Pediatric Hematopoietic Stem Cell Transplantation

DK3062_half 5/9/06 3:51 PM Page 1

Pediatric Hematopoietic Stem Cell Transplantation

DK3062_title 5/16/06 8:33 AM Page 1

Pediatric Hematopoietic Stem Cell Transplantation

edited by

Ronald M. Kline Pediatric Division Comprehensive Cancer Centers of Nevada Las Vegas, Nevada, U.S.A.

New York London

Informa Healthcare USA, Inc. 270 Madison Avenue New York, NY 10016 © 2006 by Informa Healthcare USA, Inc. Informa Healthcare is an Informa business No claim to original U.S. Government works Printed in the United States of America on acid-free paper 10 9 8 7 6 5 4 3 2 1 International Standard Book Number-10: 0-8247-2445-3 (Hardcover) International Standard Book Number-13: 978-0-8247-2445-0 (Hardcover) This book contains information obtained from authentic and highly regarded sources. Reprinted material is quoted with permission, and sources are indicated. A wide variety of references are listed. Reasonable efforts have been made to publish reliable data and information, but the author and the publisher cannot assume responsibility for the validity of all materials or for the consequences of their use. No part of this book may be reprinted, reproduced, transmitted, or utilized in any form by any electronic, mechanical, or other means, now known or hereafter invented, including photocopying, microfilming, and recording, or in any information storage or retrieval system, without written permission from the publishers. For permission to photocopy or use material electronically from this work, please access www.copyright.com (http:// www.copyright.com/) or contact the Copyright Clearance Center, Inc. (CCC) 222 Rosewood Drive, Danvers, MA 01923, 978-750-8400. CCC is a not-for-profit organization that provides licenses and registration for a variety of users. For organizations that have been granted a photocopy license by the CCC, a separate system of payment has been arranged. Trademark Notice: Product or corporate names may be trademarks or registered trademarks, and are used only for identification and explanation without intent to infringe. Visit the Informa Web site at www.informa.com and the Informa Healthcare Web site at www.informahealthcare.com

T&F_LOC_B_Master.indd 1

6/14/06 8:55:05 AM

I dedicate this book to the memory of my father: He triumphed over adversity from boyhood onwards and instilled in me the values that I live by today and will pass on to my children. Ronald Kline

Preface

“Children are not little adults.” This much-overused expression characterizes the pride that pediatricians take in their specialized knowledge of the growing and developing human being. The quote is also an admonition to our adult medicine colleagues that specialized knowledge is required for the care of children with complex diseases and therapies, not simply a dosage adjustment for size. However, because of the general good health of most children, the pediatric specialties are inherently small. As a result, practitioners of such niche subspecialties as pediatric blood and marrow transplantation have in the past been required to depend on general texts written primarily for the care of adult transplant patients. Yet as all pediatric transplanters know, “children are not little adults.” The diseases they encounter, their responses to treatment, and the types and relative risks of various complications are markedly different than in adults. Thus the time has come for a comprehensive text focused exclusively on the care of the pediatric hematopoietic stem-cell transplant patient. The purpose of this work is to provide a focused, comprehensive and up-to-date reference work for those of us caring for pediatric BMT patients. Chapter topics have been chosen with particular respect to their relevance to pediatric hematopoietic stemcell transplantation and direction has been given to the authors to focus primarily on the pediatric aspects of disease and treatment, rather than to generate a broader treatment that includes adult issues. I have been most fortunate in assembling a group of distinguished and dedicated authors to contribute to this work. I am grateful for their hard work and hope that readers will find this text both enjoyable and informative. Ronald M. Kline

v

Contents Preface : : : : v Contributors : : : : xvii

SECTION I: GENERAL PRINCIPLES 1. Supportive Care of the Pediatric Hematopoietic Stem-Cell Transplant Patient . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 Victor M. Aquino and Eric S. Sandler Introduction : : : : 1 Prevention and Management of Mucositis : : : : 1 Hepatic Veno-occlusive Disease : : : : 2 Nutrition Support : : : : 6 Hemorrhagic Cystitis : : : : 7 Prevention and Management of Renal Disease : : : : 7 Neurologic Complications of Hematopoietic Stem-Cell Transplant : : : : 9 Transfusion Support : : : : 11 Hematopoietic Growth Factor Support : : : : 16 Conclusion : : : : 19 References : : : : 19 2. Prevention and Treatment of Infectious Disease . . . . . . . . . . . . . . . 27 Scott M. Bradfield, Steven Neudorf, Elyssa Rubin, and Eric S. Sandler Bacterial Infections : : : : 27 Invasive Fungal Infections : : : : 35 Viral Infections : : : : 43 References : : : : 55 3. Acute Graft-Versus-Host Disease . . . . . . . . . . . . . . . . . . . . . . . . . . 65 Theodore B. Moore and Stephen A. Feig Pathophysiology : : : : 65 Staging/Clinical Description : : : : 66 vii

viii

Contents

Risk Factors : : : : 68 Prophylaxis/Therapy : : : : 71 Treatment of Acute Graft-Versus-Host Disease : : : : 76 References : : : : 77 4. Chronic Graft-Versus-Host Disease in Children . . . . . . . . . . . . . . . 85 David A. Jacobsohn, Georgia B. Vogelsang, and Kirk R. Schultz Overview of the Biology of Chronic Graft-Versus-Host Disease : : : : 85 Chronic Graft-Versus-Host Disease—Incidence and Risk Factors in Children : : : : 91 Classification of Chronic Graft-Versus-Host Disease : : : : 93 Treatment of Chronic Graft-Versus-Host Disease : : : : 98 References : : : : 100 5. Cellular Engineering of the Hematopoietic Graft . . . . . . . . . . . . . 111 Ralph Quinones Introduction : : : : 111 Definitions : : : : 111 Minimally Manipulated Products : : : : 117 Extensively Manipulated Products : : : : 118 T-Cell Depletion to Prevent Graft-Versus-Host Disease : : : : 119 Purging of Tumor Cells from Autologous Hematopoietic Stem Cells : : : : 122 Translational Research and the Future: Gene Therapy and Stem-Cell Expansion : : : : 126 Regulation : : : : 127 References : : : : 128 6. Issues in Pediatric Peripheral Blood Stem-Cell Collection . . . . . . 137 Stephan A. Grupp Introduction : : : : 137 Pheresis and Vascular Access : : : : 137 Collection : : : : 139 Techniques for Stem-Cell Mobilization : : : : 139 Target Dose for PBSC Infusion : : : : 140 Processing and Storage of Peripheral Blood Stem Cells : : : : 142 Tumor Cell Purging : : : : 142 Storage : : : : 143 References : : : : 143 7. Pediatric Unrelated Donor Stem-Cell Transplantation . . . . . . . . . 147 Monica Bhatia and Naynesh R. Kamani History : : : : 147 Unrelated Stem Cell Donor Registries : : : : 148 Histocompatibility : : : : 148

Contents

ix

HLA Typing : : : : 149 Registries and Donor Selection : : : : 149 Preparative Regimens : : : : 151 Complications : : : : 151 The Role of Unrelated Donor Transplants in Specific Diseases : : : : 152 References : : : : 155 8. Umbilical Cord Blood Transplantation . . . . . . . . . . . . . . . . . . . . . 161 Satkiran S. Grewal and John E. Wagner Introduction : : : : 161 Biological Features of Umbilical Cord Blood Grafts : : : : 162 Umbilical Cord Blood Transplantation Clinical Experience : : : : 163 Practical Considerations When Selecting a Donor Graft : : : : 179 Umbilical Cord Blood Transplantation for Larger Sized Recipients : : : : 181 Summary and Future Considerations : : : : 181 References : : : : 181 9. Cellular Immunotherapeutic Approaches to the Hematopoietic Stem-Cell Transplant Patient . . . . . . . . . . . . . . . . . . . . . . . . . . . . 189 Dennis Hughes and John Levine Introduction : : : : 189 Immunotherapy and Loss of Immunologic Control of Leukemia : : : : 190 Donor Leukocyte Infusion : : : : 192 Nonmyeloablative Transplant : : : : 194 Summary : : : : 196 References : : : : 196 10. Partially Mismatched Related Donor Transplantation . . . . . . . . . 201 Kuang-Yueh Chiang, P. Jean Henslee-Downey, and Kamar T. Godder Background : : : : 201 Terminology of Partially Mismatched Related Donor (Haplo-Identical) Transplant : : : : 202 Alloreactivity : : : : 202 Donor Selection Criteria : : : : 204 Methods to Cross Major-Human Leukocyte Antigen Barriers : : : : 205 Granulocyte-Colony Stimulating Factor Primed Bone Marrow Cells and Peripheral Blood Stem Cells : : : : 207 Conditioning of the Recipient : : : : 208 Engraftment : : : : 208 Graft-Versus-Host Disease and Outcomes : : : : 209 Infection and Immune Reconstitution : : : : 211

x

Contents

Comparison Between Alternative Donor Transplants : : : : 212 Summary : : : : 215 References : : : : 215 11. Nursing Care of the Pediatric Blood and Marrow Transplant Patient . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 223 Linda Z. Abramovitz and Vicki L. Fisher Introduction : : : : 223 Nursing Roles and Practice Settings : : : : 223 Nursing Education : : : : 225 Professional Nursing Organizations : : : : 226 Patient Education : : : : 227 Special Programs : : : : 228 References : : : : 232 12. Psychological Dimensions of Pediatric Hematopoietic Stem-Cell Transplantation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 235 Bryan D. Carter, William G. Kronenberger, Tanya F. Stockhammer, and Christi Bartolomucci Process-Related Stressors of Pediatric Hematopoietic Stem-Cell Transplantation on the Child and Family : : : : 235 Psychosocial Outcomes of Pediatric HSCT : : : : 237 Influences on Adjustment to Bone Marrow Transplantation : : : : 241 Psychosocial Intervention : : : : 244 Grief and Loss : : : : 246 Caring for the Professional and Psychosocial Team : : : : 247 References : : : : 247 13. Ethical Considerations in Pediatric Hematopoietic Stem-Cell Transplantation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 251 Raymond Barfield and Eric Kodish Introduction : : : : 251 Foundational Concepts : : : : 252 Consent for Stem-Cell Transplantation : : : : 253 The Second Patient : : : : 258 Research, Therapy and Human Rights : : : : 262 Quality of Life and End-of-Life Issues : : : : 266 Conclusion : : : : 267 References : : : : 267 14. Immune Reconstitution in Pediatric Patients Following Hematopoietic Stem-Cell Transplantation . . . . . . . . . . . . . . . . . . 271 Trudy N. Small Introduction : : : : 271

Contents

xi

Natural Killer Cell Reconstitution Post-hematopoietic Stem-Cell Transplantation : : : : 272 T-Cell Reconstitution : : : : 273 B-Cell Reconstitution : : : : 277 Antigen-Specific Responses : : : : 278 Adoptive Immunotherapy : : : : 280 Immunomodulatory Factors : : : : 281 Conclusion : : : : 281 References : : : : 281 15. Endocrine Complications of Childhood Hematopoietic Stem-Cell Transplantation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 287 Wassim Chemaitilly, Farid Boulad, and Charles Sklar Introduction : : : : 287 Impaired Linear Growth and Growth Hormone Deficiency : : : : 287 Disturbances of the Other Hypothalamic-Pituitary Axes : : : : 290 Thyroid Dysfunction : : : : 290 Gonadal and Reproductive Dysfunction : : : : 291 Osteoporosis : : : : 293 Disorders of Glucose Homeostasis : : : : 294 Conclusion : : : : 294 References : : : : 295 16. Future Directions in Pediatric Stem-Cell Transplantation . . . . . . 299 Edwin M. Horwitz Principles of Bone Marrow Cell Therapy : : : : 299 Principles of Gene Therapy : : : : 301 Mesenchymal Stem Cells : : : : 304 Fundamental Steps in the Development of Bone Marrow Cell Therapy : : : : 305 Patient-Based Research of Bone Marrow Cell Therapy and Gene Therapy : : : : 305 Bone Marrow Cell Therapy for Genetic Disorders of Bone : : : : 306 Clinical Trials of Gene Therapy of Severe Combined Immunodeficiency Disorders : : : : 310 Marrow Mesenchymal Stem Cells as Cell Therapy for Inborn Errors of Metabolism : : : : 311 Mesenchymal Stem Cells as Modulators of Immune Function and the Treatment of Graft-Versus-Host Disease : : : : 312 Mesenchymal Stem Cells to Facilitate Hematopoietic Stem-Cell Engraftment : : : : 312 Preclinical Models and Clinical Trials of Blood and Marrow Transplantation as Cell Therapy for Nonhematopoietic Disorders : : : : 313

xii

Contents

Parting Thoughts : : : : 315 References : : : : 315 SECTION II:

NONMALIGNANT DISEASES

17. Primary Immunodeficiencies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 321 Brett J. Loechelt and Naynesh R. Kamani Introduction : : : : 321 Special Considerations : : : : 321 Clinical Results : : : : 325 Future Directions : : : : 331 References : : : : 332 18. Hematopoietic Stem-Cell Transplantation for the Inherited Bone Marrow Failure Syndromes . . . . . . . . . . . . . . . . . . . . . . . . . 337 Adrianna Vlachos, Carole Paley, and Jeffrey Michael Lipton Introduction : : : : 337 The Syndromes : : : : 339 Perspectives on the Future : : : : 359 References : : : : 360 19. Hematopoietic Stem-Cell Transplantation for Acquired Aplastic Anemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 369 Carole Paley, Adrianna Vlachos, and Jeffrey Michael Lipton Introduction : : : : 369 Pathophysiology : : : : 370 Epidemiology : : : : 371 Clinical Features : : : : 371 Immunosuppressive (Immunomodulatory) Therapy for Severe Aplastic Anemia : : : : 371 Other Immunologic Therapies : : : : 372 Hematopoietic Stem-Cell Transplantation for Severe Aplastic Anemia : : : : 372 Graft-Versus-Host Disease : : : : 374 Survival : : : : 375 Hematopoietic Stem-Cell Transplantation Compared with Immunosuppressive Treatment : : : : 375 Alternative Donor Transplant : : : : 377 Unrelated Donor Transplant : : : : 377 HLA-Nonidentical Related Donors : : : : 378 Conclusions and Future Perspectives : : : : 378 References : : : : 379 20. Hematopoietic Stem-Cell Transplantation for the Treatment of Beta Thalassemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 383 Farid Boulad Introduction : : : : 383

