Handbook of Hematologic Malignancies - … · HANDBOOK OF HEMATOLOGIC MALIGNANCIES HANDBOOK OF ... knowledge for each chapter is included for digital download online and in ... Aggressive

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INCLUDES DOWNLOADABLE CASES WITH Q&A

Handbook of Hematologic Malignancies provides a unique, practical, and concise guide focused on the must-know points of diagnosis, prognosis, therapeutic management, and cutting edge clinical trial opportunities for each hematologic malignancy. With an ever-increasing growth of evidence and a significant expansion of available treatment options for patients with hematologic disease, remaining current and up-to-date can be extremely challenging for practicing clinicians. This comprehensive subspecialty handbook is designed and organized for the busy hematologist, hematologic oncologist, hematopathologist, and trainee in mind.

Every chapter is richly illustrated with color figures and flow diagrams, and contains helpful tables on differential diagnosis, prognostic scoring systems and therapeutic options. A concise case-based review for testing pathologic diagnosis and clinical knowledge for each chapter is included for digital download online and in the e-book. Written by experienced clinicians at the world-renowned Moffitt Cancer Center in Tampa, Florida, as well as contributions from leading academicians throughout the country, this handbook is an essential resource for anyone diagnosing, treating, or managing patients with hematologic malignancy.

Key featureS:• Contains clear prognostic and diagnostic tools (e.g., tables/flow diagrams/

pathology images) with emphasis on key differential diagnoses and diagnostic dilemmas

• Easy to use treatment recommendations with bullet point format and key references.

• Discusses the future of patient management based on practice changing clinical trials • Includes access to digitally downloadable case-based clinical scenarios and

questions with high resolution pathology images linked to each individual chapter

Handbook of Hematologic Malignancies

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New York

Handbook of Hematologic Malignancies

Editors

David A. Sallman, MDDepartment of Malignant HematologyH. Lee Moffitt Cancer Center & Research InstituteUniversity of South FloridaTampa, Florida

Ateefa Chaudhury, MDDepartment of Malignant HematologyH. Lee Moffitt Cancer Center & Research InstituteUniversity of South FloridaTampa, Florida

Johnny Nguyen, MDDepartment of HematopathologyH. Lee Moffitt Cancer Center & Research InstituteUniversity of South FloridaTampa, Florida

Ling Zhang, MDDepartment of HematopathologyH. Lee Moffitt Cancer Center & Research InstituteUniversity of South FloridaTampa, Florida

Alan F. List, MDDepartment of Malignant HematologyH. Lee Moffitt Cancer Center & Research InstituteUniversity of South FloridaTampa, Florida




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ISBN: 9781620700945e-book ISBN: 9781617052705

Supplement clinical case material ISBN: 978-0-8261-8471-9Clinical cases provided as an online resource, available at www.demosmedical.com/malignant-hematology.

Acquisitions Editor: David D’AddonaCompositor: diacriTech

Copyright © 2017 Springer Publishing Company.Demos Medical Publishing is an imprint of Springer Publishing Company, LLC.

All rights reserved. This book is protected by copyright. No part of it may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, recording, or otherwise, without the prior written permission of the publisher.

Medicine is an ever-changing science. Research and clinical experience are continually expanding our knowledge, in particular, our understanding of proper treatment and drug therapy. The authors, editors, and publisher have made every effort to ensure that all information in this book is in accordance with the state of knowledge at the time of production of the book. Nevertheless, the authors, editors, and publisher are not responsible for errors or omissions or for any consequences from application of the information in this book and make no warranty, expressed or implied, with respect to the contents of the publication. Every reader should examine carefully the package inserts accompanying each drug and should carefully check whether the dosage schedules mentioned therein or the contraindications stated by the manufacturer differ from the statements made in this book. Such examination is particularly important with drugs that are either rarely used or have been newly released on the market.

Library of Congress Cataloging-in-Publication DataNames: Sallman, David A., editor.Title: Handbook of hematologic malignancies / editors, David A. Sallman, MD [and four others], Department of Internal Medicine, Morsani College of Medicine, University of South Florida, Moffitt Cancer Center, Tampa, Florida.Description: New York : Demos Medical, [2017] | Includes bibliographical references and index.Identifiers: LCCN 2016028794 | ISBN 9781620700945Subjects: LCSH: Lymphoproliferative disorders—Handbooks, manuals, etc.Classification: LCC RC646.2 .H36 2017 | DDC 616.4/2—dc23 LC record available at https://lccn.loc.gov/2016028794

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We would like to thank our friends and families for their support during the writing of this

textbook. We would also like to recognize our mentors, past and present, for instilling in us a

passion for hematology by their example.







vii

Contributors xiiiExpert Reviewers xixForeword John M. Bennett, MD xxiPreface xxiiiAbbreviations xxv

