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Part 1 book “Handbook of hematologic malignancies” has contents: Hematopathology diagnostic techniques and assays, polycythemia vera, essential thrombocythemia, primary myelofibrosis, chronic myelogenous leukemia, chronic neutrophilic leukemia, systemic mastocytosis,… and other contents.
Davi d A Sallman , M D At e e fa Chau d h u ry, M D J o h n ny N g u y e n , M D Li n g Z han g , M D Al an F Li st, M D 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 Recommended Shelving Category: Oncology ISBN 978-1-62070-094-5 11 W 42nd Street New York, NY 10036 www.demosmedical.com 781620 700945 HANDBOOK OF HEMATOLOGIC MALIGNANCIES 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 Sallman · Chau d h u ry N g u y e n · Z han g · Li st HA ND B OOK OF HE M ATOLO G IC M A L IG NAN C IES HANDBOOK OF H EM ATO LO G I C MA L I G N A N CI E S Davi d A Sallman At e e fa Chau d h u ry J o h n ny N g u y e n Li n g Z han g Al an F Li st I NCLUDES DOW NLOADABLE CASES W I TH Q&A Handbook of Hematologic Malignancies Handbook of Hematologic Malignancies Editors David A Sallman, MD Department of Malignant Hematology H Lee Moffitt Cancer Center & Research Institute University of South Florida Tampa, Florida Ateefa Chaudhury, MD Department of Malignant Hematology H Lee Moffitt Cancer Center & Research Institute University of South Florida Tampa, Florida Johnny Nguyen, MD Department of Hematopathology H Lee Moffitt Cancer Center & Research Institute University of South Florida Tampa, Florida Ling Zhang, MD Department of Hematopathology H Lee Moffitt Cancer Center & Research Institute University of South Florida Tampa, Florida Alan F List, MD Department of Malignant Hematology H Lee Moffitt Cancer Center & Research Institute University of South Florida Tampa, Florida New York Visit our website at www.demosmedical.com ISBN: 9781620700945 e-book ISBN: 9781617052705 Supplement clinical case material ISBN: 978-0-8261-8471-9 Clinical cases provided as an online resource, available at www.demosmedical.com/ malignant-hematology Acquisitions Editor: David D’Addona Compositor: 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 Data Names: 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 9781620700945 Subjects: 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 Special discounts on bulk quantities of Demos Medical Publishing books are available to corporations, professional associations, pharmaceutical companies, health care organizations, and other qualifying groups For details, please contact: Special Sales Department Demos Medical Publishing 11 West 42nd Street, 15th Floor, New York, NY 10036 Phone: 800-532-8663 or 212-683-0072; Fax: 212-941-7842 E-mail: specialsales@demosmedical.com Printed in the United States of America by McNaughton & Gunn 16 17 18 19 20 / 5 4 3 2 1 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 Contents Contributors xiii Expert Reviewers xix Foreword John M Bennett, MD xxi Preface xxiii Abbreviations xxv Share Handbook of Hematologic Malignancies INTRODUCTION AND OVERVIEW Hematopathology Diagnostic Techniques and Assays 1 Johnny Nguyen and Ling Zhang MYELOPROLIFERATIVE NEOPLASMS Polycythemia Vera 14 Liliana Bustamante and Kenneth Zuckerman Essential Thrombocythemia 20 Susmitha Apuri and Kenneth Zuckerman Primary Myelofibrosis 26 Andrew Kuykendall and Kenneth Zuckerman Chronic Myelogenous Leukemia 33 Chetasi Talati and Javier Pinilla-Ibarz Chronic Neutrophilic Leukemia 40 Saman Nematollahi, Shweta Jain, and Utkarsh Acharya Systemic Mastocytosis 45 Andrew Kuykendall and Kenneth Zuckerman PDGFRA/PDGFRB/FGFR1 Myeloid Neoplasms 51 Joseph Clara and Eric Padron vii viii Contents Myelodysplastic and Bone Marrow Failure Syndromes Myelodysplastic Syndromes 57 Joanna Grabska, David A Sallman, and Rami Komrokji 10 Aplastic Anemia 66 Michael Shafique and Rami Komrokji 11 Paroxysmal Nocturnal Hemoglobinuria 71 Hilda Ding and Michael Jaglal MYELODYSPLASTIC/Myeloproliferative Neoplasms 12 Myelodysplastic/Myeloproliferative Overlap Syndromes 75 Jennifer Eatrides and Eric Padron 13 Chronic Myelomonocytic Leukemia 82 Alexandra Gomez and Justin M Watts ACUTE MYELOID LEUKEMIA AND RELATED SYNDROMES 