Contents

xiii

Hematopoietic Stem-Cell Transplantation from HLA-Matched Siblings : : : : 384 Hematopoietic Stem-Cell Transplantation Using Alternative Donors : : : : 386 Hematopoietic Stem-Cell Transplantation Using Alternative Sources of Stem Cells : : : : 388 Mixed Chimerism Posttransplant for Thalassemia : : : : 388 Alternative Approaches for Allogeneic Stem-Cell Transplantation for Thalassemia : : : : 389 Late Effects Posttransplantation—The “Ex-thalassemic” Patient : : : : 390 Summary : : : : 392 References : : : : 393 21. Hematopoietic Stem-Cell Transplantation for Sickle Cell Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 397 Paul Woodard Introduction : : : : 397 Bone Marrow Transplantation for Sickle Cell Disease : : : : 397 Umbilical Cord Blood Transplantation for Sickle Cell Disease : : : : 399 Acute Toxicities of Hematopoietic Stem-Cell Transplantation : : : : 399 Effects on Organs : : : : 400 Challenges to Transplantation : : : : 403 Mixed Chimerism After Transplantation : : : : 404 Alternate Sources of Allogeneic Hematopoietic Stem Cells : : : : 407 Use of Peripheral Blood Stem Cells : : : : 408 Future Directions : : : : 409 Summary : : : : 409 References : : : : 409 22. Metabolic Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 413 Charles Peters Introduction : : : : 413 Hematopoietic-Cell Transplantation : : : : 416 Mucopolysaccharidoses : : : : 417 Leukodystrophies : : : : 427 Glycoprotein Metabolic Disorders : : : : 433 Miscellaneous Disorders : : : : 434 Developing Therapies and Future Directions : : : : 437 References : : : : 438

xiv

Contents

23. Hematopoietic Stem-Cell Transplantation for Autoimmune Diseases in Children . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 449 Richard K. Burt, Larissa Verda, I. M. de Kleer, and Nico Wulffraat Introduction : : : : 449 Rationale : : : : 449 Animal Models : : : : 450 Stem-Cell Mobilization in Patients with Autoimmune Diseases : : : : 452 Ex Vivo Stem-Cell Selection : : : : 452 Rationale for Design of Autologous Autoimmune Hematopoietic Stem-Cell Transplantation (HSCT) Regimens : : : : 453 Juvenile Idiopathic Arthritis : : : : 454 Crohn’s Disease : : : : 458 Systemic Lupus Erythematosus : : : : 461 Type I Diabetes : : : : 465 Juvenile Dermatomyositis : : : : 466 Immunologic Mechanisms of Hematopoietic Stem-Cell Transplantation : : : : 467 Allogeneic Hematopoietic Stem-Cell Transplantation : : : : 468 References : : : : 468 SECTION III:

MALIGNANT DISEASES

24. Transplantation for Childhood Acute Lymphoblastic Leukemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 477 Donna A. Wall, Kirk R. Schultz, and Gregor S. D. Reid Introduction : : : : 477 Biology of Transplantation for Acute Lymphoblastic Leukemia : : : : 477 Importance of Disease Control Pretransplant : : : : 478 When to Transplant in Childhood Acute Lymphoblastic Leukemia : : : : 478 Preparative Regimens : : : : 482 Hematopoietic Stem Cell Source : : : : 483 Graft-Versus-Leukemia in Acute Lymphoblastic Leukemia: Fact or Fiction : : : : 486 Strategies to Augment Posttransplant Immune Activity : : : : 488 References : : : : 489 25. Bone Marrow Transplantation for Acute Myeloid Leukemia in Children . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 497 Allen R. Chen and Robert J. Arceci Historical Background : : : : 497

Contents

xv

Risk Groups and Prognostic Factors : : : : 498 Preparative Regimens : : : : 501 Allogeneic Transplantation : : : : 506 Autologous Transplantation : : : : 510 QOL/Late Effects : : : : 513 Future Directions and Controversies : : : : 514 References : : : : 518 26. Hematopoietic Stem-Cell Transplantation for Children with Hodgkin’s and Non-Hodgkin’s Lymphoma . . . . . . . . . . . . . . 529 Bruce Gordon and K. Scott Baker Non-Hodgkin’s Lymphoma : : : : 529 Hodgkin’s Disease : : : : 539 References : : : : 549 27. Hematopoietic Stem-Cell Transplantation for Pediatric Malignant Brain Tumors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 555 Sharon L. Gardner and Ira J. Dunkel Introduction : : : : 555 Gliomas : : : : 555 Brainstem Gliomas : : : : 558 Ependymoma : : : : 558 Medulloblastoma : : : : 559 Other Primitive Neuroectodermal Tumors : : : : 561 Germ Cell Tumors : : : : 561 Infants : : : : 562 Future Directions : : : : 563 References : : : : 565 28. Hematopoietic Stem-Cell Transplantation for Pediatric Solid Tumors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 569 ˝ zkaynak and Marcio H. Malogolowkin M. Fevzi O Ewing’s Sarcoma/Peripheral Primitive Neuroectodermal Tumors : : : : 569 Wilms Tumor : : : : 576 Rhabdomyosarcoma (RMS) : : : : 578 Hepatoblastoma : : : : 579 Osteosarcoma : : : : 580 Extracranial Germ Cell Tumors : : : : 580 References : : : : 583 29. Stem-Cell Transplantation in Neuroblastoma . . . . . . . . . . . . . . . . 589 Stephan A. Grupp Introduction : : : : 589 Autologous Transplant in Neuroblastoma : : : : 590 References : : : : 598

xvi

Contents

Appendix: A Brief Overview of Hematopoietic Stem-Cell Transplantation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 601 Vicki L. Fisher and Linda Z. Abramovitz Introduction : : : : 601 Pretransplant Considerations : : : : 603 The Transplant Process : : : : 606 Learning Disabilities : : : : 623 Conclusion : : : : 624 Index : : : : 625

Contributors

Linda Z. Abramovitz Pediatric Bone Marrow Transplant, Children’s Hospital at the University of California, San Francisco, California, U.S.A. Victor M. Aquino Texas, U.S.A.

University of Texas Southwestern Medical Center at Dallas, Dallas,

Robert J. Arceci Kimmel Comprehensive Cancer Center at Johns Hopkins, Johns Hopkins University, Baltimore, Maryland, U.S.A. K. Scott Baker Pediatric Blood and Marrow Transplant Program, University of Minnesota, Minneapolis, Minnesota, U.S.A. Raymond Barfield Division of Stem Cell Transplantation, St. Jude Children’s Research Hospital, Memphis, Tennessee, U.S.A. Christi Bartolomucci

Kids on the Move, Atlanta, Georgia, U.S.A.

Monica Bhatia Division of Pediatric Hematology and Blood and Marrow Transplantation, Columbia University, New York, New York, U.S.A. Farid Boulad Department of Pediatrics, Bone Marrow Transplant Service, Memorial Sloan-Kettering Cancer Center, New York, New York, U.S.A. Scott M. Bradfield Division of Hematology/Oncology, Mayo Clinic College of Medicine, Nemours Children’s Clinic-Jacksonville, Jacksonville, Florida, U.S.A. Richard K. Burt Division of Immunotherapy, Feinberg School of Medicine, Northwestern University Medical Center, Chicago, Illinois, U.S.A. Bryan D. Carter Kosair Children’s Hospital and University of Louisville School of Medicine, Louisville, Kentucky, U.S.A. Wassim Chemaitilly Department of Pediatrics, New York Presbyterian Hospital-Cornell Weill Medical Center, New York, New York, U.S.A.

xvii

xviii

Contributors

Allen R. Chen Kimmel Comprehensive Cancer Center at Johns Hopkins, Johns Hopkins University, Baltimore, Maryland, U.S.A. Kuang-Yueh Chiang Pediatric Blood and Marrow Transplant Program, Aflac Cancer Center and Blood Disorders Service, Children’s Healthcare of Atlanta, Emory University, Atlanta, Georgia, U.S.A. I. M. de Kleer Pediatric BMT Unit, University Medical Center Utrecht, Utrecht, The Netherlands Ira J. Dunkel The Steven D. Hassenfeld Center for Children with Cancer and Other Blood Disorders, NYU Medical Center and Memorial Sloan-Kettering Cancer Center, New York, New York, U.S.A. Stephen A. Feig Mattel Children’s Hospital at UCLA, David Geffen School of Medicine at UCLA, Los Angeles, California, U.S.A. Vicki L. Fisher Pediatric BMT Program, Rainbow Babies and Children’s Hospital, Cleveland, Ohio, U.S.A. Sharon L. Gardner The Steven D. Hassenfeld Center for Children with Cancer and Other Blood Disorders, NYU Medical Center, New York, New York, U.S.A. Kamar T. Godder Division of Pediatric Hematology Oncology, Virginia Commonwealth University, Medical College of Virginia Campus, Children’s Medical Center, and Stem Cell Transplantation, Richmond, Virginia, U.S.A. Bruce Gordon Pediatric Hematology/Oncology and Stem Cell Transplantation, University of Nebraska Medical Center, Omaha, Nebraska, U.S.A. Satkiran S. Grewal Department of Pediatrics, Division of Hematology/Oncology, Tufts University School of Medicine, Baystate Medical Center, Springfield, Massachusetts, U.S.A. Stephan A. Grupp Division of Oncology and Department of Pathology, Stem Cell Biology, Children’s Hospital of Philadelphia and University of Pennsylvania, Philadelphia, Pennsylvania, U.S.A. P. Jean Henslee-Downey EMD Pharmaceuticals, Inc., An Affiliate of Merck KGaA, Darmstadt, Germany and Durham, North Carolina, U.S.A. Edwin M. Horwitz Department of Hematology-Oncology, Divisions of Stem Cell Transplantation and Experimental Hematology, St. Jude Children’s Research Hospital, Memphis, Tennessee, U.S.A. Dennis Hughes The Children’s Cancer Hospital, MD Anderson Cancer Center, Houston, Texas, U.S.A. David A. Jacobsohn Stem Cell Transplant Program, Children’s Memorial Hospital, Northwestern University Feinberg School of Medicine, Chicago, Illinois, U.S.A.

Contributors

xix

Naynesh R. Kamani Division of Stem Cell Transplantation and Immunology, Children’s National Medical Center and The George Washington University School of Medicine, Washington, D.C., U.S.A. Eric Kodish Department of Bioethics, Cleveland Clinic Foundation, Lerner College of Medicine at Case, Cleveland, Ohio, U.S.A. William G. Kronenberger Riley Hospital for Children and Indiana University School of Medicine, Indianapolis, Indiana, U.S.A. John Levine Department of Pediatrics and Communicable Diseases, University of Michigan Comprehensive Cancer Center, Ann Arbor, Michigan, U.S.A. Jeffrey Michael Lipton Division of Pediatric Hematology, Oncology and Stem Cell Transplantation, Schneider Children’s Hospital, New Hyde Park, New York, U.S.A. Brett J. Loechelt Clinical Immunology, Division of Stem Cell Transplantation and Immunology, Children’s National Medical Center, The George Washington University School of Medicine, Washington, D.C., U.S.A. Marcio H. Malogolowkin Bone and Soft Tissue Tumor Program, Children’s Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, California, U.S.A. Theodore B. Moore Mattel Children’s Hospital at UCLA, David Geffen School of Medicine at UCLA, Los Angeles, California, U.S.A. Steven Neudorf Blood and Marrow Transplant Program, Children’s Hospital of Orange County, Orange, California, U.S.A. ˝ zkaynak Pediatric Blood and Marrow Transplantation, Division of M. Fevzi O Hematology/Oncology, Department of Pediatrics, New York Medical College, Valhalla, New York, U.S.A. Carole Paley

Novartis Pharmaceuticals, East Hanover, New Jersey, U.S.A.

Charles Peters Hematopoietic Stem Cell Transplantation, Division of Hematology/Oncology, Children’s Mercy Hospital, Kansas City, Missouri, U.S.A. Ralph Quinones Pediatric Bone Marrow Transplantation, Center for Cancer and Blood Disorders, The Children’s Hospital and Department of Pediatrics, University of Colorado School of Medicine, Denver, Colorado, U.S.A. Gregor S. D. Reid Department of Oncology, The Children’s Hospital of Philadelphia, Joseph Stokes, Jr. Research Institute, Abramson Research Center, Philadelphia, Pennsylvania, U.S.A. Elyssa Rubin Pediatric Hematology/Oncology, Children’s Hospital of Orange County, Orange, California, U.S.A.

xx

Contributors

Eric S. Sandler Hematology/Oncology, Mayo School of Medicine, Nemours Children’s Clinic-Jacksonville, Jacksonville, Florida, U.S.A. Kirk R. Schultz Division of Hematology/Oncology, Blood and Marrow Transplantation Program, British Columbia Children’s Hospital, University of British Columbia, Vancouver, British Columbia, Canada Charles Sklar Department of Pediatrics, Bone Marrow Transplant Service, Memorial Sloan-Kettering Cancer Center, New York, New York, U.S.A. Trudy N. Small Department of Pediatrics and Clinical Laboratories, Memorial SloanKettering Cancer Center, New York, New York, U.S.A. Tanya F. Stockhammer Kosair Children’s Hospital and University of Louisville School of Medicine, Louisville, Kentucky, U.S.A. Larissa Verda Division of Immunotherapy, Feinberg School of Medicine, Northwestern University Medical Center, Chicago, Illinois, U.S.A. Adrianna Vlachos Division of Pediatric Hematology, Oncology and Stem Cell Transplantation, Schneider Children’s Hospital, New Hyde Park, New York, U.S.A. Georgia B. Vogelsang Kimmel Comprehensive Cancer Center of Johns Hopkins, Johns Hopkins University, Baltimore, Maryland, U.S.A. John E. Wagner Pediatric Hematology/Oncology/Blood and Marrow Transplantation, University of Minnesota, Minneapolis, Minnesota, U.S.A. Donna A. Wall Pediatric Blood and Marrow Transplant Program, Methodist Children’s Hospital/Texas Transplant Institute, San Antonio, Texas, U.S.A. Paul Woodard Hematology/Oncology, Division of Stem Cell Transplantation, St. Jude Children’s Research Hospital, Memphis, Tennessee, U.S.A. Nico Wulffraat Pediatric BMT Unit, University Medical Center Utrecht, Utrecht, The Netherlands

SECTION I:

GENERAL PRINCIPLES

1

Supportive Care of the Pediatric Hematopoietic Stem-Cell Transplant Patient Victor M. Aquino University of Texas Southwestern Medical Center at Dallas, Dallas, Texas, U.S.A.

Eric S. Sandler Hematology/Oncology, Mayo School of Medicine, Nemours Children’s Clinic-Jacksonville, Jacksonville, Florida, U.S.A.

INTRODUCTION Hematopoietic stem-cell transplant (HSCT) is an effective therapy for a variety of malignant and nonmalignant conditions. Morbidity and mortality after HSCT are often due to toxicity of the conditioning regimen and resulting pancytopenia, acute and chronic graft versus host disease (GVHD), and the complications of drug therapy. Early recognition and treatment of the complications of HSCT will keep morbidity and mortality to a minimum. The following chapter summarizes the pathophysiology, prevention and management of the noninfectious complications encountered by HSCT recipients.

