious. Some of the most common side effects caused by chemotherapy include the following:


Decreased Blood Cell Production Red blood cells, white blood cells and platelets are constantly being produced in the bone marrow. Both chemotherapy and chemoimmunotherapy treatment may temporarily interfere with the ability of the bone marrow to produce adequate numbers of blood cells. When this occurs, it is called myelosuppression.


Some Common Side Effects Caused by Chemotherapy • Changes in taste

• Mouth sores


• Nausea/vomiting

• Diarrhea


• Fatigue

• Sterility

• Hair loss

• Secondary cancers

Anemia is the term used when myelosuppression causes a reduction in the number of red blood cells. Anemia can cause people to feel very tired and have shortness of breath. Mild or moderate anemia is common with many chemotherapy regimens, and treatment for the anemia may be necessary. Neutropenia is the term used when myelosuppression causes a decrease in neutrophils—the primary type of white blood cells found in the blood. Because neutrophils play a very important role in fighting infection, a low count may cause patients to develop serious or even life-threatening infections that require hospitalization or antibiotic therapy. Also, if the absolute neutrophil count (ANC) is too low, the chemotherapy dosage may need to be reduced or treatment delayed rather than risk infection. Infection is often accompanied by fever. Other symptoms of infection may include chills and night sweats. To prevent and control neutropenia, physicians will check patients’ white blood cell and neutrophil counts before and during each chemotherapy cycle. When neutropenia threatens a patient’s ability to receive the planned dose of chemotherapy, drugs such as filgrastim (Neupogen), pegfilgrastim (Neulasta) or sargramostim (Leukine) can be given after chemotherapy to reduce the duration and severity of neutropenia. These drugs can sometimes cause bone pain and, if in the chest, may make patients think they are having a heart attack. Nonsteroids may relieve this pain rapidly. By keeping the white blood count from dipping too low, these medications can help keep your chemotherapy doses on schedule. Occasionally, oral antibiotics are given to help prevent infection when neutrophil counts are low.


Thrombocytopenia is the term used when myelosuppression depletes the number of platelets in the blood. Platelets help start the clotting process when bleeding occurs. If platelet counts are low, patients may bruise easily. A low platelet count may also cause prolonged or excessive bleeding from cuts, nose bleeds, bleeding from the gums or bleeding without a previous injury. A platelet transfusion may be needed in some cases.

Risk of Infections A normal white blood cell count ranges from 4,000 to 10,000. Physicians regularly monitor the absolute neurtophil count (ANC), the number of neutrophils in the peripheral blood. When the ANC drops below 1,500, patients are at high risk for contracting infections. If a fever of 100.5°F or greater develops, patients should immediately contact their physician or go to the emergency room. Tips for Detecting Infection Due to Low Blood Cell Production Report these symptoms immediately to your healthcare team: • Fever (greater than 100.5°F)

• Diarrhea

• Sore throat


• Rash

• Cough

Diarrhea Diarrhea can be a side effect of chemotherapy. While most patients do not experience severe diarrhea, the most important thing to remember is to avoid dehydration (a loss of body fluids). Report any bloody diarrhea or fever with diarrhea to your healthcare team.

Fatigue Fatigue is a common side effect of many types of chemotherapy. Fatigue should go away after treatments are over, but it can take weeks or months until it is completely gone.

Hair Loss One side effect of chemotherapy is hair loss (also called alopecia). Thinning or loss of hair can occur at any place on the body, including the scalp,


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Tips for Avoiding Dehydration From Diarrhea or Vomiting • Drink plenty of liquids. • Look for signs of dehydration, including dry mouth or skin, decreased urine and dizziness or lightheadedness when you stand up. • Avoid milk products, which can worsen diarrhea. • Avoid hard-to-digest foods, such as those high in fiber, which can worsen diarrhea. • Eat plenty of bananas and other high-potassium foods (check with your physician or dietitian to make sure these foods will not interfere with your chemotherapy or other medications you are taking). • Take the medicines that your physician recommends to control diarrhea (notify your healthcare team if diarrhea occurs).

eyebrows, eyelashes, arms, legs and pelvis. The hair loss may be variable. It is important to note that hair loss does not occur with all drugs. Remember that hair loss due to chemotherapy is usually temporary. At first, the new hair growing in may be a slightly different texture or color than it was before treatment, but it oftens returns to normal.

Mouth Sores The membranes of the mouth may become red, sore or irritated during chemotherapy, which is referred to as mucositis. Infections of the mouth and throat caused by viruses or fungi may also occur. If throat soreness occurs, the healthcare team will examine the throat and may do a swab (called a culture) to check for infection, particularly herpes, fungus and bacterial infections. If an infection is present, several medications are available to treat it. To help reduce the risk of mouth infections, a physician may request a complete dental checkup and cleaning before receiving chemotherapy.

Nausea or Vomiting Chemotherapy can cause nausea or vomiting. Drugs that prevent vomiting (called antiemetics) include aprepitant (Emend), ondansetron (Zofran), granisetron (Kytril), metoclopramide (Reglan), prochloperazine (Compazine)


Tips for Coping With Fatigue • Keep a diary to help you identify when you have the most energy and what activities make you feel fatigued or give you energy. This can help you plan your activities for the times when you have the most energy. • Ask for help. This may be difficult for many people. Accept help if someone offers to assist you or if you need something you do not have the energy to do for yourself. Many family members or friends are happy to give assistance. • Exercise if your physician says it is okay to do so. But do not overdo it. Simple stretching, range-of-motion exercises or a short walk may give you more energy and not decrease the energy you have. Begin slowly and build up to the level that is right for you. Your physician, nurse or physical therapist can help you create a personal exercise plan. • Rest and sleep during therapy are very important, but try not to rest more than necessary, because it may decrease your energy level. Many patients find that taking an afternoon nap leaves them feeling less fatigued for the rest of the day, but others find that napping causes less restful nighttime sleep. If you are having trouble sleeping, talk to your healthcare team to determine the reason and what you can do about it.

Tips for Caring for Hair Loss These steps can help alleviate chemotherapy-induced hair loss: • Pat your hair dry rather than rub it with a towel after shampooing. • Use a soft-bristle brush and a wide-tooth comb when grooming your hair. • Avoid curlers and hair dryers. • Avoid coloring your hair or using chemicals on it. • Some people use a wig, scarf, turban or soft cotton hat or head wrap. Some health insurance companies cover the cost of wigs with a prescription from your physician. Check your policy to see if you are covered. • Use a hat or scarf to protect your scalp when out in the sun.


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Tips for Controlling or Minimizing Nausea and Vomiting • Consume a liquid diet before chemotherapy such as broth, consommé or water. Avoid milk. • Avoid foods that are too hot, cold, sweet or spicy. • Eat smaller and more frequent meals rather than a few large meals each day. • Avoid strong or offensive odors. Get plenty of fresh air. • Take prescribed antiemetics before chemotherapy to prevent nausea. • If vomiting occurs, be careful to avoid dehydration (loss of body fluids).

and dolasetron (Anzemet), and a variety of corticosteroids, such as Deltasone (prednisone). Nausea most frequently occurs on the day chemotherapy is administered, but it can also start several days later. Physicians may prescribe an antiemetic before chemotherapy to prevent nausea. In most cases, antiemetics can partially or completely prevent nausea and vomiting.

Sexual Dysfunction Chemotherapy can cause a drop in libido (sex drive). Usually, a normal libido returns after treatment is finished. (See “Sexuality,” on page 59.)


Sterility Chemotherapy (and radiation) can sometimes cause either temporary or permanent sterility (the ability to have children) in both men and women, because the treatment may damage sperm and egg cells. The specific dose of treatment, whether the patient has received one or several therapies and the patient’s age at the time of treatment are all contributing factors to infertility side effects. Patients should speak with their physicians about fertility presevation before starting treatment. (See “Fertility Risks,” on page 61.)

Other Possible Side Effects Some of the other possible side effects of chemotherapy include cough, a decrease in lung function, skin rashes and general weakness. Some drugs may also cause damage to the nervous system called peripheral neuropathy. Nerve damage can cause side effects such as constipation or a tingling sensation in the fingers and toes. Patients should immediately report any painful local rash (which sometimes may be accompanied by blisters) to their physician. Other possible side effects include a sore throat and a loss of balance or coordination. Although many of these effects are temporary, some may last for an extended period.

Side Effects Caused by Radiation In CLL, radiation therapy (or radiotherapy) is sometimes used to shrink an enlarged spleen or swollen lymph nodes, eliminating symptoms stemming from those growths. Radiation therapy uses an invisible radioactive ray or beam of high-energy particles aimed at specific sites to kill cancer cells. While radiotherapy is painless, there are side effects associated with the treatment. The consequences of radiation therapy depend on the treatment dose, the part of the body being treated (usually side effects occur only in the specific area of the body being radiated) and the age of the patient, among other factors. Some common side effects caused by radiation therapy in CLL patients include: • Diarrhea or constipation

• Secondary cancers

• Fatigue

• Skin reactions

• Nausea Understanding CLL/SLL 53

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Radiation may also cause a drop in the number of white blood cells, which help protect the body against infection. Therefore, white blood cells will be monitored during treatment.

Fatigue The likelihood that patients will experience fatigue depends on their disease and the specific radiation plan. (See page 51 for tips on overcoming fatigue.)

Nausea Nausea may occur after radiation treatment, especially in patients who have radiation to the abdomen. Some people can avoid nausea if they eliminate eating (especially sweet, spicy or fatty foods) a few hours before radiation treatment. Taking a medication that prevents nausea (an antiemetic) before each radiation therapy session may be recommended. (See page 52 for additional tips regarding coping with nausea and vomiting.)

Skin Reactions Radiation can cause a slight to moderate reddening of the skin and is often accompanied by discomfort, itching and flaking. These skin changes usually diminish and disappear over a few weeks. During radiation treatment, patients can protect their skin by: • Avoiding exposing areas of the skin that are receiving radiation to the sun. These areas will always need extra protection, even after treatment is completed. • Wearing a T-shirt and using plenty of sunscreen (with a high SPF) when out in the sun.

Side Effects Caused by Steroids Steroid drugs, such as cortisone, dexamethasone and prednisone, may cause a variety of side effects, including insomnia (the inability to fall asleep), increased appetite, mood or personality changes, high blood pressure and weight gain. Prednisone may also trigger diabetes in patients


prone to that disease or make the diabetes worse in patients who already have the disease. High-doses of steroids may also cause osteoporosis in at-risk patients. Patients are advised to alert family and friends that personality changes may occur. Patients should avoid making hasty decisions. If personality changes occur, the physician should be informed—the dose may need to be reduced.

Long-Term Effects and Late Effects of CLL Long-term effects are defined as toxicities that happen during cancer treatment and continue for months or several years, such as fatigue, flu-like symptoms and chronic infections due to decreases in red and white blood cells and/or platelets. Late effects are side effects of cancer treatment that become apparent only after treatment has ended and may arise many months, years or even decades after treatment is completed, such as, infertility, osteoporosis and secondary cancers. People with CLL are at an increased risk for contracting secondary cancers, especially malignant melanoma and other skin cancers, soft-tissue sarcomas, lung cancer as well as other common cancers (e.g., breast, colon). People with CLL are also at risk for developing secondary leukemias. The combination of B-lymphocyte and T-lymphocyte defects and low gammaglobulin levels all conspire to make people with CLL more susceptible to infections, which can alter the immune system’s ability to fight off cancer cells. In addition, there is some evidence to suggest that the purine analogue cladribine (Leustatin, 2-Cda) and some alkylating agents used in the treatment of CLL may further damage the immune system, possibly raising the risk for secondary cancers. The risk for developing secondary cancers from radiation therapy depends on a number of factors, including the amount of radiation given and the part of the body treated. For example, CLL patients with more extensive disease in lymph node groups below the diaphragm are at greater risk for developing gastrointestinal cancers such as colon cancer. Less common secondary cancers include basal cell skin cancer and sarcomas of the bone and soft tissue.


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Combating Side Effects Pain Management Pain may result from treatment. For example, pegfilgrastim (Neulasta), given to stimulate white blood cells, may cause bone pain. Pain may also occur as a result of procedures or tests (such as bone marrow biopsy). Pain may be acute (comes on quickly) or chronic (lasts over a long period of time). Living with pain can have a negative effect on overall quality of life. However, many medical advances have been made in the treatment of pain, including an improved understanding of how medication works to relieve it. Many healthcare teams now include pain specialists. Several techniques, such as relaxation, guided imagery and biofeedback, may also relieve pain. Keeping a journal of when pain occurs, what it feels like (sharp, throbbing, etc.), how strong it is and how long it lasts will help physicians develop the most appropriate pain management plan. For more information on managing pain, visit the American Pain Foundation’s website at painfoundation.org.

when to see your physician Your physician or a member of your healthcare team will discuss possible treatment side effects with you prior to initiating therapy. If you experience a side effect that is not expected or if your complications are prolonged, see your physician. If you experience a medical problem that cannot wait for a regularly scheduled appointment, such as high fever, shortness of breath, unremitting nausea and vomiting, chest pains and dizziness, call your physician, who will evaluate your situation and decide your next course of action. If you cannot reach your physician or a member of your medical team, go to your hospital emergency room for a medical assessment and place another call to your physician.


Exercise Regular physical activity helps keep the cardiovascular system strong and body muscles flexible. Exercise can also help alleviate breathing problems, constipation, poor appetite and mild depression. It also helps reduce stress and fatigue. Several types of exercise are particularly helpful: • General physical activity, such as swimming, dancing, mowing the lawn • Aerobic activity to improve cardiovascular fitness, such as walking, jogging, bicycling • Resistance training to strengthen muscles, protect joints and help remedy osteoporosis by building bone mass, such as lifting weights or using resistance-training equipment, push-ups, carrying and lifting • Flexibility practices to improve range of motion, balance and stability, such as stretching and yoga Patients should consult their physician before starting an exercise program.

Diet Eating a healthy diet is important during CLL treatment. Nutritionists specializing in oncology care can be helpful in developing individualized nutrition plans. Patients should consult their physician before taking dietary supplements such as multivitamins or individual vitamin supplements because they may interfere with treatments.


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Chapter 7

Sexuality

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Sexual Function During Treatment The causes of sexual dysfunction experienced by men and women during and after a cancer diagnosis are varied. Psychological factors, such as fear about illness, altered body image due to hair loss and depression, and the physical side effects of treatment, can all conspire to reduce sexual desire (libido) and function. Besides fatigue, some chemotherapy treatments can interfere with testosterone levels in men, resulting in low libido. In women, decreased estrogen production may cause vaginal dryness, hot flashes and other menopausal symptoms. In women, radiation therapy to the pelvis can cause a narrowing of the vagina, painful intercourse and ovarian failure, resulting in infertility (see “Fertility Risks,” on page 61). Some antidepressants and over-the-counter medications also lower sexual desire, as do certain lifestyle choices, such as smoking and drinking. Be assured that the lack of sexual desire and function due to treatment is usually temporary. Although many people are often too embarrassed to raise the issue of sexual function with their physician, it is important to recognize that sexuality is an integral part of life and patients should discuss this with their physician. Physicians may order tests to track hormone levels and make recommendations to see a specialist and/or prescribe medications to restore erectile function in men and hormone therapy to alleviate vaginal dryness and other menopausal symptoms in women.

When to Use Contraceptives Lymphoma is not a contagious disease, and it cannot be caused by or transferred through sexual intercourse. However, because small quantities of chemotherapy may be found in semen or vaginal fluid of people undergoing treatment, using condoms is recommended during sexual intercourse. It is especially important for men to use condoms and women


to use birth control if they are getting chemotherapy and should be mandatory when taking immunomodulatory drugs, such as thalidomide (Thalomid) and lenalidomide (Revlimid), a derivative of thalidomide, which may cause birth defects in developing fetuses. Avoiding pregnancy while on chemotherapy is necessary since chemotherapy drugs may affect the fetus. Women should alert their physician if they suspect they have become pregnant. It is also recommended that people who have undergone stem cell transplants use condoms to reduce their risk for contracting cytomegalovirus and other infections, due to a compromised immune system. To further reduce risk of infection, patients should avoid sexual intercourse if their blood counts (hemoglobin, white blood cells and platelets) are low. Patients should ask their physician when it is safe to engage in sexual intimacy.

Questions to Ask Your Physician About Sexual Function • How will my treatment affect my sexuality? • Will sexual function be restored after my treatment is completed? • How long will it take for sexual function to be restored? • Are there successful treatments for my sexual dysfunction? • What can I do to restore sexual desire and function?


Chapter 8

Fertility Risks

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Treatment for CLL, such as certain types of chemotherapy, especially alkylating agents, and radiation therapy, can interfere with fertility in several ways. In addition to killing cancer cells, these treatments can also affect healthy cells and reproductive organs, like the ovaries and testes, which produce the eggs and sperm crucial to fertility. Whether the infertility is temporary or permanent depends on a number of factors, including the patient’s sex, age at the time of treatment, the specific type and dose of radiation therapy and/or chemotherapy used and treatment duration. Patients considering having children in the future should consult their physician before treatment begins. A fertility specialist may also be consulted.

How to Protect Fertility in Men Infertility occurs in men when the testes stop producing normal sperm cells. Currently, preserving fertility in men is much easier and more effective than preserving fertility in women. It involves collecting a sampling of semen and then freezing and storing it in a process known as sperm banking. The sperm can later be thawed and used for intrauterine insemination or in vitro fertilization. For men with low sperm counts, a procedure called testicular sperm extraction (TESE) can be performed in which testicular tissue is removed. The sperm extracted from the tissue can then be frozen and stored for later use. Some men who lose fertility immediately following treatment may regain fertility in the future, although the chance of recovering fertility depends on several factors such as age (younger people are more likely to get their fertility back than older people) and the amount and duration of radiation and chemotherapy treatments.


