The Peripheral T-Cell Lymphomas 9781119671367, 1119671361

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The Peripheral T‐Cell Lymphomas

The Peripheral T‐Cell Lymphomas Edited by

Owen A. O’Connor, M.D., Ph.D. American Cancer Society Research Professor Professor of Medicine Department of Medicine Division of Hematology and Oncology Program for T‐Cell Lymphoma Research Department of Microbiology, Immunology, and Cancer Research University of Virginia Cancer Center, Charlottesville, VA, USA

Won Seog Kim Sungkyunkwan University School of Medicine Seoul, Korea

Pier Luigi Zinzani, M.D., Ph.D. Professor of Hematology Department of Medicine Program for Lymphomas and Chronic Lymphocytic Leukemia University of Bologna, Bologna Italy

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This edition first published 2021 © 2021 John Wiley & Sons Ltd All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, except as permitted by law. Advice on how to obtain permission to reuse material from this title is available at http://www.wiley.com/go/permissions. The right of Owen A. O’Connor, Won Seog Kim, and Pier Luigi Zinzani to be identified as the authors of the editorial material in this work has been asserted in accordance with law. Registered Office(s) John Wiley & Sons, Inc., 111 River Street, Hoboken, NJ 07030, USA John Wiley & Sons Ltd, The Atrium, Southern Gate, Chichester, West Sussex, PO19 8SQ, UK Editorial Office 9600 Garsington Road, Oxford, OX4 2DQ, UK For details of our global editorial offices, customer services, and more information about Wiley products visit us at www.wiley.com. Wiley also publishes its books in a variety of electronic formats and by print‐on‐demand. Some content that appears in standard print versions of this book may not be available in other formats. Limit of Liability/Disclaimer of Warranty The contents of this work are intended to further general scientific research, understanding, and discussion only and are not intended and should not be relied upon as recommending or promoting scientific method, diagnosis, or treatment by physicians for any particular patient. In view of ongoing research, equipment modifications, changes in governmental regulations, and the constant flow of information relating to the use of medicines, equipment, and devices, the reader is urged to review and evaluate the information provided in the package insert or instructions for each medicine, equipment, or device for, among other things, any changes in the instructions or indication of usage and for added warnings and precautions. While the publisher and authors have used their best efforts in preparing this work, they make no representations or warranties with respect to the accuracy or completeness of the contents of this work and specifically disclaim all warranties, including without limitation any implied warranties of merchantability or fitness for a particular purpose. No warranty may be created or extended by sales representatives, written sales materials or promotional statements for this work. The fact that an organization, website, or product is referred to in this work as a citation and/or potential source of further information does not mean that the publisher and authors endorse the information or services the organization, website, or product may provide or recommendations it may make. This work is sold with the understanding that the publisher is not engaged in rendering professional services. The advice and strategies contained herein may not be suitable for your situation. You should consult with a specialist where appropriate. Further, readers should be aware that websites listed in this work may have changed or disappeared between when this work was written and when it is read. Neither the publisher nor authors shall be liable for any loss of profit or any other commercial damages, including but not limited to special, incidental, consequential, or other damages. Library of Congress Cataloging‐in‐Publication Data Names: O’Connor, Owen A., editor. | Kim, Won Seog, editor. | Zinzani, Luigi, editor. Title: The peripheral T-cell lymphomas / edited by Owen A. O’Connor, Won Seog Kim, Pier Luigi Zinzani. Description: Hoboken, NJ : Wiley-Blackwell, 2021. | Includes bibliographical references and index. Identifiers: LCCN 2020028451 (print) | LCCN 2020028452 (ebook) | ISBN 9781119671312 (hardback) | ISBN 9781119671329 (adobe pdf) | ISBN 9781119671367 (epub) Subjects: MESH: Lymphoma, T-Cell, Peripheral Classification: LCC RC280.L9 (print) | LCC RC280.L9 (ebook) | NLM WH 525 | DDC 616.99/446–dc23 LC record available at https://lccn.loc.gov/2020028451 LC ebook record available at https://lccn.loc.gov/2020028452 Cover Design: NA Cover Images: Excellent backgrounds/Shutterstock Set in 9.5/12.5pt STIXTwoText by SPi Global, Pondicherry, India 10  9  8  7  6  5  4  3  2  1

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Contents Contributors  xix About the Companion Website  xxiii Part I  Biological Basis of the Peripheral T-cell Lymphomas  1 1 The Fundamentals of T-cell Lymphocyte Biology  3 Claudio Tripodo and Stefano A. Pileri Introduction  3­ General View of the Differentiation and Function of T Lymphocytes  3 ­The T-cell System as a Frame for Peripheral T-cell Lymphoma: Taking Plasticity into Account  5 Must Reads  7 References  7 2 Mechanisms of T-cell Lymphomagenesis  9 François Lemonnier, Philippe Gaulard and Laurence de Leval Introduction  9 ­Oncogenic Events in the Transformation of T or Natural Killer Cells  9 Genetic Lesions  9 Deregulated Pathways in Peripheral T-cell Lymphoma Oncogenesis (Figure 2.1, Table 2.1)  10 Signaling Pathways  13 Cell-cycle Control  14 Immune Surveillance  14 Role of the Microenvironment in Peripheral T-cell Lymphoma  15 The Model of Angio-immunoblastic T-cell Lymphoma and T Follicular Helper-derived Peripheral T-cell Lymphoma  15 Specific Microenvironment Components Present in Other Primary Cutaneous T-cell Lymphoma Entities  16 Underlying Factors Favoring the Tumor Transformation  18 Viruses  18 Chronic Antigenic Stimulation  19 Other Factors  19 Cell of Origin (Table 2.1)  20 ­Conclusion  22 Must Reads  22 References  22 3 Epigenetics of T-cell Lymphoma  27 H. Miles Prince, Jasmine Zain, Anas Younes, Sean Whittaker, Owen A. O’Connor and Sean Harrop ­Introduction  27 ­Epigenetic Pathways Altered in T-cell Lymphoma  27 ­Epigenetic Changes Within Specific T-cell Lymphoma Subtypes  31

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Peripheral T-cell Lymphoma Not Otherwise Specified  32 Angioimmunoblastic T-cell Lymphoma and Peripheral T-cell Lymphoma with T Follicular Helper Phenotype  32 Anaplastic Large-cell Lymphoma  33 Adult T-cell Leukemia/Lymphoma  33 Intestinal T-cell Lymphoma  34 Hepatosplenic T-cell Lymphomas  34 Extranodal Natural Killer/T-cell Lymphoma  34 Mycosis Fungoides and Sézary Syndrome  35 ­Established and Emerging Drugs Targeting the T-cell Lymphoma Epigenome  35 DNA Methyltransferase Inhibitors  35 Isocitrate Dehydrogenase Inhibitors  36 EZH2 Inhibitors  37 BET Inhibitors  38 Protein Arginine Methyltransferases Inhibitors  38 ­Combination Therapies Involving Epigenetic Targeting Agents  38 ­Future Directions  38 Must Reads  39 References  39 4 Animal Models of T-cell Lymphoma  47 Keiichiro Hattori, Raksha Shrestha, Tatsuhiro Sakamoto, Manabu Kusakabe and Mamiko Sakata-Yanagimoto Introduction  47 ­Angioimmunoblastic T-cell Lymphoma  50 The ROQUIN Mouse Model  50 The Mouse Models Recapitulating Human Angioimmunoblastic T-cell Lymphoma Genomic Features  50 Tet2 Gene Trap Mice  50 G17V RHOA Mouse Model  50 PDX Models of Angioimmunoblastic T-cell Lymphoma  51 ­Anaplastic Large T-cell Lymphoma  51 Viral and Chimeric Models  51 Transgenic Models  51 CRISPR-Based Models  52 PDX Models of Anaplastic Large-Cell Lymphomas  52 ­Human T-cell Lymphotropic Virus Type 1 Adult T-cell Leukemia/Lymphoma  52 Mice Expressing HTLV-1 Viral Proteins  52 PDX Models of Adult T-cell Leukemia/Lymphoma  52 ­Cutaneous T-cell Lymphoma  53 ­Enteropathy-associated T-cell Lymphoma  53 ­Conclusion  53 Must Reads  53 References  54 Part II  Epidemiology and Classification of the PTCL  57 5 Geographic Distribution of the Peripheral T-cell Lymphomas  59 Global Epidemiology

Amulya Yellala, Avyakta Kallam and James O. Armitage Historical Perspective  59 ­Epidemiology  60 Peripheral T-cell Lymphoma, Not Otherwise Specified  60 Angioimmunoblastic T-cell Lymphoma  61 Anaplastic Large-cell Lymphoma  61

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Adult T-cell Lymphoma/Leukemia (HTLV Associated)  62 Extranodal NK/T-cell Lymphomas  62 T-cell Prolymphocytic Leukemia  62 Large Granular Lymphocytic Leukemia  62 Primary Cutaneous Gamma/Delta PTCL  63 Enteropathy Associated T-cell Lymphomas and Monomorphic Epitheliotropic Intestinal T-cell lymphoma  63 Hepatosplenic T-cell Lymphoma  63 The Cutaneous T-cell Lymphomas  63 ­Conclusion  63 Must Reads  64 References  64 6 Classification of the Peripheral T-cell Lymphomas  69 Neval Ozkaya and Elaine S. Jaffe ­Introduction  69 ­Angioimmunoblastic T-cell Lymphoma and Other Nodal Lymphomas of T follicular Helper Cell Origin  69 Angioimmunoblastic T-cell Lymphoma  70 Follicular T-cell Lymphoma  71 Nodal Peripheral T-cell Lymphoma with T-follicular Helper Phenotype  71 ­Peripheral T-cell Lymphoma Not Otherwise Specified  71 ­Anaplastic Large-cell Lymphomas  72 Anaplastic Large-cell Lymphoma, ALK-Positive  72 Anaplastic Large-cell Lymphoma, ALK-Negative  72 Breast Implant-associated Anaplastic Large-cell Lymphoma (Provisional)  73 ­Adult T-cell Leukemia/Lymphoma  74 ­Intestinal T-cell Lymphomas  74 Enteropathy-associated T-Cell Lymphoma  75 Monomorphic Epitheliotropic Intestinal T-cell Lymphoma  76 Intestinal T-cell ymphoma, Not Otherwise Specified  76 Indolent T-cell Lymphoproliferative Disorder of the Gastrointestinal Tract (Provisional)  77 NK-Cell Enteropathy  78 ­Hepatosplenic T-cell Lymphoma  78 ­Mycosis Fungoides  78 ­Sézary Syndrome  79 ­Primary Cutaneous CD30-positive T-cell Lymphoproliferative Disorders  79 Lymphomatoid Papulosis  79 Primary Cutaneous Anaplastic Large-cell Lymphoma  80 Subcutaneous Panniculitis-like T-cell Lymphoma  80 ­Primary Cutaneous Gamma–Delta T-cell Lymphoma  80 ­Primary Cutaneous CD8+ Aggressive Epidermotropic Cytotoxic T-cell Lymphoma (Provisional)  81 ­Primary Cutaneous CD4+ Small/Medium T-Cell Lymphoproliferative Disorder (Provisional)  81 ­Primary Cutaneous Acral CD8+ T-cell Lymphoma (Provisional)  82 ­Large Granular Lymphocytic Leukemia  82 T-cell Large Granular Lymphocytic Leukemia  82 Chronic Lymphoproliferative Disorder of NK Cells (Provisional)  82 ­T-cell Prolymphocytic Leukemia  82 ­NK-cell Lymphomas  83 Extranodal NK/T-cell Lymphoma, Nasal Type  83 Aggressive NK-cell Leukemia  83 EBV-positive T-cell and NK-cell Lymphoproliferative Diseases of Childhood  83 Must Reads  84 References  84

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7 Molecular Classification of the Peripheral T-cell Lymphomas  91 Tyler A. Herek and Javeed Iqbal ­Introduction  91 ­T-cell Development and Activation: An Overview  92 ­T-cell Receptor Signaling  92 ­Derivation of Diagnostic Signatures for Molecular Classification of Peripheral T-cell Lymphomas  95 ­Angioimmunoblastic T-cell Lymphoma and Other T Follicular Helper-derived Malignancies  95 Recurrent Genetic Features  96 ­Anaplastic Large-cell Lymphomas  96 Recurrent Genetic Features  96 ­Adult T-cell Leukemia/Lymphoma  97 Recurrent Genetic Features  97 ­Peripheral T-cell Lymphoma Not Otherwise Specified  97 Recurrent Genetic Features in Two Novel Subgroups  98 ­Hepatosplenic T-cell Lymphoma  98 Recurrent Genetic Features  98 ­Extranodal natural killer/T-cell Lymphoma  98 Recurrent Genetic Features  99 ­Cutaneous T-cell Lymphomas  99 ­Conclusion  99 Must Reads  99 References  99

Part III  Discrete Clinical Subtypes of PTCL (Unique Epidemiology, Therapy and Management)  105

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Peripheral T-cell Lymphoma Not Otherwise Specified  107 N. Nora Bennani and Stephen M. Ansell ­Introduction  107 ­Epidemiology, Risk Factors, and Clinical Characteristics  107 ­Basic Principles of Disease Biology  108 ­Prognostic Tools  109 ­Frontline Therapy  110 ­Management of Relapsed or Refractory Disease  111 ­Future Directions  112 Must Reads  112 References  112

9 Angioimmunoblastic T-cell Lymphoma  115 Jehan Dupuis and Franck Morschhauser ­Introduction  115 ­Clinical and Biological Presentation  115 ­Epidemiology and Risk Factors, Disease Incidence and Prevalence  117 ­Basic Principles of Disease Biology  118 TET2 Mutations  119 IDH2 Mutations  120 DNMT3A Mutations  120 Rho A Mutations  121 CD28 Alterations  121 Other Mutations Affecting the T-cell Lymphoma Pathway  121 ­Management of Disease in the Front Line  122 ­Management of Relapsed or Refractory Disease  122