PREVENTION AND MANAGEMENT OF MUCOSITIS Mucositis is a common complication of HSCT (1,2), occurring in 99% of HSCT recipients in one series with 67.4% having severe mucositis (i.e., grade III and IV) (3). Not only is its occurrence frequent, but mucositis was rated by 42% of patients as the most debilitating side effect of HSCT (4). The etiology of mucositis is multifactorial. The inclusion of melphalan, etoposide, and total body irradiation (TBI) in the conditioning regimen is highly associated with the occurrence and severity of mucositis. Other contributing factors include the use of methotrexate for GVHD prophylaxis, the development of infection, especially herpes simplex and candida, and GVHD. The pathophysiology of mucositis is complex and includes direct cytotoxic effects of therapy on the mucosa, local inflammatory responses, lack of neutrophils for healing, and changes in the oral microflora (5). The morbidity associated with mucositis in patients is significant and includes significant pain, inability to take in adequate calories, predisposition to systemic infection, particularly with oral flora including Streptococcus viridans and anaerobes, and respiratory failure secondary to upper airway damage (6). Although mucositis is typically observed in the mouth 1

2

Aquino and Sandler

and throat, it often extends throughout the gastrointestinal tract and may result in further infection risk with gram-negative bacilli, diarrhea, nausea and vomiting, ileus, and bowel wall injury. The consequences of mucositis include an increase in the number of days of fever, greater use of parenteral antibiotics, greater need for total parenteral nutrition (TPN), and increased use of narcotic therapy. In one study, severe mucositis was associated with a 3.9-fold increase in 100-day mortality, an increase of 2.6 days of narcotic use, an average increase of 2.6 days of hospitalization, and $43,000 in additional hospital charges (7). One problem in defining effective agents for the prevention and treatment of mucositis has been the difficulty in objectively defining the severity of mucositis. There are now multiple studies utilizing different assessment instruments in studying mucositis severity (8). Mucositis may be graded by the National Cancer Institute common toxicity criteria (NCI-CTC) (9), which are summarized in Table 1. Although the treatment of established mucositis has been primarily supportive, many interventions have been studied to avoid this complication. One primary preventative therapy has been infection prophylaxis (10). Acyclovir is used commonly to prevent herpes infection and antifungals to prevent candidal infections. There has been significant controversy about the role of antibacterial prophylaxis of mucositis with topical agents, such as chlorhexidine or nonabsorbable antibiotics. Several studies have failed to clearly demonstrate the efficacy of these agents (11,12). A study by the Pediatric Blood and Marrow Transplant Consortium (PBMTC) evaluated the use of a vancomycin paste for the prevention of mucositis and, particularly, secondary systemic infection (12). Although vancomycin paste was found to significantly decrease the severity of mucositis, use of narcotics, and positive blood cultures, the agent has not been recommended for further study because of concerns for the emergence of vancomycin resistant organisms. A more recent study by this group, as well as several others, has demonstrated the efficacy of glutamine, given either intravenously or orally, in decreasing the frequency and severity of mucositis, with secondary improvement in the duration of narcotic use and hospital days (13), especially in patients undergoing allogeneic HSCT. Other studies have resulted in conflicting outcomes with several showing that glutamine given either orally or intravenously does improve outcomes and others failing to show a difference in outcome (14–16). Different results may be explained by patient selection, dosing of glutamine, or the formulation used in the study. Recently, palifermin (recombinant keratinocyte growth factor) was shown to reduce the incidence and duration of mucositis in patients undergoing HSCT (17). In addition to the improvement in clinical mucositis, there was a statistically significant reduction in the number of days of morphine and TPN use. Other agents that have shown efficacy in nonrandomized studies include topical lidocaine or “magic mouthwash preparations,” sucralfate, clarithromycin, granulocyte-macrophage colony-stimulating factor (GM-CSF) oral rinses, topical tretinoin, cryotherapy, and propantheline, an anticholinergic agent (18–22). Several other studies have attempted to decrease the severity of mucositis by decreasing the dose or number of doses of methotrexate given as GVHD prophylaxis. Another study added leucovorin after each dose of methotrexate to prevent side effects, including mucositis (23). Newer agents under study currently include Traumeel, interleukin (IL) 11, and EN3247 (2). In conclusion, mucositis is a common and significant complication of HSCT. Preventive efforts include avoidance of specific conditioning agents when possible, avoidance of high doses of methotrexate, and prophylaxis of infection. The best treatment is not currently known, and the mainstay of treatment remains supportive care with nutritional support, pain management, and treatment of infection. The efficacy of glutamine and other new agents remains to be studied.

HEPATIC VENO-OCCLUSIVE DISEASE Veno-occlusive disease (VOD) of the liver is a clinical syndrome that occurs as a result of damage to the liver by pretransplant radiation and chemotherapy. The incidence of VOD varies

None

None

Radiationinduced

HSCT

Grade 2 (moderate)

Grade 3 (severe)

Painless ulcers, erythema, Painful erythema, edema, Painful erythema, edema, or ulcers requiring IV hydration or ulcers, but can eat or or mild soreness in the swallow absence of lesions Confluent pseudomembranous Erythema of the mucosa Patchy pseudomemreaction (contiguous patches branous reaction generally O 1.5 cm in (patches generally diameter) R1.5 cm in diameter and noncontiguous) Painless ulcers, erythema, Painful erythema, edema, Painful erythema, edema, or ulcers preventing swallowing or or ulcers, but can or mild soreness in the requiring hydration or swallow absence of lesions parenteral (or enteral) nutritional support

Grade 1 (mild)

Abbreviation: HSCT, hematopoietic stem-cell transplant. Source: From Ref. 9.

None

Grade 0

Grading of Oral Mucositis According to National Cancer Institute Common Toxicity Criteria

Chemotherapyinduced

Table 1

Severe ulceration requiring prophylactic intubation or resulting in documented aspiration pneumonia

Severe ulceration or requires parenteral or enteral nutritional support or prophylactic intubation Necrosis or deep ulceration; may include bleeding not induced by minor trauma or abrasion

Grade 4 (life threatening)

Supportive Care of the Pediatric HSCT Patient 3

4

Aquino and Sandler

but appears to be more common in adult stem cell transplant recipients (7–54%) (24) than in children (11%) (25). VOD is caused by endothelial damage to the hepatic sinusoids and small hepatic venules by radiation and chemotherapy administered as part of the conditioning regimen. This damage appears to induce a local hypercoagulable state by activating the coagulation cascade, leading to occlusion of the hepatic venous outflow tract, which then leads to intrahepatic portal hypertension. As the syndrome progresses, progressive sinusoidal fibrosis appears, exacerbating the portal hypertension (26). The differential diagnosis of liver dysfunction in HSCT recipients is summarized in Table 2. VOD may occur with conventional doses of chemotherapeutic agents, such as Ara-C, 6-thioguanine, and actinomycin-D, but is much more common after high dose therapy. Chemotherapeutic agents used in HSCT preparative regimens associated with the development of VOD include busulfan, cyclophosphamide, carmustine (BCNU), lomustine (CCNU), and mitomycin-C. Risk features associated with the development of VOD include age greater than 15 years at the time of transplant, recipients of a second transplant, active hepatitis, a history of prior liver disease (viral or drug induced hepatitis), and an elevated AST prior to transplant. Children with a diagnosis of acute lymphoblastic leukemia also had a higher incidence of VOD, perhaps due to exposure of methotrexate as part of their chemotherapeutic regimen (27). Pathologic changes of VOD are centered in the terminal hepatic venules and the central lobular hepatocytes in zone 3 of the liver acinus (28). Complete or partial hepatic venular occlusion by thrombosis or endophlebitis is seen. Histologically, VOD leads to nonthrombotic obstruction of centrolobular veins by subendothelial connective tissue and centrolobular hepatocyte necrosis (29). Other pathologic changes in zone 3 include eccentric venular luminal narrowing, phlebosclerosis, sinusoidal fibrosis, and necrosis of hepatocytes (30). VOD usually occurs within the first thirty days after transplant (27). The diagnosis of VOD is made by the presence of clinical symptoms and laboratory tests. The diagnostic criteria for VOD are summarized in Table 3. The earliest clinical sign of VOD is progressive weight gain and peripheral edema due to renal sodium retention. Patients often become thrombocytopenic and may be refractory to platelet transfusion. Patients with severe VOD may develop renal dysfunction, which can progress to renal failure, pleural effusions, and hepatic encephalopathy. Multiorgan failure may develop and is associated with 90% mortality in patients with VOD. The severity of VOD, scored according to mild, moderate, and severe disease, is defined retrospectively according to outcome (33). Mild disease is defined by no apparent adverse effect with complete resolution of symptoms. Moderate disease is characterized by liver dysfunction requiring therapy, such as diuresis for fluid retention and analgesia for pain, but with complete resolution. Severe disease is defined as disease causing the death of the patient. Although histologic examination of the liver parenchyma is required for definitive diagnosis of VOD, it is rarely performed. Percutaneous liver biopsy may be helpful in differentiating VOD from other disorders of the liver, but it is difficult to perform in the patient Table 2

Causes of Liver Dysfunction After Hematopoietic Stem-Cell Transplant (HSCT)

Acute graft-versus-host disease Chronic graft-versus-host disease Veno-occlusive disease Hepatitis Viral: CMV, adenovirus, hepatitis A, B and C, Epstein-Barr virus Bacterial: Septicemia Fungal: Candida, aspergillus, cryptococcus Drug Toxicity: cyclosporine, erythromycin, metotrexate, ketoconazole, fluconazole Total parenteral nutrition Abbreviation: CMV, cytomegalovirus.

Supportive Care of the Pediatric HSCT Patient Table 3

5

Criteria for the Diagnosis of Hepatic Veno-occlusive Disease

Jones criteria (31) Hyperbilirubinemia R2 mg/dL before day 21 after transplant and at least two of the following: Hepatomegaly, usually painful Ascites Weight gain O5% from pretransplant baseline Berman scale (32) Presence of two of the following within 2 weeks of transplantation: Bilirubin R2.0 mg/dL Weight gain R2.5% from pretransplant baseline Hepatomegaly and/or right upper quadrant pain

with thrombocytopenia who responds poorly to platelet transfusion. The transjugular route can be used for both biopsy and measurement of the hepatic vein pressure gradient (34), which has been shown to correlate with histologic features of VOD (30). In patients without prior liver disease, a hepatic venous pressure gradient of more than 10 mmHg as measured by the transjugular route is highly specific (O90%) and moderately sensitive (60%) for VOD (35). Ultrasonography can detect ascites, hepatomegaly, and hepatic vein dilatation. Gall bladder wall thickening of greater than 4 mm has been described in patients with VOD, and a correlation with hepatic venous pressure gradient has been noted (36). Ultrasonography has been used to detect reversal of flow through the para-umbilical vein, but this is often a late finding in VOD (31). Fortunately, in most pediatric patients VOD is reversible. However, more than 25% of patients have irreversible disease, which usually leads to multiorgan failure and death (27,32). In a series of 335 patients with VOD, outcome was predicted by the serum bilirubin and the amount of weight gain (37). Reversal of hepatic flow on Doppler ultrasound is predictive of mortality but is often a late finding. Several drugs have been studied as prophylactic agents against the development of VOD, although the efficacy of such interventions has been disappointing. Several randomized studies have been performed using a continuous infusion of low-dose heparin, the majority of which did not show a reduction in the development of VOD (26). A recent study has shown a lower incidence of VOD in patients receiving low molecular weight heparin (38). Prophylactic use of ursodiol has been shown to reduce liver toxicity but not reduce the incidence or severity of VOD (39). Studies have failed to show that prostaglandin-E1 or pentoxifylline are effective prophylactic agents (26). The mainstay of treatment of VOD is supportive care with fluid restriction, maintenance of sodium balance, and administration of pain medication. The efficacy of low-dose dopamine to maintain renal blood flow is controversial (40). Drugs, such as heparin (41), tissue plasminogen-activator (42), and streptokinase, have been utilized with varying results. Unfortunately, the use of these agents is associated with potentially fatal bleeding, especially in patients with thrombocytopenia due to VOD. Difibrotide (43,44) is a new agent that stimulates the synthesis of thrombomodulin, increases endogenous tissue plasminogen activator, and decreases plasminogen activator inhibitor type I with very little anticoagulant activity. In one study, complete resolution of severe VOD was seen in 40% of cases without significant toxicity (45). Defibrotide has also been shown to be effective in the prevention of VOD. In one study (46), use of prophylactic defibrotide was found to reduce the maximum total bilirubin levels and to lead to an improvement in survival. Large prospective randomized trials are required to determine the efficacy of defibrotide in the management and prevention of VOD. Transjugular intrahepatic portosystemic shunting (47) and liver transplantation can be considered in patients who do not respond to conventional therapy.

6

Aquino and Sandler

In summary, VOD is a commonly seen complication of HSCT that may progress to multiorgan failure and death. Fortunately, VOD spontaneously reverses in most pediatric patients. The mainstay of therapy is early recognition, with careful fluid management and pain control. Interventions to prevent and/or treat the disorder have not been successful. Newer agents, such as defibrotide, appear promising but require further study.

NUTRITION SUPPORT Nutritional problems are extremely common after HSCT, with more than 90% of patients requiring nutritional support in some studies (48,49). These children are prone to the development of severe gastrointestinal complications as well as metabolic derangements. The results are decreased intake, increased metabolic needs, and wasting. Decreased intake is a result of: (1) mucositis secondary to conditioning and infection, (2) nausea and vomiting, (3) anorexia, (4) changes in taste, making it hard to find pleasing foods, (5) restrictions in food choices, (6) development of gastroparesis, and (7) acute and chronic GHVD (50). Wasting in the form of diarrhea and protein losing enteropathy is also common. Patients will often have increased metabolic needs as a consequence of GVHD, infection, or other complications that must be met. The end result is often protein calorie malnutrition. Nutrition support has historically been centered on TPN (51). The majority of HSCT patients start on TPN around the day of transplant, and most require several weeks of support. Often ongoing support is necessary even after recovery from other acute manifestations and hospital discharge. In those patients with acute and chronic GVHD, nutrition supplementation may continue for weeks to months. Recently, there has been an increased interest in the use of enteral support in the HSCT patient (52,53). Such support has taken the form of nasogastric feedings or placement of gastrostomy tubes (54,55). There are several advantages to the use of enteral support. Its use is associated with lower costs and less need for laboratory monitoring when compared with TPN. Enteral feeding may theoretically protect the GI enterocyte from damage caused by conditioning, especially when such agents as glutamine are added to the formula. The use of enteral feedings has also been associated with a decreased risk of infection when compared with TPN administered via a central venous catheter (56). In general, the few studies comparing parenteral and enteral support have found similar efficacy in most outcome measures but decreased complications with enteral feeding. In one study by Pietsch et al. 17 children undergoing intensive chemotherapy or HSCT received glutamine supplemented NG feeds and tolerated it well (57). They compared the costs to a similar group of patients receiving TPN and found that for the same number of days, the cost differential was $25,348 versus $112,299 for NG feeds and TPN, respectively. Another study compared 12 patients receiving NG feedings to 22 receiving TPN. Both groups achieved 85% of their nutritional needs, GI symptoms were equally frequent, but again the cost associated with the use of NG feedings was significantly less than that of TPN (14). Although several groups are currently advocating the use of enteral feeds, these are not without potential complications, including the problems of NG insertion in a patient with mucositis and the risk of vomiting and aspiration. The most important changes resulting in a decreased need for nutrition support have been in the area of general supportive care. These include the use of conditioning regimens associated with development of less severe mucositis, prevention of GVHD and infections, use of newer more effective antiemetics, and newer agents that may prevent severe mucositis and wasting. The issue of when to discontinue parenteral and enteral nutrition support is controversial. Some groups will continue support after discharge from the hospital, whereas others make every attempt to stop support at the time of discharge. One study specifically addresses this issue by randomizing patients to continued TPN or hydration fluids after discharge from the hospital.

Supportive Care of the Pediatric HSCT Patient

7

They found that patients who were discharged with fluids only had a more rapid resumption of oral intake (58). In summary, malnutrition is a frequent complication of HSCT. It is important that nutritional needs be addressed in all patients undergoing HSCT. Further studies are ongoing to define the best methods of nutritional support.