INTRODUCTION AND OVERVIEW

1. Hematopathology Diagnostic Techniques and Assays 1Johnny Nguyen and Ling Zhang

MYELOPROLIFERATIVE NEOPLASMS

2. Polycythemia Vera 14Liliana Bustamante and Kenneth Zuckerman

3. Essential Thrombocythemia 20Susmitha Apuri and Kenneth Zuckerman

4. Primary Myelofibrosis 26Andrew Kuykendall and Kenneth Zuckerman

5. Chronic Myelogenous Leukemia 33Chetasi Talati and Javier Pinilla-Ibarz

6. Chronic Neutrophilic Leukemia 40Saman Nematollahi, Shweta Jain, and Utkarsh Acharya

7. Systemic Mastocytosis 45Andrew Kuykendall and Kenneth Zuckerman

8. PDGFRA/PDGFRB/FGFR1 Myeloid Neoplasms 51Joseph Clara and Eric Padron

Contents




viii CoNTENTS

MYELODYSPLASTIC AND BONE MARROW FAILURE SYNDROMES

9. Myelodysplastic Syndromes 57Joanna Grabska, David A. Sallman, and Rami Komrokji

10. Aplastic Anemia 66Michael Shafique and Rami Komrokji

11. Paroxysmal Nocturnal Hemoglobinuria 71Hilda Ding and Michael Jaglal

MYELODYSPLASTIC/MYELOPROLIFERATIVE NEOPLASMS

12. Myelodysplastic/Myeloproliferative overlap Syndromes 75Jennifer Eatrides and Eric Padron

13. Chronic Myelomonocytic Leukemia 82Alexandra Gomez and Justin M. Watts

ACUTE MYELOID LEUKEMIA AND RELATED SYNDROMES

14. Acute Myeloid Leukemia 89Varun Dhulipala and Kendra Sweet

15. Secondary AML and AML With Myelodysplasia-Related Changes 96Seongseok Yun and Jeffrey Lancet

16. Acute Promyelocytic Leukemia 101Leidy L. Isenalumhe and Jeffrey Lancet

17. Blastic Plasmacytoid Dendritic Cell Neoplasm 107Justin Taylor, Ateefa Chaudhury, and Andrew A. Lane

ACUTE LYMPHOID LEUKEMIA

18. B-Lymphoblastic Leukemia 111Aneesha Hossain and Khaled el-Shami

19. BCR-ABL1+ B-Lymphoblastic Leukemia 119Aneesha Hossain and Khaled el-Shami

20. T-Lymphoblastic Lymphoma/Leukemia 124Keri Maher and Ravitharan Krishnadasan

ACUTE LEUKEMIA OF AMBIGUOUS LINEAGE

21. Acute Leukemia of Ambiguous Lineage 129Keri Maher and Ravitharan Krishnadasan




CoNTENTS ix

MATURE T- AND NK-CELL LEUKEMIA

22. T-Cell Prolymphocytic Leukemia 133Abhijeet Kumar, Srinath Sundararajan, and Ravitharan Krishnadasan

23. T-Cell Large Granular Lymphocytic Leukemia 137Magali Van den Bergh and Lubomir Sokol

24. Aggressive Natural Killer Cell Leukemia 142Mintallah Haider and Lubomir Sokol

PLASMA CELL DISORDERS

25. Monoclonal Gammopathy of Unknown Significance, Smoldering Myeloma, and Plasmacytomas 147Srinath Sundararajan, Abhijeet Kumar, Amit Agarwal, and Neha Korde

26. Multiple Myeloma 154Patrick Griffin and Rachid Baz

27. Waldenström’s Macroglobulinemia 161Joanna Grabska and Rachid Baz

28. Immunoglobulin Light Chain Amyloidosis 169Taxiarchis Kourelis and Morie A. Gertz

HODGKIN LYMPHOMA

29. Hodgkin Lymphoma 175Anju Nair and Micah Burch

NON-HODGKIN LYMPHOMA

30. Non-Hodgkin Lymphoma Classification and Diagnostic Evaluation 183Johnny Nguyen and Ling Zhang

MATURE B-CELL LYMPHOMA

VERY AGGRESSIVE

31. Burkitt Lymphoma 189Anju Nair and Micah Burch

AGGRESSIVE

32. Diffuse Large B-Cell Lymphoma 195Jose Sandoval-Sus and Julio Chavez




x CoNTENTS

33. Double Hit Lymphoma 203Nikhil Mukhi and Julio Chavez

34. Mantle Cell Lymphoma 207Samantha Shams and Bijal Shah

35. Primary Mediastinal Large B-Cell Lymphoma 213Andreas Saltos and Julio Chavez

36. Primary Central Nervous System Lymphoma 218Liliana Bustamante and Peter Forsyth

37. HIV-Related Lymphomas 225Danny Nguyen, Nishan Tchekmedyian, and Jeremy Abramson

INDoLENT

38. Follicular Lymphoma 233Asha Balakrishnan and Celeste Bello

39. Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma 240Ateefa Chaudhury and Javier Pinilla-Ibarz

40. Hairy Cell Leukemia 247Justin Taylor and Omar Abdel-Wahab

41. Marginal Zone Lymphoma 252Nishan Tchekmedyian, Danny Nguyen, and Celeste Bello

42. Mucosa-Associated Lymphoid Tissue Lymphoma 257Ridhi Gupta, Matthew Mastrodomenico, Nishan Tchekmedyian, and Saurabh Chhabra

MATURE T/NK-CELL LYMPHOMA

43. Adult T-Cell Leukemia/Lymphoma 264Nikhil Mukhi and Lubomir Sokol

44. Anaplastic Large Cell Lymphoma, ALK Positive 270Thomas Enzler and Changchun Deng

45. Extranodal Natural Killer/T-Cell Lymphoma 276Joseph Clara and Lubomir Sokol

46. Mycosis Fungoides 282Achuta Kumar Guddati and Lubomir Sokol

47. Hepatosplenic T-Cell Lymphoma 289Narendranath Epperla, Apoorva Jayarangaiah, and Timothy S. Fenske




CoNTENTS xi

HISTIOCYTIC/DENDRITIC CELL NEOPLASMS

48. Histiocytic Sarcoma and Langerhans Cell Histiocytosis 296Narendranath Epperla and Ehab Atallah

49. Hemophagocytic Lymphohistiocytosis 304Hilda Ding and Lubomir Sokol

BONE MARROW TRANSPLANTATION

50. Autologous Bone Marrow Transplantation 310Hemant S. Murthy and Mohamed A. Kharfan-Dabaja

51. Allogeneic Bone Marrow Transplantation 319Hemant S. Murthy, Taiga Nishihori, and Mohamed A. Kharfan-Dabaja

EMERGENCIES IN HEMATOLOGY

52. Tumor Lysis Syndrome 330Mintallah Haider, Ateefa Chaudhury, and Michael Jaglal

53. Thrombotic Microangiopathy 335Ruchika Goel, Aaron Tobian, and Ljiljana V. Vasovic

54. Therapeutic Apheresis Indications 344Amanda E. Lo, Ruchika Goel, and Ljiljana V. Vasovic

Appendix: Pathology Supplement 351Index 363







xiii

Contributors

Omar Abdel-Wahab, MDLeukemia Service, Weill-Cornell

Medical College, Memorial Sloan Kettering Cancer Center, New York, New York

Jeremy Abramson, MDCenter for Lymphoma,

Massachusetts General Hospital Cancer Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts

Utkarsh Acharya, DO, FACPDivision of Hematology and

Medical oncology, Department of Internal Medicine, ohio State University Wexner Medical Center, Columbus, ohio

Amit Agarwal, MD, MPH, FACPDivision of Hematology and

oncology, University of Arizona, Tucson, Arizona

Susmitha Apuri, MDDepartment of Malignant

Hematology, H. Lee Moffitt Cancer Center & Research Institute and University of South Florida, Tampa, Florida

Ehab Atallah, MDDivision of Hematology and

oncology, Medical College of Wisconsin, Milwaukee, Wisconsin

Asha Balakrishnan, MDDepartment of Internal Medicine,

University of South Florida, Morsani College of Medicine, Tampa, Florida

Rachid Baz, MDDepartment of Malignant


Celeste Bello, MDDepartment of Malignant


Micah Burch, MD Division of Hematology and

oncology, Baylor University Medical Center, Dallas, Texas

Liliana Bustamante, MDDepartment of Malignant


Ateefa Chaudhury, MDDepartment of Malignant





xiv CoNTRIBUToRS

Julio Chavez, MDDepartment of Malignant


Saurabh Chhabra, MDDepartment of Medicine, Division

of Hematology/oncology, Medical University of South Carolina, Charleston, South Carolina