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Conventional Chemotherapy Agents  123 Bendamustine  123 Pralatrexate  123 Romidepsin  124 Belinostat  124 Newer Targeted Therapy Approaches  125 ­Future Directions  125 Must Reads  126 References  126 10 The Spectrum of Anaplastic Large-cell Lymphoma  129 Jianping Kong and Andrew L. Feldman Introduction 129 ­Epidemiology and Risk Factors  129 ­Disease Incidence and Prevalence  131 ­Basic Principles of Disease Biology  133 ­Management of Disease in the Front Line  134 ­Management of the Relapsed or Refractory Patient  137 ­Future Directions  138 Acknowledgement  140 Must Reads  140 References  140 11 Human T-cell Lymphotropic Virus Type 1 Positive Adult T-cell Leukemia/Lymphoma  145 Wataru Munakata and Kensei Tobinai ­Epidemiology and Disease Incidence  145 ­Basic Principles of Disease Biology  145 ­CCR4 and Adult T-cell Leukemia/Lymphoma  146 ­Clinical Features of Adult T-cell Leukemia/Lymphoma  146 ­Prognosis and Prognostic Index of ATLL  147 ­Front-line Management of Aggressive Adult T-cell Leukemia/Lymphoma  149 Chemotherapy and Hematopoietic Stem-cell Transplantation  149 Mogamulizumab with Dose-intensified Chemotherapy  150 Interferon alpha and Antiretroviral Agents  151 Chemotherapy in Transplant-ineligible Patients with Aggressive   Adult T-cell Leukemia/Lymphoma  151 ­Front-line Management of Indolent ATLL  152 ­Management of Relapsed or Refractory Patients  152 Mogamulizumab Monotherapy  152 Lenalidomide Monotherapy  153 Other Treatments for Relapsed or Refractory Adult T-cell Leukemia/Lymphoma  153 ­Future Directions  154 Must Reads  154 References  154 12 Natural Killer/T-cell Lymphomas  159 Seok Jin Kim, Ritsuro Suzuki, Arnaud Jaccard, Soon Thye Lim and Wong Seog Kim ­Introduction  159 Epidemiology and Risk Factors  161 Disease Incidence and Prevalence  161 Basic Principles of Disease Biology  161 Genetic Susceptibility to NK/T-Cell Lymphoma  161 Molecular Pathogenesis  162

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JAK–STAT and Associated Pathways  162 Nuclear Factor Kappa B and Other Deregulated Pathways  163 The Programmed Cell Death 1/Programmed Death Ligand 1 Pathway  163 ­Management of Newly Diagnosed Treatment-naïve Patients  163 Diagnosis and Initial Assessment  164 Monitoring the Response  165 Treatment Strategies  165 Localized Disease  165 Disseminated Disease  167 ­Consolidation Treatment with Hematopoietic Stem-cell Transplantation  167 ­Management of Relapsed or Refractory Disease  167 Treatment of Localized Nasal Relapse  167 Treatment of a Systemic Relapse  167 Novel Agents for Relapsed or Refractory ENKTL  168 ­Future Directions  168 Must Reads  168 References  169 13 T-Prolymphocytic Leukemia  175 Dima El-Sharkawi and Claire Dearden ­Introduction  175 Incidence  175 Clinical Features  175 Laboratory Findings  175 Treatment  176 Stem-cell Transplantation  178 Treatment for Relapsed/Refractory Disease  178 Future Directions  178 Must Reads  179 References  179 14 Large Granular Lymphocyte Leukemia  183 Karolina H. Dziewulska, Katharine B. Moosic, HeeJin Cheon, Kristine C. Olson, David J. Feith and Thomas P. Loughran, Jr ­Introduction  183 ­Epidemiology and Risk Factors  183 ­Prevalence of Concomitant Disorders  184 Autoimmune Diseases  184 Hematological Disorders  184 ­Basic Principles of Disease Biology  185 Biology  185 STAT3 Dysregulation  185 STAT3 and Common Cytopenias  186 JAK–STAT Pathway  187 Other Mutated and Dysregulated Pathways  187 Chronic Activation and Large Granular Lymphocyte Clonal Malignancy  188 STAT3 and Clonality  188 Antigenic Stimulation  188 Immune System Dysregulation  189 Cytotoxic Killer Cells and Autoimmunity  189 Humoral Abnormalities  189 Abnormal Bone Marrow  190 Neutropenia and Rheumatoid Arthritis  190 Spleen Pathology  191

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­Management of Disease in the Front Line  191 Diagnosis  191 Prognosis  191 Current Treatments  192 Indications for Treatment  192 Evaluation of Treatment Response  192 Therapeutic Approach  192 Canonical Immunosuppressive Treatments  192 Non-canonical Immunosuppressive Treatments  193 Supportive Therapy  194 Summary of Therapeutic Recommendations  194 ­Management of Relapsed or Refractory Disease  194 ­Future Directions  194 JAK–STAT Pathway Targeting  194 Natural Compounds  196 Other Candidate Agents  196 ­Funding  196 Disclosures  197 Must Reads  197 References  197 15 Gamma–Delta T-cell Lymphomas  203 Francine Foss, Aadil Ahmed and Mina Xu ­Introduction  203 ­Epidemiology and Risk Factors  203 ­Biology of Primary Cutaneous Gamma–Delta T-cell Lymphoma  204 Management of Disease in the Front Line  206 Management of Relapsed/Refractory Disease  208 Must Reads  209 References  209 16 Enteropathy-Associated and Monomorphic Epitheliotropic Intestinal T-cell Lymphomas  211 Craig R. Soderquist, Jennifer Shingleton, Sandeep Dave and Govind Bhagat ­Introduction  211 ­Enteropathy-associated T-cell Lymphoma  211 Epidemiology and Risk Factors  211 Disease Incidence and Prevalence  212 Basic Principles of Disease Biology  212 Morphology and Immunophenotype  212 Molecular and Genetic Alterations  212 Management of Patients in the Front Line  213 Management of the Relapsed or Refractory Patient  214 Future Directions  214 ­Refractory Celiac Disease  214 Disease Definition, Risk Factors, Incidence, and Prevalence  214 Basic Principles of Disease Biology  214 Morphology and Immunophenotype  214 Molecular and Genetic Alterations  215 Management of Patients in the Front-Line  216 Management of the Relapsed or Refractory Patient  216 Future Directions  216 ­Monomorphic Epitheliotropic Intestinal T-Cell Lymphoma  216

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Disease Risk Factors, Incidence, and Prevalence  216 Basic Principles of Disease Biology  216 Morphology and Immunophenotype  216 Molecular and Genetic Alterations  218 Management of Disease in the Front Line  218 Management of Relapsed or Refractory Disease  218 Future Directions  218 Must Reads  218 References  219 17 Hepatosplenic T-cell Lymphomas  225 Robert N. Stuver, Mwanasha Merrill and Salvia Jain ­Epidemiology and Disease Incidence  225 ­Basic Principles of Disease Biology  227 ­Clinical Features  227 ­Management of Disease in the Front Line  228 ­Management of the Relapsed or Refractory Disease  229 ­Splenectomy  230 ­Future Directions  230 ­Funding  231 Must Reads  231 References  231 18 Cutaneous T-cell Lymphoma  235 Alejandro A. Gru, Bethanie Rooke, Kevin Molloy and Julia Scarisbrick ­Introduction  235 ­Epidemiology and Risk Factors  236 ­Basic Principles of Disease Biology  237 ­Clinical, Pathologic, and Immunophenotypic Findings  240 ­Management of Front-Line Mycosis Fungoides/Sézary Syndrome  247 Early-stage Disease (Stages IA–IIA)  248 Late-stage Disease (Stage IIB–IVA2)  250 Stage IIB (Tumor-stage Disease)  250 Stage III–IVA1 Disease (Erythrodermic Disease and Sézary)  250 Stage IVA2–IVB Disease  250 ­Management of Relapsed or Refractory Disease with Mycosis Fungoides/Sézary Syndrome  250 Early-stage Disease (Stage IA–IIA)  250 Late-stage Disease (IIB–IVA2)  251 Stage IIB (Tumor-stage Disease)  251 Stage III–IVA1 (Erythrodermic Disease)  251 Stage IVA2–IVB Disease  252 ­Front-Line Management of Non-mycosis Fungoides Cutaneous T-cell Lymphomas  252 ­Management of Relapsed or Refractory Non-mycosis Fungoides Cutaneous T-cell Lymphomas  252 ­Future Directions  252 Must Reads  253 References  253 19 Other Rare Subtypes of Peripheral T-cell Lymphoma  259 Pier Paolo Piccaluga ­Introduction  259 ­Chronic Lymphoproliferative Disorders of Natural Killer Cells  259 Epidemiology and Risk Factors  259 Disease Incidence and Prevalence  259

Contents

Basic Principles of Disease Biology  260 Management of Front-line Disease  260 ­Epstein–Barr Virus-associated T-cell and NK-cell Lymphoproliferative Disorders of Childhood  260 Systemic Epstein–Barr Virus-positive T-cell Lymphoma of Childhood  260 Epidemiology and Risk Factors  260 Basic Principles of Disease Biology  260 Management of Front-Line Disease  261 Chronic Active Epstein–Barr Virus Infection of T- and NK-cell Type, Systemic Form  261 Epidemiology and Risk Factors  261 Basic Principles of Disease Biology  261 Management of Front-Line Disease  262 Chronic Active Epstein–Barr Virus Infection of T- and NK-cell Type, Cutaneous Form  264 Hydroa Vacciniforme-like Lymphoproliferative Disorder  264 Basic Principles of Disease Biology  264 Management of Disease in the Front Line  264 Severe Mosquito Bite Allergy  265 Epidemiology and Risk Factors  265 Basic Principles of Disease Biology  265 Management of Disease in the Front-Line  265 ­Future Directions  265 Must Reads  265 References  266 Part IV  Treatment of the PTCL  269 20 Standard Front-line Therapies  271 Raphael Koch and Lorenz Truempe ­Introduction  271 ­Initial Workup and Risk Stratification  271 ­Front-line Therapy  274 Front-line Treatment Approaches for Common Subtypes  274 Systemic Anaplastic Large-cell Lymphomas  276 Breast Implant-associated Anaplastic Large-cell Lymphomas  277 Enteropathy-associated T-cell Lymphoma and Monomorphic Epitheliotropic Intestinal   T-cell Lymphoma  277 Hepatosplenic T-cell Lymphoma  278 Extranodal natural killer/T-cell Lymphoma, Nasal Type  279 T-cell Prolymphocytic Leukemia  280 Adult T-Cell Leukemia/Lymphoma  280 Must Reads  281 References  281 21 Approved Agents in the Relapsed or Refractory Setting, Excluding Brentuximab Vedotin  287 Helen Ma and Owen A. O’Connor Introduction  287­ Challenges in Developing New Drugs in Peripheral T-cell Lymphomas  288 ­Drugs Approved by the US Food and Drug Administration with an Indication in   Relapsed/Refractory Peripheral T-cell Lymphoma  288 Pralatrexate  289 Pharmacology  289 Early-phase Data  289 Pivotal Data  289 Recent Developments  291

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Histone Deacetylase Inhibitors (Including Romidepsin and Belinostat)  291 Pharmacology  291 Early Phase Data  292 Pivotal Data  292 Recent Developments  293 ­Drugs Approved by the US Food and Drug Administration But Without An Indication in Relapsed/Refractory Peripheral T-cell Lymphoma  294 Etoposide  294 Pharmacology  294 Clinical Experiences in Peripheral T-cell Lymphoma  294 Summary  294 Bortezomib  294 Pharmacology  294 Clinical Experiences in Peripheral T-cell Lymphoma  296 Recent Developments  296 Bendamustine  296 Pharmacology  296 Clinical Experience in Peripheral T-cell Lymphoma  296 Recent Developments  296 Gemcitabine  296 Pharmacology  296 Clinical Data  297 Recent Developments  297 ­Drugs Approved by International Regulatory Agencies, Not Including the United States, that Carry an Indication in Relapsed/Refractory Peripheral T-cell Lymphoma  297 Chidamide  297 Pharmacology  297 Early Phase Data  297 Pivotal Data  297 Recent Developments  297 Forodesine  297 Pharmacology  297 Early Phase Data  297 Pivotal Data  298 Recent Developments  298 Considerations in the Selection of Therapy  298 Treatment Goals  298 Aggressive Versus Indolent Disease  299 Transplant Eligible or Ineligible  299 Suitability for Chemotherapy  299 ­Conclusion  299 Must Reads  299 References  300 22 The Role of Autologous Stem-cell Transplantation in Peripheral T-cell Lymphomas  305 Juan Alejandro Ospina-Idárraga, Rolando Humberto Martinez-Cordero, Leonardo José Enciso-Olivera and Henry Idrobo-Quintero ­Introduction  305 ­Autologous Stem-cell Transplantation in First Complete Remission  306 ­Autologous Stem-cell Transplantation in Relapsed/Refractory Disease  307

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I­ nterpretation of Available Literature  307 ­Identifying the Most Relevant Determinants for Survival among Patients with Peripheral   T-cell Lymphoma Undergoing Autologous Stem-cell Transplantation  308 ­Status of Response Prior to Autologous Stem-cell Transplantation  309 ­Risk of Stage  310 ­Number of Prior Therapies and Refractory Disease  311 ­Autologous Stem-cell Transplantation on Specific Subtypes of Peripheral   T-cell Lymphoma  311 Peripheral T-cell Lymphomas Not Otherwise Specified  311 Angioimmunoblastic T Cell Lymphoma  312 Anaplastic T Large-cell Lymphoma  312 Extranodal Natural Killer/T-cell Lymphoma, Nasal Type  313 The Role of Autologous Stem-cell Transplantation in   Cutaneous T-cell Lymphomas  314 Must Reads  314 References  315 23 Allogeneic Stem-cell Transplantation  319 Anna Dodero and Paolo Corradini ­Introduction  319 ­Allogeneic Stem-cell Transplantation for Relapsed and   Refractory Disease (Focus on Nodal Hystotypes)  320 ­Allogeneic Stem-cell Transplantation as Consolidation of First Remission  322 ­Allogeneic Stem-cell Transplantation in Specific Subtypes  322 Cutaneous T-cell Lymphomas  322 Hepatosplenic T-cell Lymphomas  324 Extranodal Natural Killer/T-cell Lymphomas, Nasal Type  324 Adult T-cell Leukemia/Lymphoma  324 ­Future Directions  325 Must Reads  325 References  325 24 Emerging Immunotherapy Approaches in Peripheral T-cell Lymphomas  329 Barbara Pro and Andrei Shustov ­Introduction  329 ­Monoclonal Antibody Therapy  329 Alemtuzumab  330 Mogamulizumab  330 ­Immunoconjugate-Based Therapy for Peripheral T-Cell Lymphoma  331 Brentuximab Vedotin  332 ­Cell-Mediated or Cellular Immunotherapy in Peripheral T-Cell Lymphoma  333 PD1–PD-L1 Checkpoint Inhibition  334 AFM13 – Targeted Natural Killer Cell Immunotherapy Facilitator  335 TTI-621 – Targeted Macrophage Immunotherapy Facilitator  335 4-1BB – Enabled Adoptive Therapy of Epstein–Barr Virus-Positive Malignancies  335 IPH4102 (Anti-KIR3DL2 Monoclonal Antibody)  336 Chimeric Antigen Receptor T-cell Therapy for Peripheral T-cell Lymphoma  336 ­Challenges and Future Directions  336 Must Reads  337 References  338