How to Protect Fertility in Women Cancer treatment may cause women to go into early menopause or may result in other damage that does not allow for a successful pregnancy. Although preserving fertility in women is more difficult than it is in men, the emerging field of oncofertility—a melding of two medical specialties, oncology and assisted reproduction—is providing new hope for lymphoma survivors concerned about their ability to conceive following treatment. To date, the most widely available and successful way of preserving fertility before cancer treatment begins is by removing eggs, fertilizing them in vitro with the sperm of a spouse or donor and then freezing and storing the embryos for future use (embryo banking). Eggs may also be stored unfertilized (egg banking). Banking and using unfertilized eggs is more difficult, but it is a technique that has been recently developed. Because both of these techniques require a number of weeks of treatment to complete, they may not be advisable for women needing immediate treatment of their lymphoma. Another fertility preservation method under active investigation is ovarian tissue cryopreservation (OTC) in which an ovary is removed laparoscopically and tissue from the ovary is frozen. Eggs from the tissue follicles are then fertilized and implanted. Lupron (leurolide) injections are sometimes given to halt production of hormonal function before chemotherapy begins, limit ovarian exposure to the treatment and protect the quality of the eggs. However, evidence of its success is highly controversial. Before treatment begins, all women of childbearing age should talk to their physician and a fertility preservation expert about the options available to them. For more more information on fertility preservation techniques, visit: • Fertile Hope (Fertilehope.org) • Institute for Fertility Preservation (Fertilitypreservation.org) • Myoncofertility.org


Chapter 9

If You Relapse or Do Not Respond to Treatment

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Although the majority of CLL patients respond favorably to initial treatment, achieving either a complete or partial remission, they may relapse (the cancer recurs) or become refractory (the cancer is resistant to treatment). In general, if a patient’s cancer becomes resistant to treatment, a more aggressive form of second-line therapy, such as a stem cell transplant, may be necessary. In the relapsed setting, if the patient has a low-burden of disease, it may not be necessary to immediately restart treatment and a period of observation, or watch and wait, may be appropriate. If there is evidence of progressive disease occurring after approximately 12 months following the discontinuation of treatment, patients can usually be successfully retreated with either the same therapy or other therapies.

Treatment for Relapsed/Refractory CLL The type of relapse experienced, when it occurs, the extent of the disease, overall health and the previous therapies received, all influence the type of treatment prescribed. For relapsed patients, the second-line treatment protocol will usually include a combination of chemotherapy and immunotherapy agents. There are many single-agent monoclonal antibodies being tested in clinical trials in relapsed CLL patients. Some common single-agent therapies currently used in the relapsed setting include: • Alemtuzumab (Campath) • Fludarabine (Fludara) • Chlorambucil (Leukeran) • Rituximab (Rituxan) • Ofatumumab (Arzerra) • Bendamustine (Treanda)


Some common combination treatment regimens used in the relapsed or refractory setting include: • CVP (Cytoxan, Vincristine, Prednisone) • FR (Fludarabine, rituximab) • FCR (Fludarabine, Cytoxan, rituximab) • R-CHOP (Rituximab, Cytoxan, Adriamycin, Vincristine, Prednisone) • BR (Bendamustine and rituximab) There are many novel therapies currently under clinical trial investigation in the relapsed/refractory setting and include: • ABT-263 (an inhibitor of the Bcl-2 protein) • Flavopiridol (a cyclin-dependent kinase inhibitor) • Oblimersen sodium (Genasense) • Lumiliximab (anti-CD23 antibody) • Lenalidomide (Revlimid) • TRU-016 (anti-CD37 protein) Additional agents emerge regularly. For a complete list, patients should contact Lymphoma Helpline (800-500-9976) or speak with their physician.


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Part 4: L iving With Chronic Lymphocytic Leukemia

Chapter 10

Regaining Your Life After Cancer Coping with CLL varies among individuals. Some common coping strategies are highlighted below.

Coping Communicating It is important that patients communicate their fears and concerns about having CLL with their loved ones, friends, physicians, nurses or social workers. Writing down their fears in a journal may also help.

Overcoming Depression It is not unusual for people living with cancer to feel sad or depressed. Being diagnosed with CLL and undergoing treatment can be challenging both physically and emotionally. Signs of sadness or depression include sleeping more or less than usual, lack of energy, crying and an inability


to concentrate. In addition to challenging life circumstances, depression may also be caused by certain medications. Patients who experience any symptoms of depression that last longer than two weeks should contact a psychiatrist, social worker, psychologist or counselor. The CLL Information Group, cllinfogroup.org, also offers online group discussions with patients and medical advisors.

Coping with Physical Changes Hair loss, weight loss/gain and changes in physical appearance may occur as a result of treatment. To cope with these changes, patients should speak with their healthcare team, get ideas from other CLL survivors and use techniques most comfortable to them.

Maintaining a Healthy Lifestyle Eating a healthy diet, engaging in regular physical exercise and getting sufficient rest can help combat the stress and fatigue of CLL and its treatment (see “Combating Side Effects,” on page 56).

Life After Remission and Follow-Up Care Although finishing CLL treatment can be significant, it is normal to experience ongoing feelings of anxiety and worry about a relapse. Adjusting to the “new” normal routines of life during and after cancer may take a few weeks or months to complete. Developing a wellness plan with guidance from the healthcare team may lead to a better sense of overall well-being. Some changes to consider making: • Quit smoking • Reduce alcohol consumption • Exercise (walking, biking, swimming) • Eat a healthy diet


Follow-Up Care Most people with CLL will have a favorable response to initial treatment, enabling them to achieve either a complete remission or a partial remission. However, regardless of the type of remission achieved, it is important that each patient adhere to a schedule of regular follow-up office visits established by his or her physician. Follow-up visits can range in frequency from every few months to once a year depending on the patient’s disease progression, age, general health and time from last treatment. Upong completing treatment, the healthcare team will develop a follow-up care schedule. This will include appointments with the hematologist/ oncologist as well as regular visits with the general practitioner, OB-Gyns, etc. The hematologist/oncologist will monitor the status of the CLL through physical examination and various tests (e.g., blood, imaging, etc.).

staying proactive To stay proactive in your healthcare, be sure to get the following information from your medical team: • Copies of your medical records and a written summary of your treatment in case you switch oncologists or need to see a primary care physician for routine medical care • A list of signs of disease recurrence and late side effects from treatment At your follow-up care appointments, be sure to tell your physician about: • Any new symptoms • Pain • Physical problems that disrupt your daily life such as fatigue, insomnia, sexual dysfunction, weight gain or loss • Any new health problems, such as heart disease, diabetes or high blood pressure • Any new medications or vitamins you are taking • Emotional problems, such as anxiety or depression


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Chapter 11

Clinical Trials A clinical trial is a research study designed to answer basic questions about a new treatment or a new way of using an old treatment. There are hundreds of CLL clinical trials now underway in hospitals, cancer centers and physicians’ offices around the country. The government, pharmaceutical and biotechnology companies, universities and physician groups often sponsor clinical trials. The Food and Drug Administration (FDA) and the institutional review board of participating hospitals or institutions must approve each phase in a clinical trial.

Basics of Clinical Trials Clinical trials are performed to study new drugs and treatment strategies. Clinical trial investigations may study the following: • A novel drug • A new indication (use) for a drug already approved by the FDA as a treatment for a different disease • Compare a new treatment with a standard treatment to determine which one is more effective or has fewer side effects Understanding CLL/SLL 69

New drugs must pass through a rigorous approval process governed by the Food and Drug Administration (FDA) before it becomes a standard therapy for use in hospitals and clinics. The trials used to assess these drugs are typically divided into three types, called phases, each of which is designed to answer certain questions. Phase I tries to determine whether a potential treatment is well tolerated; phase II tests the drug’s effectiveness in a small group of patients; and phase III tests the drug’s effectiveness compared to standard therapies or other available treatments in a large, varied group of patients with a specific cancer. Patients may be eligible to take part in different stages depending on their condition, type and stage of lymphoma and the type of treatment, if any, previously given.

Phase I Phase I studies (first in human studies) are designed to assess the maximum tolerated dose (MTD), frequency of treatment and overall safety of the drug in a small number of patients.

Phase II Once the therapy dose is determined and shown to be safe in a phase I trial, it is then ready to be tested in a phase II study. Phase II studies aim to establish whether the therapies have any evidence of effectiveness in a larger group of patients with a particular type of cancer (e.g., CLL). Phase II studies might be used to generate preliminary data on a drug or to confirm data to obtain FDA approval. Phase II studies also investigate whether a therapy already approved for one type of disease is effective treatment for another.

Phase III Phase III trials are performed to determine whether the treatments developed in phase I and II studies are better than what is currently considered the “standard of care” for a specific disease. Phase III studies often require a large number of patients. Once a patient elects to enroll in a phase III study, he or she is assigned to one of two groups in a process called “randomization.” In randomization, a computer assigns the treatment the patient is to receive. One group receives the standard


therapy and the other group receives the experimental treatment. It is important to remember that this randomization process is done so that each treatment arm will have patients with similar characteristics and be free of bias. The randomization in phase III trials allows researchers to determine whether or not the new treatment is any more effective or less toxic than the standard of care.

Use of a Placebo in Phase III Trials A placebo, or sugar pill, is an inactive ingredient that is used is some types of clinical trials to ensure that the test results are unbiased. It is important to note that clinical trial participants will never receive a placebo in phase III trials if standard therapy exists. Patients would only potentially receive a placebo if there were no standard therapies to test against. Placebocontrolled trials are never done in a manner to deny patients an effective therapy. They are often done to add a new therapy to what might be the standard therapy.

Participating in a Clinical Trial Clinical trials should not be considered a “last resort” by patients. Chronic lymphocytic leukemia patients can often benefit from participation in clinical trials both in the frontline treatment setting and in the relapsed treatment setting. Clinical trials offer patients therapies that are not otherwise available to all patients and are monitored very closely.

Informed Consent During the informed consent process, the healthcare team will review the design of the study, possible risks and benefits and what will be expected of the participant. The healthcare team will answer any questions and ask the patient to sign a consent form, indicating their desire to particpate in the study.

The Cost of Being in a Clinical Trial Clinical trials are very expensive undertakings for the study sponsor. Patient costs vary depending on the study, who is sponsoring the trial, what portion of the trial-related expenses the sponsor will cover and the patient’s health insurance coverage. Some health insurance and managed healthcare providers will pay for the basic medical procedures associated with the trial, such as lab tests, scans and hospitalization when required, Understanding CLL/SLL 71

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while others may define clinical trials as “experimental” or “investigational” and not cover some of the routine costs, such as physician visits, tests or treatments. The costs vary depending on the study and the health plan. Medicare provides coverage for patient care associated with governmentsponsored clinical trials. If a patient is taking part in a National Cancer Institute (NCI) trial being conducted at the National Institutes of Health (NIH) in Bethesda, Maryland, the NCI will pay for the study drug and the costs related to the study. A stipend for travel, food and lodging is also provided. Some cancer centers provide financial assistance or discounted rates for room and board and have special research units that will pay for study-related costs. Some organizations, including the Lymphoma Research Foundation, provide financial assistance for treatment-related expenses. (See “Drug Costs: What to Do If Your Insurance Does Not Pay,” on page 44.) Patients should ask their physician what clinical trials may be most appropriate for them. Here are some additional ways to find information: • Contact the Lymphoma Helpline at the Lymphoma Research Foundation at (800) 500-9976 to request a clinical trial search. • Cancer centers in your area may also have information about trials. • Coalition of Cancer Cooperative Groups (CancerTrialsHelp.org). • NIH websites (Cancer.gov and Clinicaltrials.gov). Questions to Ask Your Physician • What is the purpose of this clinical trial? • Who is sponsoring the trial (National Cancer Institute, a cancer center, a pharmaceutical company)? • How long does the study take? • What are the risks involved? • Will I be in any discomfort or pain? • What kinds of tests, procedures or treatments will be performed; how many and how often? • Will I be able to see my own physician during the trial? • What costs will I be resonsible for?


Chapter 12

Therapies Under Investigation Many drugs are approved by the United States Food and Drug Administration (FDA) for very specific and often restricted indications. This chapter will focus exclusively on those drugs that are not currently FDA approved for CLL and may represent major advances in our efforts to cure or manage cancer better. Therefore, patients may find that these drugs are only available in clinical trials. This chapter will forego detailed discussions about presently approved agents in CLL and efforts to expand their indications in specific subtypes of the disease. Refer to Chapter 5 for more detailed description of already approved agents in CLL. It is critical to remember that today’s science is moving very fast. Therefore, the charts in this chapter may not be entirely comprehensive or accurate depending on when this information is being read. Please check with the Lymphoma Research Foundation or your physician for additional information and recent updates. Therapy


Comments

Monoclonal Antibodies MDX-1342

CD19

Relapsed/refractory

Rituximab (Rituxan)

CD20

Approved in Europe for frontline treatment of CLL; FDA approved for various types of NHL in USA; FDA approval for CLL pending in USA

Veltuzumab

CD20

Relapsed/refractory

GA-101

CD20

Relapsed/refractory

Lumiliximab

CD23

Relapsed/refractory

Ontak (denileukin)

CD25

Relapsed/refractory

Lucatumumab (HCD-122)

CD40

Relapsed/refractory

Galiximab

CD80

Relapsed/refractory

TRU-016

CD37

Relapsed/refractory


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Monoclonal Antibodies A monoclonal antibody (MAb) targets a specific antigen, which is like a beacon that attracts antibodies and immune cells. Large amounts of antibodies can now be directed to a single antigen on the cell’s surface like a guided missile. The MAb homes in on its target, the antigen on the lymphoma cell, and destroys the cell. In addition to the two monoclonal antibodies approved for CLL, alemtuzumab (Campath) and ofatumumab (Arzerra), many other monoclonal antibodies are currently under investigation. These include MAbs targeting antigens such as CD19, CD20, CD23, CD25, CD37 and CD40.

Immunomodulatory Agents (IMids) Immunomodulatory agents, referred to as IMids, may not only impact the nourishing environment of the cancer cells, but may also inhibit the formation of new blood vessels (angiogenesis). They may also induce both apoptosis (programmed cell death) and growth arrest in resistant cancer cells. These drugs have also been shown to increase the numbers of tumor fighting natural killer (NK) cells in patients’ blood. These NK cells then mount a cellular response against the lymphoma. Thalidomide (Thalomid) and lenalidomide (Revlimid) are oral agents that have been approved by FDA for other blood disorders. Recent studies have shown that they work well in patients with CLL. Particularly impressive is their efficacy in patients with certain adverse prognostic factors where conventional therapies do not seem to work well. Side effects include lowering of platelet counts, neuropathy and increased risk of blood clots. There are several ongoing studies looking into the most effective use of these agents in CLL. Therapy


Comments

Immunomodulatory Agents (IMids) Thalidomide (Thalomid)

Immunomodulatory Agents (IMids)

FDA indications in myeloma; preceded approval of lenalidomide

Lenalidomide (Revlimid)

Immunomodulatory Agents (IMids)

FDA indication in myeloma and disease of bone marow failure; now being investigated in many forms of NHL


Proteasome Inhibitors Nearly all cells in the body continually break down their own protein components to remove improperly made or damaged proteins and to control cell growth and other vital processes. The “cellular disposal” system which handles these proteins is called the “proteasome.” In this form of cellular housekeeping, the proteasome cuts up protein molecules that are no longer needed by the cell. Recently, physicians and scientists have learned that certain cancer cells are particularly vulnerable to a new class of molecules called proteasome inhibitors. Bortezomib (Velcade), a therapy first approved for a type of blood cancer called multiple myeloma, was the first drug of this type approved to treat cancer. This drug has been approved for relapsed mantle cell lymphoma and is currently being tested as a therapy for follicular lymphoma and relapsed/refractory CLL. Therapy


Comments

Proteasome Inhibitors Bortezomib (Velcade)

Proteasome Inhibitor

Approved for treatment of multiple myeloma and mantle cell lymphoma; being investigated in relapsed/ refractory CLL

Dasatinib

Proteasome Inhibitor

Relapsed/refractory

Purine Analogs Purine analogs belong to a class of drugs called antimetabolites. These drugs enter the cell and are transformed into an active form of the drug that is incorporated into cellular DNA, interfering with its function and its ability to repair itself. This effect results in cell death. Therapy


Comments

Purine Analogs Forodesine

Purine analog

Relapsed/refractory

Clofarabine

Purine analog

Relapsed/refractory


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Bcl-2 Directed Therapies Perhaps one of the most exciting new areas in cancer drug discovery over the last decade has revolved around the discovery and development of new small molecules which appear to be able to “teach” cancer cells how to die. One intrinsic feature of every tumor cell is its ability to divide when it should not and to resist dying when it should die. This “cell death thermostat” is established by the expression of a variety of proteins in the cell known as pro- and anti-apoptotic modulators. Pro-apoptotic proteins induce cell death while anti-apoptotic proteins resist cell death. Clearly, tumor cells contain an overabundance of those anti-apoptotic proteins which help the tumor cells survive even despite very toxic environments including those imposed by chemotherapy. One of the first of these drugs is called oblimersen (Genasense). Since the development of oblimersen (Genasense), a variety of new small molecules, many of which are orally available, have been developed (e.g., ABT-263 and AT-101). These drugs appear to inhibit the anti-apoptotic influence of many different proteins within the tumor cell, thereby increasing the sensitivity of the tumor cell to the induction of cell death by chemotherapy. Though these agents are now in very early development, they have so far demonstrated very promising activity in early phase clinical trials across a whole range of lymphoma. The future development of these agents will be oriented toward studying them in combination and lowering the threshold required to induce cell death when given in combination with other drugs known to be active in lymphoma. These agents have the value that they target biology that is selectively overrepresented in tumor cells and therefore are not associated with the same toxicity seen with combination chemotherapy and to date have been found to be very tolerable in early phase I and II clinical trials in patients with lymphoma.