Joseph Clara, MDDepartment of Internal Medicine,

University of South Florida, Morsani College of Medicine, Tampa, Florida

Changchun Deng, MD, PhD Center for Lymphoid

Malignancies, Columbia University Medical Center, New York, New York

Varun Dhulipala, MDDepartment of Malignant


Hilda Ding, MD, MSDepartment of Pediatrics,

University of California San Diego, Rady Children’s Hospital, San Diego, California

Jennifer Eatrides, MDDepartment of Malignant


Khaled el-Shami, MD, PhDDepartment of Hematology/

oncology, George Washington University, Washington, DC

Thomas Enzler, MD, PhDDivision of Hematology/oncology,

Department of Medicine, Columbia University Medical Center, New York, New York

Narendranath Epperla, MD Division of Hematology and


Timothy S. Fenske, MDDivision of Hematology and


Peter Forsyth, MD, FACP, MADepartment of Neuro-oncology,

H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida

Morie A. Gertz, MDDivision of Hematology, Mayo

Clinic, Rochester, Minnesota

Ruchika Goel, MDDepartment of Pathology, Weill

Cornell Medicine/New York Presbyterian Hospital-Weill Cornell Campus, New York, New York

Alexandra Gomez, MDDivision of Hematology and

Medical oncology, Weill Cornell Medicine/New York Presbyterian Hospital–Weill Cornell Campus, New York, New York

Joanna Grabska, MDDepartment of Malignant


Patrick Griffin, MDDepartment of Hematology and

Medical oncology, Texas oncology, Fort Worth, Texas




CoNTRIBUToRS xv

Achuta Kumar Guddati, MD, PhDDivision of Hematology/oncology,

State University of New York, Downstate Medical Center, Brooklyn, New York

Ridhi Gupta, MDDepartment of Medicine, Division

of Hematology/oncology, Medical University of South Carolina, Charleston, South Carolina

Mintallah Haider, MDDepartment of Malignant


Aneesha Hossain, MD Department of Internal Medicine,

George Washington University, Washington, DC

Leidy L. Isenalumhe, MDDepartment of Malignant


Michael Jaglal, MDDepartment of Malignant


Shweta Jain, MDDepartment of Nuclear Medicine,

University of North Texas Veterans Affairs, Denton, Texas

Apoorva Jayarangaiah, MD Department of Internal Medicine,

Marshfield Clinic, Marshfield, Wisconsin

Mohamed A. Kharfan-Dabaja, MD Department of Blood & Marrow

Transplantation, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida

Rami Komrokji, MDDepartment of Malignant


Neha Korde, MDMyeloma Service, Department

of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York

Taxiarchis Kourelis, MDDivision of Hematology, Mayo

Clinic, Rochester, Minnesota

Ravitharan Krishnadasan, MDDivision of Hematology/oncology,

University of Arizona, Tucson, Arizona

Abhijeet Kumar, MDDivision of Hematology and

oncology, University of Arizona, Tucson, Arizona

Andrew Kuykendall, MDDepartment of Malignant


Jeffrey Lancet, MDDepartment of Malignant





xvi Contributors

Andrew A. Lane, MD, PhDDepartment of Medical oncology,

Dana-Farber Cancer institute, Harvard Medical school, boston, Massachusetts

Amanda E. Lo, MDDepartment of Pathology, Duke

university Medical Center, Durham, north Carolina

Keri Maher, DO, MSDivision of Hematology/oncology,

university of Arizona, tucson, Arizona

Matthew Mastrodomenico, MDDepartment of Pathology, Medical

university of south Carolina, Charleston, south Carolina

Nikhil Mukhi, MDDepartment of Hematology/

oncology, Division of Medicine, state university of new York, Downstate Medical Center, brooklyn, new York

Hemant S. Murthy, MDDepartment of blood & Marrow

transplantation, H. Lee Moffitt Cancer Center & research institute, tampa, Florida

Anju Nair, MDDivision of Hematology and

oncology, baylor university Medical Center, Dallas, texas

Saman Nematollahi, MDDepartment of internal Medicine,

new York Presbyterian Hospital, Columbia university Medical Center, new York, new York

Danny Nguyen, MDDepartment of Hematology/

oncology, Pacific shores Medical Group, Huntington beach, California

Johnny Nguyen, MDDepartment of Hematopathology,

H. Lee Moffitt Cancer Center & research institute and university of south Florida, tampa, Florida

Taiga Nishihori, MDDepartment of blood & Marrow

transplantation, H. Lee Moffitt Cancer Center & research institute, tampa, Florida

Eric Padron, MDDepartment of Malignant

Hematology, H. Lee Moffitt Cancer Center & research institute and university of south Florida, tampa, Florida

Javier Pinilla-Ibarz, MD, PhDDepartment of Malignant


David A. Sallman, MDDepartment of Malignant


Andreas Saltos, MDDepartment of Malignant


Jose Sandoval-Sus, MDDepartment of Malignant





CoNTRIBUToRS xvii

Michael Shafique, MDDepartment of Malignant


Bijal Shah, MDDepartment of Malignant


Samantha Shams, MDDepartment of Malignant


Lubomir Sokol, MD, PhDDepartment of Malignant


Srinath Sundararajan, MDDivision of Hematology/oncology,

University of Arizona, Tucson, Arizona

Kendra Sweet, MDDepartment of Malignant


Chetasi Talati, MDDepartment of Malignant


Justin Taylor, MDLeukemia Service, Memorial Sloan

Kettering Cancer Center, New York, New York

Nishan Tchekmedyian, MDDepartment of Hematology/oncology,

Pacific Shores Medical Group, Huntington Beach, California

Aaron Tobian, MD, PhDDepartments of Pathology,

Medicine, and Epidemiology, Johns Hopkins University, Baltimore, Maryland

Magali Van den Bergh, MDDepartment of Malignant Hematology,

H. Lee Moffitt Cancer Center & Research Institute and University of South Florida, Tampa, Florida

Ljiljana V. Vasovic, MDDepartment of Pathology, Weill

Cornell Medicine/New York Presbyterian Hospital-Weill Cornell Campus, New York, New York

Justin M. Watts, MDDepartment of Medicine,

Hematology/oncology, University of Miami Miller School of Medicine, Sylvester Comprehensive Cancer Center, Miami, Florida

Seongseok Yun, MD, PhDDepartment of Malignant


Ling Zhang, MDDepartment of Hematopathology,


Kenneth Zuckerman, MDDepartment of Malignant Hematology,








xix

Expert Reviewers

Rachid Baz, MDChapter 25Monoclonal Gammopathy of

Unknown Significance, Smoldering Myeloma, and Plasmacytomas

Celeste Bello, MDChapter 29Hodgkin Lymphoma

Julio Chavez, MDChapter 31Burkitt Lymphoma

Eric Padron, MDChapters 6 and 13Chronic Neutrophilic Leukemia Chronic Myelomonocytic Leukemia

Bijal Shah, MDChapters 18–21B-Lymphoblastic LeukemiaBCR-ABL1+ B-Lymphoblastic

LeukemiaT-Lymphoblastic Lymphoma/

LeukemiaAcute Leukemia of Ambiguous

Lineage

Lubomir Sokol, MD, PhDChapters 44, 47, and 22Anaplastic Large Cell Lymphoma,

ALK PositiveHepatosplenic T-Cell LymphomaT-Cell Prolymphocytic Leukemia







xxi

one could ask the following question: Why does the hematology/oncology medical community need yet another handbook of hema-tologic malignancies when several are currently available?