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25 Emerging New Small Molecules in Peripheral T-cell Lymphomas  343 Alessandro Broccoli and Pier Luigi Zinzani ­Introduction  343 ­Demethylating Agents  344 ­Janus-associated Kinase–Signal Transducers and Activators of   Transcription and Spleen Tyrosine Kinase Inhibitors  345 ­Phosphatidylinositol 3-Kinase Inhibitors  345 ­Miscellaneous  347 Pro-apoptotic Small Molecules  347 Farnesyltransferase Inhibitors  347 Aurora Kinase Inhibitors  347 ­Conclusion  348 Must Reads  348 References  348 Part V  Future Directions  351 26 The Value and Relevance of T-cell Lymphoma Registries  353 Tetiana Skrypets, Martina Manni, Monica Civallero, Iryna Kriachok and Massimo Federico ­Introduction  353 ­Population-based Cancer Registries  353 ­Retrospective Studies  355 ­T-cell Lymphoma Registries  360 T-cell Project 1.0  360 COMPLETE  363 T-cell Project 2.0  363 ­Future Directions  364 ­Disclosures  364 Must Reads  364 References  365 27 Innovative Chemotherapy-free Approaches for the Treatment of Peripheral T-Cell Lymphoma  367 Enrica Marchi, Ahmed Sawas, Helen Ma, Luigi Scotto and Francesca Montanari Introduction  367 ­Targeting the Peripheral T-cell Lymphoma Epigenome  369 ­Romidepsin Plus Pralatrexate  370 Preclinical Rationale  370 Clinical Experience  370 ­Romidepsin Plus 5-Azacytidine  371 Preclinical Rationale  371 Clinical Experience  371 ­Romidepsin Plus Duvelisib  372 Preclinical Rationale  372 Clinical Experience  372 ­Romidepsin Plus Lenalidomide  373 Preclinical Rationale  373 Clinical Experience  373 ­Panobinostat and Bortezomib  373 Preclinical Rationale  373 Clinical Experience  374 ­A Glance at the Future: Building on the Active Doublets  374 Must Reads  375 References  375

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28 Global Collaborations  379 Dejan Radjeski, Eliza Hawke, Owen A. O’Connor, Pier Luigi Zinzani, Won Seog Kim and Enrica Marchi ­Introduction  379 ­The Global T-cell Lymphoma Consortium  380 The Mission  380 Structure  380 Organizational Features  380 Submission of Trial Concepts  381 Budget Negotiations  382 Institutional Review Board  383 Publications  383 ­Conclusion  384 Index  385

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Contributors Aadil Ahmed Department of Hematology, Yale University School of Medicine, New Haven, CT, USA Stephen M. Ansell Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, MN, USA James O. Armitage Division of Oncology-Hematology, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, USA N. Nora Bennani Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, MN, USA Govind Bhagat Division of Hematopathology, Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY, USA

Sandeep Dave Duke Cancer Institute, Center for Genomic and Computational Biology, Duke University, Durham, NC, USA Laurence de Leval Institut de Pathologie, Centre Hospitalier Universitaire Vaudois et Université de Lausanne, Lausanne, Switzerland Claire Dearden Department of Haematology, The Royal Marsden NHS Foundation Trust, Sutton, UK Anna Dodero Fondazione IRCCS istituto Nazionale dei Tumori, Milano, Italy; and University of Milano, Italy Jehan Dupuis Lymphoid Malignancies Unit, Henri Mondor University Hospital, Créteil, France

Alessandro Broccoli IRCCS Azienda Ospedaliero-Universitaria di Bologna Istituto di Ematologia “Seràgnoli”, Dipartimento di Medicina Specialistica, Diagnostica e Sperimentale Università degli Studi, Bologna, Italia

Karolina H. Dziewulska Department of Medicine and Department of Pathology, Division of Hematology and Oncology, University of Virginia Cancer Center, Charlottesville, VA, USA

HeeJin Cheon Department of Medicine & Biochemistry and Molecular Genetics, Division of Hematology and Oncology, University of Virginia Cancer Center, Charlottesville, VA, USA

Dima El-Sharkawi Department of Haematology, The Royal Marsden NHS Foundation Trust, Sutton, UK

Monica Civallero Department of Surgical, Medical and Dental Sciences Related to Transplant, Oncology and Regenerative Medicine, University of Modena and Reggio Emilia, Reggio Emilia, Italy Paolo Corradini Fondazione IRCCS istituto Nazionale dei Tumori, Milano, Italy; and University of Milano, Italy

Leonardo José Enciso-Olivera Programa de Investigación e Innovación en Leucemias Agudas y Crónicas (PILAC) Instituto Nacional de Cancerología, Bogotá, Colombia Massimo Federico Department of Surgical, Medical and Dental Sciences Related to Transplant, Oncology and Regenerative Medicine, University of Modena and Reggio Emilia, Reggio Emilia, Italy

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Contributors

David J. Feith Department of Medicine, Division of Hematology and Oncology, University of Virginia Cancer Center, Charlottesville, VA, USA Andrew L. Feldman Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA Francine Foss Department of Hematology, Yale University School of Medicine, New Haven, CT, USA Philippe Gaulard Assistance Publique des Hôpitaux de Paris, Paris, France; Institut Mondor de Recherche Biomédicale, INSERMU955, Université Paris Est Créteil, Créteil, France; and Département de Pathologie, Hôpitaux Universitaires Henri Mondor, Créteil, France Alejandro A. Gru Department of Pathology and Dermatology, University of Virginia, Charlottesville, VA, USA Sean Harrop Epworth Healthcare and Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia

Elaine S. Jaffe Hematopathology Section, Laboratory of Pathology, Center for Cancer Research, NCI, Bethesda, MD, USA Salvia Jain Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA, and Harvard Medical School, Boston, MA, USA Avyakta Kallam Division of Oncology-Hematology, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, USA Seok Jin Kim Division of Hematology and Oncology, Sungkyunkwan University School of Medicine, Samsung Medical Center, Seoul, Korea Won Seog Kim Division of Hematology and Oncology, Sungkyunkwan University School of Medicine, Samsung Medical Center, Seoul, Korea

Keiichiro Hattori Department of Hematology, Faculty of Medicine, University of Tsukuba Hospital, Tsukuba, Japan

Raphael Koch Department of Hematology and Medical Oncology, University Medical Center Goettingen, Goettingen, Germany

Eliza Hawke Department of Oncology and Clinical Haematology, Austin Health, Heidelberg, Victoria, Australia

Jianping Kong Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA

Tyler A. Herek Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, USA Henry Idrobo-Quintero Grupo Latinoamericano de estudio de Linfoproliferativos (GELL) Hospital Universitario del Valle, Grupo Ospedale, Universidad del Valle, Universidad Libre, Cali, Colombia. Javeed Iqbal Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, USA Arnaud Jaccard Service d’Hématologie et de Thérapie Cellulaire, Hôpital Dupuytren, CHU de Limoges, Limoges, France

Iryna Kriachok Oncohematology Department, National Cancer Institute, Kyiv, Ukraine Manabu Kusakabe Department of Hematology, Faculty of Medicine, University of Tsukuba Hospital, Tsukuba, Japan, and Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Japan François Lemonnier Unité hémopathies Lymphoïdes, Hôpitaux Universitaires Henri Mondor, Créteil, France; Assistance Publique des Hôpitaux de Paris, Paris, France; and Institut Mondor de Recherche Biomédicale, INSERMU955, Université Paris Est Créteil, Créteil, France

Contributors

Soon Thye Lim Division of Medical Oncology, National Cancer Centre Singapore, Singapore, Singapore Thomas P. Loughran, Jr Department of Medicine, Division of Hematology and Oncology, University of Virginia Cancer Center, Charlottesville, VA, USA Helen Ma Department of Medicine, Division of Hematology and Oncology, Center for Lymphoid Malignancies, Columbia University Medical Center, New York, NY, USA Martina Manni Department of Surgical, Medical and Dental Sciences Related to Transplant, Oncology and Regenerative Medicine, University of Modena and Reggio Emilia, Reggio Emilia, Italy

Owen A. O’Connor Department of Medicine, Division of Hematology and Oncology, University of Virginia Cancer Center, Charlottesville, VA, USA, and Program for T-Cell Lymphoma Research, Department of Microbiology, Immunology and Cancer Research University of Virginia Cancer Center, Charlottesville, VA, USA Kristine C. Olson Department of Medicine, Division of Hematology and Oncology, University of Virginia Cancer Center, Charlottesville, VA, USA Juan Alejandro Ospina-Idárraga Los Cobos Medical Center, Instituto Nacional de Cancerología, Universidad El Bosque, Bogotá, Colombia Neval Ozkaya Hematopathology Section, Laboratory of Pathology, Center for Cancer Research, NCI, Bethesda, MD, USA

Enrica Marchi University of Virginia Cancer Center, Charlottesville, VA, USA

Pier Paolo Piccaluga Department of Experimental, Diagnostic, and Specialty Medicine, Bologna University School of Medicine, Bologna, Italy

Rolando Humberto Martinez-Cordero Instituto Nacional de Cancerología, Universidad El Bosque, Bogotá, Colombia

Stefano A. Pileri Hematopathology Division, European Institute of Oncology, IRCCS, Milan, Italy

Mwanasha Merrill Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA

H. Miles Prince Epworth Healthcare and Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Victoria, Australia

Kevin Molloy Department of Dermatology, University Hospital, Birmingham, UK Francesca Montanari Center for Lymphoid Malignancies, Columbia University Medical Center, New York, NY, USA Katharine B. Moosic Department of Medicine and Department of Pathology, Division of Hematology and Oncology, University of Virginia Cancer Center, Charlottesville, VA, USA Franck Morschhauser Department of Hematology, Lille University Hospital, Lille, France Wataru Munakata Department of Hematology, National Cancer Center Hospital, Tokyo, Japan

Barbara Pro Division of Hematology and Oncology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA, and Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL, USA Dejan Radjeski Sir Charles Gardner Hospital, Perth, Western Australia, Australia Bethanie Rooke Department of Dermatology, University Hospital, Birmingham, UK Tatsuhiro Sakamoto Department of Hematology, Faculty of Medicine, University of Tsukuba Hospital, Tsukuba, Japan, and Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Japan

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xxii

Contributors

Mamiko Sakata-Yanagimoto Department of Hematology, Faculty of Medicine, University of Tsukuba Hospital, Tsukuba, Japan, and Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Japan Ahmed Sawas Center for Lymphoid Malignancies, Columbia University Medical Center, New York, NY, USA Julia Scarisbrick Department of Dermatology, University Hospital, Birmingham, UK Luigi Scotto Center for Lymphoid Malignancies, Columbia University Medical Center, New York, NY, USA Jennifer Shingleton Duke Cancer Institute, Center for Genomic and Computational Biology, Duke University, Durham, NC, USA Raksha Shrestha Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Japan Andrei Shustov Division of Hematology, Department of Medicine, University of Washington, Seattle, WA, USA; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA; and Seattle Cancer Care Alliance, Seattle, WA, USA Tetiana Skrypets Department of Surgical, Medical and Dental Sciences Related to Transplant, Oncology and Regenerative Medicine, University of Modena and Reggio Emilia, Reggio Emilia, Italy Craig R. Soderquist Division of Hematopathology, Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY, USA Robert N. Stuver Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA

Ritsuro Suzuki Department of Oncology and Hematology, Shimane University Hospital, Izumo, Japan Kensei Tobinai Department of Hematology, National Cancer Center Hospital, Tokyo, Japan Claudio Tripodo Tumor Immunology Unit, Department of Health Sciences, University of Palermo, Palermo, Italy, and Histopathology Unit, FIRC Institute of Molecular Oncology, Milan, Italy Lorenz Truempe Department of Hematology and Medical Oncology, University Medical Center Goettingen, Goettingen, Germany Sean Whittaker Guy’s and St Thomas’ National Health Service Foundation Trust, London, UK Mina Xu Department Pathology, Yale University School of Medicine, New Haven, CT, USA Amulya Yellala Division of Oncology-Hematology, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, USA Anas Younes Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA Jasmine Zain Department of Hematology/Hematopoietic Cell Transplantation, City of Hope Medical Center, Duarte, CA, USA Pier Luigi Zinzani IRCCS Azienda Ospedaliero-Universitaria di Bologna Istituto di Ematologia “Seràgnoli”, Dipartimento di Medicina Specialistica, Diagnostica e Sperimentale Università degli Studi, Bologna, Italia

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1

Part I Biological Basis of the Peripheral T-cell Lymphomas

3

1 The Fundamentals of T-cell Lymphocyte Biology Claudio Tripodo1,2 and Stefano A. Pileri3 1

Tumor Immunology Unit, Department of Health Sciences, University of Palermo, Palermo, Italy Histopathology Unit, FIRC Institute of Molecular Oncology, Milan, Italy 3 Hematopathology Division, European Institute of Oncology, IRCCS, Milan, Italy 2

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The natural diversity of T cells in normal immune system functions contributes  –  in part  –  to the diversity of T-cell malignancies. CD4-positive T lymphocytes, also called T helper (Th) cells, are divided into a diverse repertoire of T lymphocytes (e.g. Th1, Th2, and Th17), in part defined by the cytokine profile they elaborate.

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Th1 and Th2 lymphocytes can also be classified based on the expression of the transcription factors T-bet and GATA3. These ­factors can be prognostic in peripheral T-cell non-Hodgkin lymphomas derived from these cells (with GATA3 being associated with a poor prognosis).