HEMORRHAGIC CYSTITIS Hemorrhagic cystitis (HC), defined as greater then 100 RBC/high power field persisting for longer then 2 days, is a common complication of HSCT, occurring in 10–50% of HSCT recipients (59). Patients may develop dysuria and urinary obstruction. Early onset HC, occurring within 48 hours of conditioning treatment, is typically secondary to cyclophosphamide or ifosfamide use (60). With current preventive therapies including MESNA and aggressive hydration, it is now rarely seen. Late onset HC, occurring days to several months after transplant, predominates. The etiology of late onset disease is likely secondary to reactivation of viruses during a time of immunosuppression (61,62). The use of pretransplant cyclophosphamide and irradiation, as well as thrombocytopenia, during the time of myeloablation may increase the severity of early HC. Recent literature supports the reactivation of latent virus, including BK virus, a human polyoma virus, adenovirus, and Cytomegalovirus (CMV) as etiologic factors in the development of late HC (59,63). These viruses are ubiquitous, and once infection occurs, they remain dormant in the kidney with clinically relevant infection developing during times of immunosuppression (64,65). As a result, treatment for GVHD has been associated with an increased risk of HC. In one study of 63 patients undergoing HSCT, 11 patients developed 19 episodes of HC, with 89% having documented viruria or bacteruria (12 BK, 2 adenovirus, 1 CMV, and 3 bacteria) (59). Patients with GVHD had a significantly increased risk of HC. In another study of adult patients, 52% of patients were BK positive (66). HC occurred in 50% of those who were BK positive and in none of those who were BK negative. In a more recent study of more than 800 urine samples from 50 patients, the BK viral load in the urine was significantly higher in patients who developed HC (67). In the past, treatment of severe HC was largely supportive, including correction of coagulopathy and thrombocytopenia, hyperhydration or continuous bladder irrigation, localized treatment, including cystoscopy to evacuate clots, and local instillation of Prostaglandin-E, alum, silver nitrate, or formaldehyde (68,69). Other supportive therapies reported include the instillation of GM-CSF (70), aminocaproic acid (71), and the use of hyperbaric oxygen (72). More recently, new antiviral agents have been shown to be very effective, including ganciclovir for CMV, intravenous ribavirin for adenovirus, and cidofovir for treatment of both BK virus and adenovirus (73,74). In summary, HC is a common complication of HSCT. The early onset disease seen in the past and associated with the conditioning chemotherapy is now rarely observed. However, late onset disease, frequently seen, is associated with the level of immunosuppression and viral reactivation. New antiviral agents especially cidofovir have been extremely effective in treatment of HC.

PREVENTION AND MANAGEMENT OF RENAL DISEASE Renal dysfunction after bone marrow transplantation is a relatively frequent event, occurring in approximately 30–50% of children undergoing HSCT (75,76). Early renal injury (within the first 100 days after transplant) most often results from infection, its prophylaxis, and treatment. The causes of early renal dysfunction in HSCT recipients are summarized in Table 4. Acute tubular necrosis may arise as a direct consequence of sepsis with or without hypotension or from therapy with a variety of nephrotoxic drugs (77). Other causes of early renal injury include tumor lysis syndrome, marrow infusion-associated acute renal failure, and VOD.

8 Table 4

Aquino and Sandler Causes of Early Renal Dysfunction After Hematopoietic Stem-Cell Transplant

Septicemia Hypotension: hemorrhage, cardiac failure Veno-occlusive disease Drug induced: amphotericin, cyclosporine, aminoglycosides, vancomycin, foscarnet, acyclovir, previous chemotherapy with cisplatin or ifosfamide Total body irradiation Hypertension: cyclosoporine, steroids

Late renal injury (after 100 days post transplantation) may be caused by a syndrome similar to hemolytic-uremic syndrome and is thought to evolve from the late effects of radiation therapy and cytotoxic chemotherapy.

Nephrotoxic Drugs A variety of nephrotoxic drugs are administered to children and adolescents undergoing HSCT, as well as drugs that may potentiate the nephrotoxicity of other agents. Cyclosporine and tacrolimus, commonly used for prophylaxis of acute GVHD, are nephrotoxic. The dose of cyclosporine and tacrolimus should be reduced if patients are receiving voriconazole (78). Antibiotics, such as the aminoglycosides that are routinely administered to prevent and treat infections, are associated with renal toxicity. Drug levels should be carefully monitored in patients receiving these agents to minimize renal damage. Amphotericin-B is nephrotoxic and causes electrolyte wasting. Fluid boluses prior to infusion may reduce the nephrotoxicity of this agent. The use of liposomal amphotericin products and other new antifungal agents may reduce the risk of nephrotoxicity when compared with conventional amphotericin.

Tumor Lysis Syndrome In patients with tumor lysis syndrome, renal failure occurs after induction of massive tumor cell death, results from the rapid death of tumor cells that results in the release of tumor cell products, and the development of hyperuricemia, hyperkalemia, and hyperphosphatemia. Acute renal failure results from the accumulation of uric acid and phosphate in the renal tubules, which causes obstruction and filtration failure. Because most HSCT recipients who come to transplant receive prior antineoplastic therapy and are usually in complete or partial remission, this syndrome rarely complicates HSCT [approximately 1% of transplant patients (79)]. Prevention of tumor lysis syndrome includes the use of aggressive volume expansion, urine alkalinization, and allopurinol. Recombinant uricase (80) has been shown to be effective in reducing the amount of uric acid and the risk of renal failure. Renal dialysis may be employed if patients develop severe hyperphosphatemia and/or renal failure develops.

Marrow Infusion-Associated Acute Renal Failure Red blood cell (RBC) hemolysis with release of free hemoglobin can occur during bone marrow collection or if cold storage (freezing and thawing) is performed. Infusion of such marrow can be associated with heme protein–induced nephrotoxicity, which potentially can lead to renal failure. Heme protein cast formation, which can occur in acidic urine, renal vasoconstriction, and proximal tubular cell heme loading are the main pathogenic mechanisms that lead to this form of renal damage.

Supportive Care of the Pediatric HSCT Patient

9

Heme protein associated nephrotoxicity may be prevented by vigorous hydration and intravascular volume expansion before and during marrow infusion. This limits cast formation, renal vasoconstriction, and proximal tubular heme uptake. Potential therapeutic interventions include iron chelation therapy, the use of endothelial antagonists, and nitric oxide supplementation by L-arginine therapy (79).

Hemolytic Uremic Syndrome The most common cause of renal failure beyond the period of marrow engraftment is hemolytic uremic syndrome , which can be documented in approximately 5% to 25% of posttransplant patients (81,82). Hemolytic Uremic Syndrome (HUS) is characterized by the development of microangiopathy with end organ damage (especially the kidney and central nervous system), microangiopathic hemolytic anemia, and thrombocytopenia. HUS occurs between 3 and 12 months post–bone marrow transplant. TBI is the most likely cause of HUS, although infectious agents (e.g., CMV), immunologic reactions (e.g., GVHD), and nephrotoxic drugs (cyclosporine, tacrolimus) have also been implicated (83). The management of HUS has largely been supportive with the use of RBC and platelet transfusions and hemodialysis if renal failure develops. Although a variety of specific treatments have been studied, their efficacy in patients with HUS has been limited. Patients with severe HUS are often treated with plasmapheresis, although no compelling evidence of its efficacy has been documented to date (83). Other interventions have included discontinuation of cyclosporine, hemoperfusion over staphylococcal protein A column, and intravenous gamma-globulin therapy. The prognosis is predicted by the severity of the disease. The disease appears to undergo spontaneous resolution, although the organ damage that occurs may be permanent.

Long-Term Renal Complications of Hematopoietic Stem-Cell Transplant Late renal toxicity (O100 days) has been reported in 11–54% of patients who have received HSCT (84). It appears that the single most important risk factor in the development of late nephropathy is the use of radiation therapy as a part of the conditioning regimen (81,85). Radiation-induced nephritis usually presents 6–12 months posttransplant and is thought to be due to damage to the renal vascular epithelium (86,87), the latent period being attributed to slow endothelial turnover and progressive tissue damage (88). Radiation-induced nephritis may present acutely, as seen in hemolytic-uremic syndrome, and presents with severe anemia, microscopic hematuria, proteinuria, elevation of BUN and creatinine, hypertension and evidence of microangiopathic intravascular hemolysis (81,85). The chronic form presents with isolated renal impairment with or without hemolysis (89). A variety of other nephrotoxins may play a role in the development of late nephrotoxicity. Chemotherapeutic agents, such as cisplatin, appear to predispose patients to the development of late nephrotoxicity (85,90). Therapy with cyclosporine has been shown to cause microangiopathy, hypertension, and potentially HUS (91). Drug therapy with amphotericin and aminoglycoside antibiotics may also predispose patients to late nephrotoxicity. In summary, early and late renal dysfunction are an important cause of morbidity and mortality in children undergoing HSCT. Careful monitoring of drug levels and renal function are required to prevent long-term complications in the survivors of HSCT.

NEUROLOGIC COMPLICATIONS OF HEMATOPOIETIC STEM-CELL TRANSPLANT Neurologic complications of HSCT can be generally divided into five areas: encephalopathies, infectious complications, chemotherapy, radiation therapy, and cerebrovascular disorders (92).

10 Table 5

Aquino and Sandler Neurologic Complications After Hematopoietic Stem-Cell Transplant (HSCT)

Seizures Drug induced: busulfan, cyclosporine, imipenem Hyponatremia or H2O intoxication: cyclophosphamide, inappropriate antidiuretic hormone secretion Hypomagnesemia: cyclosporine, fanconi syndrome Hypocalcemia Hypoglycemia: inadequate infusion, pentamidine Dystonic reactions: metoclopramide or phenothiazines Encephalopathy: uremia, liver failure (e. g., veno-occlusive disease), drug induced Intracranial hemorrhage Infection: aspergillus, cryptococcus, herpesvirus encephalitis, pneumococcal meningitis, toxoplasmosis Polymyositis Thrombotic thrombocytopenia purpura

The various causes are summarized in Table 5. Significant neurologic events have been reported to occur in from 14% to O50% of HSCT recipients in various series and are associated with a mortality of up to 10% of patients (93). Risk factors for neurologic events include alternative donor transplants, development of severe GVHD, and the use of TBI (94). The most common complications are in those patients who develop encephalopathy. These encephalopathies may occur with or without seizures. The most common etiology of encephalopathy is medication related. Both busulfan and BCNU have been associated with seizures and altered mental status (95). The incidence of seizures in children receiving busulfan seems to be higher then that seen in adults. Most pediatric centers routinely prophylaxis these patients with anticonvulsants during the period of drug administration. Other medications commonly associated with seizures and/or encephalopathies are the immunosuppressant medications cyclosporine and tacrolimus. Typically patients will develop severe hypertension and headaches prior to the onset of seizures and/or encephalopathy. Neurologic complications are more likely when these patients are also treated with steroids and have hypertension or hypomagnesemia. In most cases, drug levels are elevated at the time of neurologic dysfunction. Seizures may be focal in nature, and MRI will typically show white matter changes, often in the posterior circulation. Transient cortical blindness is occasionally seen as well. Fortunately, all neurologic complications usually resolve with discontinuation of the medication and the use of antiseizure medication. Long-term sequelae are rare (96). Other drugs frequently used in the transplant setting are occasionally associated with seizures and encephalopathy as well, including antimicrobials (imipenem), narcotics, and chemotherapy agents. Depressed mental status can also be seen in patients with multiorgan failure or those with isolated liver disease who develop hyperammonemia. The development of depressed mental status in these situations is considered a poor prognostic sign. Inciting factors for depressed neurologic function may include injury due to cytokines, organ dysfunction (i.e., hypoxia secondary to pulmonary failure), or microthrombotic disease causing multiorgan function (97). CNS infection is also an ominous complication of HSCT (98). Whenever CNS dysfunction occurs in these severely immunocompromised patients, infection must be considered. Bacterial and viral meningitis/encephalitis may occur without the usual clinical manifestations of meningitis. A diagnostic lumbar puncture must be strongly considered as part of the evaluation in these circumstances. Until results of the lumbar puncture and radiographic examination are available, empiric coverage with broad-spectrum antibiotics and antiviral therapy should be strongly considered. More concerning is the high risk of opportunistic infections of the CNS, particularly in the alternative donor patient receiving significant immunosuppressive therapy. The herpes family of viruses, including HHV6, cryptococcus,

Supportive Care of the Pediatric HSCT Patient

11

fungal disease with abscess, toxoplasmosis, and nocardia infections, have all been reported in posttransplant patients. Acute changes in neurologic function, particularly those associated with focal signs, are very suggestive for cerebrovascular disease. The incidence of intracranial hemorrhage ranges from 1–30% depending on the series reviewed (99,100). Risk factors for intracranial hemorrhage include the sometimes severe thrombocytopenia commonly seen prior to engraftment, coagulation defects secondary to infection or organ dysfunction, and CNS infections. Ischemic lesions are much less common but have also been reported. This may be due to underlying infection, embolic disease, or an underlying hypercoagulability, which has now been well described in the HSCT setting (101). Although not proven, some investigators have described a CNS angitis that may be associated with both acute and chronic GVHD (102). Particularly in leukemia patients, recurrence of leukemia in the CNS may also present with neurologic signs and symptoms. In addition, the development of a somnolence syndrome approximately one month after treatment with TBI has been well described. Late CNS complications reported include not only recurrent disease but also leukoencephalopathy and secondary CNS malignancies. Other rare neurologic complications seen after HSCT include encephalopathy associated with thrombotic thrombocytopenic purpura and unusual immune mediated peripheral neuropathies associated with chronic GVHD, such as polymyositis and Guillain Barre´ Syndrome (103,104). TTP is a systemic microvascular disorder characterized by thrombocytopenia, microangiopathic hemolytic anemia, and ischemic manifestations (105) TTP and HUS were initially described as distinct disorders but are now considered different expressions of the same disease process characterize by the nonimmune destruction of platelets. TTP shares many features with HUS, including consumptive thrombocytopenia, microangiopathic hemolytic anemia, and renal dysfunction. TTP occurs in 10–15% of allogeneic patients and up to 7% of autologous patients. Risk factors include extensive prior therapy, the occurrence of GVHD and VOD, and the use of cyclosporine. A majority of patients will develop renal and neurologic symptoms. Treatment is controversial in the posttransplant setting. Studies have reported mixed results with plasmapheresis and immune suppression. Recently defibrotide has been suggested as a successful treatment of TTP (83,106,107). Any patient undergoing HSCT who develops neurologic dysfunction should have immediate assessment with a careful physical exam, CT scan, and empiric coverage for possible infection as well as correction of any coagulopathy. Strong consideration should be given to LP with CSF analysis and MRI. Prognostic implications of neurologic dysfunction are dependent on the underlying etiology.

TRANSFUSION SUPPORT Transfusion of blood products is critical to support the HSCT patient prior to engraftment. All blood products administered to HSCT recipients should be leukoreduced and irradiated prior to infusion.

Components Red Blood Cells RBCs are transfused in patients with anemia to improve oxygen carrying capacity. In general, patients with a hemoglobin greater than 10 gm/dl are asymptomatic and do not require transfusion. Although centers have different criteria for transfusion, most centers transfuse patients when their hemoglobin is less than 7–8 gm/dl. RBCs are removed from whole blood by centrifugation. The volume of the average unit of RBCs is about 350 mL, which contains 200 mL of RBCs with a hematocrit of 60%. Citrate phosphate dextrose (CPD) and CP2D are preservative solutions approved by the

12

Aquino and Sandler

Food and Drug Administration (FDA) for 21-day storage of RBCs. Blood collected in adenine-fortified CPD may be stored for 35 days. Adsol (AS-1), Nutricel (AS-3), and Optisol (AS-5) are newer preservatives that can extend the storage time to a maximum of 42 days (108). Washed RBCs are rarely used and are available for patients who have severe reactions to plasma, such as those with IgA deficiency.

