Post-Transplant Lymphoproliferative Disorders

Post-Transplant Lymphoproliferative Disorders

Vikas R. Dharnidharka Michael Green Steven A. Webber (Eds.) Post-Transplant Lymphoproliferative Disorders

Vikas R. Dharnidharka, MD, MPH Associate Professor and Chief, Fellowship Program Director Division of Pediatric Nephrology University of Florida College of Medicine Medical Director, Pediatric Kidney Transplantation, Shands Hospital at UF Gainesville, Florida, USA vikasmd@peds.ufl.edu Michael Green, MD, MPH Professor of Pediatrics and Surgery of Medicine Division of Infectious Diseases Children s Hospital of Pittsburgh Pittsburgh, Pennsylvania, USA michael.green@ chp.edu Steven A. Webber MBChB, MRCP Professor of Pediatrics, of Medicine Chief, Division of Cardiology Co-Director, Heart Center Medical Director, Pediatric Heart and Heart-Lung Transplantation Children s Hospital of Pittsburgh Pittsburgh, Pennsylvania, USA ISBN: 978-3-642-01652-3 e-isbn: 978-3-642-01653-0 DOI: 10.1007/978-3-642-01653-0 Springer Heidelberg Dordrecht London New York Library of Congress Control Number: 2009934493 Springer-Verlag Berlin Heidelberg 2010 This work is subject to copyright. All rights are reserved, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilm or in any other way, and storage in data banks. Duplication of this publication or parts thereof is permitted only under the provisions of the German Copyright Law of September 9, 1965, in its current version, and permission for use must always be obtained from Springer. Violations are liable to prosecution under the German Copyright Law. The use of general descriptive names, registered names, trademarks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. Product liability: The publishers cannot guarantee the accuracy of any information about dosage and application contained in this book. In every individual case the user must check such information by consulting the relevant literature. Cover design: estudio Calamar, Figueres/Berlin Printed on acid-free paper Springer is part of Springer Science+Business Media (www.springer.com)

Dedication We dedicate this book to the clinicians and scientists who cared for transplant patients and began the work of understanding the problem of PTLD, to the transplant recipients and their families that we care for who motivate these efforts, and to the colleagues we work with to provide care to our patients. Finally, special thanks to our families who had put up with us and supported our efforts in preparing this book and in all other things: Ramnath, Pushpa, Dimple, Shrey and Ria; Jenny, Dave, Erin, Molly, and Allison; Elizabeth, Hannah, and Katie. v

Foreword By the mid 1960s, there was evidence that the loss of tumor surveillance in immunosuppressed organ recipients could result in (1) accidental engraftment of donor malignancies, (2) accelerated growth of microscopic metastatic neoplasms of either donor or recipient origin, and (3) an increased incidence of de novo malignancies. Although real, the risks from the first two kinds of complications were promptly minimized by appropriate donor and recipient screening. In contrast, the de novo malignancies, most notably those of lymphoid origin (called posttransplantation lymphoproliferative disorders or PTLDs), have been endemic, or at times epidemic, particularly just after the advent of the T-cell-directed agents, cyclosporine, tacrolimus, and the antilymphoid antibodies. The PTLDs resemble the malignancies found in immune deficiency states, including acquired immunodeficiency syndromes. Originally referred to as reticulum cell sarcomas, they constitute a spectrum of lymphopoietic neoplasms, of which most are B-cell lymphomas that are highly, but not invariably, associated with Epstein Barr virus infection. Because PTLDs are frequently subject to immune surveillance, the pathogenesis and treatment of these lymphoblastic lesions have been of special interest to tumor biologists as well as to clinicians. Heavy immunosuppression, either applied by protocol or in a management response to rejection, usually precedes the appearance of PTLD. Most of these tumors are of host origin in the organ recipients, whereas almost all are of donor origin after bone marrow transplantation. Although PTLDs occur in all kinds of organ recipients, the highest incidence has been after transplantation of nonrenal organs. Reduction or discontinuance of immunosuppression in organ recipients allows recovery of tumor surveillance and may be followed by tumor regression. The most effective treatment is complete discontinuance of immune suppression. However, this drastic step is usually avoided in kidney recipients and is rarely taken in liver, heart, and lung recipients for whom treatment rest and artificial organ support followed by retransplantation are not feasible. Even in such cases, however, stopping immunosuppression as a last resort has been effective in some nonrenal organ recipients without rejection of their allografts. Such examples of donor-specific, but not tumor-specific, immune nonreactivity and other features of PTLD could not be explained until the mechanisms of leukocyte chimerism-dependent alloengraftment and allogeneic tolerance were elucidated with the discovery that organ recipients had leukocyte microchimerism. vii

viii Foreword The resulting fresh insight into mechanisms has suggested treatment options for PTLDs beyond stopping immunosuppression or the use of multiple-agent antilymphoma and antiviral therapies. In fact, PTLDs have evolved into a free-standing model in which some mysteries of immunology, virology, and tumor biology have been resolved while others await further discoveries that may be exploited. Meanwhile, many books have been written about transplantation, but none specifically about PTLDs. The three editors of this book are to be commended for their efforts to fill the gap. There is something here for all clinicians, and perhaps for basic scientists who also are looking for new worlds to investigate and conquer. Thomas E. Starzl, MD, PhD Professor of Surgery Thomas Starzl Transplant Institute University of Pittsburgh PA, USA