14 Acute Myeloid Leukemia 89 Varun Dhulipala and Kendra Sweet 15 Secondary AML and AML With Myelodysplasia-Related Changes 96 Seongseok Yun and Jeffrey Lancet 16 Acute Promyelocytic Leukemia 101 Leidy L Isenalumhe and Jeffrey Lancet 17 Blastic Plasmacytoid Dendritic Cell Neoplasm 107 Justin Taylor, Ateefa Chaudhury, and Andrew A Lane ACUTE LYMPHOID LEUKEMIA 18 B-Lymphoblastic Leukemia 111 Aneesha Hossain and Khaled el-Shami 19 BCR-ABL1+ B-Lymphoblastic Leukemia 119 Aneesha Hossain and Khaled el-Shami 20 T-Lymphoblastic Lymphoma/Leukemia 124 Keri Maher and Ravitharan Krishnadasan ACUTE LEUKEMIA OF AMbIGUOUS LINEAGE 21 Acute Leukemia of Ambiguous Lineage 129 Keri Maher and Ravitharan Krishnadasan Contents ix MATURE T- AND NK-CELL LEUKEMIA 22 T-Cell Prolymphocytic Leukemia 133 Abhijeet Kumar, Srinath Sundararajan, and Ravitharan Krishnadasan 23 T-Cell Large Granular Lymphocytic Leukemia 137 Magali Van den Bergh and Lubomir Sokol 24 Aggressive Natural Killer Cell Leukemia 142 Mintallah Haider and Lubomir Sokol PLASMA CELL DISORDERS 25 Monoclonal Gammopathy of Unknown Significance, Smoldering Myeloma, and Plasmacytomas 147 Srinath Sundararajan, Abhijeet Kumar, Amit Agarwal, and Neha Korde 26 Multiple Myeloma 154 Patrick Griffin and Rachid Baz 27 Waldenström’s Macroglobulinemia 161 Joanna Grabska and Rachid Baz 28 Immunoglobulin Light Chain Amyloidosis 169 Taxiarchis Kourelis and Morie A Gertz Hodgkin Lymphoma 29 Hodgkin Lymphoma 175 Anju Nair and Micah Burch NON-HODGKIN LYMPHOMA 30 Non-Hodgkin Lymphoma Classification and Diagnostic Evaluation 183 Johnny Nguyen and Ling Zhang MATURE B-CELL LYMPHOMA VERY AGGRESSIVE 31 Burkitt Lymphoma 189 Anju Nair and Micah Burch AGGRESSIVE 32 Diffuse Large B-Cell Lymphoma 195 Jose Sandoval-Sus and Julio Chavez 132 ACUTE LEUKEMIA OF AMBIGUOUS LINEAGE agents such as blinatumomab (NCT01466179) and inotuzoumab ozogamicin (NCT01925131) and anti-CD 19 chimeric antigen receptor T cells (CAR-T) are also underway (NCT02443831), and may eventually prove helpful in MPAL if the patient harbors the target to the drug in question References for Supplemental Reading Vardiman J, Thiele J, Arber D, et al The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: rationale and important changes Blood 2009;114(5):937-951 Van den Anker W, Terwijn M, Westers T, et al Acute leukemias of ambiguous lineage: diagnostic consequences of the WHO 2008 classification Leukemia 2010;24:1392-1396 Matutes E, Pickl W, Veer M, et al Mixed-phenotype acute leukemia: clinical and laboratory features and outcome in 100 patients defined according to the WHO 2008 classification Blood 2011;117(11):3163-3171 Heesch S, Neumann M, Schwartz S, et al Acute leukemias of ambiguous lineage in adults: molecular and clinical characterization Ann Hematol 2013;92(6):747-758 Wolach O, Stone R How I treat mixed phenotype acute leukemia Blood 2015;125(16):2477-2485 MATURE T- AND NK-CELL LEUKEMIA 22 T-Cell Prolymphocytic Leukemia Abhijeet Kumar, Srinath Sundararajan, and Ravitharan Krishnadasan INTRODUCTION T-cell prolymphocytic leukemia (T-PLL) is a rare, mature T-cell leukemia that accounts for approximately 2% of all T-cell leukemias T-PLL mainly affects the elderly with a mean age at presentation of 65 years Patients with ataxia telangiectasia have a greatly increased incidence of T-PLL with a much earlier median age of presentation Patients typically present with widely disseminated disease at diagnosis manifesting as significant leukocytosis, hepatosplenomegaly, lymphadenopathy, skin lesions, and serous effusions Despite advances in therapeutic approaches, the response and prognosis of these patients remain poor with a median survival of less than year DIAGNOSIS Morphology and immunophenotyping are the primary means of diagnosing T-PLL • Peripheral blood smear (PBS): A PBS is a key test to diagnose T-PLL, which reveals a population of prolymphocytes (Figure 22.1) The typical cytology of prolymphocytes consists of medium-size cells with condensed nuclear chromatin, a single prominent nucleolus, and intensely basophilic nongranular cytoplasm with cytoplasmic protrusions or “blebs.” The nuclei can be round to oval in 50% of cases, or irregular • Bone marrow (BM): Infiltration of the marrow with prolymphocytes creates a mixed pattern (diffuse and interstitial) Reticulin fibrosis is almost always present • Other tissues: Spleen histology shows infiltration of the red pulp with involvement of blood vessels, capsule, and white pulp Infiltration of the lymph nodes is diffuse (predominantly paracortical) The skin involvement reveals dermal infiltration with prolymphocytes, but lacks epidermotropism • Immunophenotype (see T-PLL clinical case 41 available at www.demosmedical.com/malignant-hematology): T-PLL cells express CD2, CD3, CD7, and CD52 CD7 expression is strong in 133 134 MATURE T- AND NK-CELL LEUKEMIA Figure 22.1 Atypical lymphocytosis in T-PLL PBS shows atypical lymphoid cells that display condensed chromatin, prominent nucleoli, and a certain amount of amphophilic cytoplasm, compatible with prolymphocytes (left, ×1000 total magnification) A touch imprint of bone marrow core biopsy reveals sheets of atypical lymphocytes wth morphologic features similar to those in peripheral blood (right, ×1000) contrast to other mature T-cell neoplasms CD52 expression is strong as well, which renders the disease susceptible to alemtuzumab (see the following) Terminal deoxynucleotidyl transferase is not expressed CD3 may be expressed on the cell membrane at low or high levels Expression of CD4 and CD8 is variable: 60% of cases are CD4+/CD8−, 25% of cases are CD4+/CD8+, and 15% of cases are CD4−/CD8+ T-PLL cells overexpress TCL1 as demonstrated by immunohistochemistry GENETICS The most common characteristic chromosome abnormality is inversion of chromosome 14 (inv 14(q11;q32)) followed by t(14;14) (q11;q32) occurring in 80% and 10% of cases, respectively Both rearrangements juxtapose the TCL1 locus with oncogenes TCL1A and TCL1B at chromosome 14q32.1 resulting in activation and expression of the proto-oncogene TCL1 TCL-1 can also be detected by flow cytometry Other genetic abnormalities include t(X;14)(q28;q11), trisomy 8/ iso8q, 12p13, and 11q23, with the latter being the locus for the ataxia telangiectasia mutated gene Abnormalities of chromosome 6 and 17, including deletion of the TP53 gene, have also been observed KEY DIFFERENTIAL DIAGNOSES B-cell prolymphocytic leukemia (B-PLL) has a similar clinical presentation and cytologic appearance to T-PLL However, skin infiltration and lymphadenopathy, which are unusual in B-PLL, are much more common in T-PLL In addition, these two entities differ in their immunophenotype (see earlier and T-PLL clinical case 41 available at www.demosmedical.com/malignant-hematology) Both T-PLL and mycosis fungoides (MF)/ Sézary syndrome are T-cell neoplasms that can involve the blood and skin The morphology of the “cerebriform” 22 T-Cell Prolymphocytic Leukemia 135 variant (Sézary cell-like) seen in 5% of patients with T-PLL resembles the Sézary cells seen in MF (see Chapter 46) Leukemic manifestation of peripheral T-cell lymphoma and CD4+ variant of large granular lymphocytic leukemia should also be included in the differential diagnosis (see Chapter 23) TREATMENT A minority of patients who present with stable or slowly p rogressive lymphocytosis without symptoms can be monitored closely without therapeutic interventions It is generally prudent to follow these patients much more closely than patients with chronic lymphocytic leukemia However, the majority of patients present with aggressive disease requiring treatment Alemtuzumab, a humanized monoclonal IgG1 antibody, has significantly improved outcomes in T-PLL patients Serious infusion reactions can occur and thus the initial dose is mg followed by titration to the standard dose of 30 mg, three times weekly Patients require Pneumocystis jiroveci and herpes virus prophylaxis along with weekly cytomegalovirus (CMV) monitoring Referral for BM transplantation should be made up front for all patients who are candidates Frontline Treatment Alemtuzumab + consolidation with a hematopoietic stem cell transplant (J Clin Oncol 1997;15(7):2667-2672) • IV administration of alemtuzumab is preferable in T-PLL versus SC route IV patients with 91% overall response rate (ORR) (29/32; 81% complete response [CR]) versus 33% (3/9) with SC route (Blood 2011;118(22):5799-5802) • Allogenic stem cell transplant offers a chance of cure and should be considered in the first remission whenever possible Autologous stem cell transplant provides a longer duration of remission and lower toxicity profile but does not cure the disease (Br J Haematol 2010;149(6):907-910) • Allografted patients still have a risk of relapse and when relapsed have a very poor prognosis with no established treatment available However, tapering of immunosuppressive therapy or donor lymphocyte infusion after re-induction therapy can result in remission Alternative Frontline Treatments • Pentostatin (can be added to alemtuzumab; J Clin Oncol 1994;12(12):2588-2593) • Fludarabine, mitoxantrone, and cyclophosphamide (FMC) × four cycles, followed by consolidation with IV alemtuzumab 3×/week × 12 weeks in responding patients (Cancer 2013;15;119(12):2258-2267) 136 MATURE T- AND NK-CELL LEUKEMIA ■■ FMC-A had an ORR of 92% (12 CR, 11 PR) with median progression-free survival (PFS) and OS of 17 and 12 months, respectively Higher TCL1 protein expression was associated with inferior PFS Relapsed Refractory T-PLL • For those patients who received induction therapy with alemtuzumab, with response duration of at least months, retreatment can be successful in achieving a second remission • Nelarabine, with or without fludarabine (J Clin Oncol 2008; 26(7):1098-1110) • Bendamustine, ORR of 53% (Br J Haematol 2015;168(6):916-919) Potential Practice-Changing Clinical Trials There is a paucity of randomized clinical trials in T-PLL due to rarity of the disease There are clinical trials looking at maintenance romidepsin, an HDAC inhibitor, after stem cell transplant (NCT02512497) Trials are also looking at combinations of alemtuzumab with purine analogs and other agents REFERENCES FOR SUPPLEMENTAL READING Damlaj M, Sulai NH, Oliveira JL, et al Impact of alemtuzumab therapy and route of administration in T-prolymphocytic leukemia: a single-center experience Clin Lymphoma Myeloma Leuk 2015;15(11):699-704 Dearden C How I treat prolymphocytic leukemia Blood 2012; 120(3):538-551 Herbaux C, Genet P, Bouabdallah, K, et al Bendamustine is effective in T-cell prolymphocytic leukaemia Br J Haematol 2015;168(6):916-919 Hopfinger G, Busch R, Pflug N, et al Sequential chemoimmunotherapy of fludarabine, mitoxantrone, and cyclophosphamide induction followed by alemtuzumab consolidation is effective in T-cell prolymphocytic leukemia Cancer 2013;119(12):2258-2267 Swerdlow SH, Campo E, Harris NL, et al WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues Lyon, France: IARC Press; 2008 http://www.nccn.org/professionals/ physician_gls/pdf/nhl.pdf 23 T-Cell Large Granular Lymphocytic Leukemia Magali Van den Bergh and Lubomir Sokol INTRODUCTION T-cell large granular lymphocytic leukemia (T-LGLL) is a rare malignancy arising from aberrant proliferation of post thymic large granular lymphocytes in the peripheral blood, bone marrow (BM), and spleen It usually presents in the sixth decade of life and affects males and females equally Its incidence is estimated at in million individuals in the United States Chronic antigenic stimulation with putative autoantigens or unknown viruses is hypothesized to contribute to its pathogenesis Clinically, an indolent behavior is most often encountered However, approximately 60% of patients will require therapy due to development of cytopenias, symptomatic splenomegaly, autoimmune disorders, or systemic B- symptoms T-LGLL has been reported to be the most common cause of secondary pure red cell aplasia in the United States Autoimmune conditions, most notably rheumatoid arthritis, Sjögren syndrome, and autoimmune cytopenias, are well-known phenomena in T-LGLL BM failure disorders such as myelodysplastic syndrome, aplastic anemia, and paroxysmal nocturnal hemoglobinuria have been described to comanifest with indolent T-LGLL DIAGNOSIS In the past, diagnosis required the presence of clonal LGL lymphocytosis of at least 2.0 × 109/L; coexpression of CD3, CD8, and CD57 immunophenotypic markers; and usually αβ T-cell receptor (TCR) positive, but may be of the γδ type More recently, lower numbers of circulating clonal T-LGLLs (