Upon review of this handbook, the answer is simple and straightforward: this pocketbook is a gem and will, in my opinion, compete very well with and/or replace the existing handbooks. Each chapter consists of an introduction, current World Health organization (WHo) Classification with superb photomicrographs, FISH and cytogenetics, staging systems, suggested laboratory evaluation, key diagnostic issues or dilemmas, prognostic scoring tables, treatment options, follow-up management, and current clin-ical trials with pertinent references. All textbooks become outdated very rapidly, particularly in the era of molecular annotation. This book highlights the paradigm shift in the management of patients with hematologic malignancy based on mutational profiling as each chapter highlights the relevance of next-generation sequenc-ing and/or related technologies on the prognosis, diagnosis, and therapeutic strategies for our patients.

More importantly, each chapter is accompanied by a case that integrates high-resolution images leading to the diagnosis with key clinical management decisions. of significant educational value, these cases can be presented to the reader as either an unknown or as a tool to reinforce the information from the chapter. The digi-tal version of this pocketbook is exemplary and provides real-time clinical utility to practitioners via direct access to prognostication tables and evidence-based management decisions, as well as rapid access to related chapters in cases of clinical uncertainty and poten-tial practice-changing clinical trials through hyperlinks embedded in each chapter. Together, this book will be an amazing resource for trainees from multiple disciplines including malignant hematology and hematopathology as well as for clinical oncologists/hematolo-gists throughout the country.

The chapters are coauthored by one of the Moffitt Cancer Center Institutes nationally recognized experts and other younger faculty

Foreword




xxii FoREWoRD

in training (great motivation) as well as from leading authorities from other centers throughout the country.

By necessity, the chapters are brief (clearly not intended to replace the several large volumes on hematologic neoplasms that already exist) and the handbook can fit nicely into a laboratory white coat pocket or be downloaded onto a smartphone or similar device.

The editors have created this cutting-edge, user-friendly pocket-book for the management of patients with hematologic malignan-cies with the ability for rapid updates given the speed of research progress. I am confident this handbook will be a critical resource for years to come.

John M. Bennett, MDProfessor of Pathology, Laboratory

Medicine and Medicine, EmeritusUniversity of Rochester Medical Center

Rochester, New York




xxiii

Hematologic malignancies and their treatment have witnessed many changes in this past decade. Innovations from improved diagnostics to therapeutics have reshaped the way these diseases are characterized and managed. The advent of molecular tech-niques such as next-generation sequencing has brought forth a paradigm shift not only in regard to diagnosis, but also in refining prognostication, monitoring residual disease burden, and identifi-cation of novel therapeutic strategies. Now, more than ever before, we as clinicians are able to apply mutational data to individual-ize treatment strategies through access to novel pharmaceuticals and clinical trials for patients who previously had limited options. As medical professionals, these are a few of the important clini-cal questions we would often discuss with fellow trainees, nurse practitioners, physician assistants, attending physicians, and phar-macists at Moffitt Cancer Center. These discussions served as the backbone to the creation of this handbook.

our goal was to create a pocket-sized practical guide that could be used by trainees in malignant hematology, internal medicine, and pathology as well as pharmacists, advanced practice profes-sionals, and attending physicians to not only provide the basic information on diagnosis and treatment, but to go a step beyond what previous resource books have offered. This resource high-lights critical differential diagnoses to consider as well as provides the most current prognostication tables for each disease in order to facilitate direct extension of this information to your patients. In addition, we have included full color pathology images that have been selected for their exceptional clarity to help the reader elu-cidate subtle morphologic differences between disease entities. We have created relevant clinical cases not only in the book, but also in accessible online cases supporting each chapter with corre-sponding questions to highlight important deliverables from every chapter. A benefit of these online cases is the reader can test the unknown and try to diagnose cases before referring to the text (in order to do so the reader is encouraged to view the cases by access-ing these at www.demosmedical.com/malignant-hematology).

Preface



http://www.demosmedical.com/malignant-hematology


xxiv PREFACE

Evidence-based algorithms guiding treatment recommendations are provided for both frontline and salvage settings with key ref-erences supporting each recommendation. our intention was to create a reference textbook that is concise and easy to read, serv-ing the needs of the medical professional dealing with hematologic malignancies. We also highlight current clinical trials that may alter our future practice decisions.

The Handbook of Hematologic Malignancies encompasses the hard work and effort of many fellows and residents, working under the mentorship and guidance of attending staff physicians at world-renowned cancer centers throughout the country, not only at Moffitt Cancer Center, but also many others including Harvard, Mayo Clinic, and Memorial Sloan Kettering Cancer Center. Specif-ically, the editors would like acknowledge Dr. Kenian Liu from the Cytogenetic Laboratory (Moffitt) for providing FISH images and Drs. Lugen Chen (Tampa General Hospital), Wilfredo Chamizo (All Children Hospital at St Petersburg), Haipeng Shao (Moffitt), Xiao-hui Zhang (Moffitt), and Jane Messina (Moffitt) for sharing unique cases to the book. The quality of their work and their willingness to contribute to make this textbook one that can serve the needs of readers across disciplines, made working on this project a reward-ing experience for us all.

Lastly, this textbook would not have been realized without the tireless commitment and outstanding contributions of our entire clinical and pathology editorial team. Dr. David Sallman and Dr. Ateefa Chaudhury directed the innovational chapter design and gave editorial oversight throughout the completion of this product. The high-quality images produced by Dr. Ling Zhang and Dr. Johnny Nguyen were critical to the exceptional hematopa-thology content. Moreover, our Senior Editor, President, and CEo of Moffitt Cancer Center, Dr. Alan List, has changed the way we approach patient care and we thank him for his mentorship and his diligent efforts to prevent and cure cancer through collaborative research. our editorial team and chapter authors truly hope that this handbook helps improve your understanding of hematologic malignancies and enhances your approach to patient care.