Agent


Comments

Other New Agents Oblimersen Bcl-2 (Genasense) ABT-263

Being studied in melanoma and CLL

Bcl-2 Lowers threshold necessary to kill cancer cells; active in CLL; may make chemotherapy more effective; broad applicability

AT-101 Bcl-2

Similar to ABT-263 above; orally available

Obatoclax mesylate (GX15-070) Bcl-2 Relapsed CLL, MCL and other forms of lymphoma

Other Agents Numerous other small molecules are under investigation in CLL. Therapy


Comments

Other New Agents Syk inhibitor

Relapsed/refractory

Flavopiridol

Cyclin-D Kinase inhibitor

Relapsed/refractory

GRN-163L

Telomerase inhibitor

Relapsed/refractory

PI3K inhibitor

Relapsed/refractory

Fostamatinib Disodium (FosD)

CAL-101


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Glossary of Medical Terms Absolute neutrophil count (ANC): A measurement of the number of mature neutrophils (a type of white blood cell) that are available for fighting infection. A low ANC increases the risk for infection.

Advanced disease: Disease that has spread to multiple locations. Aggressive lymphomas: Lymphomas that are fast growing and generally need to be treated immediately. Also called intermediate-grade or high-grade lymphomas. Allogeneic transplant: A procedure in which a patient receives bone marrow or stem cells donated by another person. Alopecia: Hair loss. Alopecia from chemotherapy is almost always temporary; hair grows back when therapy is finished.

Anemia: A shortage of red blood cells, causing weakness and fatigue. Angiogenesis: The process of developing new blood vessels. Antiangiogenesis therapies: Drugs that prevent tumors from developing new blood vessels, thereby stopping or limiting tumor growth. Antibody: A substance made by B-lymphocytes that reacts with antigens on toxins, bacteria and some cancer cells and either kills or marks them for removal. Antiemetic: A drug that reduces or prevents nausea and vomiting. Antigen: Identifying proteins located on the surface of all cells. The immune system uses antigens to determine whether cells are a necessary part of the body or need to be destroyed.


Autologous transplant: A type of bone marrow or stem cell transplantation in which a patient receives his or her own cells. Beta (2) microglobulin (B2M): A protein found in the blood. Higher levels of B2M suggest that the lymphoma may be more aggressive. Understanding CLL/SLL 79


Biopsy: Removal of a small piece of tissue for evaluation under a microscope.

Bone marrow: Spongy material found inside the bones containing stem cells that develop into three types of cells: red blood cells that deliver oxygen to the body and take away carbon dioxide; white blood cells that protect the body from infection; and platelets that help the blood to clot.

Bulky tumor: A large tumor, usually greater than five, seven or ten centimeters. Cancer: Abnormal cell growth that cannot be controlled by the body’s natural defenses. Cancerous cells can grow and eventually form tumors.


Cerebrospinal fluid: Fluid that is present around the spine and brain. It may be examined to determine if NHL has spread to these parts of the body. Chemotherapy: Treatment with drugs to stop the growth of rapidly dividing cancer cells, including lymphoma cells.


Chemotherapy regimen: Combinations of anticancer drugs given at a certain dose in a specific sequence according to a strict schedule. Clinical trial: A research study in which a new treatment is given to patients to determine whether it is safe, more effective or less toxic than current therapies. Combination Chemotherapy: Several drugs given together to increase response rate of certain tumors.



CT or CAT (computerized axial tomography) scan: This imaging test provides a series of detailed pictures of inside the body using an X-ray machine linked to a computer.

Cure: There are no signs or symptoms of lymphoma, and a significant period of time (usually defined by years) has passed during which there are no relapses. Decreased blood cell production: A decrease in the production of red blood cells, white blood cells and platelets that may occur as a side effect of cancer or cancer therapies. Also called myelosuppression.

Diaphragm: The muscle below the lungs and heart that separates the abdomen from the chest. Disease progression: The term used if the disease worsens despite treatment (also called treatment failure).

DNA: Abbreviation for deoxyribonucleic acid, an essential component of genes.

Dose intensity: A term used to describe giving the highest possible doses of drugs over a specific period of time with acceptable side effects.

Durable remission: When a complete response lasts for years. Dysgeusia: When familiar foods taste differently. Echocardiogram: Use of ultrasound to examine the heart. It is ordered when potential cardiotoxic chemotherapy is used. Etiology: The study of the causes of a disease. Extranodal disease: NHL that has spread outside the lymphatic system. Fatigue: A decreased capacity for activity that is often accompanied by feelings of weariness, sleepiness or irritability. Understanding CLL/SLL 81

Gallium (radioisotope) scan: When injected into the body, radioactive gallium is a chemical that collects in some tumors. The body is then scanned to see whether the gallium has collected in a tumor.

Generalized disease: A cancer that has spread throughout the body. Genes: The basic building blocks of heredity that are present in all cells. Genes are comprised of DNA and other materials.

Gene therapy: Therapy approaches that alter the genetic structure of tumor cells, making them more susceptible to either the immune system or chemotherapy drugs.

Grade: A method of classifying a tumor on the basis of how aggressively it is growing. Graft versus host disease (GVHD): Occurs when a donor’s bone marrow (graft) recognizes the recipient of the marrow (the host) as foreign. In response, the immune cells in the donor marrow attack the foreign cells in the host. Harvesting: A procedure in which stem cells are obtained from the blood or bone marrow for use in repopulating the body’s cells after high-dose chemotherapy.

Hematologist: A physician who specializes in treating diseases of the blood and blood-forming tissues.


Hodgkin lymphoma: One of the two major types of lymphoma that begin in the lymph nodes and tissues of the lymphatic system. All other lymphomas are classified as non-Hodgkin lymphomas. Hodgkin lymphoma has a characteristic cell, the Reed-Sternberg cell, seen by the pathologist under the microscope when looking at the tissue from the biopsy.

Hypogeusia: When the flavors of foods are not as strong as normal. 82 Understanding CLL/SLL

Hypothyroidism: A condition in which there is lower than normal production of thyroid hormone. Low thyroid levels can lead to a variety of effects, including mild weight gain, dry skin, fatigue and sleepiness.


Immune system: One of the body’s defense mechanisms. All lymphomas are diseases of the immune system. Immunological tests: Blood tests that detect the presence of diagnostic proteins or antigens on a tumor. Immunotherapy: See biologic therapy. Improvement: This term is used if a tumor shrinks following therapy but is still more than one-half of its original size.

Indolent lymphoma: Lymphoma that is slow growing and has few symptoms. Also called low-grade lymphoma. Lactate dehydrogenase (LDH): An enzyme found in the blood. Higher levels of LDH suggest that the lymphoma may be more aggressive.

Laparoscopy: Passing a tube through the abdominal wall to obtain a small sample of tissue for examination under the microscope.

Leukemia: Disease generally characterized by the overproduction of abnormal or immature white blood cells that circulate or are present in the blood. Leukopenia: A shortage of white blood cells, resulting in the inability to fight infecting organisms such as bacteria, fungi and viruses. Localized disease: A cancer that is only present in a limited part of the body, for example, the neck or armpits. Understanding CLL/SLL 83

Local therapy: A therapy that only affects a small area. Low-grade lymphoma: Lymphoma that grows slowly and has few symptoms. Also called indolent lymphoma. Lymph: The watery fluid in the lymph system that contains white blood cells (lymphocytes). Lymph nodes: Small bean-shaped glands located in the small vessels of the lymphatic system. There are thousands of lymph nodes located throughout the body, with clusters of them in the neck, under the arms, the chest, abdomen and groin. Lymph nodes filter lymph fluid, trapping and destroying potentially harmful bacteria and viruses. Lymphatic system: The channels, tissues and organs that store and carry lymphocytes that fight infection and other diseases. Lymphocyte: A type of white blood cell. Lymphocytes, carried along by the lymph fluid, are part of the immune system and fight infection.

Lymphoma: A malignant disease that begins in the lymph nodes, organs and tissues of the lymphatic system (immune system). Hodgkin lymphoma is one type of lymphoma; the other major type is called non-Hodgkin lymphoma. There are approximately 61 types of nonHodgkin lymphoma.

Malignant: Cancerous—a malignant tumor is a cancerous tumor. Medical oncologist: A physician who specializes in the use of chemotherapy, hormone therapy and many other types of biologic therapies to treat cancer.

Memory cells: Memory cells are types of B-lymphocytes and T-lymphocytes. After a foreign invader or unwanted cell has been destroyed, surviving B- and T-lymphocytes develop into specialized memory cells that remain on watch and can provide protection if the invader is encountered in the future.



Monoclonal antibodies: Biologic therapies that act specifically against a particular antigen. Scientists can produce large amounts of antibody that can be directed to a single target (or antigen) on the cell’s surface. Monoclonal antibodies have been developed to help combat specific cancers, including some forms of non-Hodgkin lymphoma.

MRI (magnetic resonance imaging): MRI uses magnets and radio frequency waves to produce images of inside the body. MRIs can provide information about tissues and organs that is not available from other imaging techniques.


Myelosuppresion: A reduction in the bone marrow’s ability to make red blood cells, white blood cells and platelets. Neutropenia: An abnormally low level of neutrophils (the white blood cells responsible for fighting bacterial infections).

Neutrophils: The primary type of white blood cells found in the blood that fight bacteria, etc. Non-bulky tumor: A small tumor, usually less than five centimeters (approximately two inches) Non-Hodgkin lymphoma (NHL): A group of several closely related cancers that arise from the lymphatic system. Although the different types of NHL have some things in common, they differ in what the cancer cell looks like under a microscope, how the cells grow and how the tumor affects the body. Oncologist: A physician who specializes in treating cancer. Some specialize in chemotherapy (medical oncologists), radiotherapy (radiation oncologists) or surgery (surgical oncologists).



Partial remission (PR): The term used when a cancer has shrunk in size by at least half but has not totally disappeared. The cancer can still be detected, and other treatments may be recommended.

Pathologist: A physician who specializes in studying disease through microscopic evaluation of body tissues and organs. Any tissue suspected of being cancerous must first be examined by a pathologist to confirm the diagnosis.

PCR (Polymerase chain reaction): A molecular test that can identify small amounts of genetic material. This test is done if looking for minimal residual disease.

Performance status: A term used to describe a person’s ability to follow a typical lifestyle.


PET (positron emission tomography) scan: A type of test that may be used instead of gallium scans to identify areas in the body that are affected by non-Hodgkin lymphoma. This test evaluates metabolic activity in different parts of the body using a radioisotope.


Primary therapy: The first therapy given after a diagnosis of cancer. Prognosis: The likely outcome of a disease, including the chance of recovery.



Radiation field: The part of the body that receives radiation therapy. Radiation oncologist: A physician who specializes in treating cancer with radiation.

Radiation therapy: The use of radiation beams (X-rays) to treat a cancer. High doses of high-energy radiation beams carefully focused on a tumor will kill cancer cells. Radiation therapy (with or without chemotherapy) is used to treat certain lymphomas. Radioimmunotherapy: A therapy that is prepared by attaching a radioactive isotope to a monoclonal antibody. Radionuclide tests: Tests that use radioactive substances to help evaluate the function of tissues.


Relapse: The return of cancer after treatment. Lymphoma may recur in the area where it first started, or it may occur in another place.

Remission: The absence of disease. A patient is considered in remission when the lymphoma has been treated and tumors have diminished by at least 50 percent (partial) or have totally disappeared (complete). Remission does not necessarily mean cure. Patients with intermediate or aggressive lymphomas must achieve a complete remission and maintain it for a period of time, usually five or more years, before there is consideration of cure. Patients with low-grade tumors are usually not considered cured because the disease can reappear even with a long remission of many years. Patients may have a complete or partial remission.

Understanding UnderstandingCLL/SLL CLL/SLL 87

Risk factors: Factors that may increase the chance that a person will develop NHL. It is important to note that most people with risk factors never develop lymphoma, and many who are diagnosed have no identifiable risk factors.


Spleen: An organ on the left side of the upper abdomen, near the stomach. A key component of the lymphatic system, the spleen produces and stores lymphocytes and releases them when required as part of the body’s response to infections and other stimuli. The spleen may store blood and remove old blood cells from circulation.

Stable disease: The disease does not get better or worse following therapy. Stage: The extent of cancer in the body, including whether the disease has spread from the original site to other body parts.

Standard therapy: The most widely used primary therapy. Synergism: The term used when two or more drugs given together provide a better anti-cancer effect than expected from the additive effects from the medications alone.

Systemic symptoms: Symptoms that affect the entire body. Examples of these include fever, night sweats and weight loss.


Thymus gland: A gland located behind the sternum (breastbone) that enhances the reproduction and development of lymphocytes. T-lymphocytes are processed in the thymus.



Tumor: An abnormal mass or swelling of tissue. Tumors may occur anywhere in the body. A tumor may be benign (non-cancerous) or malignant (cancerous). Vaccine: A substance or group of substances meant to cause the immune system to respond. A vaccine can help the body recognize and destroy cancer cells. Lymphoma vaccines often combine cancer antigens with a substance to stimulate the patient’s own natural defenses to fight the disease. These vaccines in lymphoma are custom-made for each patient, using a sample of tumor obtained from the patient’s lymph nodes.

VEGF (Vascular Endothelial Growth Factor): One of a number of substances that stimulate angiogenesis, blood vessel formation—a process necessary for tumor growth.

Watchful waiting: An approach in which no immediate medical, surgical or radiation therapy is given. Patients are followed closely to make sure the cancer does not progress. Watchful waiting is an appropriate option for some patients with indolent (slow-growing) non-Hodgkin lymphoma.

Xerostomia: A temporary reduction in the production of saliva or “dry mouth.”

X-ray: Radiation that is used in low doses to provide images of the inside of the body and in high doses to treat cancer.





About CLL (Chronic Lymphocytic Leukemia) Information Group (CIG) The CLL Information Group (CIG) was created in the autum of 2004 to provide disease-specific information to CLL/SLL patients and their caregivers. The CLL Information Group is a membership network of CLL patients and currently serves nearly 1,000 members. The CLL Information Group organizes teleconferences with renowned CLL specialists, provides educational webcasts on CLL-specific topics and assists in the creation of various seminars and workshops for CLL patients.

Website (cllinfogroup.org) In 2007, CIG launched an educational website. The site is frequently updated with the latest information on CLL-specific treatments and research, making it a complete and comprehensive resource for CLL patients.

Internet Discussion Group An internet-based discussion group exists in relation to CIG ([email protected]), which focuses on the medical, educational and technical issues CLL patients currently face. The group is regularly joined by CLL expert Richard Furman, MD, of the New YorkPresbyterian Hospital, Weill Medical College of Cornell University.

Contact Information To join CIG, send an e-mail to [email protected], or log on to the web site above. To join the discussion group, send an e-mail to [email protected] and follow instructions.





About the Lymphoma Research Foundation The Lymphoma Research Foundation (LRF) is the nation’s largest lymphomafocused nonprofit health organization devoted exclusively to funding lymphoma research and providing patients and healthcare professionals with the most current information on the disease. The Foundation’s mission is to eradicate lymphoma and serve those touched by this disease. The Lymphoma Research Foundation was formed in 2001 with the merger of the Cure For Lymphoma Foundation (CFL) and the Lymphoma Research Foundation of America (LRFA). Both organizations were founded by lymphoma advocates who wanted to turn a life-altering diagnosis into a positive experience for others with the disease. Ellen Glesby Cohen founded LRFA in Los Angeles in 1991. Until her death in 2000, Ellen was a tireless champion for patients and their families who created new education and support programs and served as a staunch advocate for improved government legislation. Jerry and Barbara Freundlich founded CFL in 1994 in New York City. Jerry is a long-term survivor of non-Hodgkin lymphoma.

Resources for Patients, Survivors and Loved Ones Receiving a diagnosis of lymphoma can be challenging. Whether you or someone you love is newly diagnosed or a long-term survivor, understanding the latest medical information and accessing appropriate support services may help. Lymphoma Research Foundation offers a wide array of programs and support services to assist you from the point of diagnosis through long-term survivorship.

Patient Services and Support Lymphoma Helpline and Clinical Trials Information Service Through this phone and email service, trained staff members are available to answer your questions and provide individual support to you and your loved ones. Services are available in any language.



Lymphoma Newsline Lymphoma-related news can be distributed to you directly through this free electronic news services. Sign up by clicking on the “register” icon on LRF’s homepage at lymphoma.org.

In-Person Patient Education Programs North American Educational Forum on Lymphoma This two-day national forum is held annually and provides critical information about the latest in lymphoma research, making the best decisions about treatment options and patient support issues.

Lymphoma Workshop: Understanding Lymphoma Basics and Current Treatment Options These regional, full-day educational programs provide the latest information about lymphoma, current treatment options and patient support issues.



Podcasts Podcasts (video format) can be viewed on LRF’s website.


Teleconferences Teleconferences are hour-long interactive telephone programs that provide an opportunity to learn more about lymphoma, treatments and promising research from leading lymphoma experts. These are conducted live, and the archived version is available after the program.

Publications Patient Guides In addition to this publication, LRF also produces Understanding Non-Hodgkin Lymphoma: A Guide for Patients, Survivors and Loved Ones and Understanding Hodgkin Lymphoma: A Guide for Patients, Survivors and Loved Ones.

Fact Sheets Fact sheets with the latest disease- and treatment-specific information are available in either hard copy or in PDF on LRF’s website. New topics are added on a regular basis; check to see if the topic you are looking for is available.

Newsletters To keep you abreast of LRF research and news in the wider lymphoma community, you can sign up to receive any of LRF’s regular newsletters either electronically or via mail. Any of LRF’s publications may be ordered by visiting lymphoma.org. Individual and bulk copies are available free of charge.

Resources for Children and Young Adults Lymphoma in Your Teens, 20s and 30s The Foundation offers a wide array of webcasts and podcasts for individuals affected by lymphoma as teens or young adults, including topics specifically designed to help friends and family. Visit lymphoma. org/youngadults to access these programs.


LIVESTRONG Young Adult Alliance The Lance Armstrong Foundation’s LIVESTRONG Young Adult Alliance is a coalition of organizations with the goal to improve the survival rates and quality of life for young adults with cancer between the ages of 15 and 40. By visiting livestrong.org/yaa you can access the websites of all member organizations that specifically provide services for young adults with cancer.