­Introduction The T-cell system is conventionally regarded as an enabler of diverse compartments, which correspond to different steps of differentiation and functional subsets of mature cells taking part in the immune response in the peripheral lymphoid and non-lymphoid tissues. In this chapter, we give a overview of the T-cell system, more functionally than anatomically oriented, to reflect its extreme plasticity. This plasticity is thought to lie at the heart of the diversity of T-cell malignancies now recognized by the World Health Organization.

­ eneral View of the Differentiation G and Function of T Lymphocytes The immune system can be classified into two basic component: (i) the innate immune system, and (ii) the acquired immune system. The innate immune system is considered to be relatively agnostic to any specific antigen, and is often described as invariant. The innate immune response is the first line of defense, and typically exhibits limited specificity. Examples of innate immune response may include

phagocytosis by macrophages, barriers to infection ­provided by the skin and tears, natural killer and mast cells, and complement-mediated cytolysis. In contrast, the adaptive (or sometimes called acquired) immune response develops in response to specific antigen, being “custom” designed for the antigen in question. It usually occurs later in the immune response, and has the ability to recall the response to past infections. Components of a functioning acquired immune response might involve antigen-presenting cells presenting antigen or T cells, the activation of specific T cells which would signal to B cells enlisting their engagement in the response and the production of highly specific antibody capable of binding specific antigen. T and B lymphocytes are the major types of lymphocytes found in the human body, where they can constitute 20–40% of all white blood cells, with only about 2–3% being found in the peripheral circulation, the remainder being localized to various lymphoid organs (lymph nodes, spleen, submucosal tissue). Remarkably, the total mass of lymphocytes in the body can approximate the mass of the brain and liver. As shown in Figure 1.1 [1], T lymphocytes arise from a bone marrow precursor, which undergoes maturation and

The Peripheral T-Cell Lymphomas, First Edition. Edited by Owen A. O’Connor, Won Seog Kim and Pier Luigi Zinzani. © 2021 John Wiley & Sons Ltd. Published 2021 by John Wiley & Sons Ltd. Companion website: www.wiley.com/go/OConnor/Peripheral_T-cell_Lymphomas

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1  The Fundamentals of T-cell Lymphocyte Biology BM

Thymus

Peripheral Lymphoid Tissue

Th1

T-reg Follicular T-helper

Pre-thymocyte

Subcapsular thymocyte

CD4

CD4

CD4

Medullary thymocyte

Naïve Peripheral T-cell

Peripheral Antigen

Th17

Th2

Cortical thymocyte

CD8

CD8

γ/δ

CD8

Memory

Effector

Figure 1.1  Schematic overview of T-cell ontogeny and differentiative trajectories. Source: Claudio Tripodo, Stefano Pilleri.

functional orientation in the thymus. Antigen-specific T cells mature in the thymic cortex, where the elements recognizing self-peptides and major histocompatibility antigens expressed by cortical epithelial cells and thymic nurse cells are eliminated via apoptosis. Failure to eliminate those T cells recognizing self-peptides is thought to give rise to a host of autoimmune disorders. Cortical thymocytes exhibit an immature T-cell phenotype and express a characteristic repertoire of proteins including TdT, CD1a, CD3, CD5, and CD7. CD3 is expressed in the cytoplasm until completion of T-cell receptor (TCR) gene rearrangement and is then exported to the cell membrane. Cortical thymocytes are initially CD4/CD8 double negative. Medullary thymocytes exhibit a phenotype similar to that of mature T cells of the peripheral lymphoid organs with segregation of CD4 and CD8 antigens. Based on the structure of the variable portion of the TCR, T cells have been divided into two classes, including alpha/beta and gamma/delta T cells. They are both associated with the CD3 complex, which contains gamma, delta, and epsilon chains. Gamma and delta T cells usually lack expression of CD4, CD8, and CD5, although a subpopulation can expresses CD8. They represent less than 5% of normal T lymphocytes and are primarily located in the splenic red pulp, intestinal epithelium, and other epithelial sites. They also have a restricted range of antigen recognition and take part in the innate immune reaction, serving as a first line of defense against bacterial peptides. They are often involved in responses to mycobacterial infections and in mucosal

immunity. T lymphocytes of the adaptive immune system, which are heterogeneous and functionally complex, include naïve, effector (regulatory and cytotoxic), and memory T cells. CD4+ T cells are primarily regulatory in nature. Based on their cytokine secretion profiles, they are divided into two major types: T helper (Th) 1 cells and Th2 cells. Th1 cells secrete interleukin (IL) 2 and interferon gamma, while Th2 cells secrete IL4, IL5, IL6, and IL10. Th1 cells provide help mainly to other T cells and macrophages, whereas Th2 cells provide help mainly to B cells in antibody production. CD4+ T cells can both help and suppress immune responses and consist of multiple subpopulations. Recent studies have shown overexpression of the transcription factors TBX21 (also known as T-bet) and GATA3 in Th1 and Th2 lymphocytes, respectively. T regulatory (Treg) cells suppress immune responses to cancer and limit inflammatory responses in tissues. These CD4-positive cells, which are thought to play an important role in preventing autoimmunity, express a high density CD25 and the transcription factor FOXP3. Th17 lymphocytes correspond to a subset of CD4+ effector T cells, characterized by expression of the IL17 family of cytokines, and play a role in immune-mediated inflammatory diseases and other conditions. Recently, there has been a rapidly evolving literature around a unique CD4+ T-cell subset that takes part in the natural functions of normal germinal centers. These cells, called T follicular helper (Tfh) cells, support B cells in the context of the germinal center reaction. They reveal a distinctive phenotype with expression

­The T-cell System as a Frame for Peripheral T-cell Lymphoma: Taking Plasticity into Accoun  5

of the germinal center markers BCL6 and CD10 together with CD57, ICOS and CD279/PD1 and produce the chemokine CXCL13 as well as its receptor CXCR5. CXCL13 causes proliferation of follicular dendritic cells and facilitates the migration of B and T lymphocytes expressing CXCR5 into the germinal center.

­ he T-cell System as a Frame T for Peripheral T-cell Lymphoma: Taking Plasticity into Account The mature T-cell system consists of different subsets of lymphoid T cells variably trafficking between peripheral blood, lymphoid, and peripheral tissues. These cells display diversified functional phenotypes, participating in immune responses as effectors or though the orchestration of other immune cellular and non-cellular contributors. This gross distinction also implies that one major branch of the T-cell functional differentiation tree displays transcriptional and synthetic machineries allowing cytotoxic effector functions, including for example EOMES transcription factor expression, granzymes, perforins, and key proinflammatory cytokines such as TNFα and interferon gamma (IFN-γ). Another major branch is strictly bound, in its activity, to microenvironmental clues of the immune contexture. In this regard, the described differentiated phenotypes of CD4+ Th-cell subsets are known to include Th1 and Th2 clusters identified by the activity of T-bet and GATA3 transcription factors [2]; the Th17 and Th22 clusters driven by RORC1 transcriptional regulation  [3, 4]; the FOXO1 and interferon regulatory factor 4 (IRF4) controlled Th9 cluster [5]; the Tfh cluster, which is dependent upon BCL6 and TOX2 activity [6], and the regulatory T-cell cluster associated with FOXP3 [7]. This repertoire of discrete and differentiated cells imparts a considerable degree of plasticity to the immune system, enabling it to respond potently with high selectivity. Th subsets of CD4 positive cells are defined by the activity of selected transcription factors, including diversified signal transducers and activators of transcription (STAT) family members, whose signaling and preferential synthesis of specific cytokines, may respond to polarizing stimuli from the surrounding environment by reshaping their phenotypic differentiation, eventually undergoing conversion to a different functional subset  [8, 9]. Specific cytokines that characterize most of the pathogen-associated or sterile inflammatory responses, such as IL6, TNFα, and IL12 may drive Th cell polarization toward Th1 (STAT4-dominant), Tfh, Th17, or Th22 fates (all three STAT3-dominant), according to their relative abundance and association with

other regulatory cytokines such as IL1b, IL21, and IL23 [8]. Similarly, the pleiotropic cytokine transforming growth factor beta is involved in the induction and/or conversion of Treg (STAT5-dominant), Th2 and Th9 (both STAT6dominant) in combination with other polarizing cytokines such as IL2 and IL4 [8]. With this background, the predominant functional polarization of T cells within a specific immune context is fated to change according to the timing of the response and to the establishment of different immune/stroma interfaces. In this setting, a notable example is represented by the induction of tertiary lymphoid structures in tissues of patients with autoimmune diseases or cancer. In this context, the polarization of programmed cell death 1 receptor-positive (PD1+) Tfh cells from adaptive or tissue-resident innate-like T cells [10] is entwined with the formation of a follicular dendritic cell network from vessel-associated mesenchymal stromal cells (Figure 1.2) [11]. This process leads to the establishment of a specialized stroma-T-cell interface that may be either aberrantly expanded or variably disrupted in different lymphoma subtypes related to the germinal center, such as is seen with angioimmunoblastic T-cell lymphoma [12], and the follicular lymphomas [13], respectively. Besides primary polarization and conversion dictated by the cytokine milieu and stromal micro niches, an emerging role for TCR specificity in determining fate specification of tissue-resident T cells at sites of persistent antigenic challenge, such as the intestinal lamina propria, is emerging [14]. Clonal TCR rearrangements of peripheral FOXP3+ Treg (pTreg) promote the generation of distinct pTreg CD4 intraepithelial T-cell phenotypes, which show comparable dependence on microbiota-derived antigenic stimuli and different reliance on intraclonal competition. Intraclonal competition driven by TCR-antigen signaling is a limiting factor in natural and pTreg development, with low clonal precursor frequencies being required for their generation [15]. The specific issue of intraclonal competition and “small niche” requirement as a potential determinant of T-cell subclones’ fate specification in the presence of self- and/or microbiota-derived antigenic represents a still unchallenged level of complexity in peripheral T-cell lymphoma (PTCL) research. In this regard, single-cell RNA sequencing (Sc-RNA-seq) provides a dramatically higher level of resolution of the developmental and functional heterogeneity of T-cell subsets, which is applicable to the PTCL setting. Sc-RNA-seq has provided reference maps for circulating and tissue-based T cells and their functional hierarchies  [16]. Among relevant transcriptional differences between peripheral blood and tissue-based T cells, cytoskeleton, cell–matrix interaction, and cell proliferation modules have emerged, underscoring the transcriptional

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1  The Fundamentals of T-cell Lymphocyte Biology

PD1

NGFR

CD146

CD23

Figure 1.2  Representative immunohistochemical staining for PD1 (upper left) and NGFR/CD271 (upper right) highlighting the presence of PD1+ T follicular helper cells and of a formed meshwork of follicular dendritic cells within a tertiary lymphoid follicle in a case of non-small-cell lung carcinoma. Immunohistochemical staining for CD146 (lower left) and CD23 (lower right) highlighting the early branching of perivascular CD146+ mesenchymal elements that partially display CD23 expression as a marker of follicular dendritic cell differentiation in the same non-small-cell lung carcinoma. Source: Claudio Tripodo, Stefano Pilleri.

imprint of tissue microenvironment. This information must be considered in the interpretation of gene expression profiling studies on PTCL, which have mostly relied on the differential comparison with normal T-cell subsets from peripheral blood and/or cell lines. Moreover, at the Sc-RNA-seq level, a clear dichotomy in the CD8+ effector T-cell cluster emerges as conserved across tissue sites, based on the predominance of cytotoxicity-related genes or cytokine and chemokine genes [16]. Tissue-conserved Sc-RNA-seq transcriptional clustering also identifies distinct Treg, CD4+ naïve/central memory resting and CD4+/CD8+ resting clusters, IFN response, and proliferation gene clusters characterizing different CD4+ T-cell activation states [16]. Interestingly, hallmarks of such transcriptional modules feature the concomitant expression of genes coding for transcription factors involved in divergent-fate specifications (e.g. FOXP3, IRF4, and TOX2), highlighting the dynamical regulation of promiscuous transcription factors [17, 18]. Again, this concept may represent a relevant note of caution in the interpretation of transcription factor expression data in PTCL clonal

populations as hallmarks of stable clone differentiative/ phenotypic states. The expression and activity of specific transcription factors involved in fate specification, such as T-bet and IRF4, is bound to that of the pleiotropic transcription factor MYC in enabling TCR-driven immune function through the regulation of T-cell proteomic and metabolic landscape [19]. MYC proficiency has been demonstrated to be required for adapting protein expression to TCR engagement in CD4+ and CD8+ cells. Through the regulation of amino acid transporter expression, MYC impacts on translational activity and on the associated increase of effector T-cell biomass (Figure  1.3)  [19], which relates with the higher Myc expression levels in CD8+ T cells. Moreover, upon T-cell activation, MYC controls lactate transporter expression, regulating the feedback on glycolytic flux fueling T-cell synthetic programs and proliferative attitude  [19]. In PTCL-NOS not otherwise specified, overexpression of MYC and its transcriptional targets involved in cell proliferation has been implicated in the worse prognosis of GATA3-positive cases [20]. Nevertheless,

 ­Reference Peri-tumoral Effector T cells

Intra-tumoral Effector T cells

CD8

CD8

Figure 1.3  The biomass of CD8+ effector T cells is dramatically different between peritumoral (left panel) and intratumoral (right panel) compartments of a high-grade carcinoma. Intra-tumoral CD8+ effectors corresponding to an activated state showing a larger size. Source: Claudio Tripodo, Stefano Pilleri.

in the light of the profound effects on the metabolic adaptation to TCR sensing, MYC may represent an underrated determinant of inter/intraclonal competition [21] underlying PTCL progression. This introductory chapter provides an updated view of the mature T-cell constellation, in a less static view, as compared with canonical ontogeny-focused outlines, providing information on the biological foundations of functional

plasticity, phenotypical heterogeneity, and transcriptional dynamics that are recapitulated and magnified in peripheral T-cell malignancies. It is imperative to recognize that the diversity, and complex function of normal T cells, is central to appreciating the many histologic and genetic subtypes of PTCL, and may aid in explaining the diverse behavior and presentation of these challenging and heterogeneous diseases.

Must Reads ●●

Litman, G.W., Cannon, J.P., and Dinshaw, L.J.. (2005). Reconstructing immune phylogeny: new perspectives. Nat Rev Immunol 5(11): 866–879.

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Restifo, N.P. and Gattinoni, L. (2013). Lineage relationship of effector and memory T-cell. Curr Opin Immunol 25(5): 556–563. Withers, D.R. (2016). Innate lymphoid cells regulation of adaptive immunity. Immunology 149(2): 123–130.