David A. Sallman, MDAteefa Chaudhury, MD

Johnny Nguyen, MDLing Zhang, MDAlan F. List, MD




xxv

aCML Atypical Chronic Myelogenous LeukemiaAFB Stain Acid-Fast Bacilli StainAIDS Acquired Immunodeficiency SyndromeAITL Angioimmunoblastic T-Cell LymphomaALCL Anaplastic Large Cell LymphomaALK Anaplastic Lymphoma KinaseALP Alkaline PhosphataseALT Alanine TransaminaseAML Acute Myeloid LeukemiaAMML Acute Myelomonocytic LeukemiaANC Absolute Neutrophil CountAPL Acute Promyelocytic LeukemiaAST Aspartate TransaminaseATLL Adult T-Cell Leukemia/LymphomaB-ALL B-Acute Lymphoblastic LeukemiaBM Bone MarrowBMT Bone Marrow TransplantBMP Basic Metabolic PanelBPDCN Blastic Plasmacytoid Dendritic Cell NeoplasmBSA Body Surface AreaBX BiopsyCBC Complete Blood CountCCUS Clonal Cytopenia of Undetermined SignificanceCD Cluster of DifferentiationCHIP Clonal Hematopoiesis of Indeterminate PotentialCHL Classical Hodgkin LymphomaCLL/SLL Chronic Lymphocytic Leukemia/Small Lymphocytic

LymphomaCML Chronic Myelogenous LeukemiaCMML Chronic Myelomonocytic LeukemiaCMP Complete Metabolic PanelCNL Chronic Neutrophilic LeukemiaCNS Central Nervous SystemCr CreatinineCR Complete ResponseCRi Complete Remission With Incomplete Blood Count RecoveryCRP C Reactive ProteinCSF Cerebrospinal Fluid CT Scan Computerized (or Computed) Tomography Scan

Abbreviations




xxvi ABBREVIATIoNS

CTX ChemotherapyDel(5q) Deletion of 5qDFS Disease-Free SurvivalDIC Disseminated Intravascular CoagulopathyDiff DifferentialDLBCL Diffuse Large B-Cell LymphomaDVT Deep Vein ThrombosisEBV Epstein-Barr VirusEBER Epstein-Barr Virus Encoded RNAeGFR Estimated Glomerular Filtration RateEMH Extramedullary HematopoiesisESR Erythrocyte Sedimentation RateET Essential ThrombocythemiaFDC Follicular Dendritic CellFGFR1 Fibroblast Growth Factor Receptor 1FISH Fluorescence In Situ HybridizationFL Follicular LymphomaFNA Fine Needle Aspirate GI GastrointestinalGMS Grocott-Gomori’s Methenamine Silver StainH&E Hematoxylin and EosinHCL Hairy Cell LeukemiaHCT Hematopoietic Cell TransplantationHGB HemoglobinHGBL High-Grade B-Cell LymphomaHHV8 Human Herpes Virus 8HIV Human Immunodeficiency VirusHL Hodgkin LymphomaHLH Hemophagocytic LymphohistiocytosisHRS Hodgkin Reed-Sternberg CellsHSCT Hematopoietic Stem Cell TransplantationHSTCL Hepatosplenic T-Cell LymphomaI-PIG International PNH Interest GroupICUS Idiopathic Cytopenia of Undetermined SignificanceIHC ImmunohistochemistryINR International Normalized RatioIOL Intraocular LymphomaIPI Internal Prognostic IndexIPS International Prognostic ScoreIPSS International Prognostic Scoring SystemISCL International Society for Cutaneous LymphomasISH In Situ HybridizationISM Indolent Systemic MastocytosisISRT Involved Site Radiation TherapyISSWM International Prognostic Scoring System for WMIST Immunosuppressive therapyIT IntrathecalITP Immune Thrombocytopenic PurpuraIVIG Intravenous ImmunoglobulinJMML Juvenile Myelomonocytic LeukemiaKPI Korean Prognostic Index




ABBREVIATIoNS xxvii

LBCL Large B-cell LymphomaLCH Langerhans Cell HistiocytosisLDH Lactate DehydrogenaseLDHL Lymphocyte Depleted cHLLFT Liver Function TestLGL Large Granular LymphocyteLN Lymph NodeLOH Loss of HeterozygosityLP Lymphocyte PredominantLPD Lymphoproliferative DisorderLPL Lymphoplasmacytic LymphomaM-spike Monoclonal SpikeMALT Mucosa-Associated Lymphoid Tissue MCL Mantle Cell LymphomaMCV Mean Cell VolumeMDS Myelodysplastic SyndromesMDS/MPN Myelodysplastic/Myeloproliferative NeoplasmMDS-U Myelodysplastic Syndrome, UnclassifiableMF Mycosis FungoidesMGUS Monoclonal Gammopathy of Undetermined SignificanceMLL Mixed Lineage LeukemiaMM Multiple Myeloma (Plasma Cell Myeloma)MMUD Mismatched Unrelated DonorMPAL Mixed Phenotype Acute LeukemiaMPD Myeloproliferative DisordersMPN Myeloproliferative NeoplasmsMPO MyeloperoxidaseMR Minor ResponseMRD Minimal Residual Disease; Matched Related DonormTOR Mammalian Target of RapamycinMTX MethotrexateMUD Matched Unrelated DonorMUGA Scan Multigated Acquisition ScanMZL Marginal Zone LymphomaNCCN National Comprehensive Cancer NetworkNCI National Cancer InstituteNF-κB Nuclear Factor-κBNGS Next Generation SequencingNHL Non-Hodgkin LymphomaNK Natural KillerNKPI NK/T-cell Lymphoma Prognostic IndexNLPHL Nodular Lymphocyte Predominant Hodgkin LymphomaNMZL Nodal Marginal Zone LymphomaNOS Not otherwise SpecifiedOS overall SurvivalPAS Stain Periodic Acid–Schiff–Diastase StainPB Peripheral BloodPBL Plasmablastic LymphomaPBS Peripheral Blood SmearPCR Polymerase Chain Reaction




xxviii ABBREVIATIoNS

PDGFRA Platelet-Derived Growth Factor Receptor, AlphaPDGFRB Platelet-Derived Growth Factor Receptor, BetaPET/CT Positron Emission Tomography/Computed TomographyPFS Progression Free SurvivalPh+ Philadelphia Chromosome PositivePIT Prognostic Index for T-CellPLT PlateletPMBL Primary Mediastinal B-Cell LymphomaPMF Primary MyelofibrosisPMLBCL Primary Mediastinal Large B-Cell LymphomaPNH Paroxysmal Nocturnal HemoglobinuriaPR Partial ResponsePS Performance StatusPT Prothrombin TimePTCL Peripheral T-Cell LymphomaPTGC Progressive Transformation of Germinal CentersPTLD Post-Transplant Lymphoproliferative DisorderPTT Partial Thromboplastin TimePUVA Psoralen-UV-APV Plasma Volume; Polycythemia VeraRA Refractory Anemia (MDS Subtype)RAEB Refractory Anemia With Excess Blasts (MDS Subtype)RARS Refractory Anemia With Ring Sideroblasts (MDS Subtype)RBC Red Blood CellRCMD Refractory Cytopenia With Multilineage Dysplasia (MDS Subtype)RCMD-RS Refractory Cytopenia With Multilineage Dysplasia and Ring