Planet Cancer Planet Cancer (a program of the Lance Armstrong Foundation) is a peer support community for young adults going through the tremendously isolating experience of cancer between the ages of 18 and 40. On Planet Cancer, young adult patients and survivors connect 24 hours a day, 7 days a week through a dynamic and irreverent social networking website and face-to-face retreats. Planet Cancer also provides advocacy programs to build awareness about the unique medical and psychosocial needs of this oftenoverlooked age group. Visit planetcancer.org to access these services. Ulman Cancer Fund for Young Adults This organization focuses on how cancer affects young adults and offers scholarships, community grants, advocacy services and a guidebook. Visit ulmanfund.org for more information.

How to Access Programs and Services Many of the aforementioned programs are available on LRF’s website at lymphoma.org. For additional information about these resources, call (800) 500-9976 or email us at [email protected]. If you would like to order additional copies of Understanding CLL/SLL: A Guide for Patients, Survivors and Loved Ones, please call (800) 500-9976 or visit lymphoma.org.



Start or Join a Local Chapter Chapter volunteers work tirelessly to educate people about lymphoma, conduct outreach, raise funds for research and participate in public policy and advocacy initiatives. To learn more about a chapter in your area or how to start one, please visit lymphoma.org/chapters or call (800) 235-6848.


Join Team LRF Team LRF is a program through which people across the country raise much-needed funds and awareness for lymphoma research through sporting events such as marathons, half marathons, triathlons, hiking adventures, bowling tournaments, soccer matches, bike rides, lacrosse tournaments, paddling events, dance-a-thons, spin-a-thons, yoga-a-thons and much more. Join Team LRF in an existing LRF-partnered event in your area, or join Team LRF Teammates Across the Country if you wish to raise funds by starting your own event or by participating in an event in which LRF does not have official charity entries. For more information, visit lymphoma.org/teamlrf.


Notes _____________________________________________________________



Three easy ways to give: Website: lymphoma.org/donatenow Call: (800) 235-6848 M ail: Cut out this form and mail it to Lymphoma Research Foundation, 115 Broadway, 13th Floor, New York, New York 10006 or FAX Fax: (212) 349-2886

Amount of donation $ Make checks payable to the Lymphoma Research Foundation. You may also specify that your gift be used for CLL-specific research, or that it be channeled to the CLL Information Group (CIG). If so, please indicate this on your check or enclose a note.

Charge my n Amex

Credit Card #

n Visa

n MasterCard

Exp. Date

Name

Address

City

State

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Telephone (day)

(evening)

Email address


Notes _____________________________________________________________



This patient guide is supported through an unrestricted educational grant from: Presenting Sponsor

Understanding

Childhood Non-Hodgkin Lymphoma A Guide for Patients, Survivors and Loved Ones First Edition

Understanding

Childhood Non-Hodgkin Lymphoma A Guide for Patients, Survivors and Loved Ones First Edition

This guide is an educational resource compiled by the Lymphoma Research Foundation providing general information on childhood non-Hodgkin lymphoma. Publication of this information is not intended to take the place of medical care or the advice of your physician. Patients are strongly encouraged to talk to their physician for complete information on how their disease should be treated and followed. Before starting treatment, patients should discuss the potential benefits and side effects of cancer therapy with their physician.

National Headquarters 115 Broadway, 13th Floor New York, NY 10006 (212) 349-2910 phone (212) 349-2886 fax Helpline: (800) 500-9976 [email protected] Website: lymphoma.org Email: [email protected]

This project is supported through Cooperative Agreement Number 1U58DP001110 from the Centers for Disease Control and Prevention. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the Centers for Disease Control and Prevention. © 2010 Lymphoma Research Foundation Information contained herein is the property of the Lymphoma Research Foundation (LRF). Any portion may be reprinted or reproduced provided that LRF is acknowledged to be the author.

ACKNOWLEDGMENTS The Lymphoma Research Foundation wishes to acknowledge those individuals listed below who have given generously of their time and expertise. We thank them for their contributions, editorial wisdom and advice, which have truly enhanced this publication. Without their dedication and efforts this publication would not have been possible. We hope those in the lymphoma community will now be better informed and have a better understanding of their illness because of the gracious efforts of those involved in the planning and execution of this comprehensive disease guide. Editorial Board Laura J. Eisenberg, BSN, MN, ARNP, Seattle Children’s Anna R. Franklin, MD, MD Anderson Cancer Center Melanie Goldish, SuperSibs! Rebecca H. Johnson, MD, Seattle Children’s Barbara L. Jones, PhD, University of Texas at Austin School of Social Work Jennifer Mills, LMSW, MPH, New York University School of Social Work Sandi Ring, MS, CCLS, SuperSibs! Stuart E. Siegal, MD, Childrens Hospital Los Angeles James Testaverde, BS, Lymphoma Research Foundation Brian Tomlinson, MPA, BSW, Lymphoma Research Foundation Tim Walker, MA, National Marrow Donor Program

ii Understanding Childhood Non-Hodgkin Lymphoma

Table of Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 Chapter 1 Cancer Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Lymphoma Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Non-Hodgkin Lymphoma Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Common Types of Childhood Non-Hodgkin Lymphoma . . . . . . . . . . . . . . . . . . . . The Causes of Non-Hodgkin Lymphoma in Children . . . . . . . . . . . . . . . . . . . . . . .

3 3 6 7 9

Chapter 2 Diagnosing Childhood Non-Hodgkin Lymphoma . . . . . . . . . . . . . . . . . . . . . . . . . Use of Conscious Sedation When Performing Diagnostic Tests . . . . . . . . . . . . . Common Diagnostic Tests . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Staging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

11 11 12 15

Chapter 3 Childhood Cancer Clinical Trials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Unique Features of Childhood Cancer Clinical Trials . . . . . . . . . . . . . . . . . . . . . . Enrolling Children in Clinical Trials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Understanding the Clinical Trial Process . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Use of a Placebo in Phase III Trials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

17 17 18 20 21

Chapter 4 Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Chemotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Radiation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . What Happens If Relapse Occurs? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

23 23 27 27

Chapter 5 Supportive Care . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35 Side Effects of Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35 Chapter 6 Coping with Childhood Lymphoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . What Children Need and Hope For After a Lymphoma Diagnosis . . . . . . . . . . . . Emotional Coping for Parents, Adult Family Members and Friends . . . . . . . . . . Support for Siblings of Children with Lymphoma . . . . . . . . . . . . . . . . . . . . . . . .

41 41 43 44

Chapter 7 Long-Term and Late Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49 Glossary of Medical Terms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53 Resources . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65 Childhood Cancer Resources . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65 Young Adult Cancer Resources . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67 About the Lymphoma Research Foundation . . . . . . . . . . . . . . . . . . . . . . . . . . . 69 Donate Now . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75

Understanding Childhood Non-Hodgkin Lymphoma iii


lymphoma.org

iv Understanding Childhood Non-Hodgkin Lymphoma

Introduction This guide is designed for parents and loved ones of children and teens diagnosed with non-Hodgkin lymphoma (NHL) below the age of 18. If you are looking for resources on adults diagnosed with lymphoma, please refer to the Lymphoma Research Foundation’s comprehensive guides on adult lymphomas (www.lymphoma.org/ aboutlymphoma). If you are looking for resources on children diagnosed with Hodgkin lymphoma, please visit the Leukemia and Lymphoma Society’s website (www.lls.org.). Since the 1970’s research has led to significant improvements in outcome for children with NHL. With appropriate medical therapy, childhood NHLs are curable for over 80 percent of patients. Recent data suggests cure rates as high as 90 percent to 95 percent, depending on the type of tumor. Even for those children who develop recurrent disease, cures can often be achieved. It is important to remember that childhood NHLs are very different from other types of cancer in this respect. Furthermore, childhood cancers, as a group, have better outcomes than adult cancers. Because of the significant differences that exist between adult NHL and childhood NHL, it is crucial to find a designated pediatric cancer center for advice and treatment and to use childhood-specific NHL information for reference. This guide is divided into seven chapters. The material provides an overview of lymphoma and discusses: the different subtypes of lymphoma most common among children and teens, how lymphoma is diagnosed, the importance of clinical trials, available treatment options, supportive care issues, how to cope with the diagnosis, and the long-term and late effects that result from lymphoma treatments.

Understanding Childhood Non-Hodgkin Lymphoma 1


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2 Understanding Childhood Non-Hodgkin Lymphoma

1 Chapter 1

Cancer Overview This chapter will present a broad overview of cancer and, more specifically, non-Hodgkin lymphoma. Childhood lymphomas are divided into two categories: Hodgkin lymphoma (HL) and nonHodgkin lymphoma (NHL). This chapter will focus exclusively on describing the biology of NHL in childhood.

Cancer Overview The human body is composed of millions of cells that grow and divide in an orderly fashion to support thousands of biological functions. Cells divide routinely to replace cells that are damaged or dying. Cancer results from an uncontrolled growth and spread of abnormal cells. Cancer cells develop when there is damage to the cell’s DNA (the hereditary material found in every cell). This damage can be caused by an inherited genetic abnormality and/or exposure to something in the environment, such as smoking. The body’s immune system usually destroys damaged cells, but sometimes these abnormal cells evade the body’s defenses and grow uncontrollably, eventually forming a cancerous tumor.

Lymphoma Overview Lymphoma, a type of blood cancer, is more common in adults than in children. Approximately 98 percent of all NHLs occur in adults, with only 1.7 percent occurring in those under the age of 20. In children, lymphoma is the third most common cancer. Lymphoma usually develops when a genetic error, or mutation, occurs within a lymphocyte (a white blood cell), causing the abnormal lymphocyte to duplicate faster, or live longer, than a normal lymphocyte. Cancerous lymphocytes can travel to many parts of the body, through the blood stream and the lymphatic system, and form tumors.





Thymus Lymph nodes


Spleen


Appendix

Bone marrow



1 Immune System Invaders

Many of these invaders come from outside the body. The immune system is the body’s defense. It acts like a shield to detect and defeat these invaders.

Bacteria

Viruses

Parasites

Fungi

Pollution

Toxins


Sometimes the threat comes from within the body. Cancer occurs when abnormal cells cannot be controlled and continue to grow and multiply.





The Lymphatic System The lymphatic system is a circulatory system made up of a series of thin tubes called lymph vessels, which branch out like blood vessels into all tissues of the body. Lymph vessels carry lymph, a fluid that contains lymphocytes. Within this vast network of vessels are groups of small, bean-shaped organs called lymph nodes. Thousands of lymph nodes are found throughout the body, including the neck, armpits, groin and elbows. Lymph fluid flows through lymph nodes and specialized lymph tissues, such as the spleen, tonsils, bone marrow and thymus gland. Lymph nodes filter lymph fluid, removing bacteria, viruses and other foreign substances from the body. How Lymphocytes Work Lymphocytes, a type of white blood cell, are made in the bone marrow, spleen and lymph nodes, and circulate in the blood and lymph vessels. There are two main types of lymphocytes: B-lymphocytes and T-lymphocytes. Each type of lymphocyte plays a role in helping the body fight infections.

Non-Hodgkin Lymphoma Overview The two main forms of lymphoma are Hodgkin lymphoma and non-Hodgkin lymphoma (NHL). The World Health Organization has identified six types of Hodgkin lymphoma and 61 types of NHL. Although the various types of NHL have some things in common, such as their lymphatic origin, they differ in their appearance under the microscope, the proteins found on the surface of the cancer cells, their growth patterns and their impact on the body. Different forms of NHL require different therapies. Non-Hodgkin lymphoma has grown from being a relatively uncommon disease to being the fifth most common cancer in the United States, nearly doubling in incidence since the early 1970s. According to the American Cancer Society, over 65,000 new cases of NHL are diagnosed annually in the United States.


1 Non-Hodgkin lymphoma is divided into two major groups: B-cell lymphomas and T-cell lymphomas. B-cell lymphomas develop from abnormal B-lymphocytes (“B” because B-lymphocytes come from the bone marrow) and account for 85 percent of all NHLs. T-cell lymphomas develop from abnormal T-lymphocytes (“T” because normally T-lymphocytes spend part of their lifespan in the thymus gland, a small organ in the chest) and account for the remaining 15 percent of NHLs.

Common Types of Childhood Non-Hodgkin Lymphoma There are many different types of NHL. Correctly identifying or diagnosing the type of lymphoma a child has is critical because an accurate diagnosis allows the physician to select the most appropriate treatment for the child. (Diagnostic tests are described in Chapter 2.) Childhood NHLs can be broadly divided into four categories: 1. Lymphoblastic Lymphoma Lymphoblastic lymphoma is a type of NHL. However, this disease is often treated using protocols originally developed for a specific type of leukemia (a different form of blood cancer), called acute lymphoblastic leukemia. The survival rate for children with advanced stage lymphoblastic lymphoma is 60 percent to 80 percent. 2. Mature B-cell NHL Burkitt Lymphoma Burkitt lymphoma is an aggressive B-cell NHL that occurs in children and young adults far more commonly than in older adults. It accounts for approximately 50 percent of childhood NHL in the United States. There are three main types of Burkitt lymphoma: sporadic, endemic and immunodeficiency-related disease. While sporadic Burkitt lymphoma occurs throughout most of the world, endemic Burkitt lymphoma is found mostly in Africa, with the vast majority of cases associated with the Epstein-Barr virus (EBV). Immunodeficiencyrelated Burkitt lymphoma is diagnosed most often in people with


Common Types of Childhood Non-Hodgkin Lymphoma Childhood NHL

Lymphoblastic Lymphoma

Mature B-Cell Lymphoma

Diffuse Large BCell Lymphoma (DLBCL)

Anaplastic Large Cell Lymphoma (ALCL)

Other Rare Subtypes: (PTCL/NK)

Burkitt Lymphoma

congenital immunodeficiency or those infected with HIV. Common sites of disease include the jaw, central nervous system, bone marrow, bowel, kidneys, ovaries and testes. Burkitt lymphoma is considered one of the fastest growing cancers—the number of tumor cells doubles every 24 hours. Despite its fast growth, this type of lymphoma is often very responsive to chemotherapy. This is because the faster a tumor cell divides the more likely it is to be killed by treatment. Therefore, the treatments are usually very intense, with only a short time interval between courses of chemotherapy, so that tumors do not re-grow. The overall survival rate for children diagnosed with Burkitt lymphoma in the United States is 90 percent. Diffuse Large B-cell Lymphoma Diffuse large B-cell lymphoma (DLBCL) is the most common form of NHL in adults, but it is relatively rare in children. The disease is an aggressive (fast-growing) lymphoma and can arise in the lymph nodes or outside of the lymphatic system. It may be localized or generalized (spread throughout the body). Despite being an aggressive lymphoma, DLBCL is usually curable. Survival rates are extremely high for children diagnosed with DLBCL.


1 3. Anaplastic Large Cell Lymphoma Anaplastic large cell lymphoma (ALCL) is an aggressive T-cell lymphoma comprising 10 percent to 30 percent of all lymphomas in children and 3 percent of all lymphomas in adults. It is the most common T-cell malignancy in children. Anaplastic large-cell lymphoma can appear in the skin or in other organs throughout the body, also known as systemic ALCL. Patients with systemic ALCL are divided into two groups, depending on the expression of a protein called anaplastic lymphoma kinase (ALK). The prognosis is different based on whether a patient is ALK positive (expresses the protein) or ALK negative (does not express the protein). While both subtypes are treated with chemotherapy, ALK positive disease often responds permanently to chemotherapy, putting most patients in long-term remission or cure. A larger percentage of patients with ALK negative ALCL will relapse and potentially require more aggressive chemotherapy. 4. Other Rare Subtypes Other rare subtypes of childhood NHL exist. For more information on these rare subtypes, consult a physician specializing in pediatric lymphomas.

The Causes of Non-Hodgkin Lymphoma in Children Although the exact causes of NHL remain unknown, some common factors appear to have an impact on risk. The disease is more common among people with depressed immune systems and those exposed to environmental carcinogens, pesticides, herbicides, viruses and certain bacteria. The risk for developing lymphoma may be higher in individuals who: • have a family history of NHL • are immune-deficient due to either an inherited immunodeficiency (such as common variable immunodeficiency or autoimmune lymphoproliferative syndrome, also known as ALPS) or an infection (such as human T-lymphotropic virus type 1, also known as HTLV-1, or HIV/AIDS) Understanding Childhood Non-Hodgkin Lymphoma 9

• have received an organ transplant • have been exposed to chemicals such as pesticides, fertilizers or organic solvents for a long period • have been infected with viruses such as Epstein-Barr (which causes mononucleosis), which is associated with Burkitt lymphoma It is important to note that having one or more of these risk factors does not mean a person will develop NHL. In fact, most people with risk factors never develop the disease, and most of those diagnosed with lymphoma have never been exposed to clearly identifiable risk factors. While researchers do not know why NHL develops, they do know that it cannot be caused by injury or caught from someone who has the disease.


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2

Chapter 2

Diagnosing Childhood NHL Determining what type of lymphoma a patient has and where it is located in the body is important information for both the physician and the patient. An accurate diagnosis of childhood non-Hodgkin lymphoma (NHL) requires a number of tests. Physicians may use some or all of the following tests as well as the patient’s medical history and results from the physical examination to assess the best course of treatment: (1) blood tests, (2) biopsy, (3) imaging tests, (4) bone marrow examination and (5) lumbar puncture. Why these tests are needed and how they are performed will be described in this chapter.

Use of Conscious Sedation When Performing Diagnostic Tests Some of the tests described below can be painful, including biopsies, bone marrow biopsies and lumbar punctures (note that blood work does not involve pain beyond a needle prick). To prevent children from suffering, some physicians use a technique called “conscious sedation.” Conscious sedation drugs create an altered state of consciousness, like sleeping lightly, to minimize pain and discomfort. During conscious sedation, a patient can usually speak and respond to verbal cues. Patients that are given these drugs usually experience a brief period of amnesia, erasing any memory of the procedure. Parents should note that these drugs are administered only by physicians with specific training in conscious sedation. Pediatricians, oncologists or anesthesiologists may perform the sedation. These healthcare professionals carefully monitor breathing and vital signs throughout the procedure. Children undergoing conscious sedation will never be left unmonitored.