­References 1 Swerdlow, S.H., Campo, E., Harris, N.L. et al. (2017). WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. Revised 4e. Lyon: IARC. 2 Kanhere, A., Hertweck, A., Bhatia, U. et al. (2012). T-bet and GATA3 orchestrate Th1 and Th2 differentiation through lineage-specific targeting of distal regulatory elements. Nat Commun 3: 1268. 3 Yang, X.O., Pappu, B.P., Nurieva, R. et al. (2008). T helper 17 lineage differentiation is programmed by orphan nuclear receptors RORα and RORγ. Immunity 28 (1): 29–39.

4 Plank, M.W., Kaiko, G.E., Maltby, S. et al. (2017). Th22 cells form a distinct Th lineage from Th17 cells in vitro with unique transcriptional properties and Tbet-dependent Th1 plasticity. J Immunol 198 (5): 2182–2190. 5 Malik, S., Sadhu, S., Elesa, S. et al. (2017). Transcription factor Foxo1 is essential for IL-9 induction in T helper cells. Nat Commun 8 (1): 815. 6 Xu, W., Zhao, X., Wang, X. et al. (2019). The transcription factor Tox2 drives T follicular helper cell development via regulating chromatin accessibility. Immunity 51 (5): 826–839.

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7 Chen, W.J., Jin, W., Hardegen, N. et al. (2003). Conversion of peripheral CD4+CD25− naive T cells to CD4+CD25+ regulatory T cells by TGF-β induction of transcription factor Foxp3. J Exp Med 198 (12): 1875–1886. 8 Tripathi, S.K. and Lahesmaa, R. (2014). Transcriptional and epigenetic regulation of T-helper lineage specification. Immunol Rev 261 (1): 62–83. 9 Vahedi, G., Takahashi, H., Nakayamada, S. et al. (2012). STATs shape the active enhancer landscape of T cell populations. Cell 151 (5): 981–993. 10 Klose, C.S.N. and Artis, D. (2016). Innate lymphoid cells as regulators of immunity, inflammation and tissue homeostasis. Nat Immunol 17: 765–774. 11 Fousteri, G. and Zhu, J. (2018). T follicular helper-like cells in inflamed non-lymphoid tissues. Front Immunol 9: 1707. 12 Tripodo, C., Gri, G., and Piccaluga, P.P. (2010). Mast cells and Th17 cells contribute to the lymphoma-associated proinflammatory microenvironment of angioimmunoblastic T-cell lymphoma. Am J Pathol 117 (2): 792–802. 13 Pepe, G., Di Napoli, A., Cippitelli, C. et al. (2018). Reduced lymphotoxin-beta production by tumour cells is associated with loss of follicular dendritic cell phenotype and diffuse growth in follicular lymphoma. J Pathol 4 (2): 124–134. 14 Bilate, A.M., Bousbaine, D., Mesin, L. et al. (2016). Tissue-specific emergence of regulatory and intraepithelial T cells from a clonal T cell precursor. Sci Immunol 1 (2): eaaf7471.

15 Boutista, J.L., Lio, C.W.J., Lathrop, S.K. et al. (2009). Intraclonal competition limits the fate determination of regulatory T cells in the thymus. Nat Immunol 10: 610–617. 16 Szabo, P.A., Levitin, H.M., Miron, M. et al. (2019). Single-cell transcriptomics of human T cells reveals tissue and activation signatures in health and disease. Nat Commun 10 (1): 4706. 17 Miyao, T., Floess, S., Setoguchi, R. et al. (2020). Plasticity of Foxp3+ T cells reflects promiscuous Foxp3 expression in conventional T cells but not reprogramming of regulatory T cells. Immunity 36 (2): 262–275. 18 Trüb, M., Barr, T.A., Morrison, V.L. et al. (2017). Heterogeneity of phenotype and function reflects the multistage development of T follicular helper cells. Front Immunol 8: 489. 19 Marchingo, J.M., Sinclair, L.V., Howden, A.J.M., and Cantrell, D.A. (2020). Quantitative analysis of how Myc controls T cell proteomes and metabolic pathways during T cell activation. eLife 9: e53725. 20 Manso, R., Bellas, C., Martín-Acosta, P. et al. (2016). C-MYC is related to GATA3 expression and associated with poor prognosis in nodal peripheral t-cell lymphomas. Haematologica 101: e336–e338. 21 Levayer, R., Hauert, B., and Moreno, E. (2015). Cell mixing induced by myc is required for competitive tissue invasion and destruction. Nature 524: 476–480.

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2 Mechanisms of T-cell Lymphomagenesis François Lemonnier1,2,3, Philippe Gaulard2,3,4 and Laurence de Leval5 1

Unité hémopathies Lymphoïdes, Hôpitaux Universitaires Henri Mondor, Créteil, France Assistance Publique des Hôpitaux de Paris, Paris, France 3 Institut Mondor de Recherche Biomédicale, INSERMU955, Université Paris Est Créteil, Créteil, France 4 Département de Pathologie, Hôpitaux Universitaires Henri Mondor, Créteil, France 5 Institut de Pathologie, Centre Hospitalier Universitaire Vaudois et Université de Lausanne, Lausanne, Switzerland 2

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The peripheral T-cell lymphomas (PTCL) are characterized by the accumulation of mutations in genes that govern multiple epigenetic pathways, with some entities like PTCL-follicular helper T cell and angioimmunoblastic T-cell lymphomas (AITL), representing the subtypes most enriched for these genetic events. Mutation-induced activation of signaling pathways that play a key role in normal T and natural-killer (NK) cell physiology, like the Janus kinase/signal transducers and activators of

­Introduction Peripheral T-cell lymphomas (PTCLs) collectively include neoplasms of mature (i.e. post-thymic) T or natural killer (NK) cells. As in other cancers, the neoplastic transformation encompasses a multistep process altering pivotal cellular pathways to allow for the survival and expansion of the neoplastic clone, and the recruitment of a favorable microenvironment. Interestingly, neoplastic T or NK cells retain some features related to their cellular differentiation, which affects the clinical, pathological, and biological presentation of the diseases, as well as their outcomes. In this chapter, we review the main types of genetic alterations found in PTCL, discuss the role and importance of the tumor microenvironment and the underlying conditions favoring T-cell transformation, and the relevance of cell-of-origin to T-cell lymphoma genesis and biology.

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transcription pathway or T-cell receptor signaling, are highly recurrent and common to many entities. Extranodal NK/T-cell lymphoma and adult T-cell leukemia/ lymphoma represent two remarkable models lymphomas induced by viruses with superimposed genetic lesions. The tumor microenvironment, and the nature of its cellular milieu, plays an important role in PTLC lymphomagenesis, especially in AITL.

­ ncogenic Events in the O Transformation of T or Natural Killer Cells Genetic Lesions Tumor transformation is driven by genetic events that modify a biological function. Among structural variants first described is the chromosomal translocation involving the ALK oncogene at 5q35 locus. In this translocation, ALK is fused to various partners, most often NPM (nucleophosmin), resulting in abnormal expression of ALK hybrid proteins in anaplastic large-cell lymphomas (ALCL) [1]. Thus, anaplastic lymphoma kinase positive (ALK+) ALCL was the first genetically defined T-cell lymphoma entity. With the development of high-throughput sequencing methods, especially RNA sequencing, many other chromosomal translocations or gene fusions have subsequently been described in PTCL,

The Peripheral T-Cell Lymphomas, First Edition. Edited by Owen A. O’Connor, Won Seog Kim and Pier Luigi Zinzani. © 2021 John Wiley & Sons Ltd. Published 2021 by John Wiley & Sons Ltd. Companion website: www.wiley.com/go/OConnor/Peripheral_T-cell_Lymphomas

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2  Mechanisms of T-cell Lymphomagenesis

deregulating various oncogenes such as DUSP22  [2], TP63  [2], VAV1  [3], CD28-ICOS, or CD28-CTLA4  [4, 5]. Besides these translocations and fusions, copy number variants (CNV) are frequent in PTCL. Some CNV are unique to some subtypes of the disease, including for example, gains in chromosomes 5 and 21 in IDH2R172-mutated angioimmunoblastic T-cell lymphomas (AITL)  [6]. In addition, complex genetic changes appear frequent in GATA3-positive PTCL not otherwise specified (PTCL-NOS), which have a high frequency of alterations in PTEN-PI3K and CDKN2A-TP53 pathways, highlighting the implication of P53 loss in the development of genomic instability  [6]. More rarely, chromothripsis, an episode of catastrophic chromosomal rearrangement  [7], has been described  [8], but no dedicated study has been conducted to evaluate its incidence. Next-generation targeted, whole-exome or wholegenome sequencing studies have reported single-nucleotide variants or indel mutations in coding sequences, leading to the loss of function of a tumor suppressor gene, impacting epigenetic regulation or cell-cycle control, or a gain of function of a proto-oncogene, resulting for example in increased signaling, in most PTCL entities. Splice site mutations in tumor suppressor genes like TET2 or DNMT3A frequently occur and result in loss of function. Coding sequences represent only a small fraction of the genome, and genetic events altering noncoding regions have been identified. Although the functional consequences of

many of them are largely unknown, some events altering the noncoding region may have important biological consequences. For example, structural variants altering 3′ untranslated region (UTR) of PDL1 resulting in PDL1 overexpression and immune escape, have been described in adult T-cell leukemia/lymphoma (ATLL)  [9] or in extranodal NK/T-cell lymphoma (ENKTL), nasal-type [10], two diseases related to viral infections. Dysregulation of non-coding RNA is also observed; some microRNA [11] or small nucleolar RNA [12] signatures are entity specific and could aid in diagnosis, while some may play a role in oncogenesis. However, the role of the anomalies affecting the non-coding genome is largely unexplored. Beyond the genetic and epigenetic anomalies, viruses can directly or indirectly play a role in the oncogenic transformation. Two viruses with oncogenic properties, human T-cell lymphotropic virus type 1 (HTLV1) and Epstein–Barr virus (EBV) are causally linked to a spectrum of lymphoproliferations derived from T or NK cells (see below).

Deregulated Pathways in Peripheral T-cell Lymphoma Oncogenesis (Figure 2.1, Table 2.1) Epigenetic Regulation

Genomic studies have highlighted epigenetic regulators as the category of genes most frequently altered in PTCL. Indeed, integrated molecular analyses of Sézary syn-

Epigenetic regulators

Signaling

DNA methylation TET2 TFH IDH2 DNMT3A Histone methylation MEITL SETD2 HSTL KDM2A Others ARIDIA

ALK fusions ALK+ALCL TCR signaling ITK-SYK TFH CD28 fusions CTCL PLCG1 CARD11 CD28 ATLL RHOAG17V ALK-ALCL DUSP22 NF-KappaB ALCL LGL JAK/STAT pathway EATL MEITL STAT3 STAT5B ENKTCL HSTL JAK1 JAK3

PTCL

SOCS1 Cell-cycle regulation TP53 family CDKN2A Others

All All

Immune surveillance PDL1 3’ UTR HLA-A HLA-B B2M CD58

ATLL ENKTCL PTCL-NOS

Figure 2.1  Summary of deregulated signaling pathways in peripheral T-cell lymphoma. Orange boxes: lymphoma entities of the adaptive type; purple boxes: lymphoma entities of the innate type. ALCL, anaplastic large-cell lymphoma; ALK, anaplastic lymphoma kinase; ATLL, adult T-cell leukemia/lymphoma; CTCL, cutaneous T-cell lymphoma; EATL, enteropathy-associated T-cell lymphoma; ENKTL: extranodal natural killer/T-cell lymphoma; HSTL, hepatosplenic T-cell lymphoma; JAK, Janus-associated kinase; LGL, large granular lymphocyte leukemia; MEITL, monomorphic epitheliotropic T-cell lymphoma; PTCL: peripheral T-cell lymphoma; PTCL-NOS, peripheral T cell not otherwise specified; STAT, signal transducers and activators of transcription; TCR, T-cell receptor; TFH, T follicular helper cells.

­Oncogenic Events in the Transformation of T or Natural Killer Cell  11

Table 2.1  Main nodal and extranodal mature T-cell neoplasms with summary of their main characteristics. Major mature T-cell neoplasms

Postulated cell of origin

Main genetic features

Lymphoma of mature Tfh cells: AITL Follicular T-cell lymphoma Nodal PTCL with Tfh phenotype

Tfh cell subset

Epigenetic: mutations in TET2 (~80%), DNMT3A (~30%), IDH2R172 (20–30%) Signaling: mutations in RHOAG1V (50–70%), CD28, PLCG1, (5–15% each), VAV1; fusions: ITK-SYK (follicular T-cell lymphomas), ICOS-CD28, ICOSCTLA4, VAV1-STAP2 Other: rare TP53 anomalies Abundant microenvironment encompassing stromal and reactive cells Virus: Epstein–Barr virus in B cells

ALCL, ALK-positive

Activated cytotoxic T cells

Signaling: ALK fusion resulting from t(2;5)(~ 80% cases) or t(2;X) (~20%) involving NPM or another partner gene, respectively, and consequently STAT3 activation

ALCL, ALK-negative

Activated cytotoxic T cells

Epigenetic: mutations in KMT2 family genes (especially in breast implant-associated ALCL) Signaling: DUSP22 rearrangement (30%), frequently associated with MSCE116K mutation and lack of STAT3 activation Mutations in JAK1, STAT3 (20%), fusions involving ROS1, TYK2, or FRK, all resulting in STAT3 activation Other: TP63 rearrangement (2–8%)

PTCL-NOS

Activated mature T cell, mostly CD4+ central memory type of the adaptive immune system; include Th1 and Th2 cell subsets

Molecular subsets defined on the basis of gene expression signatures and expression of Th1 (TBX21) vs. Th2 (GATA3) transcription factors, may be clinically relevant: PTCL-TBX21 enriched in mutations in DNA methylators PTCL-GATA3 with frequent loss/mutations in tumor suppressors (CDKN2A/B-TP53 and PTEN/PI3K pathways)