Sideroblasts (MDS Subtype)RS Ring SideroblastsSM Systemic MastocytosisSM-AHN Systemic Mastocytosis With an Associated Hematologic

Neoplasm (Formerly SM-AHNMD—Systemic Mastocytosis With Associated Hematologic Non-Mast Cell Lineage Disease)

SMZL Splenic Marginal Zone LymphomaSVT Superficial Venous ThrombosisT-ALL T-Lymphoblastic Leukemiat-AML Therapy-Related Acute Myeloid LeukemiaT-LBL T-Lyphoblastic Lymphomat-MDS Therapy-Related Myelodysplastic Syndromet-MN Therapy-Related Myeloid NeoplasmsT-PLL T-Cell Prolymphocytic LeukemiaTdT Terminal Deoxynucleotidyl TransferaseTHRLBCL T-Cell/Histiocyte Rich Large B-Cell LymphomaTTP Thrombotic Thrombocytopenic PurpuraVTE Venous ThromboembolismXRT Radiation TherapyWBC White Blood CellWHO World Health organizationWM Waldenström’s Macroglobulinemia




203

33INTRODUCTIONDouble hit lymphoma (DHL) is a genetically defined subset of diffuse large B-cell lymphomas that has a significantly poorer prognosis. By definition, it is characterized by the detection of chro-mosomal breakpoint affecting the MYC/8q24 locus in combination with the breakpoint in BCL2/18q21, or less commonly BCL6/3q27 (Figure 33.1). Rarely, MYC gene rearrangement can occur in con-junction with both BCL2 and BCL6 and is known as “triple hit” lym-phoma. It is not recognized as a separate subtype in the 2008 World Health Organization (WHO) classification of tumors of hematopoi-etic and lymphoid tissues, but is usually classified under diffuse large B-cell lymphoma (DLBCL), not otherwise specified (NOS) or B-cell lymphoma unclassifiable (BCLU), with features intermediate between DLBCL and Burkitt lymphoma. In most studies, it accounts for 2% to 12% of DLBCL and 32% to 78% of BCLU, and its incidence increases with patient age.

Double Hit Lymphoma

Nikhil Mukhi and Julio Chavez

Figure 33.1 Fluorescence in situ hybridization (FISH) representation of double hit lymphoma (DHL) by demonstration of MYC/BCL2 rearrangement. (A) FISH test using c-MYC break apart probe: one isolated red, one isolated green, and one fusion indicate presence of c-MYC gene rearrangement. (B) One red (BCL2), one green (IgH), and two fusion signals (IgH/BCL2/t(14;18)(q32;q21)). (C) Fish test using BCL6 break apart probe, two fusion signals indicate no BCL6 gene rearrangement.

A B C




204 MATURE B-CELL LYMPHOMA

GENETIC BASISMYC rearrangement is seen in 5% to 14% of DLBCL cases and is a poor prognostic marker for patients treated with R-CHOP or CHOP. BCL2 or BCL6 are each rearranged in 30% of DLBCL cases, but their negative impact is not well established in the absence of MYC. An example of fluorescence in situ hybridization (FISH) studies for MYC, BCL2, and BCL6 rearrangements are demon-strated in Figure 33.1. Concurrently, these abnormalities portend a significantly poor prognosis and survival is often measured in months (12–22 months) (see DHL clinical case 50 available at www .demosmedical.com/malignant-hematology).

DIAGNOSTIC DIFFERENTIATION FROM DOUBLE EXPRESSORSIt is now recognized that high expression of MYC and BCL2 proteins can occur via mechanisms other than gene rearrange-ments. Tumors with high expression of these proteins detected by immunohistochemistry (IHC) known as “double expressor” (DE) cases have a poor prognosis as well. In one Danish study, investigators compared patients who were DHL by FISH with FISH negative DE by IHC. Both groups demonstrated a similar inferior overall survival (OS). Interestingly, 91% patients with DHL by FISH had tumors of germinal center B-cell (GCB) ori-gin and 73% of DE patients had non-GCB tumors. This study defined DE as greater than 40% cells staining with MYC IHC and greater than 70% cells staining for BCL2, but there is a lack of consensus on the threshold for MYC and BCL2 positivity by IHC. For now, the gold standard to diagnose DHL is by FISH. In conclusion, both DHL and DE seem to be separate entities with poor prognosis.

TREATMENT AND OUTCOMESOver the past two decades, R-CHOP has become the standard initial chemotherapy for large B-cell lymphomas and has led to signifi-cant improvement in OS. However, this regimen remains ineffec-tive in DHL with a median survival of approximately 1.5 years. The majority of data in DHL comes from retrospective review of patients treated with a variety of regimens. Current data suggest that more aggressive regimens, such as DA-EPOCH-R and R-hyper-CVAD confer higher complete remission (CR) rates and event free survival (EFS), but its impact on OS is still not well determined (Table 33.1). Some experts advocate autologous hematopoietic stem cell transplant (HSCT) in first CR, which could be considered in high-risk cases (high- Internal Prognostic Index Score) and fit/






33. DOUBLE HIT LYMPHOMA 205

younger patients. Relapsed/refractory disease is treated similar to large B-cell lymphomas with salvage regimens such as RICE (rituximab, ifosfamide, carboplatin, etoposide) followed by autol-ogous HSCT in responders. Retrospective reviews have not shown an improvement in survival with autologous transplant.

Table 33.1 Retrospective Analyses of Outcomes in DHL Based on Chemotherapy Regimen

StudyNumber of patients Treatments Outcomes

Li, et al. Mod Pathol. 2012;25(1): 145-156

52 19 R-CHOP30 Hyper-CVAD3 Others

Median OS: 18.6 mo; more intensive therapy (P = .54) not associated with better outcome

Oki et al.4 129 57 R-CHOP34 Hyper-CVAD28 DA-EPOCH-R10 Other

Median OS: 18 mo;CR rates:R-CHOP: 40%.DA-EPOCH-R 68%, (P = .017);R-Hyper-CVAD 68%, (P = .011)EFS and OS:similar with R-CHOP or R-Hyper-CVADR-EPOCH better EFS (HR .38, P = .008) and longer OS at 3 years (76 % vs. 35%)

Petrich et al.3 311 100 RCHOP65 R-Hyper-CVAD65 DA-EPOCH-R44 R-CODOX-M/IVAC37 Other

PFS 10.9 moOS 21.9 moR-CHOP vs. intensive regimens PFS: 7.8 vs. 21.6 moNo difference between intensive regimens

CR, complete remission; DHL, double-hit lymphoma; EFS, event free survival; PFS, progression free survival; OS, overall survival.R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, predni-sone); R-Hyper-CVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone alternating with high-dose methotrexate [MTX], cytarabine with rituximab); DA-EPOCH-R (infusional etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin and rituximab); R-CODOX-M/IVAC (cyclophosphamide, vincristine, doxorubicin, high-dose MTX with rituximab/IVAC: ifosfamide, etoposide, cytarabine with rituximab). CNS prophylaxis not uniform but frequent intrathecal methotrexate ± cytarabine.