What You Should Know If Your Child Receives Conscious Sedation Planning for Conscious Sedation • Children should not eat anything several hours before receiving conscious sedation. The exact number of hours varies by institution. Your child’s oncologist will inform you of the instructions. What to Expect After Conscious Sedation • Your child will not remember anything from the procedures. • Most children wake up quickly, and recovery from conscious sedation is fairly rapid. Most children recover in one hour or less. • Children can resume eating immediately after conscious sedation.

Common Diagnostic Tests Blood Tests A complete blood count (CBC) may be performed to determine whether different types of blood cells, including red blood cells, white blood cells and platelets, are normal in number and appearance when viewed under the microscope. Abnormalities in these blood cells may be the first sign of lymphoma. Various blood tests may also be performed to determine whether lymphoma is affecting certain tissues or organs, such as the liver or kidneys, or to identify specific substances circulating in the blood that may help physicians select the most appropriate treatment option. For example, levels of the enzyme lactate dehydrogenase (LDH) and/or the protein beta (2) microglobulin (B2M) are commonly measured because higher levels of either or both suggest that the lymphoma may be more aggressive, indicating that a more intensive treatment may be needed. Biopsy A biopsy is a procedure in which a piece of tissue from an area of suspected disease is removed from the body and examined under a


microscope in order to determine which type of cancer the patient has. The type of biopsy performed often depends on the location of the lymphoma. Excisional Biopsy During an excisional biopsy, an entire lymph node or a large portion of it is surgically removed. This technique is often preferred because attempting to make a diagnosis from a small tissue specimen may lead to errors in diagnosis and sub-optimal therapy. Surgery may be necessary to obtain a sufficient sample of the tumor for examination. Needle Biopsy When tumors or lymph nodes are in locations that are difficult to biopsy (e.g., deep in the chest or abdomen), a needle biopsy (also called a core biopsy) may be performed. For this type of biopsy, a needle is inserted into a lymph node suspected of being cancerous and a small tissue sample is removed. Fine Needle Aspirate A fine needle aspirate (FNA) uses a very small gauge needle to collect a sample of cells from a cancerous lymph node. Such needle biopsies are more often used to confirm a relapse rather than an initial diagnosis because they generally do not produce sufficient tissue to establish a precise diagnosis. After a biopsy is performed, the sample is examined by a pathologist (a physician who studies tissues and cells to identify diseases) who develops a report. The oncologist uses this report along with results from other tests to confirm the diagnosis. However, if the pathologist’s interpretation of the biopsy is uncertain, the report should be reviewed by a hematopathologist (a pathologist who focuses on the identification of hematologic malignancies). Bone Marrow Biopsy Lymphoma is often found in the bone marrow, a material found within bones, which contains cells that develop into red blood cells,


2

white blood cells and platelets. To determine whether lymphoma is present in the bone marrow, a physician will insert a hollow needle into an area of the pelvic bone and extract a small tissue sample. The sample is then studied for signs of lymphoma by a pathologist. Lumbar Puncture NHL can sometimes spread to the nervous system. When this happens, the fluid present around the spinal cord and the brain (cerebrospinal fluid) may be abnormal and contain cancer cells. To determine whether this has occurred, the physician may recommend a test called a spinal tap or a lumbar puncture, in which a thin needle is inserted into the lower back. A small sample of fluid is then removed, and the cerebrospinal fluid is examined for chemical content and abnormal cells. Imaging Tests Physicians will often order imaging tests that provide pictures of areas inside the body. Most of these tests are painless. Some young children will be sedated if they are not able to lie completely still for the scans. Several types of imaging procedures may be needed to help best evaluate lymphoma, including the following: X-rays X-rays use radiation to take pictures of areas inside the body. For children with NHL, a chest X-ray is the most common type of X-ray. CT (computerized axial tomography) Scan A CT scan takes X-rays from different angles around the body. The pictures obtained are then combined using a computer to give a detailed image. People with NHL often have CT scans of the neck, chest, abdomen and pelvis. These tests are useful in determining how many lymph nodes are involved, how large they are and whether internal organs are affected by the disease.


MRI (magnetic resonance imaging) An MRI is similar to a CT scan, but uses magnets and radiofrequency waves instead of X-rays. An MRI can provide important information about tissues and organs, particularly the nervous system, which is not available from other imaging techniques. Because this testing technique creates clear images of the bones, brain and spinal cord, an MRI may be ordered to see whether the lymphoma has spread in these areas. PET (positron emission tomography) Scan PET scans have largely replaced gallium scans (in which radioactive gallium was injected into the body) in many cancer centers, because the technique is more convenient and more sensitive. This test evaluates NHL activity in all parts of the body. To perform the test, a radioactive substance is first injected into the body. A positron camera is then used to detect the radioactivity and produce cross-sectional images of the body. Unlike gallium scans, which are used primarily to detect response to treatment, PET scans are useful for both determining how much disease is present (staging) and how well it is responding to treatment. While CT scans show the size of a lymph node, gallium and PET scans show if the lymph node is active (still has disease). Today, CT and PET scans are often being combined into one test (CT/PET). Ultrasound Exam An ultrasound utilizes high-energy sound waves to create an image called a sonogram. This technique can be used for examining the abdomen.

Staging Childhood NHL is divided into four stages, based on how far the disease has spread in the body. Staging the disease helps physicians predict outcome (prognosis) and determine the most appropriate treatment approach.


2

Staging Stage

Description

I The lymphoma is found in one group of lymph nodes or one area outside the lymph nodes. To be identified as Stage I, the lymphoma cannot appear in the abdomen or mediastinum (the area between the lungs).

II The lymphoma is found in: (1) one group of lymph nodes and lymph nodes nearby; (2) two or more areas on the same side of the diaphragm; or (3) the stomach or intestines, but can be completely removed through surgery. III The lymphoma is found: (1) on both sides of the diaphragm; (2) in the chest; (3) in the abdomen, but cannot be completely removed through surgery; or (4) near the spine. IV The lymphoma is found in the: (1) bone marrow; (2) brain; or (3) cerebrospinal fluid.

Childhood NHL may also be categorized and treated according to the ABC grouping system. The number of chemotherapy cycles administered may differ by group. • Group A: Tumors that can be completely removed. • Group B: Tumors occurring in the chest or abdomen that cannot be surgically removed. • Group C: Tumors occurring in the bone, bone marrow, brain or other location outside of the lymphatic system.


Chapter 3

Childhood Cancer Clinical Trials Clinical trials are research studies designed by physicians and researchers to answer questions about new treatments or new ways of using existing treatments. The majority of children with cancer are treated in clinical trials. Over the past several decades, high clinical trial enrollment has led to rapid increases in the survival rates of children and teens with cancer. This chapter will discuss the unique features of childhood cancer clinical trials, describe the process of enrolling children in clinical trials, provide an overview of clinical trials and identify resources for more information.

Unique Features of Childhood Cancer Clinical Trials Today, over 80 percent of children diagnosed with cancer will be cured. This is a stark contrast to 50 years ago, when few children survived childhood cancer. Several strategic decisions within the scientific community led to this rapid increase in survival rates, including the following: • Collaboration: Progress in research only occurs when adequate numbers of patients are enrolled in clinical trials. For example, because childhood cancers are so rare, if one institution tried to enroll the relatively small number of patients with Burkitt lymphoma into a trial it would take decades before enough patients could be enrolled. Therefore, to make significant advances in the understanding and treatment of childhood cancers more quickly, the decision was made to establish strong clinical trial collaborations across institutions and countries. • Design: Clinical trials for children are based on what physicians and researchers know to be the “gold standard” of care for a particular subtype. Therefore, each clinical trial is designed to improve on the


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best therapies that modern medicine currently has to offer. Improvements may include how to give smaller doses or how to maximize effectiveness by adding an additional drug to an already effective regimen. • Consistency of Treatment: Due to the collaboration described above, the majority of children with the same type of non-Hodgkin lymphoma (NHL) will receive the same treatment regimen. For example, a child diagnosed with DLBCL in Kansas will likely receive the same treatment as a child diagnosed with DLBCL in Washington. When all children with lymphoma are treated as a group, researchers can learn things more quickly. Children’s Oncology Group Trials The success of the strategies listed above serves as the foundation for how children diagnosed with lymphoma are treated today. The Children’s Oncology Group (COG) consists of 5,000 childhood cancer experts from more than 200 institutions throughout the United States. COG designs, implements and evaluates the large-scale clinical trials conducted with children diagnosed with cancer today. Therefore, it is very likely that a child diagnosed with lymphoma will be treated on a protocol (term used to describe the details of a research study) designed by COG. It is important to note that COG trials for lymphoma often continue for five to ten years after they are initiated. Therefore, it is likely that the majority of children treated within a specific time period will receive the same treatment.

Enrolling Children in Clinical Trials Pediatric hematologists/oncologists will discuss the details of the specific trial and why it is most appropriate for the patient. Once the physician has explained the details of the trial, the parent(s) will be asked to give “informed consent” for their child to be “enrolled” in the study. These details will include:


• Name of the trial • Drugs used in the trial

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• Schedule of treatment • What to expect during treatment • Long-term effects of treatment For children under the age of 18 years, parents must provide consent for treatment. At some institutions, children over the age of 14 must also consent to receiving treatment. This also applies to children as young as seven at some institutions. It is important to remember that hundreds of physicians from around the country come together to design each trial and participants are carefully monitored while enrolled. Every trial must be approved by institutional review boards (IRBs) to ensure that the trial is ethical and that patients are kept safe. Clinical Trial Process Diagnostic Tests Conducted and Evaluated

Physician Evaluates Which Clinical Trial is Most Appropriate

Children are Closely Monitored Throughout Treatment

Treatment Begins

Physician Discusses Details of Clinical Trial with Parents (process known as “informed consent”)

Parents Consent on Behalf of Their Children


Understanding the Clinical Trial Process There are hundreds of NHL clinical trials now underway in hospitals, cancer centers and physicians’ offices around the country. The government, pharmaceutical and biotechnology companies, universities and physician groups often sponsor clinical trials. However, in childhood lymphoma trials, the majority are coordinated through the COG, as described above. Clinical Trial Phases Clinical trials are divided into three phases, as described below. Phase I Phase I studies (first in human studies) are designed to assess the maximum tolerated dose (MTD), frequency of treatment and overall safety of the drug in a small number of patients. Phase II Once the therapy dose is determined and shown to be safe in a phase I trial, it is then ready to be tested in a phase II study. Phase II studies aim to establish whether the therapies have any evidence of effectiveness in a larger group of patients with a particular type of cancer (e.g., Burkitt lymphoma). Phase II studies might be used to generate preliminary data on a drug or to confirm data to obtain United States Food and Drug Administration (FDA) approval. Phase II studies also investigate whether a therapy already approved for one type of disease is effective treatment for another. Phase III Phase III trials are performed to determine whether the treatments developed in phase I and II studies are better than what is currently considered the “standard of care” for a specific disease. Phase III studies often require a large number of patients. Once a patient elects to enroll in a phase III study, he or she is assigned to one of two groups in a process called “randomization.” In randomization, a computer assigns


the treatment the patient is to receive. One group receives the standard therapy and the other group receives the experimental treatment. It is important to remember that this randomization process is done so that each treatment arm will have patients with similar characteristics and be free of bias. The randomization in phase III trials allows researchers to determine whether or not the new treatment is more effective or less toxic than the standard of care.

Use of a Placebo in Phase III Trials A placebo, or sugar pill, is an inactive ingredient that is used is some types of clinical trials to ensure that the test results are unbiased. It is important to note that clinical trial participants will never receive a placebo in a phase III trial if standard therapy exists. Patients would only potentially receive a placebo if there were no standard therapies to test against. Placebo-controlled trials are never done in a manner to deny patients an effective therapy. In trials that include placebo medications for some patients, all patients are notified in advance about the possibility of receiving a placebo. The Cost of Being in a Clinical Trial Clinical trials are very expensive undertakings for the study sponsor. In children’s cancer the sponsor is usually the Children’s Oncology Group (i.e., funded by the federal government). Patient costs vary depending on the study, who is sponsoring the trial, what portion of the trial-related expenses the sponsor will cover and the patient’s health insurance coverage. Some health insurance and managed healthcare providers will pay for the basic medical procedures associated with the trial, such as lab tests, scans and hospitalization when required, while others may define clinical trials as “experimental” or “investigational” and not cover some of the routine costs, such as physician visits, tests or treatments. The costs vary depending on the study and the health plan. Medicare provides coverage for patient care associated with government-sponsored clinical trials.


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If a patient is taking part in a National Cancer Institute (NCI) trial being conducted at the National Institutes of Health (NIH) in Bethesda, Maryland, the NCI will pay for the study drug and the costs related to the study. A stipend for travel, food and lodging is also provided. Some cancer centers provide financial assistance or discounted rates for room and board and have special research units that will pay for study-related costs. Some organizations provide financial assistance for treatment-related expenses. Parents or patients should ask the physician what clinical trials would be most appropriate. Here are some additional ways to find information: • Contact the Lymphoma Helpline at the Lymphoma Research Foundation at (800) 500-9976 to request a clinical trial search. • Cancer centers in your area may also have information about trials. • Coalition of Cancer Cooperative Groups (CancerTrialsHelp.org). • NIH websites (Cancer.gov and Clinicaltrials.gov).


lymphoma.org


Chapter 4

Treatment Treatment options for children with non-Hodgkin lymphoma (NHL) are quite different from those used to treat adults with NHL. The most common treatment option for children with NHL is chemotherapy. As described in the previous chapter, because of the rarity of childhood cancers, most children diagnosed at any given point in time are treated in a similar manner on a specific clinical trial (also known as a “protocol”). This chapter will discuss information parents need to know about common childhood NHL chemotherapy regimens, including how it is given and what to expect. Other treatment options will be presented.

Chemotherapy Chemotherapy (“chemo”) is treatment with drugs (as opposed to radiation, for example). Combining Chemotherapy Drugs Chemotherapy for NHL often consists of giving several drugs together (combination chemotherapy) in a defined way (schedule), called a treatment regimen. Drug combinations are used because different medications damage or kill cancer cells in different ways, making them more vulnerable to the treatment. Combining chemotherapy drugs provides a more effective way to kill tumor cells, because using the drugs together greatly augments the impact of each drug (called synergism). In addition, when some drugs are added together in lower doses, it helps reduce the likelihood of side effects without reducing the overall amount of effective chemotherapy. For example, the combination of three drugs (cyclophosphamide, vincristine, and prednisone) is referred to as COP. This combination uses drugs that are given in somewhat less toxic amounts while sustaining a full or


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augmented (synergistic) capacity to destroy NHL. Another reason for combination chemotherapy is to prevent the emergence of drug resistance. Chemotherapy Cycles Chemotherapy is usually given in cycles in which each treatment is followed by a period of rest and recovery. Together, each period of treatment and non-treatment is called a “chemotherapy cycle.” Clinical trials have determined how often chemotherapy should be given to kill the most tumor cells while minimizing side effects. However, timing may vary depending on the specific treatment. Most childhood chemotherapy cycles are given every three to four weeks. Also, most regimens include frequent vincristine (Oncovin) as well as oral steroids within the three week cycles.

Chemotherapy Cycles Most children present with symptoms and advanced disease

Draw blood on initial visit

Scans

Child allowed to go home and come to clinic for chemotherapy (goal: maintain as much normalcy as possible)

Admitted to hospital and given initial chemotherapy


How Chemotherapy Is Given Depending on the regimen, chemotherapy may be administered in pill form, as an injection or as an intravenous drip. For patients receiving intravenous drugs (ones that are given through a vein) for multiple cycles, an intravenous catheter may be inserted to make it easier to give drugs. Catheters may be left in place temporarily or permanently. There are several types of implanted catheters, which are inserted using a minor surgical procedure. One type, called a Hickman-Broviac catheter, consists of one to three tubes inserted through the chest wall into a vein. Six to twelve inches of tubing remain outside the skin. The main advantage of this type of catheter is that blood tests can be drawn and drugs given without having to pierce the skin. Disadvantages include: (1) the possibility of infection if the catheter is exposed to any bacteria found on a needle during a blood draw or if the catheter is not cared for properly, and (2) the tubes on the outside of the body make it more obvious that a catheter is in place. Patients with catheters will receive specific instructions from their healthcare team regarding proper care and cleaning. Where Chemotherapy is Given Some chemotherapy is given in the hospital (referred to as in-patient) and some is given on an out-patient basis where the child lives at home and comes to a clinic to receive the treatment. The goal is to maintain as much normalcy as possible in the lives of children living with NHL. Common Types of Chemotherapy Regimens Used to Treat Childhood NHL The most common types of chemotherapy regimens currently used to treat childhood NHL are presented in the table on the next page. It is important to remember that today’s science is moving very fast. Therefore the chart in this chapter may not be entirely comprehensive or accurate depending on when this information is being read (i.e., please refer to the date of print of this publication). Parents should speak to their child’s oncologist to see if any trials have closed or if any new trials have opened. Understanding Childhood Non-Hodgkin Lymphoma 25

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Lymphoma Subtype

Protocol Name

Drugs Used

Lymphoblastic lymphoma

1. Berlin-FrankfurtMunster (BFM) Study

1. BFM Study • Vincristine • Corticosteroids • Anthracyclines • L-asparaginase • 6-thioguanine

2. COPG A5971: A randomized Phase III study for the treatment of newly diagnosed disseminated lymphoblastic lymphoma or localized lymphoblastic lymphoma

2. COPG A5971 • Vincristine • Daunorubicin • L-asparaginase • Cytarabine • Methotrexate • Prednisone • 6-Mercaptopurine • Cyclophosphamide • Thioguanine • Doxorubicin • Dexamethasone

1. Berlin-FrankfurtMunster (BFM) Study

1. BFM Study • Vincristine • Corticosteroids • Anthracyclines • L-asparaginase • 6-thioguanine

2. French LMB

2. French LMB (COPAD or COPAD-M) • Cyclophosphamide • Vincristine • Prednisone • Methotrexate • Doxorubicin • Hydrocortisone • Cytarabine • Leucovorin

Anaplastic large cell lymphoma

Treatment protocols may vary by institution.