Adult T-cell leukemia/ lymphoma

T –cells, usually CD4, with a regulatory phenotype

Epigenetic: mutations in TET2 (10%), EP300 and others Signaling: mutations in PLCG1 (30%), PRKCB, CARD11, other NFκB genes, mutations in RHOA, activating NOTCH1 mutations Immune surveillance: mutations in HLA, beta 2 microglobulin or CD58, structural variants involving PDL1 3′ untranslated region Others: alterations in TP53, CDKN2A Virus: clonal integration of HTLV1, resulting in expression of TAX and HBZ oncogenic viral proteins during the initiation or maintenance of the tumor

Cutaneous T-cell lymphoma (Sézary syndrome, mycosis fungoides)

CD4 T-cell

Epigenetic: multiple mutations, the most frequent being ARIDIA Signaling: mutations in; PLCG1, PTEN, CARD11, fusions involving ICOS-CD28 or CTLA4, alterations inTNFRSF1B Other: CDKN2A deletion, mutation/deletion in TP53

Adaptive immune system

(Continued)

12

2  Mechanisms of T-cell Lymphomagenesis

Table 2.1  (Continued) Major mature T-cell neoplasms

Postulated cell of origin

Main genetic features

ENKTL, nasal type

Activated NK cell (> 70%) > Tγδ or Tαβ cytotoxic cell

Epigenetic: mutations in BCOR, KMT2D, TET2 ARID1A, EP300 and ASXL3 Signaling: mutations in STAT3, STAT5B, JAK3 Immune surveillance: structural variants involving PDL1 3′ untranslated region Others: mutations in DDX3X, TP53 Virus: EBV constantly present in neoplastic cells (latency II) Association to constitutive genetic HLA-DPB1 variants

Enteropathy-associated T-cell lymphoma

Intestinal intraepithelial T lymphocyte (Tαβ > Tγδ)

Epigenetic: mutations in TET2, SETD2 (uncommon) Signaling: mutations in JAK1, JAK3, STAT3, RAS Others: alterations in TP53 HLA association: DQ2-DQ7 Frequent gains in 9q31.3 Association with celiac disease (gluten intolerance)

MEITL

Intestinal intraepithelial T lymphocyte (Tγδ > Tαβ)

Epigenetic: mutations and/or deletions in SETD2 (> 90%) Signaling: mutations in STAT5B, more rarely JAK3 Others: alterations in TP53 No reported HLA association Lack of association to celiac disease

Hepatosplenic T-cell lymphoma

Tγδ > > Tαβ cytotoxic cell of the innate immune system

isochromosome 7q (~ 60–70%) Epigenetic: mutations in SETD2 (~ 40%) Signaling: mutations in STAT5B (~ 30%), STAT3 (10%)

Innate immune system

ALCL, anaplastic large-cell lymphomas; ENKTL, human T-cell leukemia/lymphoma virus 1; HLA, human leukocyte antigen; HTLV1, human T-cell lymphotropic virus type 1; MEITL, monomorphic epitheliotropic intestinal T-cell lymphoma; PTCL, peripheral T-cell lymphoma; PTCL-NOS, peripheral T-cell lymphoma not otherwise specified; Tfh, T follicular helper.

drome [13], ATLL [10], or PTCL of T follicular helper (Tfh) origin [14, 15] has revealed anomalies in epigenetic regulators in up to 90% of the cases. For example, mutations in TET2 [14–16], DNMT3A [17] and IDH2 [18] are observed in 80%, 30%, and 20–30% of PTCL derived from Tfh cells, respectively. These three mutations induce changes in cytosine methylation and hydroxymethylation levels. TET2 is an α-ketoglutarate-dependent dioxygenase involved in the successive oxidation of 5-methylcytosine to 5-hydroxymethylcytosine (5hmC) to 5-formylmethylcytosine and 5-­carboxymethylcytosine, resulting in the demethylation of 5-cytosine, through the thymine DNA glycosylase-mediated base excision system  [19]. Although TET2 was initially thought to play an important role in active cytosine demethylation, evidence is emerging that TET2 is pivotal in the generation of 5hmC, which is critical for enhancer functions [20]. DNMT3A is a de novo DNA methyltransferase, supporting the transformation of 5-cytosine to 5-methylcytosine.

Mutations in TET2 and DNMT3A are loss of function and distributed along the coding sequences of the genes, with few hotspots, like the dominant-negative DNMT3AR882X mutant [20]. IDH2 mutations confer a neoenzymatic activity producing D-2 hydroxyglutarate. This metabolite, often referred to as an oncometabolite, is physiologically present at very low levels, and inhibits numerous α-ketoglutaratedependent dioxygenases, including TET proteins or histone demethylases  [21]. While IDH1/2 and TET2 mutations in acute myeloid leukemia are mutually exclusive, both resulting in a specific methylation profile, they frequently coexist in AITL. Although TET2, DNMT3A, and IDH2 mutations have in principle opposite effects on cytosine methylation levels, they all individually result in decreased 5hmC levels. Interestingly, compared with normal Tfh cells, 5hmC levels are decreased in AITL, and more generally in PTCL (with the exception of hepatosplenic T-cell lymphoma [HSTL]),

­Oncogenic Events in the Transformation of T or Natural Killer Cell  13

irrespective of the mutational status, suggesting that epigenetic dysregulation is a common feature of PTCLs  [22]. However, the functional consequences of these changes in cytosine methylation/hydroxymethylation are still poorly understood and warrant further comprehensive studies. Other epigenetic regulators preferentially involved in post-translational modifications of histones are also the target of genetic alterations. For example, inactivating mutations and/or deletions of SETD2, a histone methyltransferase adding methyl groups on the lysine residue 36 of histone 3, are almost constant in monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL; > 90% of cases)  [23] and are also frequent in HTCL (about 30% of cases)  [24]. These inactivating mutations result in decreased H3K36me3 levels, a histone mark which is usually associated with active transcription. Alterations of the KMT2 family of genes (KMT2D and KMT2C), encoding methyltransferases involved in the methylation of H3K4, an important process regulating gene transcription, have been reported in PTCLs such as Sézary syndrome  [13], ENKTL [25, 26], PTCL-NOS [27] and breast implant-associated ALCL, where they correlate with a loss of H3K4 mono- and trimethylation  [28]. Recurrent mutations in other epigenetic modifiers such as CHD2, CREBBP, or EP300 have also been reported in various PTCLs. Signaling Pathways

Epigenetic alterations are not sufficient per se to drive tumor transformation. Indeed, most patients with isolated TET2 or DNMT3A mutations in hematopoietic progenitors develop clonal hematopoiesis of indeterminate potential [29, 30], and will not further develop a clinical hematologic malignancy  [29, 30]. Furthermore, transgenic mice models that inactivate TET2 or DNMT3A do not develop spontaneous lymphoid malignancies or they develop with a very low penetrance [31, 32]. Both observations suggest that disruption of an epigenetic regulator is not sufficient and requires “second-hit” events, especially affecting the cell signaling to drive T-cell lymphomagenesis. In normal T cells, T-cell receptor (TCR) engagement by a specific peptide presented by the major complex of histocompatibility, when associated with activation signals from co-stimulatory pathways, activates the transmission of positive signals using several critical signaling pathways. These will result in proliferation, activation, and metabolism adaptation. The main co-stimulatory receptors are CD28 and ICOS, whereas PD1 and CTLA4 are responsible for negative regulation. Activation of TCR signaling induces activation of calcium mobilization, RAS activation, resulting in mitogen-activated protein kinase, nuclear factor kappa B (NF-κB) and activator protein 1 (AP-1) activation, and cytoskeletal reorganization [33].

Converging data support an important role of TCR s­ ignaling in T-cell lymphomagenesis. First, a specific translocation [t(5,9)(q33;q22)] has been reported in some PTCLs, which leads to the generation of an abnormal ITK-SYK fusion protein [34] and to the development of a PTCL with constitutively activated TCR signaling in a transgenic mice [35]. Interestingly, independently of SYK/ITK fusion, SYK overexpression appears common to many PTCLs [36]. Second, 50–70% of Tfh-derived PTCLs harbor a mutation in RHOA encoding for the p.G17V substitution  [4, 14, 37]. Although the expression of the RHOAG17V variant in T cells was associated with disruption of the classical functions of RHOA, it induced increased cell proliferation and invasiveness in in vitro models  [14, 37]. These effects could be explained by a change in the interactome of RHOAG17V mutant, which binds VAV1, resulting in VAV1 phosphorylation and NFAT signaling activation, indicating that RHOA mutation could be a major player in T-cell signaling activation [38]. The link between RHOAG17V mutation and VAV1 activation is reinforced by the observation that VAV1 activating mutations or translocations are mutually exclusive to RHOAG17V mutations  [38]. Interestingly, mouse models combining TET2 loss with expression of the RHOAG17V mutant in T cells, especially when combined with TCR stimulation by immunization, develop AITL-like disease, confirming the concept that combination of TET2 and RHOA mutations can drive Tfh PTCL oncogenesis [39, 40]. In addition, sparse mutations among other genes involved in proximal or distal TCR signaling, such as CD28, PLCG1, and PI3K elements, have been detected in 50% of patients with PTCL, resulting in increased cell activation and proliferation [41]. Furthermore, in addition to CD28 activating mutations, CD28-ICOS or CD28-CTLA4 fusions, resulting in CD28 signaling activation, are present in around 5% of PTCL, notably in Tfh-derived PTCL [5]. Alterations in genes involved in TCR or co-stimulation pathways are also found in other PTCL entities, especially cutaneous T-cell lymphomas (CTCL), where PLCG1 mutations are frequent  [42]. DUSP22, a gene found to be rearranged in around 30% of systemic and cutaneous ALK-negative ALCL, is a tumor suppressor gene encoding a dual-specificity phosphatase, which inhibits TCR signaling and growth and promotes apoptosis in experimental models [43]. Interestingly, DUSP22-rearranged ALCLs lack activation of signal transducers and activators of transcription 3 (STAT3), in contrast to other ALCLs, but associates with recurrent mutations in the musculin (MSC) gene, which in turn drive expression of the CD30–IRF4–MYC axis and cell cycle progression  [44]. PTEN anomalies, resulting in PI3K signaling activation are also described in a significant proportion of cases [45]. In ATLL, integrative genomic studies also demonstrated the presence of mutations altering the TCR

14

2  Mechanisms of T-cell Lymphomagenesis

and NF-κB pathway, such as mutations in PLCG1, PRKCB, CARD11, VAV1, IRF4, FYN, CCR4, and CCR7 [46]. The inactivation of inhibitory signals can also result in T-cell activation. Recent progress in immunotherapy revealed that PD1 is a critical element for T-cell inhibition. A mouse model revealed that PD1 inactivation, mostly by deletion of Pdcd1, the gene encoding for PD1, allowed for tumor transformation in T cells harboring the ITK-SYK translocation  [47]. PDCD1 deletions are found in several PTCLs, but especially CTCL [47]. This potential tumor suppressor role of PD1 in PTCL raises some questions regarding the use of PD1–PDL1 checkpoint inhibitors in PTCL, which are currently under investigation. The Janus-associated kinase (JAK)–STAT pathway is also pivotal for T-cell regulation, as it is critical for the transmission of the signal from cell membrane receptors to the nucleus. Engagement of a type I or type II cytokine receptor by a cytokine or growth factor induces JAK transphosphorylation and subsequent recruitment, phosphorylation and dimerization of STAT proteins that will enter to the nucleus to activate gene expression. There are four members of the JAK family (JAK1, JAK2, JAK3 and TYK2) and seven STAT proteins (STAT1, STAT2, STAT3, STAT4, STAT5a, STAT5b, and STAT6). JAK–STAT signaling is involved in T-cell activation and proliferation. In addition, the functional differentiation of CD4+ cells relies on different JAK–STAT family members (for example, STAT1/STAT4 seems to be involved in Th1 differentiation, STAT6 in Th2, STAT3 in Th17 and STAT5 in Treg polarization)  [48]. Activation of the JAK– STAT pathway is common to several PTCLs, and is particularly frequent in cytotoxic lymphomas. In ALK-positive ALCLs ALK fusion proteins lead to activation of the JAK– STAT3 signaling  [49]. Alternative mechanisms of JAK– STAT3 activation are observed in the majority of ALK-negative ALCLs, including mutations in JAK1 and/or STAT3 in up to 20% ALK-negative ALCL and fusions involving ROS1, TYK2, or FRK. In these lymphomas, co-occurring mutations in two genes of the JAK/STAT pathway for example in STAT3 and JAK1 could act synergistically to amplify JAK/STAT signaling and sustain cell transformation  [28, 50]. STAT3 mutations are detected in one third of large granular lymphocyte leukemia  [51]; JAK3, STAT3, and STAT5B mutations in a proportion of ENKTL, nasal type [26, 52]; JAK3 and above all STAT5B mutations in up to 60% of MEITL [23], whereas STAT5B, or more rarely STAT3 are mutated in 30 and 10% of HSTL, respectively [24]. These mutations are associated with increased JAK–STAT signaling, as suggested by the increased nuclear expression of pSTAT3 or pSTAT5 in mutated cases. In addition, inactivating mutations in negative regulators (SOCS1, SOCS3, PTPN1, and others) of the pathway may also contribute to increasing JAK–STAT signaling [28].