206 MATURE B-CELL LYMPHOMA

POTENTIAL PRACTICE-CHANGING CLINICAL TRIALSThus far, data are clear that DHL represents a patient population group with poor outcomes, and retrospective data suggest that dose intensification improves outcomes. To help address this ques-tion, the Cancer and Leukemia group B (CALGB 50303) is running a randomized phase 3 of R-CHOP versus DA-EPOCH-R with molec-ular profiling in untreated de novo DLBCL to assess the optimal treatment strategies for these lymphomas (NCT00118209).

REFERENCES FOR SUPPLEMENTAL READING

1. Dunleavy K. Double-hit lymphomas: current paradigms and novel treatment approaches. Hematology Am Soc Hematol Educ Program. 2014;1:107-112.

2. Swerdlow SH. Diagnosis of ‘double hit’ diffuse large B-cell lymphoma and B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and Burkitt lymphoma: when and how, FISH versus IHC. Hematology Am Soc Hematol Educ Program. 2014;1:90-99.

3. Petrich AM, Gandhi M, Jovanovic B, et al. Impact of induction regimen and stem cell transplantation on outcomes in double hit lymphoma: a multicentric retrospective analysis. Blood. 2014;124(15):2354-2361.

4. Oki Y, Noorani M, Lin P, et al. Double hit lymphoma: the MD Anderson Cancer Center clinical experience. Br J Hematol. 2014;166(6):891-901.

5. Landsburg DJ, Petrich AM, Abramson JS. Impact of oncogene rearrangement patterns on outcomes in patients with double-hit non-Hodgkin lymphoma. Cancer. 2015. doi:10.1002/cncr.29781.




https://clinicaltrials.gov/ct2/show/NCT00118209

252

41INTRODUCTIONThe 2016 World Health Organization (WHO) classification divides marginal zone lymphoma (MZL) into three subtypes: (a) extran-odal MZL of mucosa-associated lymphoid tissue (MALT); (b) nodal MZL (NMZL); and (c) splenic MZL (SMZL; Blood. March 2016;pii: blood-2016-01-643569). MALT lymphoma, NMZL, and SMZL com-prise 7% to 8%, 1.5% to 1.8%, and less than 2% of all B-cell lympho-mas, respectively. MZL is often associated with either infection or autoimmune conditions, which cause antigenic stimulation of lym-phoid tissues (see Chapter 42). Specifically, hepatitis C seropositivity has been associated with up to 35% of NMZL, SMZL, and nongastric MALT (Ann Oncol. 2007;18(2):346-350; Cancer. 2004;100(1):107-115). The classic features of MZL include an infiltrate of centrocyte-like small cleaved cells, monocytoid B-cells, or small lymphocytes some-times with expanded marginal zones. The cells express B-cell mark-ers such as CD20 and CD19 but do not express CD5, CD10, and CD23, and lack cyclin D1 positivity, which helps in distinguishing MZL from most cases of chronic lymphocytic leukemia/small lymphocytic lym-phoma (CLL/SLL), mantle cell lymphoma (MCL), and follicular lym-phoma (FL) (see Chapters 39, 38, and 34, respectively).

DIAGNOSIS2008 International Workshop Guidelines on the Diagnosis of Nodal MZL

• The growth pattern and architecture of NMZL encompasses a spectrum of morphologies, including nodular, diffuse, marginal zone-like/perifollicular, “inverse follicular,” interfollicular, persinu-soidsal, or follicular colonization of reactive follicles (infiltration of neoplastic lymphocytes into reactive follicles). NMZL cells morpho-logically are heterogeneous, small- to medium-sized monocytoid B-cells that comprise the marginal zone including centrocyte-like monocytoid B-cells (up to three times the size of normal lympho-cytes, round to irregular nuclei with clumped chromatin, with abundant pale cytoplasm), small lymphocytes, and scattered larger, transformed B-cells.

Marginal Zone Lymphoma

Nishan Tchekmedyian, Danny Nguyen, and

Celeste Bello




41. MArgiNAL ZONe LyMpHOMA 253

• Clonality can be established, and tumor cells typically express igM.• phenotype: pan B-cell marker positive (e.g., CD20, CD19, and

CD79a) and negative for CD5, CD10, CD23, and cyclin D1.• plasmacytic differentiation is common and a serum parapro-

teinemia is detected in one third of cases.• Localized or generalized lymphadenopathy; one third of cases

represent nodal dissemination of MALT lymphoma.• BCL2 positive in most cases. CD43 (pan T-cell marker) is reported

in approximately half of all cases of NMZL.• Translocations of MALT not detected (see Chapter 42).

2008 International Workshop Guidelines on the Diagnosis of SMZL

• Small B lymphocytes replace the splenic white pulp germinal centers, efface the follicle mantle, and merge with the marginal zone and invade the red pulp.

• The spleen, splenic hilar nodes, and bone marrow (BM) are often involved.

• The peripheral blood may also contain characteristic circulating lymphoma cells termed “villous lymphocytes” (named for their bipolar villous cytoplasmic projections).

• Splenomegaly and often autoimmune thrombocytopenia or anemia.

Laboratory evaluation includes complete blood count (CBC) with differential, complete metabolic panel (CMp) and lactate dehydro-genase (LDH). Serologic evaluation of hepatitis B/C and HiV should be done prior to treatment with rituximab. excisional lymph node biopsy is preferred in the diagnosis of NMZL. BM biopsy and aspi-rate are recommended in NMZL to document stages i to ii disease, and also in SMZL given the high frequency of BM involvement. Staging scans with either diagnostic CT chest, abdomen, pelvis with contrast or peT-CT scan should be performed.

KEY DIAGNOSTIC DILEMMAMZL is a small/medium B-cell lymphoma that expresses pan B-cell markers such as CD20. MCL and SLL, which both express CD5, should be ruled out by showing lack of expression of CD5. in rare cases, MZL can be CD5 positive, but absence of cyclin-D1 positivity distinguishes it from MCL. FL should generally be excluded by lack of CD10 expres-sion. The neoplastic hairy cells in hairy cell leukemia (HCL) may mimic the villous lymphocytes seen in cases of SMZL; however, the absence of annexin A1 expression and other markers such as the combination of CD11c, CD25, and CD103, essentially excludes HCL (see Chapter 40 and MZL clinical case 49 available at www.demosmedical.com/malignant-hematology).