Contents 1 Introduction... 1 Vikas R. Dharnidharka, Michael Green, and Steven Webber 2 Historical Perspective on the Early Studies of Posttransplant Lymphoproliferative Disorders (PTLD)... 5 Douglas W. Hanto 3 Epidemiology of PTLD... 17 Vikas R. Dharnidharka 4 The Biology of Epstein Barr Virus and Posttransplant Lymphoproliferative Disease... 29 Olivia M. Martinez 5 Epstein Barr Viral Load Testing: Role in the Prevention, Diagnosis and Management of Posttransplant Lymphoproliferative Disorders... 45 Jutta K. Preiksaitis 6 Clinical Features and Diagnostic Evaluation of Posttransplant Lymphoproliferative Disorder... 69 Upton D. Allen 7 Pathology... 89 Steven H. Swerdlow 8 Prognostic Factors for PTLD... 105 Tapan Maniar and Donald Tsai 9 Treatment of PTLD... 117 Steven A. Webber ix

x Contents 10 Prevention of Epstein Barr Virus Infection and Posttransplant Lymphoproliferative Disease Following Transplantation... 133 Michael Green and Marian Michaels 11.a Organ Specific Issues of PTLD Kidney... 145 Sophie Caillard 11.b Posttransplantation Lymphoproliferative Disorder (PTLD) in Liver and Small Bowel Transplant Recipients... 153 Jaime Pineda and George V. Mazariegos 11.c Heart and Lung Transplantation... 163 Silke Wiesmayr and Steven A. Webber 11.d Posttransplant Lymphoproliferative Disease (PTLD) in Hematopoietic Stem Cell Transplantation (HSCT)... 173 Thomas G. Gross 12 Research Priorities and Future Directions... 183 Vikas R. Dharnidharka, Michael Green, and Steven A. Webber Index... 187

Contributors Upton D. Allen Department of Pediatrics, Division of Infectious Diseases, Hospital for Sick Children, University of Toronto, Toronto, ON, Canada Sophie Caillard Nephrology-Transplantation Department, Hopitaux Universitaires de Strasbourg, Strasbourg, France Vikas R. Dharnidharka Division of Pediatric Nephrology, University of Florida College of Medicine, Gainesville, FL, USA Pediatric Kidney Transplantation, Shands Hospital at UF, University of Florida College of Medicine, Gainesville, FL, USA Michael Green Departments of Pediatrics and Surgery, Division of Infectious Diseases, of Medicine, Pittsburgh, PA 15213, USA Thomas G. Gross Department of Pediatrics, The Ohio State University School of Medicine, Columbus, OH, USA Division of Hematology/Oncology/BMT, Nationwide Children s Hospital, Columbus, OH 43205, USA Douglas W. Hanto Division of Transplantation, The Transplant Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA Tapan Maniar University of Pennsylvania, Philadelphia, PA, USA Marian Michaels Division of Infectious Diseases, of Medicine, Pittsburgh, PA, USA Olivia M. Martinez Department of Surgery, Division of Transplantation and the Program in Immunology, Stanford University School of Medicine, Palo Alto, CA 94305-5492, USA George V. Mazariegos Hillman Center for Pediatric Transplantation, Thomas E. Starzl Transplantation Institute, of Medicine, Pittsburgh, PA 15213, USA xi

xii Contributors Jaime Pineda Hillman Center for Pediatric Transplantation, Pittsburgh, PA, USA Jutta K. Preiksaitis Division of Infectious Diseases, University of Alberta, Edmonton, AB, Canada Provincial Public Health Laboratory, University of Alberta, Edmonton, AB, Canada T6G 2J2 Steven H. Swerdlow Division of Hematopathology, of Medicine, Pittsburgh, PA 15213, USA Donald E. Tsai Division of Hematology/Oncology, University of Pennsylvania, Philadelphia, PA, USA Steven A. Webber Department of Pediatrics, of Medicine, Pittsburgh, PA, USA Division of Cardiology, 3705 5th Avenue, Pittsburgh, PA 15213, USA Silke Wiesmayr Division of Cardiology, of Medicine, Pittsburgh, PA, USA