One potential combination: • Vincristine • Doxorubicin • Methotrexate • Prednisone • 6-Mercaptopurine

Rare Subtypes

Treatment protocols may vary by institution.

Diffuse large B-cell lymphoma and Burkitt lymphoma


Details No Children’s Oncology Group (COG) clinical trials were open at the time of this guide’s printing.

COG recently completed a pilot study incorporating rituximab (Rituxan) into the LMB backbone.

Treatment can range from 24 months to several years.

Discuss treatment options with physician.

Radiation Radiation is not a common treatment option for children with NHL. Most subtypes of NHL seen in children are “chemo-sensitive,” which means they respond well to chemotherapy and do not require radiation.

What Happens If Relapse Occurs? Secondary Therapies Every parent’s concern during their child’s treatment is “what happens if this treatment does not work?” This is a very normal fear, and one that is shared by most people who care for someone undergoing cancer treatment. The fact is that the large majority of children diagnosed with NHL today will be cured by the first treatment regimen they are given. If a child does not respond to the first treatment regimen they receive, their disease may be considered “refractory” (resistant to treatment). A “relapse” (sometimes called a recurrence) is when a child’s disease returns after treatment. Most relapses happen shortly after treatment, decreasing in frequency as time passes after the completion of therapy. If a relapse is going to occur in a child with B-cell NHL, it will generally happen within the first 18 months. If a relapse is going to occur in a child with T-cell NHL, it will generally happen early. However, there are some children who may experience a recurrence three to four years later. Close monitoring and early identification of relapse is important. All patients will be carefully watched for five years following diagnosis. Parents whose child experiences a relapse or refractory diagnosis should not lose hope. Complete remission may still be achieved following a diagnosis of relapsed or refractory lymphoma. The type of treatment used for children who relapse or have refractory disease depends on two factors: (1) the disease type (e.g., Burkitt, anaplastic large cell lymphoma) and (2) stage. Treatments used after the first treatment (also known as primary treatment) are often referred to as “second line” or “secondary” treatments. These treatments are described on the following pages. Understanding Childhood Non-Hodgkin Lymphoma 27

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Chemotherapy Plus Rituximab (Rituxan) For children with B-cell NHL, most secondary treatment options include a combination of chemotherapies plus rituximab (Rituxan), which is a monoclonal antibody—a drug that selectively targets specific cancerous B-cells within the body. A commonly used secondary treatment option is RICE, which includes rituximab (Rituxan) plus a combination of chemotherapies (ifosfamide, carboplatin, etoposide). Rituximab (Rituxan) was the first monoclonal antibody approved for cancer therapy by the United States Food and Drug Administration (FDA) as a single agent in the treatment of relapsed or refractory adult lymphoma patients with CD20 positive, B-cell non-Hodgkin lymphoma. This drug was subsequently approved for additional indications by the FDA. It has not yet been approved for use in children, but may be used to treat relapsed or refractory disease in children with NHL. Stem Cell Transplantation Current Perspectives on Transplantation in Children with NHL Physicians may consider stem cell transplants as a treatment option for children who have relapsed or refractory NHL. Factors affecting the success of transplants include: (1) type of disease and (2) disease status. One of the largest transplant-specific studies to date examined the records of 182 relapsed or refractory NHL patients who had received either an autologous (using a child’s own stem cells) or allogeneic (using cells from a sibling or unrelated donor). The study found no difference between autologous and allogeneic transplantation for children with Burkitt, DLBCL or ALCL. Therefore, autologous transplants are more commonly used than allogeneic to treat these three diseases. Some debate exists regarding which transplant is most effective for lymphoblastic lymphoma and currently, either type may be used, depending on an individual’s specific situation.


Understanding Transplantation Bone marrow transplants are now called stem cell transplants because they use three types of blood-forming stem cells: • Bone marrow • Peripheral (circulating) blood (also called peripheral blood stem cells or PBSC) • Cells collected from an umbilical cord after a baby is born A transplant using any one of these cells can replace a child’s damaged marrow with healthy blood-forming cells, resulting in a new blood and immune system. With these new cells working in the child’s bone marrow (the spongy material found inside our bones) the marrow can once again form healthy: • Red blood cells, which carry oxygen to all parts of the body • White blood cells, which fight infections • Platelets, which control bleeding by helping blood to clot To get the child’s body ready for a transplant, he/she will receive chemotherapy and/or radiation. This will destroy or suppress the immune system. Physicians call this a preparative regimen, or conditioning. The new stem cells grow in the body, and take over the blood-forming machinery in the marrow. Because a transplant places great strain on a patient’s body, it is not an option for everyone. Among the things to consider are age, medical history, cancer stage, current medical condition and response to previous therapy. In some patients, a reduced-intensity conditioning regimen can be used, which lowers the strain on the body. There are two types of stem cell transplants: allogeneic, in which patients receive stem cells from another person, and autologous, in which patients receive their own cells.


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• Autologous Transplantation: In this procedure, a patient’s own stem cells are removed—while the patient is in remission—and frozen. When it is time for the transplant, the patient will receive very high-dose chemotherapy and/or radiation, after which the thawed stem cells are re-infused back into the patient’s body. The cells go into the bloodstream, where they make their way to the bone marrow where they belong. • Allogeneic Transplantation: In allogeneic transplantation, a donor’s stem cells are used. Finding a compatible donor is important because the body will reject stem cells if they are too different from the patient’s own cells. The new cells may also react against the patient’s body, a condition called graft-versus-host disease (GVHD). However, allogeneic transplants have one important potential advantage: the donor’s immune cells can destroy any lymphoma cells in the body not killed by the conditioning regimen. Very sensitive tests are used to see if someone is a suitable transplant donor. The best candidates are siblings, but there is only a one in four chance that a sibling will be a close enough match for a transplant. If no family members are a match, a search for an unrelated donor (or a cord blood unit) in a large registry of volunteers can be initiated. For more information on transplantation, please visit the National Marrow Donor Program’s website at marrow.org.


How Transplants Are Done Transplants are performed in four steps: Step 1: Collecting stem cells Stem cells are collected (harvested) in one of three ways: • Bone Marrow - To harvest bone marrow, physicians use a hollow needle inserted into the hip bone. This is done in an operating room and the donor receives general anesthesia. Once the marrow is harvested, it is either quickly transported to the waiting patient receiving an allogeneic transplant or frozen until needed for an autologous transplant. • Peripheral Blood Stem Cells (PBSC) - The second, and now more common way to collect stem cells from an adult, is by harvesting PBSCs from the blood. In this case, the donor takes a drug called a growth factor that causes the stem cells in the marrow to move into the peripheral blood. The stem cells are then removed from the donor’s blood using a process called apheresis. Blood is taken from a vein in one of the donor’s arms and passes through an apheresis machine, which separates out the stem cells. The rest of the blood, minus the stem cells, is returned to the donor through a different vein. This is done while the donor (in an allogeneic transplant) or patient (in an autologous transplant) is awake. • Cord Blood - Cord blood is collected at birth from a newborn’s umbilical cord. After the delivery is complete, trained technicians pierce the base of the cord with a sterile needle and drain the blood into a collection bag. The cord blood cells are then processed, tested and frozen until needed for a patient. Step 2: Processing or preserving stem cells In autologous transplants, marrow and PBSC collections are frozen for later re-infusion. In allogeneic transplants, cells undergo minimal processing and are given to the waiting patient as soon as possible. Cord blood cells (almost exclusively used in allogeneic transplants) are shipped frozen to the patient’s hospital, where they are kept until the patient is conditioned and ready to receive them. Step 3: Pre-transplant conditioning Before receiving the cells, patients are conditioned with chemotherapy and/or radiation. High-dose conditioning is always used in autologous transplants. In allogeneic transplants, the type and dose of the conditioning depends on the stage and type of disease, whether it is a recurrence and the condition of the patient. Step 4: Infusing the stem cells When the patient is ready, the stem cells are infused into the patient’s bloodstream through a needle inserted into a vein in one arm. The infused cells travel through the bloodstream, pass through the bones and implant themselves in the marrow. There, they slowly begin to make healthy new blood cells. Over time, the marrow produces enough healthy cells to completely restore the patient’s blood and immune system. Until these new cells are created, patients are more susceptible to infections.


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Novel Therapies It is an exciting time in lymphoma drug development. Now, more than ever before, drugs are being approved by the United States Food and Drug Administration (FDA) to treat lymphoma in adults. Many of the new drug approvals are not chemotherapy agents, but rather attack the lymphoma using novel techniques. The differences in biology between children and adults make it difficult to rely on data from drugs investigated only with adult populations. Therefore, studies are now underway to examine many of the novel therapies (already approved and those still under investigation) specifically with children. Some trials specifically designed for adults will lower their minimum age limit to sometimes include children over the age of 12, as well. The following chart describes some of these treatment options. It is critical to remember that today’s science is moving very fast. Therefore, the charts in this chapter may not be entirely comprehensive or accurate depending on when this information is being read. Some treatments may be found to be ineffective. Others may advance to the front-line setting. Please check with the Lymphoma Research Foundation or your physician for additional information and recent updates.


Agent


Comments

Monoclonal Antibodies

Rituximab (Rituxan)

CD20 monoclonal antibody

Approved for B-cell NHL in adults; under investigation in children

Epratuzumab


Ongoing clinical trials in adults with NHL and children with acute lymphoblastic leukemia (ALL)

SGN-35


Ongoing separate clinical trials in adults and children

Nelarabine

Nucleoside analog

Ongoing clinical trials in adults and children with lymphoblastic lymphoma

Clofarabine

Deoxyadenosine analog

Clinical trials completed as well as ongoing in children and adults with acute lymphoblastic leukemia (ALL) and acute myelogenous leukemia (AML)

Forodesine hydrochloride

Purine nucleotide phosphorylase inhibitor

Phase I study complete in children with T-cell cancers; being studied in other B-and T-cell NHLs

Bortezomib (Velcade)

Proteasome inhibitor

Approved for relapsed/refractory mantle cell lymphoma in adults; under investigation in children

Other

* For more information on any of the drugs included in this chart, visit lymphoma.org/booklets to read the Understanding Non-Hodgkin Lymphoma: A Guide for Patients, Survivors and Loved Ones or call the Lymphoma Research Foundation at (800) 500-9976.


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lymphoma.org


Chapter 5

Supportive Care Children with non-Hodgkin lymphoma (NHL) may have side effects, also called toxicity, from the cancer treatment they receive. Fortunately, there are many effective ways to make them more tolerable. Parents and patients should ask their healthcare team about possible treatment side effects and inform the physician if the patient experiences any. In many cases, side effects can be lessened with medications or lifestyle changes. This chapter discusses some of the more common treatment-related side effects and how they are treated.

Side Effects of Treatment Some of the most common side effects of NHL treatment are described below, along with strategies for minimizing their affect on children. Decreased Blood Cell Production Red blood cells, white blood cells and platelets are constantly being produced in the bone marrow. Both chemotherapy and chemoimmunotherapy treatment may temporarily interfere with the ability of the bone marrow to produce adequate numbers of blood cells. When this occurs, it is called myelosuppression. Anemia is the term used when myelosuppression causes a reduction in the number of red blood cells. Anemia can cause people to feel very tired, get headaches and have shortness of breath. Mild or moderate anemia is common with many chemotherapy regimens, and treatment with red blood cell transfusions may be necessary, depending on the degree of anemia. Neutropenia is the term used when myelosuppression causes a decrease in neutrophils—the primary type of white blood cells found in the blood. Because neutrophils play a very important role in fighting Understanding Childhood Non-Hodgkin Lymphoma 35

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infection, a low count increases a patient’s risk for developing a serious or even life-threatening infection that may require hospitalization or antibiotic therapy. If the absolute neutrophil count (ANC) is too low, the chemotherapy dosage may need to be reduced or treatment may be delayed rather than risk infection. The first sign of infection may include fevers, chills or a general “unwell” appearance. To prevent and control neutropenia, physicians will check patients’ white blood cell and neutrophil counts before and during each chemotherapy cycle. When neutropenia threatens a patient’s ability to receive the planned dose of chemotherapy, drugs such as filgrastim (Neupogen), pegfilgrastim (Neulasta) or sargramostim (Leukine) can be given after chemotherapy to reduce the duration and severity of neutropenia. These drugs can sometimes cause bone pain. By keeping the white blood count from dipping too low, these medications can help keep chemotherapy doses on schedule. Thrombocytopenia is the term used when myelosuppression depletes the number of platelets in the blood. Platelets help start the clotting process when bleeding occurs. If platelet counts are low, patients may bruise easily. A low platelet count may also cause prolonged or excessive bleeding from cuts, nose bleeds, bleeding from the gums or bleeding without a previous injury. A platelet transfusion may be needed in some cases. Mucositis (Mouth Sores) The membranes of the mouth may become red, sore or irritated during chemotherapy, which is referred to as mucositis. Infections of the mouth and throat caused by viruses, bacteria or fungi may also occur. If throat soreness occurs, the healthcare provider will examine the throat and may do a swab (called a culture) to check for infection. If an infection is present, several medications are available to treat it. Pain medication may be recommended if it becomes difficult to eat or drink, and occasionally a child will need to receive intravenous fluids to stay hydrated while the sores heal. 36 Understanding Childhood Non-Hodgkin Lymphoma

Nausea or Vomiting Chemotherapy can cause nausea or vomiting. Fortunately, advances over the last few decades have made it much easier to prevent nausea. Drugs that prevent vomiting (called antiemetics) commonly used with children undergoing chemotherapy include: • Aprepitant (Emend) (for children over 10 years of age) • Benadryl

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• Granisetron (Kytril) • Lorazepam (Ativan) • Metoclopramide (Reglan) • Ondansetron (Zofran) • Promethazine (Phenergan) • Scopolamine patch (for children over 10 years of age) Because nausea is more easily prevented than controlled, physicians will likely prescribe one of the above medications before chemotherapy to prevent nausea from occurring at all. In most cases, these drugs can partially or completely prevent nausea and vomiting. Treatment-Induced Diabetes Sometimes the steroids that are given as part of the chemotherapy regimen can cause treatment-induced diabetes. This means that during treatment, some children may develop temporary diabetes. This happens most often to children who are pre-diabetic, though children with no risk factors for developing diabetes may also be affected. Treatment-induced diabetes occurs because the steroids affect the body’s ability to handle sugar. If frequent urination occurs or the child is unusually thirsty, the physician will check the child’s blood sugar levels. Most treatment-induced diabetes can be managed by decreasing the amount of sugar and carbohydrates the child eats and drinks, for example, eliminating soda and fruit juice. Insulin may be given if Understanding Childhood Non-Hodgkin Lymphoma 37

limiting sugar intake does not work. It is important to note that the vast majority of children who experience treatment-induced diabetes will return to their normal blood sugar levels once the steroids have ended. This means that if a child had to receive insulin, the child may be able to stop taking insulin shortly after the steroid treatment has stopped. Treatment-Induced Hypertension Hypertension (high blood pressure) can occur in children with NHL while they are receiving treatment. The steroids given in most treatment regimens cause the body to hold onto salt, which results in water retention and extra fluid in the bloodstream. The causes of hypertension include: • Lymphoma in the kidneys • Hyperuricemia, which is a build up of uric acid in the kidneys that can cause the kidneys to become blocked. A drug called allopurinol (Zyloprim) may be given to treat hyperuricemia. Infection Most children with NHL will be at an increased risk for getting infections while they are receiving chemotherapy. The immune system does not work as well as it does in a healthy person, making it easier for viruses, fungi and bacteria to invade the body. Infections may happen from the following: • Exposure to people with colds or flu • Bacteria that normally live in our bodies enter the blood stream from sores in the mouth or along the gut • Bacteria can enter the body from a cut in the skin • Bacteria that enter the bloodstream from a Hickman catheter, PICC line or through the skin after accessing a Port-a-Cath • Complications following a viral illness, such as pneumonia


Infections can happen suddenly, and can be very serious. Most children will develop a fever or chills with a serious infection. It is important to call your child’s health care provider immediately and report any signs of infection. Most infections can be treated effectively with antibiotics, either in the hospital or as an outpatient, if treatment is started promptly. Constipation Vincristine (Oncovin) is a chemotherapy drug frequently used in the treatment of NHL. Vincristine (Oncovin) can affect the nerves that line the inside of the colon, resulting in the colon’s inability to contract and push stool along, leading to constipation. It is important to drink extra fluids, remain active and increase dietary fiber to help prevent constipation. It may be necessary to take a stool softener such as colace, or a laxative such as miralax. Cardiac Issues Anthracycline drugs, such as doxorubicin (Adriamycin), can damage the heart. The impact on the heart is usually not clinically significant until a specific amount of the drug has been given. However, some children are more sensitive to anthracycline drugs and experience problems at a lower dose. Therefore, children will be carefully monitored during and after treatment with echocardiograms or radionuclide scans. The goal is to identify signs that the drugs may be affecting the heart before the problem becomes severe. Occasionally, the dose of anthracycline may need to be reduced or held off. Cardiac muscle failure can occur, but only in a small number of children. Rarely does anthracycline cause heart arrhythmias (changes in the heart rhythm). If this does occur, the drug can be stopped or anti-arrhythmic drugs can be administered. The drug dexrazoxane (Zinecard) may also be given along with anthracycline drugs to protect the heart.


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lymphoma.org


Chapter 6

Coping with Childhood Lymphoma Lymphoma not only affects the child, but also the child’s siblings, friends, parents and extended family. This chapter will discuss the common experiences of children with lymphoma and ways parents can help both the child and their siblings cope with the diagnosis. Strategies for acknowledging and alleviating challenges as a parent caring for a child with lymphoma will also be presented.