254 MATUre B-CeLL LyMpHOMA

PROGNOSISClinically, extranodal MZLs are indolent lymphomas with 10-year overall survival (OS) of 90%. in contrast, the 5-year OS of NMZL is 60% to 70%. Arcaini and colleagues published the intergruppo ital-iano Linfomi (iiL) prognostic model for SMZL utilizing hemoglobin less than 12 g/dL, elevated LDH, and albumin less than 3.5 g/dL, which classified three prognostic risk groups. Five-year OS was 88%, 73%, and 50% for patients with 0, 1, or 2 to 3 risk factors, respectively.1 remember that patients with MZL can undergo his-tologic transformation into more aggressive diffuse large B-cell lymphoma (see Chapter 32).

TREATMENTFrontline Treatment: Asymptomatic PatientsAsymptomatic and low-risk patients can be clinically observed with CBC, CMp, and LDH every 3 to 6 months.

CD5-/CD10-

MZL

LPLMYD88 mutated

HCLAnnexin A1+CD11c+CD103+CD25+

CD5+

MCLcyclin D1 ort(11;14)

CLLCD23+

CD10+FL

t(14;18)

Figure 41.1 Simplified bull’s eye diagram to distinguish the immunophenotypes of low grade B-Cell lymphomas.CLL/SLL, chronic lymphocytic leukemia/small lymphocytic lymphoma; FL, follicular lymphoma; HCL, hairy cell leukemia; LpL, lymphoplasmacytic lymphoma; MCL, mantle cell lymphoma; MZL, marginal zone lymphoma.




41. MArgiNAL ZONe LyMpHOMA 255

Treatment of NMZLThe treatment for NMZL is similar to the treatment of FL as pro-spective trials isolated to MZL patients are sparse (see Chapter 38).There is no general consensus regarding treatment.

A posttreatment peT-CT that shows either a partial response (pr) or a complete response (Cr) should prompt consideration for maintenance rituximab for 2 years (Lancet. 2011;377(9759):42-51).

Frontline Treatment: Symptomatic Patients or Localized Disease, NMZL

• patients with stage i or ii NMZL should receive radiation to the involved lymphoid region; if extrapolated from FL, about half of these patients may be cured (J Clin Oncol. 1996;14(4):1282-1290).

• patients with symptomatic stage iii/iV NMZL or with disease that is threatening organ function, causing cytopenias, or bulky disease (>7 cm), can be treated with six to eight cycles of alkylator-based therapy including Br (bendamustine, ritux-imab), rCHOp (rituximab, cyclophosphamide, doxorubicin, vin-cristine, prednisone), or rCVp (rituximab, cyclophosphamide, vincristine, predisone; Blood. 2014;123(19):2944-2952. Blood. 2005;106(12):3725-3732. Lancet. 2013;381(9873):1203-1210).

Second-Line Treatment of NMZLif there is adequate BM reserve, treatment with radioimmunotherapy (yttrium-90—ibritumomab tiuxetan) can be considered versus an alternative first-line regimen (Leuk Lymphoma. 2015;56(6): 1750-1755; J Clin Oncol. 2002;20(10):2453-2463; Br J Haematol. 2014;167(2):207-213).

Frontline Treatment: Symptomatic Patients, SMZLHepatitis C negative patients: Splenectomy or rituximab alone5 (Clin Lymphoma. 2002;3(1):41-47; Leuk Lymphoma. 2014;55(8): 1854-1860). Hepatitis C positive patients: Treatment of hepatitis C infection with the addition of splenectomy or rituximab in recal-citrant cases.3

Second-Line Treatment Options, SMZLSecond-line options for SMZL include chemoimmunotherapy typi-cally used for FL or NMZL (see Chapter 38 and the preceding).

SURVEILLANCEin general, all patients can undergo clinical follow-up every 3 to 6 months with CBC, CMp, and LDH and with imaging only as indi-cated by symptoms.




256 MATUre B-CeLL LyMpHOMA

POTENTIAL PRACTICE-ChANGING CLINICAL TRIALSTargeting of the B-cell receptor signaling has led to a paradigm shift in the treatment of multiple B-cell lymphomas. ibrutinib, a Bruton’s tyrosine kinase (BTK) inhibitor that impedes downstream signaling and inhibits B-cell proliferation, is being tested in a phase 2, open-label study for patients with relapsed/refractory MZL (NCT01980628). Another targeted agent, idelalisib, which is a pi3- kinase delta inhibitor, has shown promising results in patients with FL refractory to rituximab and alkylating agents. in this pivotal study leading to approval in FL (n = 125), 15 patients had MZL (N Engl J Med. 2014;370(11):1008-1018). Subset analysis by tumor type is not currently available but there is interest in this drug for treatment of MZL (NCT01282424). Duvelisib is a small molecule inhibitor of both pi3-kinase delta and pi3-kinase gamma and is being combined with Br in a phase 3 study of patients with indolent NHL including MZL (NCT02576275 “BrAVUrA”). A phase 3 study (NCT01938001) is randomizing patients with relapsed/refractory indolent NHL including MZL to rituximab plus placebo versus rituximab plus lenalidomide; a separate phase 3B study is randomizing patients to lenalidomide versus rituximab maintenance after treatment with lenalidomide plus rituximab (NCT01996865 “MAgNiFy”). A phase 2 study is investigating radioimmunotherapy with 131i-rituximab in patients with relapsed, refractory MZL (NCT01678404). immune checkpoint inhibition is being studied in NHL including MZL; for example, a phase 2 study combines pembrolizumab (anti-pD-1) with idelalisib or ibrutinib in patients with relapsed, refractory disease (NCT02332980).

REFERENCES FOR SUPPLEMENTAL READING

1. Arcaini L, Lazzarino M, Colombo N, et al. Splenic marginal zone lymphoma: a prognostic model for clinical use. Blood. 2006;107(12):4643-4649.

2. Franco V, Florena AM, iannitto e. Splenic marginal zone lym-phoma. Blood. 2003;101(7):2464-2472.

3. Hermine O, Lefrère F, Bronowicki J-p, et al. regression of splenic lymphoma with villous lymphocytes after treatment of hepatitis C virus infection. N Engl J Med. 2002;347(2):89-94.

4. Thieblemont C, Felman p, Callet-Bauchu e, et al. Splenic marginal-zone lymphoma: a distinct clinical and pathological entity. Lancet Oncol. 2003;4(2):95-103.

5. Tsimberidou AM, Catovsky D, Schlette e, et al. Outcomes in patients with splenic marginal zone lymphoma and marginal zone lymphoma treated with rituximab with or without chemo-therapy or chemotherapy alone. Cancer. 2006;107(1):125-135.











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