Platelets Platelets are transfused in order to prevent or treat bleeding complications related to thrombocytopenia. There are two types of platelet concentrates: those prepared from centrifugation of whole blood (“random-donor”) and those collected by apheresis. Platelets are then stored in anticoagulant containing CPD or citrate-phosphate-dextrose-adenosine and then stored on elliptical, circular, or flat-bed agitators. Platelets can be stored for up to five days at temperatures of 20 to 248C, after which the increased risk of bacterial contamination mandates the discarding of the unit. In general, one random unit of platelets per 5 kilograms of patient body weight will raise the platelet count by 40,000–50,000/mm3. A single apheresis unit of platelets will raise the platelet count of an adolescent or adult to 50,000/mm3. The decision as to whether to administer platelet transfusions depends on the cause of the thrombocytopenia, the anticipated duration of the thrombocytopenia, the patient’s platelet count, and the clinical condition of the patient. The risk of serious spontaneous bleeding when the platelet count is above 20,000/mm3 is small but increases with lower platelet counts. Most centers administer platelet counts on a prophylactic basis when the patient’s platelet count decreases to less than 20,000/mm3 in an otherwise asymptomatic patient. The trigger for platelet transfusion may be higher in patients at increased risk of bleeding such as mucositis. Patients who receive multiple platelet transfusions are at risk of developing refractoriness to platelet transfusions. Platelet refractoriness should be suspected in patients who do not get the expected increase in platelet count after a platelet transfusion. There are two general causes of platelet refractoriness. Patients with immune mediated thrombocytopenia develop antibodies to HLA class I molecules, ABO blood group antigens, or platelet membrane specific antigens. The platelet refractory state may be prevented by the use of single donor platelets, and leukoreduced platelet products. These patients can be managed with the use of HLA-matched or ABO compatible platelet transfusions if available. Nonimmune platelet refractoriness is caused by sequestration of platelets (such as in patients with splenomegaly) or due to increased platelet destruction [such as disseminated intravascular coagulation (DIC) or fever]. The use of a one-hour posttransfusion platelet count may help to differentiate these two conditions. Patients with no increase in the one-hour posttransfusion platelet count are likely to have immune-mediated platelet destruction. Granulocytes Infections that occur prior to engraftment and in the immediate posttransplant period are a major cause of morbidity and mortality in children and adolescents undergoing stem cell transplant. Such patients even after recovery from postconditioning neutropenia exhibit neutrophil dysfunction and may manifest defective cellular and humoral immunity for months following HSCT. It appears that granulocyte infusions are effective for the treatment of gramnegative bacteremia in neutropenic neonates (109). However, the efficacy of granulocyte infusion in patients undergoing HSCT is less clear. Early studies were limited by the administration of low doses of granulocytes and the unavailability of hematopoietic growth factors (CSFs) to increase the number of peripheral blood neutrophils. The use of granulocytes harvested from cytokine-stimulated donors has not been well studied. Recent data also suggests that compatibility testing of granulocytes may contribute to prolonged granulocyte survival and may improve their efficacy (110).

Supportive Care of the Pediatric HSCT Patient

13

Granulocytes are collected by apheresis and are separated based upon density. Granulocyte collections taken by centrifugation from healthy, unstimulated donors usually yield approximately 0.5–1.0!1010 granulocytes per liter of donor blood. Donor granulocyte counts may be increased by the administration of agents, such as steroids or CSFs, that mobilize granulocytes from the marginal pool into the circulating pool or increase their production. Granulocytes are then irradiated prior to infusion to prevent the development of transfusion related graft-versus-host-disease. Reactions after granulocyte transfusions are common. Fever, chills, dyspnea, chest tightness, acrocyanosis, hypoxia, and pulmonary infiltrates on chest X-ray may be seen. These episodes may take up to 12 hours to resolve. The concurrent administration of amphotericin B and granulocyte concentrates has been reported to cause pulmonary reactions, the mechanism of interaction is unknown (111). However, separating the administration of granulocytes and amphotericin B by several hours may avoid this adverse effect.

Fresh Frozen Plasma Plasma is removed from whole blood by centrifugation and frozen at K188C or lower within 8 hours of collection and may be stored for up to seven years. The volume of a unit of fresh frozen plasma is 200–250 mL. FFP is indicated for the correction of documented deficiencies of coagulation factors, after massive RBC transfusion or for the correction of the coagulopathy associated with DIC. The usual dose of FFP is 10–15 ml/kg administered over one to two hours. Each unit of FFP contains an average of 1 unit/ml of factors II, V, VIII, IX, and X. FFP does not require irradiation prior to infusion in immunocompromised patients. Cryoprecipitate Cryoprecipitate is the cold insoluble portion of FFP thawed at 1–68C and is stored at K188C. Cryoprecipitate contains Factor VIII, fibrinogen, and von Willebrand factor. The main indication for cryoprecipitate is for the replacement of fibrinogen in patients with DIC. A bag of cryoprecipitate contains approximately 200 to 250 mg of fibrinogen. An appropriate dose of cryoprecipitate is one bag for each 5–10 kilograms of body weight.

Processing of Blood Products Prior to Infusion Leukocyte Depletion Leukocytes may be removed from blood products by centrifugation or by filtration. The current filters in use are able to remove 99.9% of leukocytes (112,113). The filters may be used either in the blood bank or at the bedside as the RBCs are being transfused. Leukocyte depletion leads to a decrease in febrile transfusion reactions, prevention of CMV transmission, prevention of alloimmunization, and prevention of the immunomodulatory effects of transfusion.

Irradiation of Blood Products All blood products are irradiated prior to administration to HSCT recipients to prevent transfusion associated GVHD. Blood units are irradiated with either a cesium (137Cs) or cobalt (60Co) radiation source. Most blood banks use radiation doses between 1500 and 3500 cGy. Irradiation damages the lymphocytes by forming electrically charged particles or ions that alter the DNA, rendering the lymphocytes unable to proliferate. After irradiation, there is no reduction in the life span of the cells transfused, and granulocytes appear to maintain their function.

14

Aquino and Sandler

Management of ABO Incompatibility Between Donor and Recipient ABO incompatibility between donor and recipient is encountered in approximately 25% of all allogeneic HSCT. A major incompatibility exists in which the recipient plasma contains isohemagglutinins directed against the donor’s ABO antigens (example O recipient and A, B, or AB donor). This situation can lead to immediate transfusion reaction (see above). In this situation, the donor’s RBCs must be removed by centrifugation prior to infusion. A minor incompatibility exists when the donor plasma contains isohemagglutinins directed against the recipient’s RBCs (example A, B, or AB recipient and O donor). In this situation, the donor’s plasma must be removed by centrifugation prior to infusion. If the donor and recipient have a bidirectional mismatch (donor A and recipient B or vice versa), then both RBCs and plasma must be removed prior to infusion. Studies have shown no significant effect of major or minor ABO mismatch on the incidence of graft rejection, GVHD, or survival, although in one cohort analysis bidirectional mismatch was associated with a poorer survival post-HSCT (114). The ABO and Rh type of the stem cell donor and recipient must be considered in RBC transfusion of the HSCT recipient. Acute and delayed transfusion reactions may result secondary to major and minor incompatibilities. Table 6 summarizes the guidelines for RBC transfusion of recipients of ABO-incompatible stem cell grafts.

Complications of Transfusion Therapy Transfusions may be associated with either febrile or allergic reactions. Febrile reactions are caused by cytotoxic or agglutinating antibodies in the recipient’s plasma that react with antigens on transfused white blood cells or cytokines. The frequency of febrile reactions is roughly 0.5% to 1.0% per unit of RBCs infused and 20% of all platelet infusions. An allergic transfusion reaction occurs when the patient has been previously sensitized to a plasma protein in the platelet concentrate. The reaction may be mild, with erythema, urticaria, and pruritus, or severe, progressing to anaphylaxis. Such reactions occur in 1% to 2% of blood product infusions. These reactions can be managed by stopping the infusion and administering intravenous diphenhydramine and/or methylprednisolone.

Hemolytic Transfusion Reactions Immediate hemolytic transfusion reactions are most often due to ABO incompatibility between the donor and the recipient. These events are usually due to a “clerical error,” such as mislabeling the unit to be transfused or a unit being transfused into the wrong patient. These reactions are characterized by fever, chills, abdominal and lower back pain, tachycardia, Table 6 Transfusion Support in Hematopoietic Stem-Cell Transplant Recipients Transplanted from ABO Incompatible Donors Recipient type A A A B B B AB AB AB Source: From Ref. 115.

Donor type

Transplant incompatibility

Type of RBCs to transfuse

Type of plasma to transfuse

O B AB O A AB O A B

Minor Major Major Minor Major Major Minor Minor Minor

O O A, O O O B, O O A, O B, O

A, AB AB A, AB B, AB AB B, AB AB AB AB

Supportive Care of the Pediatric HSCT Patient

15

hypotension, nausea, and hemoglobinuria, leading to oliguria and anuria. If a hemolytic transfusion reaction is suspected, the blood transfusion should be stopped immediately, and a blood sample should be sent to the laboratory for a Coombs test to confirm the diagnosis. Therapy consists of intravenous hydration and maintenance of urinary output. Diuretic therapy with furosemide or mannitol may be required to maintain urine output. Delayed hemolytic transfusion reactions may also occur. Primary immunization is mild and can occur weeks after transfusion. This rarely causes significant hemolysis and should be suspected when an unexplained decrease in hemoglobin occurs two to three weeks after transplant. An anamnestic response occurs 3 to 10 days after transfusion and is related to sensitivity to minor blood groups. These reactions can result in profound anemia. The diagnosis is confirmed with a Coombs test and the development of antibodies to one of the minor blood groups.

Transfusion Associated Lung Injury Transfusion associated lung injury (TRALI) is the third leading cause of death related to transfusions (116). Clinically, TRALI is similar to acute respiratory distress syndrome. TRALI may occur after transfusion with whole blood components, FFP, cryoprecipitate, or intravenous gamma-globulin. Within six hours of receiving a blood transfusion containing plasma, the patient develops fever, tachypnea, and dyspnea. Chest X-ray shows pulmonary edema. The mortality associated with TRALI is approximately 10%. Patients are managed with oxygen and supportive care, with some patients requiring mechanical ventilation. Bacterial Contamination of Blood Units Bacterial contamination of blood units can be seen and potentially lead to the development of shock and ultimately death. Bacterial contamination is most often due to inadequate cleaning of the skin before the venous puncture is performed prior to blood collection and is occasionally due to a transient bacteremia in the donor. As expected, the most common cause of blood product contamination is due to bacterial skin flora. Platelets are more commonly contaminated than RBCs because platelets are stored at 20–248 C. In one study, one in 4300 platelet units were contaminated, and the risk of contamination was higher in pooled platelets when compared to apheresis platelets (117). Transfusion Transmission of Viral Infection Transfusions may also be associated with the transmission of certain infectious agents, including viruses, parasites, and potentially prions, although the risk of such infections is small. The aggregate risk of infection from a blood transfusion in a unit of blood that has passed both donor and viral testing is one in 34,000 units transfused, with hepatitis B and C accounting for 88% of the infections (118). Approximately 300 cases of virally transmitted infection occur each year in transfusion recipients. Hepatitis A is usually transmitted by the fecal-oral route, and its transmission in blood is rare. Symptoms of infection occur early in the illness, and the duration of viremia is short. Currently blood products are not routinely screened for hepatitis A. Hepatitis D and E are also rarely transmitted by transfusion. Hepatitis B and C virus are the most common viral pathogens transmitted by blood transfusions (118). Donors with viremia from these infections can be healthy without a history of symptoms. Hepatitis B virus (HBV) can be identified in one in 63,000 units. Infection with HBV can be associated with acute fulminant hepatitis. Hepatitis C (HCV) can be seen one in 103,000 units. Eighty percent of those infected are asymptomatic (119). Hepatitis C can be associated with relapsing hepatitis. Infection with HBV and HCV can be associated with both chronic persistent and chronic active hepatitis, and both are associated with an increased risk of developing hepatocellular carcinoma.

16

Aquino and Sandler

Hepatitis G is a new RNA virus that has been identified in some patients with non-A, non-B, non-C hepatitis. From 1% to 4% of otherwise normal blood donors are carriers of hepatitis G. Currently, donors are not screened routinely for hepatitis G. Human immune deficiency virus (HIV) can be transmitted by blood transfusion, although only a very small number of new cases of acquired immunodeficiency syndrome (AIDS) are caused by infection via blood transfusion. Currently, antibody testing can detect antibodies in 98% to 100% of HIV C donors, and testing and donor screening has greatly reduced the risk of HIV infection from a blood transfusion. The risk of HIV infection from a screened unit is estimated to be one in 493,000 units transfused (118). Human T-lymphocyte virus (HTLV) is a retrovirus that has been associated with the development of T-cell leukemia in adults and is associated with the development of a form of myelopathy in humans. The incidence of HTLV-1 antibodies in blood donors is 0.025%. Currently blood units are screened for this infection. CMV is a herpes virus that causes infections in all age groups. CMV is likely harbored in neutrophils and can be transmitted via blood transfusion. The risk of primary infection from a blood transfusion ranges from 2.5% to 12%. It appears that the risk of infection is directly related to the number of leukocytes transfused. Although the issue of whether to provide blood products at low risk of transmitting CMV is controversial, it appears that the use of leukofiltration is adequate in preventing primary CMV infection in patients with malignancy or those undergoing HSCT (120). Transfusion of parvovirus B19 and infection is rare and may be transmitted by plasma products and albumin (121). It is estimated that one in 3300–50,000 units are contaminated with parvovirus B19 and can transmit the virus. The risk of transfusion of Creutzfeldt-Jakob disease (CJD) is unknown. The disease is thought to be caused by a prion, though the exact etiologic agent is unknown. CJD is known to be transmitted by the transplantation of dura or cornea and by the administration of pituitary derived growth hormone. Although no evidence of blood transmission has been identified, the fact that a blood donor subsequently developed CJD has raised fears about the potential for transfusion-borne infection. In summary, the use of blood products is critical to the success of HSCT. The risks of transfusion can be reduced by improving donor selection, improving testing for potential infectious agents, and reducing the number of blood units transfused.

HEMATOPOIETIC GROWTH FACTOR SUPPORT Infectious complications after HSCT are due to prolonged neutropenia induced by myeloablation and neutrophil dysfunction in the early phase of recovery after transplantation. Therefore, shortening of the period of neutropenia should reduce the risk of life-threatening infection and improve survival after transplant. Both recombinant granulocyte CSF (G-CSF) and GM-CSF have been shown to increase the number of stem cells harvested from the peripheral blood or bone marrow. Hematopoietic CSFs have also been shown to shorten the duration of neutropenia and decrease the incidence of infectious complications in HSCT patients. The optimal dose, schedule and method of administration of growth factors remain to be standardized. Guidelines for the use of CSFs in HSCT recipients have been published by the American Society of Clinical Oncology (122,123).

Growth Factors in the Priming of Donors Prior to the Collection of Bone Marrow Administration of G-CSF before harvesting autologous or allogeneic bone marrow may be of benefit to both the donor and the recipient. However, the optimal dose and duration of G-CSF to be used for bone marrow priming prior to harvest is unknown. In one study, administration of

Supportive Care of the Pediatric HSCT Patient

17

2 mg/kg/day of G-CSF for five days increased the number of harvested CD34C cells and granulocyte macrophage colony-forming (GM-CFU) in the donor’s bone marrow exceeding baseline values by 4.2-fold and 1.6-fold, respectively, when compared with unprimed donors (124). The use of G-CSF priming allowed the collection of an average of 180 ml less bone marrow in the primed group when compared to the unprimed group. However, G-CSF primed bone marrow did not shorten the time to trilineage engraftment or the duration of hospitalization compared with unprimed bone marrow. Morton et al. (125) randomized patients undergoing allogeneic transplant to G-CSF primed bone marrow or G-CSF primed PBSCs. The median time to neutrophil and platelet engraftment was similar in the two groups. The use of the G-CSF primed peripheral blood stem cells (PBSCs) was associated with steroid-refractory acute GVHD, chronic GHVD, and prolonged requirements for immunosuppressive therapy. Survival was similar for the two groups. However, a study by Couban et al. (126) demonstrated an acceleration in neutrophil and platelet engraftment in patients receiving G-CSF primed bone marrow when compared to PBSCs.