What Children Need and Hope For After a Lymphoma Diagnosis Unless they have had experiences with cancer, children may not immediately know the meaning of the words “cancer” or “lymphoma.” Therefore, at first, they may not be as scared or worried about the words or diagnosis itself. Often, it is the reactions of adults around them that inform their response, making them feel safe or scared. Strategies for sharing information about their diagnosis may vary by age. Keeping messages hopeful and grounded in simple facts can help the child feel safe. Numerous resources exist to help parents with this communication. (To find some available resources, refer to the Resource chapter of this guide). Practical Aspects of Lymphoma from the Eyes of a Child Practical Medical Concerns Children may be more concerned about the practical rather than theoretical issues (e.g., what will having cancer today mean for me 10 years from now). Common questions running through the mind of a child with cancer include: • Will this hurt? • Am I going to be alone? • Is it going to be scary? Understanding Childhood Non-Hodgkin Lymphoma 41

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Establishing ways to reinforce their safety and letting them know that they will not be alone will help. For example, in preparation for receiving chemotherapy, explain to the child what to expect, including the physical and practical pieces. Describe what they will feel during and after chemotherapy. Make it clear that every step will be taken to minimize pain or the “ouchies.” Children do not like surprises. Tell them details such as: • What will happen first, second, third, etc. • Who will be in the room when they get specific tests/procedures • Mom and/or dad will be there the whole time The more they can be prepared for what to expect, the better. When they are not told, they may be concerned that adults are lying to them and lose trust in future medical situations. Children can often tell when adults are being honest or trying to hide things. Tell them that the physician and adults will be honest with them. Work with the child to identify how much information they like to receive before each procedure and how involved they would like to be in their own treatment. Some children want everything explained to them step by step, while others may just want to “get it over with.” The Benefit of Routine It is a common reaction for parents of children with cancer to want to relax rules and routines for their sick child and well siblings. This sometimes helps temporarily minimize guilt for the parent and stress on the child. However, developmentally, children thrive with structure and routines. It makes them feel safe because they are able to anticipate what to do, how to do it and what is expected of them. Suspending rules and routines may make the child concerned that they are much sicker than everyone is telling them. Reasonable changes to help the child feel more comfortable if they become nauseous, fatigued, etc. can help, but extreme changes should be made with caution.


Social Workers and Child Life Specialists Social workers and child life specialists are skilled at helping parents with children affected by cancer. They are there to serve as partners for parents during and after lymphoma treatment. Numerous books, web-based resources and tools exist to help parents communicate with their children about cancer, as well as ways for them to cope. Speaking with a social worker or child life specialist can help save time because they have access to the most appropriate resources for families, based on the child’s age and other specific needs.

Emotional Coping for Parents, Adult Family Members and Friends As a parent of a child with cancer, it is completely understandable and reasonable to be sad and scared. The following specific strategies may help parents and children at the same time: • Children sense what their parent is feeling. Therefore, it is best to be honest and say something like, “Yes, Mommy is worried, but that is okay. Here is what we are going to do (lay out a plan).” This acknowledges what the child instinctually senses and also quickly makes them feel secure and that the parent is in control. • Emotional breakdowns and feeling overwhelmed may happen frequently or come on all at once for a parent. The important thing to do is to find a suitable outlet or source of support to help. Rely on friends and family members for emotional support. This will help ensure that when the parent interacts with their child they are not overwhelmed with their own emotions and are fully supportive and nurturing. Coping with Guilt Parents often believe that they can protect their children from everything. This feeling is natural and expected. It is critical to recognize that feeling frustrated, tired and guilty is inevitable. The causes of lymphoma are not known, so nothing anyone “did” caused the disease. Childhood cancers in general are very rare and out of the ordinary experiences of


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parenthood. However, due to recent treatment advances, the large majority of children will survive their lymphoma diagnosis and grow into healthy adults. Furthermore, research shows that many childhood cancer survivors experience something referred to as “post-traumatic growth,” and report that their lives were positively impacted by their cancer experience. For example, teenagers often say that they quickly realized what is important in life, as compared to their cancer-free peers. Many of the positive aspects occur years later. Parents are encouraged to engage children in conversations about their experience as they are going through it so that they are supported in the present and prepared for the future. While parents are actively supporting their children through lymphoma treatment, they need to do their best to also be compassionate to themselves. Ask for and receive practical support from friends, neighbors and healthcare providers. Talk to a social worker and ask for resources.

Support for Siblings of Children with Lymphoma Childhood lymphoma affects more than the child diagnosed. Fear, sadness and extra tasks enter the daily lives of family members and friends. Brothers and sisters of the child diagnosed with lymphoma are uniquely impacted. Siblings of sick children may feel neglected, angry, sad, scared, like their needs do not matter and are often forced to grow up quicker than normal. Parents should remain aware of all children in the family and look out for changes in behavior. One unique resource for siblings of children with cancer is a nationwide non-profit organization called SuperSibs!. The organization is dedicated to ensuring that the brothers and sisters of children with cancer are honored, supported and recognized. They do this by providing free, ongoing comfort and care support to children between the ages of 4 and 18, who reside in the United States and Canada, and who have (or have had) a brother or sister with cancer. (See the


Resource section of this guide for contact information.) In addition to this direct support, SuperSibs! works with hospitals, clinics and organizations across the country to provide the most effective tools and resources so that sibling awareness and support can be a part of the help that families receive from their medical, social and emotional support staff. A few strategies may help siblings better cope with their brother or sister’s cancer: • Try to assess the child’s awareness of cancer and what it is. Simply ask, “Have you heard of cancer? What do you know about it?” Aim to deliver age-appropriate descriptions. Numerous resources exist to help parents do this. • Spend one-on-one time with the well sibling(s). Do an activity of their choice that opens up the possibility for talking about how they are doing. Siblings of children with lymphoma may quickly diminish their needs to “accommodate” their sibling’s needs. Therefore, it is critical that you ask them about their day, their dreams and what they would like to do. Listening is even more important than asking. Take in what your child says and ask more questions. • Gently ask hospital staff and other people to refer to the sibling by their name, as opposed to “the patient’s brother or sister.” This will help remind them that their identity matters too. • Siblings often take on extra responsibility. Be careful of asking the sibling to do more than they should at their age. For example, babysitting younger siblings may not be appropriate before a certain age. This should not change even with a sick child. • Ask siblings if they want to be involved. If the answer is yes, then find ways they can contribute. Being in charge of daily communication with family, for example, may help the sibling feel connected, but not overburdened.


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Talking to Siblings About Cancer By Age Ages 2-5 For this age group it is very important to keep things very simple. One example for explaining lymphoma: “Tommy’s blood is very sick. The doctors are going to give him some medicine to help his blood get better. Sometimes Tommy will have to get his medicine at the hospital and sometimes Tommy will take the medicine at home. The doctors are going to do everything they can to make Tommy’s blood get better.” Kids this age just want to be close to their parents. It is important to help your kids feel connected. Some suggestions include: • Record several of the child’s favorite books and songs on tape for them to listen to and hear your voice. • Make picture frames together and put a picture of yourself inside. • Make a blanket together or pick one out together and identify it as the item that can “HUG” you while mom and dad have to be away.

Ages 6-10 For this school age group, you can use the actual words. One example for explaining lymphoma: “Tommy has cancer. Have you ever heard that word before? There are different kinds of cancer and Tommy has a kind called lymphoma. That means the cancer is in his lymphatic system, which helps the body fight off infections and germs. The doctors are going to give Tommy a very strong medicine called chemotherapy. You can call it “chemo” for short. The chemo will help to make the lymphoma go away.” (Re-iterating): “The doctors and nurses are going to do everything they can to make the lymphoma go away.” Questions to Spark Conversation: • What do you know about lymphoma or cancer? • Do you think someone did something “bad” to cause lymphoma or cancer? (That’s not what causes cancer!) • Do you think you can catch cancer from someone else? (No, it’s not “catchy!”) • How is your life different now? • What is the biggest change in your life? • What do you want/need from us grownups? • How do you know you are loved?


AGES 11 - 18 Start with the basics and elaborate, depending on how much information your teen wants to hear. Some want a lot of information, some want to read it themselves and some want it kept to only what they NEED to know. Questions to Spark Conversation: • What do you know about lymphoma or cancer? • Do you think cancer is contagious? (It’s not!) • Do you think cancer is caused by something that someone did? (It’s not!) • How is your life different now? • What additional things do you have to do at home now? • What do you want/need from us, your parents? • What do you want/need from your friends? • What do you want/need from school?

The information from this section was adapted from the SuperSibs! new parent toolkit. If you have not received a new parent toolkit, contact SuperSibs! at 866-444-SIBS(7427) or supersibs.org.


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lymphoma.org


Chapter 7

Long-Term and Late Effects Survival rates for children with lymphoma are extremely high, resulting in a growing number of childhood lymphoma survivors. Some of these survivors are at risk of developing treatment-related health problems that could occur months, or even years, following their last treatment. Lymphoma treatments are designed to destroy cancer cells. However, some of these treatments unintentionally damage healthy cells in the process. This damage can effect the development and proper functioning of various tissues and organs and could result in the development of secondary cancers later in life. Most childhood lymphoma survivors do not develop treatmentrelated health problems. For those who do, the effects are generally mild. However, a limited number of childhood lymphoma survivors may experience severe or chronic effects. There are several factors that can affect the risk of developing treatment-related health problems, including: • The type and amount of treatment the child receives • The age at which the child is treated • What area of the body is treated • The child’s gender • The child’s overall health Treatment-related health problems are placed into two categories. Those that continue for months or years following treatment are called “long-term effects” and those that do not appear until months or years after treatment are called “late effects.” Understanding Childhood Non-Hodgkin Lymphoma 49

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Long-term and late effects vary by treatment. Some treatments may: • Cause cognitive impairment, such as difficulties learning, problem solving and concentrating • Affect the proper functioning of organs, such as the lungs, kidneys, liver, thyroid and spleen • Damage the digestive, musculoskeletal and central nervous systems • Affect the reproductive system, resulting in the delay of puberty, low sperm count, irregular periods, ovarian failure, premature menopause and infertility • Cause damage to the heart • Result in the development of secondary cancers, such as breast and thyroid cancer

The following are examples of some common therapies and their potential long-term or late effects: • Anthracyclines: Anthracyclines, a form of chemotherapy, may increase the risk of developing heart damage and heart failure. Examples of anthracyclines include doxorubicin (Adriamycin) and daunorubicin (Daunomycin). • Alkylating agents: Alkylating agents, a form of chemotherapy, may increase the risk of developing heart failure and acute myelogenous leukemia (AML). A commonly used alkylating agent includes cyclophosphamide (Cytoxan) and ifosfamide (Ifex). • Radiation: Radiation to the head and neck may cause vision or hearing problems and could affect the thyroid. Radiation to the chest and abdomen could impair the heart (with severe cases resulting in heart failure) and lungs, and could increase the risk of developing breast and thyroid cancer.


Due to the various medical conditions that can result from treatment, it is important that parents discuss the potential risks of all treatment options with their child’s oncologist before treatment. Once a treatment is completed, parents and the child’s oncologist should create a “follow-up care plan” that: • Provides a treatment summary, which includes information such as age and date of diagnosis, staging, the types of chemotherapy drugs administered, and response to treatment. • Indicates the type and frequency of medical tests that a survivor should routinely undergo over their lifespan. This follow-up care plan should be written and provided to the parent upon completion of treatment. As children grow up and move around, this document will serve as a history for their primary care physician. The follow-up care plan also ensures that any late effects will be diagnosed and treated as early as possible. Childhood lymphoma survivors should receive regular medical exams from a physician who is familiar with their medical history as well as the treatments they have received. Survivors and their caregivers are encouraged to keep copies of all medical records and test results as well as information on the types, amounts and duration of all treatments received. This documentation will be important for keeping track of, and treating, any late effects resulting from treatment. Scientific investigators are constantly testing new treatments and varying amounts of old treatments in hopes of reducing the long-term and late effects of lymphoma treatment or eliminating them altogether. Because greater numbers of children with lymphomas are now surviving for many decades following cancer treatment, new discoveries about the late effects of cancer are frequently being made. Guidelines are periodically updated to reflect this new information.


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The Children’s Oncology Group has created a document for physicians, which provides recommendations for managing the late effects of treatment, entitled Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent and Young Adult Cancers. To view the document, visit survivorshipguidelines.org

Resources


lymphoma.org


Glossary of Medical Terms

Absolute neutrophil count (ANC): A measurement of the number of mature neutrophils (a type of white blood cell) that are available for fighting infection. A low ANC increases the risk for infection. Advanced disease: Disease that has spread to multiple locations. Aggressive lymphomas: Lymphomas that are fast growing and generally need to be treated immediately. Also called intermediate-grade or high-grade lymphomas. Allogeneic transplant: A procedure in which a patient receives bone marrow or stem cells donated by another person. Alopecia: Hair loss. Alopecia from chemotherapy is almost always temporary; hair grows back when therapy is finished. Anemia: A shortage of red blood cells, causing weakness and fatigue. Angiogenesis: The process of developing new blood vessels. Antiangiogenesis therapies: Drugs that prevent tumors from developing new blood vessels, thereby stopping or limiting tumor growth. Antibody: A substance made by B-lymphocytes that reacts with antigens on toxins, bacteria and some cancer cells and either kills or marks them for removal. Antiemetic: A drug that reduces or prevents nausea and vomiting. Antigen: Identifying proteins located on the surface of all cells. The immune system uses antigens to determine whether cells are a necessary part of the body or need to be destroyed. Apheresis: The part of the stem cell transplantation procedure in which stem cells are removed from the blood. Autologous transplant: A type of bone marrow or stem cell transplantation in which a patient receives his or her own cells. Beta (2) microglobulin (B2M): A protein found in the blood. Higher levels of B2M suggest that the lymphoma may be more aggressive. ChildhoodLymphoma Lymphoma 53 UnderstandingUnderstanding Childhood Non-Hodgkin

Biologic therapy: Treatment that uses or stimulates the immune system or other body systems to fight infection and disease. Biopsy: Removal of a small piece of tissue for evaluation under a microscope. Bone marrow: Spongy material found inside the bones containing stem cells that develop into three types of cells: red blood cells that deliver oxygen to the body and take away carbon dioxide; white blood cells that protect the body from infection; and platelets that help the blood to clot. Bulky tumor: A large tumor, usually greater than five, seven or ten centimeters. Cancer: Abnormal cell growth that cannot be controlled by the body’s natural defenses. Cancerous cells can grow and eventually form tumors. Catheter (intravenous access): A device that is temporarily or permanently put into a vein that makes it easier to give medications. Cerebrospinal fluid: Fluid that is present around the spine and brain. It may be examined to determine if NHL has spread to these parts of the body. Chemotherapy: Treatment with drugs to stop the growth of rapidly dividing cancer cells, including lymphoma cells. Chemotherapy cycle: Term used to describe the process in which chemotherapy is given, followed by a period of rest in which the body is allowed to recover. Chemotherapy regimen: Combinations of anticancer drugs given at a certain dose in a specific sequence according to a strict schedule. Clinical trial: A research study in which a new treatment is given to patients to determine whether it is safe, more effective or less toxic than current therapies. Combination chemotherapy: Several drugs given together to increase response rate of certain tumors.

54 Understanding UnderstandingChildhood ChildhoodLymphoma Non-Hodgkin Lymphoma 54

Complete remission (CR): Term used when all signs of the disease have disappeared after treatment. About LRF

**Insert from other booklets** CT or CAT (computerized axial tomography) scan: This imaging test

provides a series of detailed pictures of inside the body using an X-ray machine linked to a computer. Cure: There are no signs or symptoms of lymphoma, and a significant period of time (usually defined by years) has passed during which there are no relapses. Decreased blood cell production: A decrease in the production of red blood cells, white blood cells and platelets that may occur as a side effect of cancer or cancer therapies. Also called myelosuppression. Diaphragm: The muscle below the lungs and heart that separates the abdomen from the chest. Disease progression: The term used if the disease worsens despite treatment (also called treatment failure). DNA: Abbreviation for deoxyribonucleic acid, an essential component of genes. Dose intensity: A term used to describe giving the highest possible doses of drugs over a specific period of time with acceptable side effects. Durable remission: When a complete response lasts for years. Dysgeusia: When familiar foods taste differently. Echocardiogram: Use of ultrasound to examine the heart. It is ordered when potential cardiotoxic chemotherapy is used. Etiology: The study of the causes of a disease. Extranodal disease: NHL that has spread outside the lymphatic system. Fatigue: A decreased capacity for activity that is often accompanied by feelings of weariness, sleepiness or irritability. Understanding Childhood Non-Hodgkin Lymphoma 55

Gallium (radioisotope) scan: When injected into the body, radioactive gallium is a chemical that collects in some tumors. The body is then scanned to see whether the gallium has collected in a tumor. Generalized disease: A cancer that has spread throughout the body. Genes: The basic building blocks of heredity that are present in all cells. Genes are comprised of DNA and other materials. Gene therapy: Therapy approaches that alter the genetic structure of tumor cells, making them more susceptible to either the immune system or chemotherapy drugs. Grade: A method of classifying a tumor on the basis of how aggressively it is growing. Graft versus host disease (GVHD): Occurs when a donor’s bone marrow (graft) recognizes the recipient of the marrow (the host) as foreign. In response, the immune cells in the donor marrow attack the foreign cells in the host. Harvesting: A procedure in which stem cells are obtained from the blood or bone marrow for use in repopulating the body’s cells after high-dose chemotherapy. Hematologist: A physician who specializes in treating diseases of the blood and blood-forming tissues. Histology: The study of tissue characteristics that may lead to identifying a specific type of tumor. Hodgkin lymphoma: One of the two major types of lymphoma that begin in the lymph nodes and tissues of the lymphatic system. All other lymphomas are classified as non-Hodgkin lymphomas. Hodgkin lymphoma has a characteristic cell, the Reed-Sternberg cell, seen by the pathologist under the microscope when looking at the tissue from the biopsy. Hypogeusia: When the flavors of foods are not as strong as normal.