Cell-cycle Control

TP53, the gene that encodes for p53, the guardian of the genome, is probably the most studied tumor suppressor gene. P53 regulates multiple cellular functions, such as DNA repair, cell-cycle arrest, apoptosis, senescence, and metabolism. TP53 mutations or deletions are found in around 50% of cancers, and commonly correlate with chemoresistance and poor prognosis. Inactivating TP53 mutations are reported with a variable frequency, being uncommon in Tfhderived PTCL, and more frequent in PTCL-NOS. In particular, a PTCL-NOS subset characterized by genomic instability and a poorer prognosis, partially overlapping with the GATA3–3-positive molecular subgroup  [6] is enriched in TP53 anomalies [6, 53]. In ATLL, TP53 mutations are found in less than 20% of the patients, where they associate with chemoresistance and short survival [46]. They are also common in extranodal PTCL, such as ENKTL [25] and enteropathy-associated T-cell lymphoma (EATL) [54]. In addition to TP53 inactivation, CDKN2A deletions have also been reported in several PTCLs. CDKN2A, located on chromosome 9, encodes for two transcripts, p16INK4a and p14ARF. p16INK4a is involved in cell-cycle regulation, via inhibition of cdk4 and cdk6, resulting in activation of retinoblastoma proteins, while p14arf controls MDM2 activity via sequestration. MDM2 is an E3 ubiquitin ligase that recognizes the N-terminal transactivation domain of the p53 tumor suppressor, resulting in its degradation. Thus, CDKN2A deletion can result in increased MDM2 function and excessive p53 degradation. CDKN2A deletions are frequent in CTCL, especially in aggressive forms, as they are observed in more than 50% of patients in transformed mycosis fungoides or Sézary syndrome, while they are rare in CD30+ cutaneous ALCL [55]. In ATLL, CDKN2A deletions are reported in 50% of patients with the acute form, but in only 20% of patients with chronic clinical variants of the disease [56]. Deletion of CDKN2A, found in up to 50% of patients with PTCL-NOS with enrichment in GATA3/ Th2 signature, is reported to correlate with shorter survival and poor prognosis [6, 53]. TP63 is rearranged in a small proportion ( 6.2

[89]

Chidamide

Hydroxamic acid-based pan-HDACi

PTCL

79

28

14

2.1

9.9

[90]

Belinostat

Hydroxamic acid-based pan-HDACi

PTCL

120

26

11

1.6

13.6

[70]

Pralatrexate

Folate antagonist, modulation of genes involved with DNA methylation

PTCL/CTCL

109

29

11

3.5

12.1

[91]

Azacitidine

Hypomethylation agent

PTCL

19

53

26

nr

nr

[72]

CR, complete response; CTCL, cutaneous T-cell lymphoma; DOR, duration of response; HDACi, histone deacetylase inhibitor; nr, not reported; ORR, overall response rate; PFS, progression-free survival; PTCL, peripheral T-cell lymphoma.

represent the first class of epigenetic modulating drugs to be approved by the Federal Drug Administration (FDA). These drugs are pyrimidine nucleoside analogues of cytosine that have the ability to become incorporated into DNA and form covalent bonds between the 5-azacytosine ring and the DNMT enzyme, thus causing irreversible DNMT inactivation [92]. Logically, DNMT inhibitors would seem likely to function by reversing the silencing of tumor-suppressor genes, although the precise mechanism of action of DNMT inhibitors is poorly understood. While this phenotype of increased CpG methylation is a well-established and a recurrent pathological feature across many types of cancer, mutations in important genes governing DNA methylation leading to a hypermethylated phenotype in PTCL suggest that drugs such as 5-azacitidine and decitabine can be an important component of future combination regimens in select subtypes of these diseases. In ATLL, an in vitro study revealed that 5-azacitidine inhibits growth of tumor cells by demethylation of the promotor region of a tumor suppressor and inhibition of the cyclin dependent kinase, p16INK4a [93]. In a study published by Delarue et al., injectable 5-azacitidine, as a single agent, produced an overall response rate of 53% in 19 patients with relapsed or refractory PTCL [72]. Of the 19 patients in this study, 12 had a diagnosis of AITL and, in this patient population, the overall response rate was as high as 75% (9/12), with a complete response rate of 50% [94]. Interestingly, all the patients with AITL harbored TET2

mutations, with 58% harboring two mutations. In addition, 33% patients had DNMT3A mutations, 41% had RHOA mutations, with most of them having pG17V substitution. The impact of the mutation status on response was not evaluable as all the patients had the mutation [72]. Interesting, a recent report demonstrated a durable response to azacitidine in the absence of any identifiable mutations [95].

Isocitrate Dehydrogenase Inhibitors Isocitrate dehydrogenase (IDH) catalyzes the oxidative decarboxylation of isocitrate to α-ketoglutarate as part of the tricarboxylic acid (or Krebs) cycle. Mutations in either IDH1 or IDH2 lead to the accumulation of 2-hydroxyglutarate (2HG). This metabolite has been shown to inhibit several demethylation pathways, such as those driven by TET or Jumonji proteins, thus indirectly acting as an epigenetic regulator. As a result of 2-HG accumulation, aberrant DNA or histone methylation can occur [96]. As a consequence of this aberrant regulation, IDH mutations can essentially be viewed as gain-of-function mutations and are potentially targetable. Among lymphoid malignancies, dysregulation of the IDH epigenetic pathway has been best characterized in TCL. The detection of recurrent IDH2 mutations in AITL, especially with substitutions at R172 has suggested a therapeutic target in the treatment of this difficult disease [45, 97]. Whole-exome sequencing of peripheral TCL samples

­Established and Emerging Drugs Targeting the T-cell Lymphoma Epigenom  37

has demonstrated that approximately 30% of patients with AITL have IDH2 mutations, although such mutations occur less frequently in other subtypes of PTCL  [35, 50, 98]. Similar to acute myeloid leukemia (AML), R172 is the most prevalent IDH mutation. It is associated with having the highest levels of 2-HG compared with the other two hotspot mutations, IDH1R132 and IDH2R140  [97], and should be considered an important biomarker for the selection of patients to receive IDH inhibitors, potentially regardless of tumor histology. Interestingly, according to results published in the past few years, all cells harboring IDH2 mutations are PD-1+ and are associated with downregulation of Th1 cell-like differentiation genes (such as STAT1 and IFNG) [35, 50, 98]. Furthermore, an analysis of gene expression signatures demonstrated increased methylation of the promoters that regulate T-cell receptor signaling and T-cell differentiation in IDH2R172K cell lines, illustrating a potential mechanism of lymphomagenesis  [50]. No data are currently available from preclinical studies testing IDH inhibitors specifically in models of IDH-mutant lymphomas, such as AITL or chronic lymphocytic leukemia (CLL). Both the IDH2 inhibitor enasidenib and, subsequently, the IDH1 inhibitor ivosidenib have been approved in the past two years for patients with relapsed and/or refractory AML who carry mutations in IDH2 or IDH1, respectively  [99, 100]. Enasidenib (AG-221), a novel IDH2 inhibitor, has been found to be effective in patients with R/R acute myeloid leukemia who have IDH2 R140 and R172 mutations, leading to its approval in this population  [99]. Currently, no results are available from trials of IDH inhibitors in lymphoma. However, clinical trials investigating inhibitors of IDH2 (enasidenib), IDH1 (ivosidenib) and both IDH1 and IDH2 (vorasidenib) in patients with advanced-stage hematological malignancies are currently underway. Of particular note, enasidenib is currently being investigated in a phase I/II trial specifically for patients with IDH2-mutated AITL (NCT02273739).

EZH2 Inhibitors Another novel epigenetic target is the EZH2. EZH2 is the enzymatic subunit of polycomb repressor complex 2 along with EED and SUZ12 involved with histone acetylation and subsequent epigenetic gene suppression [101]. EZH2 is the enzymatic subunit that catalyzes the methylation of Lys27 of histone H3 (H3K27) with as many as three methyl groups. EZH2 has an essential role in germinal centers B (GCBs) that give rise to follicular lymphoma and DLBCL, as documented in mouse models in which deletion of this gene completely abrogated the formation of germinal centers. This effect is mediated by the EZH2-mediated silencing of genes encoding cell cycle checkpoint proteins and those

involved in plasma cell differentiation [102–104]. Mutations in EZH2 are highly prevalent in patients with B cell lymphomas and occur specifically in GCB-DLBCLs and follicular lymphomas, with an incidence of approximately 15–20% in both tumor types  [105, 106]. The vast majority of these genetic lesions involve point mutations resulting in substitution of tyrosine 641 (Y641; either Y641F, Y641N, Y641S, or Y641H) within the histone methyl-transferase domain of EZH2. These alterations lead to a gain-of-function effect whereby the mutant form of this protein enables more efficient trimethylation of H3K27  [107]. EZH2 inhibitors first entered clinical trials in 2013. Results from these initial trials have since been reported for tazemetostat, valemetostat, and GSK2816126, and generally show encouraging preliminary results for B cell lymphomas [108–110]. In contrast to B-cell lymphomas, EZH2 acts as a tumor suppressor in T-cell malignancies, which manifest loss-offunction mutations of EZH2 and genes encoding other components of PRC2 [111]. In particular, genes encoding components of PRC2 have an especially high rate of deletions or sequence mutations in early T-cell precursor acute lymphoblastic leukemia (ALL) [112]. Homozygous inactivation of EZH2 in mouse models of leukemia was found to accelerate the progression of early T-cell precursor ALL, in part through activation of the STAT3 pathway [113]. EZH2 has been found to be expressed in many types of PTCL, including ALCL (ALK positive and negative as well as primary cutaneous subtypes), PTCL-NOS, AITL, NKTL, and ATLL by immunohistochemistry [53, 114]. EZH2 has been found to be necessary for Tax-dependent cell growth and immortalization [75]. Lymphocyte activation by anti-CD3/ CD28 stimulation or polymethacrylate/ionomycin increases EZH2 expression. In ATLL, NF-κB activation plays a critical role in the chronic expression of EZH2. Targeting this pathway with EZH2 inhibitors may reverse the reprogramming and specifically eliminate cancerous cells while sparing normal CD4+ T cells. Early-phase clinical trials are ongoing to test this hypothesis [53, 115, 116]. Dual inhibition of EZH1 and EZH2 might lead to greater suppression of H3K27 trimethylation and provide higher levels of anti-lymphoma activity than inhibition of EZH2 alone [117]. This discovery has led to the development of valemetostat, which has indeed shown good levels of activity across a range of B- and T-cell NHL subtypes (53% overall response rate and 86% clinical benefit rate in a phase I trial involving 15 patients). Of particular note, an 80% overall response rate was reported in patients with TCL [110]. Given the encouraging clinical activity and tolerability of this class of drugs, tazemetostat is being investigated in various patient populations and drug combinations such as with chemotherapy (NCT02889523) or immunotherapy (NCT02220842).

38

3  Epigenetics of T-cell Lymphoma

BET Inhibitors Bromodomains are protein motifs that recognize and bind to acetylated lysine moieties located on histone tails. BETs consist of two amino-terminal tandem bromodomains and an extra-terminal (non-bromodomain) region. The BET family includes BRD2, BRD3 and BRD4 and bromodomain testis-specific protein  [118]. Upon binding to acetylated lysine groups, BETs induce gene expression either directly by recruiting transcription factors to DNA and initiating transcription or indirectly by interacting with gene superenhancers (non-coding regions of DNA that bind to transcription factors and activate nearby target genes controlling cellular identity). Thus, BETs contribute to the development and progression of malignancies by both activating and potentiating the expression of key oncogenes [119]. Although BET mutations or translocations are rare, BETs can be overexpressed [120]. Consequently, BET inhibition has been shown to be effective in preclinical studies across multiple types of cancers, including breast, neuroendocrine, ovarian, and hematological malignancies, as well as in rhabdomyosarcoma and glioma [121–125]. BET inhibitors appear to be active in CTCL, EBV-associated lymphoproliferative disease and primary effusion lymphoma and have been shown to decrease the rate of tumor growth and disease progression in mouse xenograft models [126– 128]. Several phase I trials designed to test BET inhibitors, including molibresib, CC-90010, and INCB054329, are currently ongoing for patients with various advanced-stage malignancies. In December 2018, data from 27 patients with various subtypes of non-Hodgkin lymphoma treated with molibresib were presented at the American Society of Hematology annual meeting. The overall response rate among the entire cohort was 18.5%, with one patient with DLBCL having a sustained complete remission after receiving treatment for 54 weeks. Also of note, three of six patients with TCL had a partial response [129]. However, at the time of writing no further studies with molibresib were planned for lymphoma.

Protein Arginine Methyltransferases Inhibitors Protein arginine methyltransferases inhibitors (PRMTs) catalyze the monomethylation or dimethylation of arginine residues on histone and non-histone proteins. A total of nine human PRMTs are known to exist, although PRMT5 seems to be the most relevant to oncogenesis. PRMT5 is a type II PRMT that specifically catalyzes the symmetrical dimethylation of arginine residues located on the H3 or H4 proteins, resulting in gene silencing  [118]. PRMT5 might also have a role in the development of TCLs. Similar to EBV-transformed lymphoma, PRMT5 expression is upregulated in human T-cell lymphotropic virus

type 1 (HTLV)-transformed ATLL, and PRMT5 inhibition was shown to have selective cytotoxic effects on HTLV+ lymphoma cells [130]. Overexpression of PRMT5 in ATLL seems to interact with oncogenic CCND1, MYC, and NOTCH1 in driving lymphomagenesis and might also directly silence p53 [131]. No PRMT inhibitors have thus far received FDA approval, and the first clinical trial designed to investigate a PRMT5 inhibitor (GSK3326595) commenced in 2016 for patients with solid tumors or nonHodgkin lymphoma (NCT02783300). Despite this lack of clinical evidence, a growing body of data from preclinical studies has demonstrated a potentially important role of this class of drug, specifically for the treatment of lymphoid malignancies. Activating mutations in PRMT5 have not been reported in patients with lymphoma, although PRMT5 is overexpressed in different subtypes and might potentially serve as a biomarker.

­Combination Therapies Involving Epigenetic Targeting Agents One of the more exciting areas in PTCL research involves the development of combination therapies that target, either in part or in unison, some of the dysregulated epigenetic biology discussed above. While these experiences are discussed in more detail in other chapters (and is summarized here in Table  3.3), it is becoming increasingly clear that drugs targeting the epigenome may well form the cornerstone of future PTCL-directed combination therapies. As this experience evolves, it will be incumbent on the scientific community to decipher, as best it can, the relationships between clinical activity of these combinations and the underlying epigenetic biology. In this fashion, it will be likely that very targeted epigenetic predicated platforms could emerge in a subtype directed manner.

­Future Directions As discussed above, there are many lines of evidence that suggest that the T-cell malignancies harbor many lesions that underscore its gross epigenetic dysregulation. In addition, it is clear that efficacy of epigenetic-based monotherapies, which exhibit a clear lineage specific selectivity in the TCL, is only the first step in trying to leverage our growing understanding of these diseases in a treatment focused fashion in is limited. Combinations of drugs predicated on a HDAC inhibitor backbone appear to improve the efficacy of these agents, as demonstrated in phase I and phase II trials investigating HDAC or DNMT inhibitors. The combination of epigenetic modulating agents with immunotherapy

 ­Reference

Table 3.3  Combination agents targeting the T-cell lymphoma epigenome.

Drug combinations

Class/Mechanism

Disease

Panobinostat/Bortezomib

HDACi and proteasome PTCL inhibitor

Romidepsin/Pralatrexate

Median PFS Median DOR Patients (n) ORR (%) CR (%) (months) (months) Refs.