Growth Factors in the Mobilization and Collection of Peripheral Blood Stem Cells PBSCs from autologous donors have replaced bone marrow as the preferred source of hematopoietic stem cells, based upon the ease of collection and the rapidity of engraftment. G-CSF mobilized PBSCs have also been used in allogeneic HSCT. Although the incidences of grade II-IV acute GVHD have been similar for patients receiving allogeneic PBSC when compared with bone marrow (127,128), the incidence of chronic GVHD has been higher in PBSC recipients (127,129). It also appears that the chronic GHVD that has been experienced has been more difficult to treat, requiring a greater number of immunosuppressive regimens (130). PBSCs are collected by leukapheresis, stored, and then infused after the administration of myeloablative chemotherapy and radiation. Harvesting PBSCs without the use of priming with either chemotherapy and/or CSFs requires multiple pheresis procedures and yields a relatively small number of stem cells (131). Although administration of non-myeloablative doses of chemotherapy, such as cyclophosphamide, can be used to increase the number of circulating stem cells, the use of G-CSF and GM-CSF either alone or in combination with chemotherapy allows for the collection of larger numbers of PBSCs. G-CSF stimulated donors have a 2.5- to 5.5-fold increase in the number of mononuclear cells recovered during PBSC collection when compared with collection from unstimulated donors (132). The peak number of stem cells is seen 4–8 days after CSF treatment alone or shortly after recovery from neutropenia when CSFs are given after recovery from chemotherapy. It appears that higher doses of G-CSF (10 mcg/kg per day or higher) may yield a higher content of CD34C cells during PBSC collection (133).

Use of Colony-Stimulating Factors During Autologous Transplantation Both G-CSF and GM-CSF have been studied in randomized, placebo controlled studies in adult patients undergoing autologous bone marrow transplantation (134,135). Recovery from severe neutropenia was reduced from 20 to 13 days in patients receiving CSFs in one randomized study (136). Use of G-CSF or GM-CSF prophylaxis after autologous BMT demonstrated reduction in the duration of fever, days of antibiotic use and number of hospital days (137). The benefit of post-transplant CSFs in recipients of autologous PBSC HSCT is less clear. Several studies have shown no significant benefit for post infusion G-CSF in terms of neutrophil recovery, raising the possibility that the larger number of progenitor cells infused obviates the beneficial effects of CSFs therapy. In one randomized trial, although faster neutrophil recovery was associated with the use of G-CSF (mean of 10 vs. 12 days), there was no difference in

18

Aquino and Sandler

the incidence and severity of infection, days of fever or days of antibiotic use (138). No financial benefit was associated with the use of G-CSF in this study.

Use of Colony-Stimulating Factors During Allogeneic Transplantation The benefits of the use of CSFs in the allogeneic setting have been less pronounced than those seen in patients undergoing autologous transplant. In randomized trials which evaluated the use of CSFs after allogeneic bone marrow transplant the time to neutrophil recovery has usually been shortened (135); however this has not translated into a reduction in the number of infections or the number of hospital days. Several studies have reported potential negative side effects of CSF use. Several authors have noted that the time to platelet engraftment has been delayed in patients receiving CSFs (139,140). CSFs have been noted to increase the levels of soluble IL-2 receptor-a, which can potentially aggravate GVHD (141). However, there have been conflicting reports of whether the use of growth factors results in a clinically detectable increase in the incidence of acute and chronic GVHD (115,136,140,142–145).

Use of Colony-Stimulating Factors in Umbilical Cord Blood Transplantation As more experience has been gained with the use of umbilical cord blood units for transplant, engraftment appears delayed when compared with bone marrow and peripheral stem cells, likely due to the lower cell doses transplanted (146,147). Growth factors have been used in umbilical cord blood transplant to hasten engraftment although the efficacy of this approach is controversial. Ex vivo expansion of cord blood using stem cell growth factors may improve engraftment time and allow their use in adult donors (148).

Use of Colony-Stimulating Factors for the Management of Engraftment Failure After Hematopoietic Stem-Cell Transplant G-CSF and GM-CSF have been studied in patients in whom engraftment does not occur, is delayed, or is lost after the return of granulopoiesis. Recipients of T cell depleted grafts, patients who received grafts purged with chemotherapy in vitro, patients whose donors are HLA-C mismatched, and patients who receive a relatively low cell dose are at increased risk of graft failure. Most studies have evaluated the use of GM-CSF in patients who failed to show evidence of engraftment by 3–4 weeks after autologous bone marrow transplant. Neutrophil responses are seen in approximately one-half to two-thirds of patients (133). These trials are limited by the fact that results are compared with historical controls, and the response rates are difficult to compare to the variable incidence of spontaneous neutrophil recovery. The role of CSFs in this patient population requires further study.

Role of Erythropoietin in Hematopoietic Stem-Cell Transplantation In order to reduce the RBC transfusions in stem cell transplant recipients, interest has arisen in the use of human recombinant erythropoietin (EPO). During the time of bone marrow hypoplasia during the first two weeks following myeloablative therapy, the levels of EPO increase and are disproportionately high relative to the degree of anemia (149). EPO has been shown to be efficacious in decreasing the number of RBC transfusions and in improving the quality of life of patients receiving conventional chemotherapy (150,151). A reduction in the number of PRBC transfusions has been demonstrated in small numbers of patients undergoing allogeneic HSCT (152,153). In one study, the number of RBCs transfusions was reduced from an average of 10 to 5 units (152). However, in several trials

Supportive Care of the Pediatric HSCT Patient

19

involving autologous HSCT recipients, there appears to be no reduction in the number of RBC transfusions associated with the use of EPO (153). In autologous HSCT recipients with delayed engraftment and prolonged anemia (hemoglobin less than 9 g/dL at more than 30 days from transplant), a response rate of 83% was seen (154). EPO has also been studied in patients undergoing hematopoietic progenitor cell mobilization and harvest. In one retrospective study of 34 patients, EPO increased the number of colony-forming unit-granulocyte macrophage progenitors and CD34C cells in patients who received G-CSF plus EPO versus those who received G-CSF plus placebo (154). However, there was no associated decrease in RBC transfusion or time to engraftment in the patients who received G-CSF/EPO stimulated stem cells.

Use of Thrombopoietic Agents in Hematopoietic Stem-Cell Transplant Recipients Due to the expense and complications associated with the use of platelet transfusions, the development of agents with thrombopoietic activity would be an important advance in the management of patients undergoing HSCTs. A variety of molecules, including IL-3, GMCSF/IL-3 fusion product (PIXY), IL-11 and recombinant thrombopoietin, have been developed and evaluated in preliminary studies and have demonstrated only a modest decrease in platelet transfusion requirements (155). Currently, only IL-11 is commercially available. In a randomized trial of patients undergoing autologous transplant for breast cancer, there was no statistically significant difference in the number of platelet transfusions associated with the use of IL-11 (156). A pegylated recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF) has recently been tested in phase II trials in women with breast cancer undergoing autologous transplant (157). Although well tolerated, no significant differences in the kinetics of early thrombopoiesis or number of platelet transfusions after autologous HSCT were observed. In summary, the use of G-CSF and GM-CSF has been shown to be of benefit to patients undergoing HSCT when used in peripheral stem cell collection and in patients undergoing autologous HSCT. Their benefit in allogeneic transplant is not as pronounced and the use of growth factors in this patient group remains controversial. The efficacy of EPO in HSCT patients is not well studied. Although the reduction in RBC transfusions may be modest at best, the improvement in quality of life associated with the use of EPO in patients receiving conventional chemotherapy may be present in HSCT recipients and requires further study. The efficacy of thrombopoietic agents to date has not been demonstrated, although newer molecules currently in phase II or III testing may be shown to be of benefit.

CONCLUSION The use of supportive care is critical to successful HSCT. A variety of preventive and interventional strategies have been developed to optimize the prevention and treatment of the noninfectious complications associated with HSCT. Further studies are necessary to refine preexisting regimens and to develop new strategies to reduce the morbidity and mortality of HSCT recipients.

REFERENCES 1. Demarosi F, Bez C, Carrassi A. Prevention and treatment of chemo- and radiotherapy-induced oral mucositis. Minerva Stomatol 2002; 51:173–186. 2. Stiff P. Mucositis associated with stem cell transplantation: current status and innovative approaches to management. Bone Marrow Transplant 2000; 27:S3–S11.

20

Aquino and Sandler

3. Wardley AM, Jayson GC, Swindell R, et al. Prospective evaluation of oral mucositis in patients receiving myeloablative conditioning regimens and haemopoietic progenitor rescue. Br J Haematol 2000; 110:292–299. 4. Bellm LA, Cunningham G, Durnell L, et al. Defining clinically meaningful outcomes in the evaluation of new treatments for oral mucositis: oral mucositis patient provider advisory board. Cancer Invest 2002; 20:793–800. 5. Blijlevens NM, Donnelly JP, DePaw BE. Mucosal barrier injury: biology, pathology, clinical counterparts and consequences of intensive treatment for haematological malignancy: an overview. Bone Marrow Transplant 2000; 25:1269–1278. 6. Ruescher TJ, Sodeifi A, Scrivani SJ, et al. The impact of mucositis on alpha-hemolytic streptococcal infection in patients undergoing autologous bone marrow transplantation for haematologic malignancies. Cancer 1998; 82:2275–2281. 7. Sonis ST, Oster G, Fuchs H, et al. Oral mucositis and the clinical and economic outcomes of hematopoietic stem-cell transplantation. J Clin Oncol 2001; 19:2201–2205. 8. McGuire DB, Peterson DE, Muller S, et al. The 20 item oral mucositis index: reliability and validity in bone marrow and stem cell transplant patients. Cancer Invest 2002; 20:893–903. 9. DCTD, NCI, NIH et al. Cancer therapy evaluation program: common toxicity criteria version 1998; 2.0. 10. Gomez RS, Carneiro MA, Souza LN, et al. Oral recurrent human herpes virus infection and bone marrow transplantation survival. Oral Surg Oral Med Pathol Oral Radiol Endod 2001; 91:552–556. 11. Bondi E, Baroni C, Prete A, et al. Local antimicrobial therapy of oral mucositis in paediatric patients undergoing bone marrow transplantation. Oral Oncol 1997; 33:322–326. 12. Gamis A, Personal communication. 2003. 13. Aquino VM, Harvey A, Garvin JH, et al. The use of supplemental glutamine to decrease morbidity in children undergoing stem cell transplantation: A pediatric blood and marrow transplant consortium study. Bone Marrow Transplant 2005. In press. 14. Coghlin-Dickson TM, Wong RM, Offrin RS, et al. Effect of oral glutamine supplementation during bone marrow transplantation. JPEN J Parenter Enteral Nutr 2000; 24:61–66. 15. Cockerham MB, Weinberger BB, Lerchie SB. Oral glutamine for the prevention of oral mucositis associated with high-dose paclitaxel and melphalan for autologous bone marrow transplantation. Ann Pharmacother 2000; 34:300–303. 16. Schloerb PR, Skikne BS. Oral and parenteral glutamine in bone marrow transplantation: a randomized, double-blind study. JPEN J Parenter Nutr 1999; 23:117–122. 17. Spielberger R, Stiff P, Bensinger W, et al. Palifermin for oral mucositis after intensive therapy for hematologic cancers. N Engl J Med 2004; 351:2590–2598. 18. Bez C, Demarosi F, Sardella A, et al. GM-CSF mouth rinses in the treatment of severe oral mucositis: a pilot study. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1999; 88:311–315. 19. Castagna L, Benhamou E, Pedraza E, et al. Prevention of mucositis in bone marrow transplantation: a double blind randomised controlled trial of sucralfate. Ann Oncol 2001; 12:953–955. 20. Cohen G, Elad S, Or R, et al. The use of tretinoin as oral mucositis prophylaxis in bone marrow transplantation patients: a preliminary study. Oral Dis 1997; 3:243–246. 21. Yuen KY, Woo PC, Tai JW, et al. Effects of clarithromycin on oral mucositis in bone marrow transplant recipients. Haematologica Budap 2001; 86:554–555. 22. Elad S, Cohen G, Zylber-Katz E, et al. Systemic absorption of lidocaine after topical application for the treatment of oral mucositis in bone marrow transplantation patients. J Oral Pathol 1999; 28:170–172. 23. Nevill TJ, Tirgan MH, Deeg HJ, et al. Influence of post-methotrexate folinic acid rescue on regimen-related toxicity and graft-versus-host disease after allogeneic bone marrow transplantation. Bone Marrow Transplant 1992; 9:349–354. 24. Carreras E, Bertz H, Arcese W, et al. Incidence and outcome of hepatic veno-occlusive disease after blood or marrow transplantation: a prospective cohort study of the European Group for Blood and Marrow Transplantation Chronic Leukemia Working Party. Blood 1998; 92:3599–3604. 25. Meresse V, Hartmann O, Vassal G, et al. Risk factors for hepatic veno-occlusive disease after highdose busulfan-containing regimens followed by autologous bone marrow transplantation: a study in 136 children. Bone Marrow Transplant 1992; 10:135–141. 26. Carreras E. Veno-occlusive disease of the liver after hemopoietic cell transplantation. Eur J Haematol 2000; 64:281–291.