56 Understanding UnderstandingChildhood ChildhoodLymphoma Non-Hodgkin Lymphoma

Hypothyroidism: A condition in which there is lower than normal production of thyroid hormone. Low thyroid levels can lead to a variety of effects, including mild weight gain, dry skin, fatigue and sleepiness. Idiotype: A unique “fingerprint” portion of an antibody present on the surface of B-cells. Idiotype vaccine: A lymphoma vaccine that is custom-made to attack an individual patient’s lymphoma and contains idiotype (unique) tumor material and an immune stimulant. Immune system: One of the body’s defense mechanisms. All lymphomas are diseases of the immune system. Immunological tests: Blood tests that detect the presence of diagnostic proteins or antigens on a tumor. Immunotherapy: See biologic therapy. Improvement: This term is used if a tumor shrinks following therapy but is still more than one-half of its original size. Indolent lymphoma: Lymphoma that is slow growing and has few symptoms. Also called low-grade lymphoma. Lactate dehydrogenase (LDH): An enzyme found in the blood. Higher levels of LDH suggest that the lymphoma may be more aggressive. Laparoscopy: Passing a tube through the abdominal wall to obtain a small sample of tissue for examination under the microscope. Leukemia: Disease generally characterized by the overproduction of abnormal or immature white blood cells that circulate or are present in the blood. Leukopenia: A shortage of white blood cells, resulting in the inability to fight infecting organisms such as bacteria, fungi and viruses. Localized disease: A cancer that is only present in a limited part of the body, for example, the neck or armpits. Understanding Childhood Non-Hodgkin Lymphoma 57

Local therapy: A therapy that only affects a small area. Low-grade lymphoma: Lymphoma that grows slowly and has few symptoms. Also called indolent lymphoma. Lymph: The watery fluid in the lymph system that contains white blood cells (lymphocytes). Lymph nodes: Small bean-shaped glands located in the small vessels of the lymphatic system. There are thousands of lymph nodes located throughout the body, with clusters of them in the neck, under the arms, the chest, abdomen and groin. Lymph nodes filter lymph fluid, trapping and destroying potentially harmful bacteria and viruses. Lymphatic system: The channels, tissues and organs that store and carry lymphocytes that fight infection and other diseases. Lymphocyte: A type of white blood cell. Lymphocytes, carried along by the lymph fluid, are part of the immune system and fight infection. Lymphoma: A malignant disease that begins in the lymph nodes, organs and tissues of the lymphatic system (immune system). Hodgkin lymphoma is one type of lymphoma; the other major type is called non-Hodgkin lymphoma. There are approximately 61 types of non-Hodgkin lymphoma. Malignant: Cancerous—a malignant tumor is a cancerous tumor. Medical oncologist: A physician who specializes in the use of chemotherapy, hormone therapy and many other types of biologic therapies to treat cancer. Memory cells: Memory cells are types of B-lymphocytes and T-lymphocytes. After a foreign invader or unwanted cell has been destroyed, surviving B- and T-lymphocytes develop into specialized memory cells that remain on watch and can provide protection if the invader is encountered in the future.

58 Understanding UnderstandingCLL/SLL Childhood Non-Hodgkin Lymphoma

Metastasize: To spread to other organs of the body. Cancer may spread from its primary site to other sites or organs. Monoclonal antibodies: Biologic therapies that act specifically against a particular antigen. Scientists can produce large amounts of antibody that can be directed to a single target (or antigen) on the cell’s surface. Monoclonal antibodies have been developed to help combat specific cancers, including some forms of non-Hodgkin lymphoma. MRI (magnetic resonance imaging): MRI uses magnets and radio frequency waves to produce images of inside the body. MRIs can provide information about tissues and organs that is not available from other imaging techniques. Mucositis: Inflammation of the lining of tissues and organs. In the mouth, it is characterized by sores or inflammation. Myelosuppresion: A reduction in the bone marrow’s ability to make red blood cells, white blood cells and platelets. Neutropenia: An abnormally low level of neutrophils (the white blood cells responsible for fighting bacterial infections). Neutrophils: The primary type of white blood cells found in the blood that fight bacteria, etc. Non-bulky tumor: A small tumor, usually less than five centimeters (approximately two inches) Non-Hodgkin lymphoma (NHL): A group of several closely related cancers that arise from the lymphatic system. Although the different types of NHL have some things in common, they differ in what the cancer cell looks like under a microscope, how the cells grow and how the tumor affects the body. Oncologist: A physician who specializes in treating cancer. Some specialize in chemotherapy (medical oncologists), radiotherapy (radiation oncologists) or surgery (surgical oncologists).


Palliation: Treatment that is given to remove or relieve symptoms. Para-aortic: The area close to the aorta. The aorta is the largest vessel in the body and rises from the heart. Partial remission (PR): The term used when a cancer has shrunk in size by at least half but has not totally disappeared. The cancer can still be detected, and other treatments may be recommended. Pathologist: A physician who specializes in studying disease through microscopic evaluation of body tissues and organs. Any tissue suspected of being cancerous must first be examined by a pathologist to confirm the diagnosis. PCR (polymerase chain reaction): A molecular test that can identify small amounts of genetic material. This test is done if looking for minimal residual disease. Performance status: A term used to describe a person’s ability to follow a typical lifestyle. Peripheral neuropathy: Damage to the nerves. This condition can be caused by some drugs and is usually characterized by tingling and weakness or numbness in the extremities. PET (positron emission tomography) scan: A type of test that may be used instead of gallium scans to identify areas in the body that are affected by non-Hodgkin lymphoma. This test evaluates metabolic activity in different parts of the body using a radioisotope. Plasma cell: A mature B-cell that makes antibodies—these antibodies help the body destroy or remove toxins, bacteria and some cancer cells. Primary therapy: The first therapy given after a diagnosis of cancer. Prognosis: The likely outcome of a disease, including the chance of recovery.


Pulmonary function test: A procedure for determining the capacity of the lungs to exchange oxygen and carbon dioxide efficiently. Radiation field: The part of the body that receives radiation therapy. Radiation oncologist: A physician who specializes in treating cancer with radiation. Radiation therapy: The use of radiation beams (X-rays) to treat a cancer. High doses of high-energy radiation beams carefully focused on a tumor will kill cancer cells. Radiation therapy (with or without chemotherapy) is used to treat certain lymphomas. Radioimmunotherapy: A therapy that is prepared by attaching a radioactive isotope to a monoclonal antibody. Radionuclide tests: Tests that use radioactive substances to help evaluate the function of tissues. Refractory disease: A cancer that is resistant to treatment. Regimen: A specific combination of drugs (chemotherapy), their doses and their schedules of administration. A regimen may also include radiotherapy. Relapse: The return of cancer after treatment. Lymphoma may recur in the area where it first started, or it may occur in another place. Remission: The absence of disease. A patient is considered in remission when the lymphoma has been treated and tumors have diminished by at least 50 percent (partial) or have totally disappeared (complete). Remission does not necessarily mean cure. Patients with intermediate or aggressive lymphomas must achieve a complete remission and maintain it for a period of time, usually five or more years, before there is consideration of cure. Patients with low-grade tumors are usually not considered cured because the disease can reappear even with a long remission of many years. Patients may have a complete or partial remission.


Risk factors: Factors that may increase the chance that a person will develop NHL. It is important to note that most people with risk factors never develop lymphoma, and many who are diagnosed have no identifiable risk factors. Salvage therapy: Therapy that is given if the primary therapy is not successful or if the disease disappears and then comes back. Spleen: An organ on the left side of the upper abdomen, near the stomach. A key component of the lymphatic system, the spleen produces and stores lymphocytes and releases them when required as part of the body’s response to infections and other stimuli. The spleen may store blood and remove old blood cells from circulation. Stable disease: The disease does not get better or worse following therapy. Stage: The extent of cancer in the body, including whether the disease has spread from the original site to other body parts. Standard therapy: The most widely used primary therapy. Synergism: The term used when two or more drugs given together provide a better anti-cancer effect than expected from the additive effects from the medications alone. Systemic symptoms: Symptoms that affect the entire body. Examples of these include fever, night sweats and weight loss. Thrombocytopenia: A shortage of platelets in the blood, which reduces the ability of the blood to clot. Thymus gland: A gland located behind the sternum (breastbone) that enhances the reproduction and development of lymphocytes. T-lymphocytes are processed in the thymus. Toxicities: The unwanted side effects of cancer therapies, such as a decrease in blood cells, nausea and vomiting, and hair loss.


Tumor: An abnormal mass or swelling of tissue. Tumors may occur anywhere in the body. A tumor may be benign (non-cancerous) or malignant (cancerous). Vaccine: A substance or group of substances meant to cause the immune system to respond. A vaccine can help the body recognize and destroy cancer cells. Lymphoma vaccines often combine cancer antigens with a substance to stimulate the patient’s own natural defenses to fight the disease. These vaccines in lymphoma are custom-made for each patient, using a sample of tumor obtained from the patient’s lymph nodes. VEGF (Vascular Endothelial Growth Factor): One of a number of substances that stimulate angiogenesis, blood vessel formation—a process necessary for tumor growth. Watchful waiting: An approach in which no immediate medical, surgical or radiation therapy is given. Patients are followed closely to make sure the cancer does not progress. Watchful waiting is an appropriate option for some patients with indolent (slow-growing) non-Hodgkin lymphoma. Xerostomia: A temporary reduction in the production of saliva or “dry mouth.” X-ray: Radiation that is used in low doses to provide images of the inside of the body and in high doses to treat cancer.



lymphoma.org


Resources Childhood Cancer Resources Candlelighters Childhood Cancer Foundation (CCCF) (800) 366-2223 candlelighters.org CCCF is a national non-profit organization whose mission is to educate, support, serve and advocate for families whose children have been diagnosed with cancer, survivors of childhood cancer, and the professionals who care for them. Children’s Cancer Association (CCA) (503) 244-3141 childrenscancerassociation.org The Children’s Cancer Association is a one-of-a-kind nonprofit organization bringing support, resources, award-winning programs and above all, joy to seriously ill kids/teens and their families in Oregon, SW Washington and nationally. CureSearch (800) 458-6223 curesearch.org CureSearch unites the world’s largest childhood cancer research organization, the Children’s Oncology Group, and the National Childhood Cancer Foundation to cure childhood cancer. CureSearch also provides advocacy, public education, referrals and clinical trial information.


National Children’s Cancer Society (NCCS) (314) 241-1600 children-cancer.org The NCCS provides financial assistance, advocacy, emotional support and education to families who have children diagnosed with cancer. Pediatric Oncology Resource Center acor.org/ped-onc The Pediatric Oncology Resource Center provides a website by parents of children with cancer for parents of children with cancer. This website offers patient-friendly resources as well as links to various support groups. Special Love, Inc. (888) 930-2707 speciallove.org Special Love, Inc. sponsors Camp Fantastic and 19 other events for children with cancer and their families in the Mid-Atlantic region. Starlight Children’s Foundation (800) 315-2580 starlight.org Starlight Children’s Foundation is an international non-profit organization dedicated to improving the quality of life for seriously ill children and their families through a variety of in-hospital and outpatient programs and services.


SuperSibs! (866) 444-SIBS (7427) supersibs.org SuperSibs! provides services free of charge to honor, support and recognize brothers and sisters of children, teens and young adults with cancer.

Young Adult Cancer Resources Camp Mak-A-Dream (406) 549-5987 campdream.org Camp Mak-A-Dream is a medically supervised, cost-free Montana experience, in an intimate community setting, for children, young adults and families affected by cancer. Lance Armstrong Foundation LIVESTRONG Young Adult Alliance (866) 673-7205 livestrong.org/yaa The LIVESTRONG Young Adult Alliance is a coalition of organizations with the goal to improve the survival rates and quality of life for young adults with cancer between the ages of 15 and 40. This website provides access to the websites of all member organizations. Lymphoma Research Foundation (800) 500-9976 lymphoma.org/youngadults The Lymphoma Research Foundation offers a wide array of webcasts and podcasts for individuals affected by lymphoma in their teens, 20s and 30s, including topics specifically designed to help friends and family.


Planet Cancer planetcancer.org Planet Cancer’s website is a 24 hour, 7 days a week online community providing peer support, information and humor for young adult cancer patients and survivors. Teens Living with Cancer teenslivingwithcancer.org TLC focuses on teen issues, presents information about cancer and treatment written at teens’ level of interest, provides opportunities to interact with other teens living with cancer and offers links to relevant sites. Ulman Cancer Fund for Young Adults (888) 393-3863 ulmanfund.org Ulman Cancer Fund focuses on how cancer affects young adults. The Ulman Cancer Fund offers scholarships, community grants, advocacy services and a guidebook.


About the Lymphoma Research Foundation The Lymphoma Research Foundation (LRF) is the nation’s largest lymphoma-focused nonprofit health organization devoted exclusively to funding lymphoma research and providing patients and healthcare professionals with the most current information on the disease. The Foundation’s mission is to eradicate lymphoma and serve those touched by this disease. The Lymphoma Research Foundation was formed in 2001 with the merger of the Cure For Lymphoma Foundation (CFL) and the Lymphoma Research Foundation of America (LRFA). Both organizations were founded by lymphoma advocates who wanted to turn a life-altering diagnosis into a positive experience for others with the disease. Ellen Glesby Cohen founded LRFA in Los Angeles in 1991. Until her death in 2000, Ellen was a tireless champion for patients and their families who created new education and support programs and served as a staunch advocate for improved government legislation. Jerry and Barbara Freundlich founded CFL in 1994 in New York City. Jerry is a long-term survivor of non-Hodgkin lymphoma.

Resources for Patients, Survivors and Loved Ones Receiving a diagnosis of lymphoma can be challenging. Whether you or someone you love is newly diagnosed or a long-term survivor, understanding the latest medical information and accessing appropriate support services may help. The Lymphoma Research Foundation offers a wide array of programs and support services to assist you from the point of diagnosis through long-term survivorship.


Patient Services and Support Lymphoma Helpline and Clinical Trials Information Service Through this phone and email service, trained staff members are available to answer your questions and provide individual support to you and your loved ones. Services are available in any language. Lymphoma Support Network (LSN) This national one-to-one peer support program matches lymphoma patients or caregivers with volunteers who have had similar lymphoma-related experiences. Lymphoma Newsline Lymphoma-related news can be distributed to you directly through this free electronic news services. Sign up by clicking on the “register” icon on LRF’s homepage at lymphoma.org.

In-Person Patient Education Programs North American Educational Forum on Lymphoma This two-day national forum is held annually and provides critical information about the latest in lymphoma research, making the best decisions about treatment options and patient support issues. Lymphoma Workshop: Understanding Lymphoma Basics and Current Treatment Options These regional, full-day educational programs provide the latest information about lymphoma, current treatment options and patient support issues.



Webcasts Webcast programs offer you the opportunity to navigate through a synchronized audio and slide presentation. Podcasts Podcasts (video format) can be viewed on LRF’s website. Teleconferences Teleconferences are hour-long interactive telephone programs that provide an opportunity to learn more about lymphoma, treatments and promising research from leading lymphoma experts. These are conducted live, and the archived version is available after the program.

Publications Patient Guides In addition to this publication, LRF also produces Understanding Non-Hodgkin Lymphoma: A Guide for Patients, Survivors and Loved Ones, Understanding Hodgkin Lymphoma: A Guide for Patients, Survivors and Loved Ones, and Understanding CLL/SLL: A Guide for Patients, Survivors and Loved Ones. Fact Sheets Fact sheets with the latest disease- and treatment-specific information are available in either hard copy or in PDF on LRF’s website. New topics are added on a regular basis; check to see if the topic you are looking for is available. Newsletters To keep you abreast of LRF research and news in the wider lymphoma community, you can sign up to receive any of LRF’s regular newsletters either electronically or via mail. Any of LRF’s publications may be ordered by visiting lymphoma.org. Individual and bulk copies are available free of charge.


How to Access Programs and Services Many of the aforementioned programs are available on LRF’s website at lymphoma.org. For additional information about these resources, call (800) 500-9976 or email us at [email protected]. If you would like to order additional copies of Understanding Childhood Non-Hodgkin Lymphoma: A Guide for Patients, Survivors and Loved Ones, please call (800) 500-9976 or visit lymphoma.org.



Start or Join a Local Chapter Chapter volunteers work tirelessly to educate people about lymphoma, conduct outreach, raise funds for research and participate in public policy and advocacy initiatives. To learn more about a chapter in your area or how to start one, please visit lymphoma.org/chapters.


Join Team LRF Team LRF is a program through which people across the country raise much-needed funds and awareness for lymphoma research through sporting events such as marathons, half marathons, triathlons, hiking adventures, bowling tournaments, soccer matches, bike rides, lacrosse tournaments, paddling events, dance-a-thons, spin-a-thons, yoga-athons and much more. Join Team LRF in an existing LRF-partnered event in your area, or join Team LRF Teammates Across the Country if you wish to raise funds by starting your own event or by participating in an event in which LRF does not have official charity entries. For more information, visit lymphoma.org/teamlrf. Understanding Childhood Non-Hodgkin Lymphoma 73


lymphoma.org


Donate Now The Lymphoma Research Foundation (LRF) is a nonprofit health organization with 501(c)(3) status. If you would like to support LRF, your generous gift will help us move closer to finding a cure, while helping those affected by the disease. Three easy ways to give:

Website: lymphoma.org/donatenow

Call: (800) 235-6848

Mail: Cut out this form and mail it to Lymphoma Research Foundation, 115 Broadway, 13th Floor, New York, New York 10006 or FAX

Fax: (212) 349-2886

Amount of donation $ Make checks payable to the Lymphoma Research Foundation.

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lymphoma.org



This project is supported through Cooperative Agreement Number 1U58DP001110 from the Centers for Disease Control and Prevention. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the Centers for Disease Control and Prevention.

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