Supportive Care of the Pediatric HSCT Patient

21

27. McDonald GB, Sharma P, Matthews DE, et al. Venoocclusive disease of the liver after bone marrow transplantation: diagnosis, incidence, and predisposing factors. Hepatology 1984; 4:116–122. 28. Allen JR, Carstens LA, Katagiri GJ. Hepatic veins of monkeys with veno-occlusive disease. Sequential ultrastructural changes. Arch Pathol 1969; 87:279–289. 29. Shulman HM, Gown AM, Nugent DJ. Hepatic veno-occlusive disease after bone marrow transplantation. Am J Pathol 1987; 127:549–558. 30. Shulman H, Fisher LB, Schoch HG, et al. Venoocclusive disease of the liver after marrow transplantation: histological correlates of clinical signs and symptoms. Hepatology 1994; 19:1171–1181. 31. Yoshimoto K, Yakushiji K, Ijuin H, et al. Colour Doppler ultrasonography of a segmental branch of the portal vein is useful for early diagnosis and monitoring of the therapeutic course of venoocclusive disease after allogeneic haematopoietic stem cell transplantation. Br J Haematol 2001; 115:945–948. 32. Jones RJ, Lee KSK, Beschorner WE, et al. Venoocclusive disease of the liver following bone marrow transplantation. Transplantation 1987; 44:778–783. 33. McDonald GB, Hinds MS, Fisher LD, et al. Veno-occlusive disease of the liver and multiorgan failure after bone marrow transplantation: a cohort study of 355 patients. Ann Intern Med 1993; 118:255–267. 34. Azoulay D, Castaing D, Lemoine A, et al. Transjugular intrahepatic portosystemic shunt (TIPS) for severe veno-occlusive disease of the liver following bone marrow transplantation. Bone Marrow Transplant 2000; 25:987–992. 35. Shulman H, Gooley T, Dudley MD, et al. Utility of transvenous liver biopsies and wedged hepatic venous pressure measurements in sixty marrow recipients. Transplantation 1995; 59:1015–1022. 36. Nicolau C, Bru C, Carreras E, et al. Sonographic diagnosis and hemodynamic correlation in venoocclusive disease of the liver. J Ultrasound Med 1993; 12:437–440. 37. Bearman SI, Anderson GL, Mori M, et al. Venoocclusive disease of the liver: development of a model for predicting fatal outcome after marrow transplantation. Blood 1993; 11:1729–1736. 38. Or R, Nagler A, Shpilberg O, et al. Low molecular weight heparin for the prevention of venoocclusive disease of the liver in bone marrow transplantation patients. Transplantation 1996; 61:1067–1071. 39. Ruutu T, Eriksson B, Remes K, et al. Ursodeoxycholic acid for the prevention of hepatic complications in allogeneic stem cell transplantation. Blood 2002; 100:1977–1983. 40. Bacq Y, Gaudin C, Hadengue A, et al. Systemic, splanchnic and renal hemodynamic effects of a dopaminergic dose of dopamine in patients with cirrhosis. Hepatology 1991; 14:483–487. 41. Simon M, Hahn T, Ford LA, et al. Retrospective multivariate analysis of hepatic veno-occlusive disease after blood or marrow transplantation: possible beneficial use of low molecular weight heparin. Bone Marrow Transplant 2002; 27:627–633. 42. Kulkarni S, Rodriguez M, Lafuente A, et al. Recombinant tissue plasminogen activator (rtPA) for the treatment of hepatic veno-occlusive disease (VOD). Bone Marrow Transplant 1999; 23:803–807. 43. Chopra R, Eaton JD, Grassi A, et al. Defibrotide for the treatment of hepatic veno-occlusive disease: results of the European compassionate-use study. Br J Haematol 2000; 111:1122–1129. 44. Abescasis MM, Conceicao S, Ferreira I, et al. Defibrotide as salvage therapy for refractory venoocclusive disease of the liver complicating allogeneic bone marrow transplantation. Bone Marrow Transplant 1999; 23:843–846. 45. Richardson P, Elias AD, Krishnan A, et al. Treatment of severe veno-occlusive disease with defibrotide: compassionate use results in response without significant toxicity in a high-risk population. Blood 1998; 92:737–744. 46. Chalandon Y, Roosnek E, Mermillod B, et al. Prevention of veno-occlusive disease with defibrotide after allogeneic stem cell transplantation. Biol Blood Marrow Transplant 2004; 10:347–354. 47. Fried MW, Connaghan DG, Sharma S, et al. Transjugular intrahepatic portosystemic shunt for the management of severe venoocclusive disease following bone marrow transplantation. Hepatology 1996; 24:588–591. 48. Papadopoulou A, Lloyd DR, Williams MD, et al. Gastrointestinal and nutritional sequelae of bone marrow transplantation. Arch Dis Child 1996; 75:208–213. 49. Papadopoulou A, MacDonald A, Williams MD, et al. Enteral nutrition after bone marrow transplantation. Arch Dis Child 1997; 77:131–136.

22

Aquino and Sandler

50. Hermann VM, Petruska PJ. Nutrition support in bone marrow transplant patients. Nutr Clin Pract 1993; 8:19–27. 51. Lipman TO. Clinical trials of nutritional support in cancer. Parenteral and enteral therapy. Hematol Oncol Clin North Am 1991; 5:91–102. 52. Langdana A, Tully N, Molloy E, et al. Intensive enteral nutrition support in paediatric bone marrow transplantation. Bone Marrow Transplant 2001; 27:741–746. 53. Mercadante S. Parenteral versus enteral nutrition in cancer patients: indication and practice. Support Care Cancer 1998; 6:85–93. 54. Barron MA, Duncan DS, Green GJ, et al. Efficacy and safety of radiologically placed gastrostomy tubes in paediatric haematology/oncology patients. Med Pediatr Oncol 2000; 34:177–182. 55. Sefcick A, Anderton D, Byrne JL, et al. Naso-jejunal feeding in allogeneic bone marrow transplant recipients: results of a pilot study. Bone Marrow Transplant 2001; 28:1135–1139. 56. Pencharz PB. Aggressive oral, enteral or parenteral nutrition: prescriptive decisions in children with cancer. Int J Cancer Suppl 1998; 11:73–75. 57. Pietsch JB, Ford C, Whitlock JA. Nasogastric tube feedings in children with high-risk cancer: a pilot study. J Pediatr Hematol Oncol 1999; 21:111–114. 58. Charuhas PM, Fosberg KL, Bruemmer B, et al. A double-blind randomized trial comparing outpatient parenteral nutrition with intravenous hydration: effect on resumption of oral intake after marrow transplantation. JPEN J Parenter Enteral Nutr 1997; 21:157–161. 59. Russell SJ, Vowels MR, Vale T. Haemorrhagic cystitis in paediatric bone marrow transplant patients: an association with infective agents, GVHD and prior cyclophosphamide. Bone Marrow Transplant 1994; 13:533–539. 60. Greene JN, Sandin RL, Fields KK, et al. Hemorrhagic cystitis in bone marrow transplant patients: is it an infection or chemotherapy toxicity? Cancer Control 1994; 1:411–415. 61. Vogeli TA, Peinemann F, Burdach S, et al. Urological treatment and clinical course of BK polyomavirus-associated hemorrhagic cystitis in children after bone marrow transplantation. Eur Urol 1999; 36:252–257. 62. Bogdanovic G, Priftakis P, Taemmeraes B, et al. Primary BK virus (BKV) infection due to possible BKV transmission during bone marrow transplantation is not the major cause of hemorrhagic cystitis in transplanted children. Pediatr Transplant 1998; 2:288–293. 63. Akiyama H, Kurosu T, Sakashita C, et al. Adenovirus is a key pathogen in hemorrhagic cystitis associated with bone marrow transplantation. Clin Infect Dis 2001; 32:1325–1330. 64. Pahari A, Rees L. BK virus-associated renal problems—clinical implications. Pediatr Nephrol 2003. In press. 65. Holt DA, Sinnott JT, IV, Oehler RL, et al. BK virus. Infect Control Hosp Epidemiol 1992; 13:738–741. 66. Bedi A, Miller CB, Hanson JL, et al. Association of BK Virus with failure of prophylaxis against hemorrhagic cystitis following bone marrow transplantation. J Clin Oncol 1995; 13:1103. 67. Leung AY, Suen CK, Lie AK, et al. Quantification of polyoma BK viruria in hemorrhagic cystitis complicating bone marrow transplantation. Blood 2001; 98:1971–1978. 68. Trigg ME, O’Reilly J, Rumelhart S, et al. Prostaglandin E1 bladder instillations to control severe hemorrhagic cystitis. J Urol 1990; 143:92–94. 69. deVries CR, Freiha FS. Hemorrhagic cystitis: a review. J Urol 1990; 143:1–9. 70. Vela-Ojeda J, Tripp-Villanueva F, Sanchez-Cortes E, et al. Intravesical rhGM-CSF for the treatment of late onset hemorrhagic cystitis after bone marrow transplant. Bone Marrow Transplant 1999; 24:1307–1310. 71. Lakhani A, Raptis A, Frame D, et al. Intravesicular instillation of E-aminocaproic acid for patients with adenovirus-induced hemorrhagic cystitis. Bone Marrow Transplant 1999; 24:1259–1260. 72. Hattori K, Yabe M, Matsumoto M, et al. Successful hyperbaric oxygen treatment of life-threatening hemorrhagic cystitis after allogeneic bone marrow transplantation. Bone Marrow Transplant 2001; 27:1315–1317. 73. Gavin PJ, Katz BZ. Intravenous ribavirin treatment for severe adenovirus disease in immunocompromised children. Pediatrics 2002; 110:e9. 74. Miyamura K, Hamaguchi M, Taji H, et al. Successful ribavirin therapy for severe adenovirus hemorrhagic cystitis after allogeneic marrow transplant from close HLA donors rather than distant donors. Bone Marrow Transplant 2000; 25:545–548. 75. Kist-van Holte J, van-Zwet JM, Brand R, et al. Bone marrow transplantation in children: consequences for renal failure shortly after and one year post-BMT. Bone Marrow Transplant 1998; 22:559–564.

Supportive Care of the Pediatric HSCT Patient

23

76. Van Why SK, Friedman AL, Wei LJ, et al. Renal insufficiency after bone marrow transplantation in children. Bone Marrow Transplant 1991; 7:383–388. 77. Zager RA, O’Quigley J, Zager BK, et al. Acute renal failure following bone marrow transplantation: a retrospective study of 272 patients. Am J Kidney Dis 1989; 13:210–216. 78. Romero AJ, Pogamp PL, Nilsson LG, et al. Effect of voriconazole on the pharmacokinetics of cyclosporine in renal transplant patients. Clin Pharmacol Ther 2002; 71:226–234. 79. Zager RA. Acute renal failure syndromes after bone marrow transplantation. Adv Nephrol Necker Hosp 1997; 27:263–280. 80. Pui CH, Jeha S, Irwin D, et al. Recombinant urate oxidase (rasburicase) in the prevention and treatment of malignancy-associated hyperuricemia in pediatric and adult patients: results of a compassionate-use trial. Leukemia 2001; 15:1505–1509. 81. Tarbell NJ, Guinan EC, Chin L, et al. Renal insufficiency after total body irradiation for pediatric bone marrow transplantation. Radiother Oncol 1990; 18:139S–142S. 82. Loomis LJ, Aronson AJ, Rudinsky R. Hemolytic uremic syndrome following bone marrow transplantation: a case report and review of the literature. Am J Kidney Dis 1989; 14:324–328. 83. Pettitt AR, Clark RE. Thrombotic microangiopathy following bone marrow transplantation. Bone Marrow Transplant 1994; 14:495–504. 84. Lieper AD. Non-endocrine late complications of bone marrow transplantation in childhood: part I. Br J Haematol 2002; 118:3–22. 85. Guinan E, Tarbell NJ, Niemeyer CM, et al. Intravascular hemolysis and renal insufficiency after bone marrow transplantation. Blood 1988; 72:451–455. 86. Keane WF, Crossan JT, Staley NA, et al. Radiation-induced renal disease. a clinicopathologic study. Am J Med 1996; 60:127–137. 87. Luxton RW, Kunkler PB. Radiation nephritis. Acta Radiol Ther Phys Biol 1997; 2:169–178. 88. Baker DG, Krochak RJ. The response of the microvascular system to radiation: a review. Cancer Invest 1989; 7:287–294. 89. Lonnerholm G, Carlson K, Bratteby LE, et al. Renal function after autologous bone marrow transplantation. Bone Marrow Transplant 1991; 8:129–134. 90. Tarbell NJ, Guinan E, Miemeyer C, et al. Late onset of renal dysfunction in survivors of bone marrow transplantation. Int J Radiat Oncol Biol Phys 1988; 15:99–104. 91. Shulman H, Striker G, Deeg HJ, et al. Nephrotoxicity of cyclosporin A after allogeneic marrow transplantation: glomerular thromboses and tubular injury. N Engl J Med 1981; 305:1392–1395. 92. Krouwer HGJ, Wijdicks EFM. Neurologic complications of bone marrow transplantation. Neurol Clin N Am 2003; 21:319–352. 93. Antonini G, Ceschin V, Morino S, et al. Early neurologic complications following allogeneic bone marrow transplant for leukemia: a prospective study. Neurology 1998; 50:1441. 94. Crenshaw H, Slatkin NE. Neurological complications. In: Hematopoietic Cell Transplantation, 1999:45–54. 95. Shah AK. Cyclosporine. A neurotoxicity among bone marrow recipients. Clin Neuropharmacol 1999; 22:67–73. 96. Gordon B, Spadinger A, Hodges E, et al. Effect of granulocyte-macrophage colony-stimulating factor on oral mucositis after hematopoietic stem-cell transplantation. J Clin Oncol 1994; 12:1917. 97. Faraci M, Lanino E, Dini G, et al. Severe neurologic complications after hematopoietic stem cell transplantation in children. Neurology 2002; 59:1895–1904. 98. Bleggi-Torres LF, deMedeiros BC, Werner B, et al. Neuropathologic findings after bone marrow transplantation: an autopsy study of 180 cases. Bone Marrow Transplant 2000; 25:301–307. 99. Bleggi-Torres LF, Werner B, Gasparetto EL, et al. Intracranial hemorrhage following bone marrow transplantation: an autopsy study of 58 patients. Bone Marrow Transplant 2002; 29:29–32. 100. Kaufman PA, Jones RB, Greenberg CS, et al. Autologous bone marrow transplantation and factor XII, factor VII, and protein C deficiencies. Cancer 1990; 66:512–521. 101. Gallardo D, Ferra C, Berlanga JJ, et al. Neurologic complications after allogeneic bone marrow transplantation. Bone Marrow Transplant 1996; 18:1135–1139. 102. Ma M, Barnes G, Pullilam J, et al. CNS angiitis in graft vs host disease. Neurology 2002; 59:1994–1997. 103. Anderson B, Young V, Kean WF, et al. Polymyositis in chronic graft versus host disease. Arch Neurol 1982; 39:188–190. 104. Greenspan A, Deeg HJ, Cottler-Fox M, et al. Incapacitating peripheral neuropathy as a manifestation of chronic-graft-versus-host disease. Bone Marrow Transplant 1990; 5:349–352.

24

Aquino and Sandler

105. Tsai HM. Molecular mechanisms in thrombotic thrombocytopenic purpura. Semin Thromb Hemost 2004; 30:549–557. 106. Fuge R, Bird JM, Fraser A, et al. The clinical features, risk factors and outcome of thrombotic thrombocytopenic purpura occurring after bone marrow transplantation. Br J Haematol 2001; 113:56–64. 107. Elliot MA, Nichols WLJ, Plumhoff EA, et al. Posttransplantation thrombotic thrombocytopenic purpura: a single-center experience and a contemporary review. Mayo Clin Proc 2003; 78:421–430. 108. Quirolo KC. Transfusion medicine for the pediatrician. Pediatr Clin North Am 2002; 49:1211–1238. 109. Strauss RG. Current status of granulocyte transfusions to treat neonatal sepsis. J Clin Apheresis 1989; 5:25–29. 110. Adkins D, Goodnough LT, Shenoy S, et al. Effect of leukocyte compatibility on neutrophil increment after transfusion of granulocyte colony-stimulating factor-mobilized prophylactic granulocyte transfusions and on clinical outcomes after stem cell transplantation. Blood 2000; 95:3605–3612. 111. Wright DG, Robichaud KJ, Pizzo PA, et al. Lethal pulmonary reactions associated with the combined use of amphotericin B and leukocyte transfusions. N Engl J Med 1981; 304:1185–1189. 112. Sirchia G, Rebulla P, Parravicini A. Leukocyte depletion of red cells. Curr Stud Hematol Blood Transfus 1994; 60:6–17. 113. Sirchia G, Rebulla P, Parravicini A, et al. Quality control of red cell filtration at the patient’s bedside. Transfusion (Paris) 1994; 34:26–30. 114. Stussi G, Muntwyler J, Passweg JR, et al. Consequences of ABO incompatibility in allogeneic hematopoietic stem cell transplantation. Bone Marrow Transplant 2003; 30:87–93. 115. Powles R, Smith C, Milan S, et al. Human recombinant GM-CSF in allogeneic bone-marrow transplantation for leukaemia: double-blind, placebo-controlled trial. Lancet 1990; 336:1417. 116. Silliman CC. Transfusion-related lung injury. Transfus Med Rev 1999; 13:177–186. 117. Ness P, Braine H, King K, et al. Single-donor platelets reduce the risk of septic platelet transfusion reactions. Transfusion (Paris) 2001; 41:857–861. 118. Schreiber GB, Busch MP, Kleinman SH. The risk of transfusion-transmitted viral infections. N Engl J Med 1996; 334:1685–1690. 119. Weiland O, Schvarcz R. Hepatitis C: virology, epidemiology, clinical course, and treatment. Scand J Gastroenterol 1992; 27:337–342. 120. Verdonck LF, de Graan-Hentzen YC, Dekker AW, et al. Cytomegalovirus seronegative platelets and leukocyte poor red blood cells can prevent primary cytomegalovirus infection after bone marrow transplantation. Bone Marrow Transplant 1987; 2:73–78. 121. Lefrere JJ, Mariotti M, de la Croix I, et al. Albumin batches and B19 parvovirus DNA. Transfusion (Paris) 1995; 35:389–391. 122. American Society of Clinical Oncology. Recommendations for the use of hematopoietic colonystimulating factors: evidence-based, clinical practice guidelines. J Clin Oncol 1996; 11:2471–2508. 123. Ozer H, Armitage J, Bennett CL. 2000 update of recommendations for the use of hematopoietic colony-stimulating factors: evidence based, clinical practice guidelines. J Clin Oncol 2000; 22:227–241. 124. MacHida U, Tojo A, Takahashi S, et al. The effect of granulocyte colony-stimulating factor administration in healthy donors before bone marrow harvesting. Br J Haematol 2000; 108:747–753. 125. Morton J, Hutchins C, Durrant ST. Granulocyte-colony-stimulating factor (G-CSF)-primed allogeneic bone marrow: significantly less graft-versus-host-disease and comparable engraftment to G-CSF-mobilized peripheral blood stem cells. Blood 2001; 98:3186–3191. 126. Couban S, Messner HA, Andreous P, et al. Bone marrow mobilized with granulocyte colonystimulating factor in related allogeneic transplant recipients: a study of 29 patients. Biol Blood Marrow Transplant 2000; 6:422–427. 127. Couban S, Simpson DR, Barnett MJ, et al. A randomized multicenter comparison of bone marrow and peripheral blood in recipients of matched sibling allogeneic transplants for myeloid malignancies. Blood 2002; 100:1525–1531. 128. Vigorito AC, Marques Junior JF, Aranha FJ, et al. A randomized, prospective comparison of allogeneic bone marrow and peripheral blood progenitor cell transplantation in the treatment of hematologic malignancies: an update. Haematologia (Budap) 2001; 86:665–666.

Supportive Care of the Pediatric HSCT Patient

25

129. Schmitz N, Beksac M, Hasenclever D, et al. Transplantation of mobilized peripheral blood cells to HLA-identical siblings with standard-risk leukemia. Blood 2002; 100:761–767. 130. Mohty M, Kuentz M, Michallet M, et al. Chronic graft-versus-host disease after allogeneic blood stem cell transplantation: long-term results of a randomized study. Blood 2002; 100:3128–3134. 131. Kessinger A, Armitage J. The evolving role of autologous peripheral stem cell transplantation following high-dose therapy for malignancies. Blood 1991; 77:211. 132. Teshima T, Harada M, Takamatsu Y, et al. Granulocyte colony-stimulating factor (G-CSF)-induced mobilization of circulating haemopoietic stem cells. Br J Cancer 1993; 84:570. 133. Nademanee A, Sniecinsk iI, Schmidt GM, et al. High-dose therapy followed by autologous peripheral-blood stem-cell transplantation for patients with Hodgkin’s disease and non-Hodgkin’s lymphoma using unprimed and granulocyte colony-stimulating factor-mobilized peripheral-blood stem cells. J Clin Oncol 1994; 12:2176–2186. 134. Armatage JO. Emerging applications of recombinant human granulocyte-macrophage colonystimulating factor. Blood 1998; 92:4491–4508. 135. Lieschke G, Burgess A. Granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor (first of two parts). N Engl J Med 1992; 327:28. 136. Gisselbrecht C, Haioun C, Lepage E, et al. Placebo-controlled phase III trial of lentogastrim (glycosylated recombinant human granulocyte colony-stimulating factor) in aggressive nonHodgkin’s lymphoma: factors influencing chemotherapy administration. Leuk Lymphoma 1997; 25:289–300. 137. Schmitz N, Dreger P, Zander AR, et al. Results of a randomised, controlled, multicentre study of recombinant human granulocyte colony-stimulating factor (filgrastim) in patients with Hodgkin’s disease and non-Hodgkin’s lymphoma undergoing autologous bone marrow transplantation. Bone Marrow Transplant 1995; 15:261. 138. Ojeda E, Garcia-Bustos J, Aguado MJ, et al. A prospective randomized trial of granulocyte colonystimulating factor therapy after autologous blood stem cell transplantation. Bone Marrow Transplant 1999; 24:601–607. 139. Ringde´n O, Barrett AJ, Zhang M, et al. Decreased treatment failure in recipients of HLA-identical bone marrow or peripheral blood stem cell transplants with high CD34 cell doses. Br J Haematol 2003; 121:874–885. 140. Ringden O, Labopin M, Gorin N-C, et al. Treatment with granulocyte colony-stimulating factor after allogeneic bone marrow transplantation for acute leukemia increases the risk of graft-versushost disease and death: a study from the acute leukemia working party of the European group for blood and marrow transplantation. J Clin Oncol 2004; 22:416–423. 141. Kobayashi S, Imamura M, Hashino S, et al. Possible role of granulocyte colony-stimulating factor in increased serum soluble interleukin-2 receptor-alpha levels after allogeneic bone marrow transplantation. Leuk Lymphoma 1999; 33:559–566. 142. Hiraoka A, Masaoka T, Mizoguchi H, et al. Recombinant human non-glycosylated granulocytemacrophage colony-stimulating factor in allogeneic bone marrow transplantation: double-blind placebo-controlled phase III clinical trial. Jpn J Clin Oncol 1994; 24:205. 143. De Witte T, Vreugdenhil G, Shattenberg A. Prolonged administration of recombinant granulocytemacrophage colony-stimulating factor (GM-CSF) after T-cell-depleted allogeneic bone marrow transplantation. Transplant Proc 1993; 25:37. 144. Eapen M, Horowitz MM, Klein JP, et al. Higher mortality after allogeneic peripheral-blood transplantation compared with bone marrow in children and adolescents: the histocompatibility and alternate stem cell source working committee of the international bone marrow transplant registry. J Clin Oncol 2004; 22:4872–4880. 145. Ho VT, Mirza NQ, del Junco D, et al. The effect of hematopoietic growth factors on the risk of graftvs-host disease after allogeneic hematopoietic stem cell transplantation: a meta-analysis. Bone Marrow Transplant 2003; 32:771–775. 146. Cairo MS, Wagner JE. Placental and/or umbilical cord blood: an alternative source of hematopoietic stem cells for transplantation. Blood 1997; 90:4665–4678. 147. Locatelli F, Rocha V, Chastang C, et al. Factors associated with outcome after cord blood transplantation in children with acute leukemia. Blood 1999; 93:3662–3671. 148. Shpall EJ, Quinones R, Giller R, et al. Transplantation of ex vivo expanded cord blood. Biol Blood Marrow Transplant 2002; 8:368–376. 149. Ireland RM, Atkinson K, Concannon A, et al. Serum erythropoietin changes in autologous and allogeneic bone marrow transplant patients. Br J Haematol 1990; 76:128–134.

26

Aquino and Sandler

150. Henry DH. Epoetin alfa and high-dose chemotherapy. Semin Oncol 1998; 25:54–57. 151. Demetri GD, Kris M, Wade J, et al. Quality-of-life benefit in chemotherapy patients treated with epoetin alfa is independent of disease response or tumor type: results from a prospective community oncology study. Procrit Study Group. J Clin Oncol 1998; 16:3412–3425. 152. Klaesson S, Ringden O, Ljungman P, et al. Reduced blood transfusions requirements after allogeneic bone marrow transplantation: results of a randomised, double-blind study with highdose erythropoietin. Bone Marrow Transplant 1994; 13:397–402. 153. Locatelli F, Zecca M, Pedrazzoli P, et al. Use of recombinant human erythropoietin after bone marrow transplantation in pediatric patients with acute leukemia: effect on erythroid repopulation in autologous versus allogeneic transplants. Bone Marrow Transplant 1994; 13:403–410. 154. Olivieri A, Offidani M, Cantori I, et al. Addition of erythropoietin to granulocyte colony-stimulating factor after priming chemotherapy enhances hemopoietic progenitor mobilization. Bone Marrow Transplant 1995; 16:765–770. 155. Maslak P, Nimer SD. The efficacy of IL-3, SCF, IL-6, and IL-11 in treating thrombocytopenia. Semin Hematol 1998; 35:253–260. 156. Vredenburgh JJ, Hussein A, Fisher D, et al. A randomized trial of recombinant human interleukin11 following autologous bone marrow transplantation with peripheral blood stem cell support in patients with breast cancer. Biol Blood Marrow Transplant 1998; 4:134–141. 157. Schuster MW, Beveridge R, Frei-Lahr D, et al. The effects of pegylated recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF) on platelet recovery in breast cancer patients undergoing autologous bone marrow transplantation. Exp Hematol 2002; 30:1040–1044.

2 Prevention and Treatment of Infectious Disease Scott M. Bradfield Division of Hematology/Oncology, Mayo Clinic College of Medicine, Nemours Children’s Clinic-Jacksonville, Jacksonville, Florida, U.S.A.

Steven Neudorf Blood and Marrow Transplant Program, Children’s Hospital of Orange County, Orange, California, U.S.A.

Elyssa Rubin Pediatric Hematology/Oncology, Children’s Hospital of Orange County, Orange, California, U.S.A.

Eric S. Sandler Hematology/Oncology, Mayo School of Medicine, Nemours Children’s Clinic-Jacksonville, Jacksonville, Florida, U.S.A.

Infection and disease recurrence are the two major causes of death in the stem-cell transplant recipient. Although current advances in hematopoietic stem cell transplant (HSCT) have attempted to improve overall survival by limiting these complications, few have been able to simultaneously decrease both. More intensive therapies reduce the risk of relapse at the cost of increasing infectious risk, whereas efforts to reduce infectious death often require less intensive conditioning regimens with a resultant increase in relapse rate. Infection continues to be a major obstacle to the goal of successful cure of the pediatric stem-cell transplant patient. This section will address the issues surrounding bacterial infection in this population, including risk factors, as well as prevention and treatment options.

BACTERIAL INFECTIONS Epidemiology The pediatric patient undergoing HSCT is at risk for a number of opportunistic bacterial pathogens, in addition to the “normal” infections seen in same-aged healthy children. Due to the immunosuppressive therapy involved in HSCT, opportunistic pathogens account for the majority of culture isolates. These bacteria are often found colonizing human body surfaces (e.g., respiratory tract, skin, gastrointestinal system) or commonly encountered environmental objects (e.g., plants, tap water sources). In the clinical context of transplant, they may become 27

28

Bradfield et al.

pathogenic. In the early years of bone marrow transplantation, gram-negative bacteria accounted for most bloodstream infections, and had a mortality rate approaching 40% (1). Changes in antibiotic therapy, transplant regimens, and supportive care techniques (e.g., surgically implanted central venous catheter use) have significantly impacted these statistics, such that gram-positive organisms now account for the majority of culture-positive infections in epidemiological studies of both adult and pediatric transplant populations (1–5). In a large pediatric study, gram-positive cocci seen included coagulase-negative Staphylococcus (16%), Enterococcus (15%), and Staphylococcus aureus (8%). Less common organisms were alphahemolytic Streptococcus and Streptococcus viridans, Streptococcus pneumoniae and Streptococcus sanguis. Gram-negative organisms cultured included Klebsiella (11%), Pseudomonas (8%), Enterobacter (6%), and Escherichia coli (5%). Acinetobacter, Stenotrophomonas, Citrobacter, and Serratia were also significant findings. Clostridium difficile, through isolation of its toxin in stool, accounted for 7% of bacterial infections (3). The fact remains, however, that in the neutropenic patient with fever, only an estimated 25% will have confirmed bacteremia (1). With viral and fungal isolates much less common, this leaves a substantial percentage of patients with unexplained fevers, representing possible culture-negative bacterial infections. They are regularly treated as if they do have such an infection, and the epidemiology of these “possible” organisms is unknown. The risk of antibiotic resistance must be considered. The tremendous genetic variability of bacteria allows the continued emergence of new mechanisms of resistance to antibacterial therapy. Thorough monitoring of resistance patterns at a local level is required, and this data must be factored into any recommendations or analysis of published literature. The concern for emerging antibiotic resistance should affect choices for antibiotic prophylaxis, empiric treatment, and definitive treatment choices made after identifying a bacterial organism. In choosing antibacterial medications, the transplant physician has a duty to both current and future patients to use thoughtful, rational decision-making, with attention to potential future antibacterial resistance.

Patient Risk Factors The risk of fever in the posttransplant period approaches 100% (6). Assessment of the febrile patient’s true risk for serious infection depends on a variety of factors. The transplant course is often divided into three phases [early or preengraftment, postengraftment through day [(D)C100, and late or after DC100] for evaluating infectious risk factors (Fig. 1). The epidemiology of infectious organisms has been shown to vary according to the phase following stem-cell infusion. This variation reflects the patient’s count recovery and immune status during each of these stages. The early, or preengraftment stage, characteristically represents the period of maximal neutropenia and the period of recovery from conditioning regimen toxicities. Of course, in the patient with relapse of a hematologic malignancy or severe aplastic anemia, this period may actually predate the stem-cell infusion. The type of transplant affects the length of this stage postinfusion. Unrelated volunteer donor and umbilical cord blood transplants typically have delayed engraftment, whereas peripheral blood stem cell donors often provide more rapid engraftment. Nonmyeloablative conditioning regimens may avoid neutropenia and significant conditioning toxicity altogether. When a conditioning regimen is received as an outpatient, the patient may avoid the risk of nosocomial infections, which often have increased antibiotic resistance. Growth factor use may shorten the preengraftment period. The toxicities inherent to the conditioning regimen give potential clues as to the organisms responsible for infection in this early stage. Severe mucositis is a result of total body irradiation, many chemotherapeutic regimens and methotrexate as graft-versus-host disease (GVHD) prophylaxis. It results in a breakdown of the mucosal barrier immune function and creates a ripe situation for transmigration of gastrointestinal or oral bacteria into the bloodstream. The gram-negative Enterobacteriaciae are, therefore, a common isolate during this stage, and gastrointestinal

Prevention and Treatment of Infectious Disease Phase I, Pre-engraftment, < 30 days

Phase II, Postengraftment, 30-100 days

Neutropenia, mucositis, and acute graft-versushost disease

Host immune system defect

29 Phase III, Late phase, < 100 days

Impaired cellular immunity and acute and chronic graftversus-host disease

Impaired cellular and humoral immunity and chronic graft-versus-host disease

Central line

Device risk

Respiratory and enteric viruses

Allogeneic patients

Herpes simplex virus* Cytomegalovirus* Varicella-zoster virus Epstein-Barr virus lymphoproliferative disease Facilitate gram-negative bacilli

Staphylococcus epidermidis Encapsulated bacteria (e.g., Pneumococcus)

Gastrointestinal tract Streptococci species All Candida species

Aspergillus species

Aspergillus species Pneumocystis carini Toxoplasma gondii Strongyloides stercoralis

0

30

100

360

Days after transplant *Without standard prophylaxis Primarily among persons who are seropositive before transplant

High incidence (> _10%) Low incidence (40 kg) or 50 mg PO Q12h (for patients 40 kg) or 100 mg PO Q12h (for patients 500/mm3

(A)

0.8

0.6

> 100 million/kg (n=65) 50 million-99 million/kg (n=121) 25 million-49 million/kg (n=198) 7 million-24 million/kg (n=162)

0.4

0.2 P