25

43

22

2.6

5.6

[132]

HDACi and folate antagonist

PTCL/CTCL 14

71

29

4.4

4.3

[133]

Romidepsin/Alisertib

HDACi and Aurora A kinase inhibitor

PTCL/CTCL 3

33

33

> 6

nr

[134]

Romidepsin/Duvelisib

HDACi and PI3Kδ, −γ inhibitor

PTCL/CTCL 11

64

36

nr

nr

[135]

Romidepsin/Lenalidomide HDACi and immunomodulatory agent

PTCL/CTCL 10

50

0

13.5 weeks

nr

[136]

Romidepsin/Azacitidine

PTCL

73

54

7.9

NR

[52]

AITL

14

CR, complete response; CTCL, cutaneous T-cell lymphoma; DOR, duration of response; HDACi, histone deacetylase inhibitor; nr, not reported; NR, not reached; ORR, overall response rate; PFS, progression-free survival; PTCL, peripheral T-cell lymphoma.

provides perhaps the most exciting avenue for future research. Histone modification typically results in closed chromatin states at the MHC class II promoters, and in MCL and DLBCL cells this can be reversed by HDAC inhibition, thus enhancing antigen-specific immune recognition and activation [137, 138]. In addition, DNMT inhibitors seem to increase sensitivity to immune-checkpoint inhibition [139, 140]. Presently, a number of studies are systematically exploring the combination of immune checkpoint

inhibitors with many of the agents descried above (romidepsin, decitabine, azacytidine, pralatrexate) as well as with various doublet combinations (ex 5-azacytidine plus romidepsin, decitabine plus pralatrexate, and pralatrexate plus romidepsin). It is anticipated that, in the near future, these two- or three-drug combinations will lead to a paradigm change in the disease, with a shift from the indiscriminate cytotoxic effects of chemotherapy, to likely immunoepigenetic-based platforms.

Must Reads ●●

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Choi, J., Goh, G., Walradt, T. et al. (2015). Genomic landscape of cutaneous T cell lymphoma. Nat Genet 47(9):1011–1019. Dunleavy, K., Wilson, W.H., Jaffe, E.S. (2007). Angioimmunoblastic T cell lymphoma: pathobiological insights and clinical implications. Curr Opin Hematol 14(4):348–353. Iqbal, J., Wright, G., Wang, C. et al. (2014). Gene expression signatures delineate biological and prognostic

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4 Animal Models of T-cell Lymphoma Keiichiro Hattori1, Raksha Shrestha2, Tatsuhiro Sakamoto1,2, Manabu Kusakabe1,2 and Mamiko Sakata-Yanagimoto1,2 1

Department of Hematology, Faculty of Medicine, University of Tsukuba Hospital, Tsukuba, Japan Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Japan

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Mouse models of T-cell lymphomas have been established based on the analysis of mutational profiles or gene/protein expression profiles of human samples. Patient-derived xenograft models of T-cell lymphomas have been also generated as potential preclinical tools for translational research.

­Introduction Peripheral T-cell lymphomas (PTCL) are a heterogeneous group of blood cancers with varying pathological and clinical features. Standard chemotherapy approaches for most PTCL are not yet well established, with the exception of anaplastic lymphoma kinase positive (ALK+) anaplastic large-cell lymphoma (ALCL). Thus, better understanding of the molecular pathogenesis of these intractable diseases is warranted to develop effective therapies. In that effort, analysis of samples collected from patients with PTCL has been the gold standard for analysis of gene and protein expression, as well gene mutational profiles. However, it remains challenging to discover fundamental mechanisms that could be targeted based on analysis of samples with such heterogeneous backgrounds. Also, both the initiation and dynamic course of these diseases are difficult to pinpoint due to limitations on sample collection by their rarity. Nonetheless, recent analysis of patient samples has identified some mutational profiles and expression signatures for various types of PTCL that can be modeled in mice, which is an essential step in developing novel treatments.

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Mouse models have helped to unveil the pathogenesis and signaling pathways in T-cell lymphomas. Mouse models provide tools to achieve higher rates of successful translation of basic research to clinical trials.

In this chapter we describe several mouse lines e­ stablished for angioimmunoblastic T-cell lymphoma (AITL), ALCL, adult T-cell leukemia/lymphoma (ATLL), cutaneous T-cell lymphoma (CTCL) and enteropathyassociated T-cell lymphoma (EATL) (Summarized in Table 4.1). Most of the mouse lines are established by transgenic or knock-in strategies commonly used to express oncogenes identified in patient samples. One advantage of transgenic models is that the transgene can be engineered to be expressed tissue-specifically or responsive to a particular drug. Knock-in models are superior to transgenic models in that oncogenic genes are expressed at physiological levels. Clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9, a powerful genome-editing tool has begun to be incorporated in this research area. Moreover, patient-derived xenograft (PDX models have been established by inoculating patient samples into immunodeficient mice. Ultimately, a combination of all these approaches will be necessary to understand mechanisms driving initiation and progression of PTCL.

The Peripheral T-Cell Lymphomas, First Edition. Edited by Owen A. O’Connor, Won Seog Kim and Pier Luigi Zinzani. © 2021 John Wiley & Sons Ltd. Published 2021 by John Wiley & Sons Ltd. Companion website: www.wiley.com/go/OConnor/Peripheral_T-cell_Lymphomas

Table 4.1  Mouse models of peripheral T-cell lymphomas (PTCL) Types of PTCL

AITL

Models

Methods san

Others (downstream signaling, etc.)

Reference

Roquin

Heterozygous for Roquin : a missense (M199R) sanroque mutation in the Roquin gene

Increase of TFH cells AITL‐like disease around 4 to 15 months

No ROQUIN gene alterations in human AITL

Ellyard4

Tet2 gene trap

A gene‐trap vector inserted into the Tet2 second intron

Development of T‐cell lymphomas with TFH‐like phenotype around 67 weeks

Hypermethylation of silencer region of Bcl6 gene

Muto10

G17V RHOA

G17V RHOA cKI mice crossed with CD4Cre‐ERT2

Increase of TFH cells

Cortes14

G17V RHOA transgenic mice under the Cd4 promoter

Increase of TFH cells Autoimmunity

Ng15 Nguyen16

G17V RHOA transgenic mice under the CD2 promoter

No phenotype

Retroviral transduction of G17V RHOA mutant cDNA into Tet2‐null T cells

Increase of TFH cells CD4+ proliferation

Inactivation of FoxO1

Zang13

G17V RHOA cKI mice crossed with CD4CreERT2 and Tet2cKO with SRBC immunization

AITL‐like disease around 25 weeks

ICOSL‐ICOS signaling Activation of PI3K‐mTOR signaling

Cortes14

G17V RHOA transgenic mice crossed with Tet2cKO x Vav‐Cre, and OT‐II mice with NP‐40‐Ovalbumin immunization

AITL‐like disease around 38 weeks

Activation of PI3K‐mTOR signaling

Ng15

G17V RHOA transgenic mice crossed with Tet2cKO x Mx1‐Cre mice

AITL‐like disease around 48 weeks

Activation of T‐cell receptor signaling

Nguyen16

PDX

Inoculation of cells from lymph nodes of AITL patients into NOD/Shi‐scid, IL2Rgammanull (NOG) mice

AITL‐like disease

Detection of human immunoglobulin G/A/M in the sera

Sato18

NPM1‐ALK

Retroviral transduction of NPM1‐ALK cDNA into 5‐ fluorouracil‐treated murine BM

B‐lineage large cell lymphomas around 4‐6 months

Kuefer20

Retroviral transduction of NPM1‐ALK cDNA with low versus high multiplicity of infection (MOI)

Plasmacytomas around 12‐16 weeks with lower MOI, Histiocytic malignancies around 3‐4 weeks with higher MOI

Miething21

Retroviral transduction of Lox‐STOP‐Lox‐NPM1‐ALK encoding vector in BM expressing Cre under the LyzM‐ promotor or GrzmB‐promotor

Histiocytic malignancies around 4‐6 weeks for LyzM, Mixed phenotype of T‐cell lymphoma/ histiocytic malignancy around 4‐6 weeks for GrzmB

Miething22

NPM1‐ALK transgenic mice under the Cd4 promoter

Thymic lymphomas and plasmacytomas around 18 weeks

NPM1‐ALK transgenic mice under the Vav1 promoter

Diffuse large B‐cell lymphomas with high copy number Plasmacytomas with low copy number

G17V RHOA‐Tet2 null

ALCL

san

Phenotypes of mice

Activation of Stat3 signaling

Chiarle23,24 Turner25

NPM1‐ALK transgenic mice under the Cd2 promoter

ATL

CRISPR‐based models to make Npm1‐Alk in HSC

ALCL, ALK+‐like disease

Rajan27

PDX

Cells from a patient with systemic CD30+ ALCL resistant to chemotherapy were inoculated into SCID mice

ALCL, ALK+‐like disease

Pfeifer28

TAX

Tax transgenic mice under the control of viral promoters, HTLV‐1 LTR

Mesenchymal tumors, arthritis, and osteoporosis

Nerenberg30, Habu31, and Ruddle32

Tax transgenic mice under the Cd3‐epsilon promoter

Mesenchymal tumors, and salivary and mammary adenomas

Hall33

Tax transgenic mice under the Lck proximal promoter

Thymic T‐cell lymphomas

Hasegawa34

Tax transgenic mice under the GrzmB promoter

LGL and hypercalcemia

Grossman35 Gao36

HBZ transgenic mice under the Cd4 promoter

Increase of effector/memory and regulatory CD4+ T cells Inflammation of lung and skin ATL‐like disease after long latencies

Satou37

HBZ transgenic mice under the GrzmB promoter

ATL‐like disease with osteoporosis and hypercalcemia around 18 months

Esser38

PDX

Inoculation of cells from ATL patients to immunodeficient (SCID and NOD/SCID) mice

ATL‐like disease

Kawano40

IL‐15

Transgenic mice expressing a modified IL‐15 cDNA under the MHC class I promoter

A leukemic form of CTCL around 12‐30 weeks

JAK3A572V mutant

Retroviral transduction of JAK3A572V into 5‐fluorouracil‐ treated murine BM

A leukemic form of CTCL

Cornejo44

JAK3A572V knock‐in mouse model

A leukemic form of CTCL

Rivera‐Munoz45

Setd2 conditional knockout mice crossed with Lck‐Cre transgenic mice

Increase of the intraepithelial γδ‐positive T cells

Moffitt47

HBZ

CTCL

EATL

Turner26

B‐cell lymphomas with variable histological features

Setd2

Upregulation of HDAC

Fehniger41

PTCL, peripheral T‐cell lymphoma; AITL, angioimmunoblastic T‐cell lymphoma; ALCL, anaplastic large cell lymphoma; ATL, adult T‐cell leukemia/lymphoma; CTCL, cutaneous T‐cell lymphoma; EATL, enteropathy‐associated T‐cell Lymphoma; TFH, T follicular helper; cKI, conditional knock in; cKO, conditional knockout; SRBC, sheep red blood cells; PDX, patient‐derived xenograft; BM, bone marrow; LyzM, Lysozyme M; GrzmB, granzyme B; HSC, hematopoietic stem cells; SCID, severe immunodeficient mice; LTR, long terminal repeat; LGL, large granular lymphocytic leukemia

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4  Animal Models of T-cell Lymphoma

­ ngioimmunoblastic T-cell A Lymphoma Gene expression profiling and immunohistochemical staining indicate that AITL tumor cells exhibit a T follicular helper (Tfh) phenotype  [1]. Tfh cells exist in follicles of lymph nodes and spleen, and support B-cell survival, proliferation, migration, and differentiation [2]. Tfh phenotypes, both in the context of normal helper T cells and in AITL cells, are determined by expression of co-stimulatory molecules such as inducible T-cell co-stimulator (ICOS) and programmed cell death 1, as well as by chemokine receptors, such as C-X-C motif chemokine receptor 5 and C-X-C motif chemokine ligand 13, and membrane metalloendopeptidase, such as CD4 and CD10, and a key transcription factor governing Tfh development, namely, B-cell lymphoma 6 protein (BCL6, [1]). Several animal models have been established to assess AITL pathogenesis.

The ROQUIN Mouse Model ROQUIN is a ubiquitin ligase that reportedly limits expression of Icos by binding to Icos mRNA and promoting its degradation [3]. Icos protein is critical for Tfh cell survival. The missense (M199R) sanroque mutation in the Roquin gene (Roquinsan) increases Icos expression by blocking Icos mRNA degradation [3]. Ellyard et al. reported that mice heterozygous for the Roquinsan allele exhibited dysregulated Tfh cells and develop AITL-like tumors [4]. However, to date ROQUIN gene alterations have not been found in human AITL [5].

The Mouse Models Recapitulating Human Angioimmunoblastic T-cell Lymphoma Genomic Features AITL samples harbor recurrent somatic mutations in genes encoding epigenetic regulators such as tet methyl cytosine dioxygenase 2 (TET2), DNA methyl transferase 3 alpha and isocitrate dehydrogenase 2 [6]). All of these mutations occur frequently in numerous hematologic malignancies, whereas TET2 mutations are detected more frequently in PTCL exhibiting a TFH phenotype compared to those without a TFH phenotype  [7]. The p.Gly17Val mutations in the ras homologue family member A (RHOA) (designated as the G17V RHOA mutations) are specifically found in up to 50–70% of AITL and its related lymphomas with a Tfh phenotype [6, 8, 9].

Tet2 Gene Trap Mice Homozygous Tet2 gene trap(Tet2gt/gt) mice harbor a genetrap vector in the Tet2 second intron  [10]. Muto et  al.

reported that 70% of Tet2gt/gt mice developed T-cell lymphomas with Tfh-like gene expression patterns around 67 weeks old [10]. DNA methylation analysis revealed that lymphoma cells of Tet2gt/gt mice exhibited increased methylation at transcriptional start sites, gene bodies and CpG islands, and decreased hydroxymethylation at transcriptional start site regions [10]. Hypermethylation of the first intronic silencer region of the Bcl6 gene reportedly has been known to inhibit CCCTC-binding factor (CTCF) binding to this locus and promotes Bcl6 transcription [11]. Density of methylation was increased in lymphoma cells of Tet2gt/gt mice compared with control CD4+ cells  [10]. Upregulation of Bcl6, encoding a master transcriptional regulator in Tfh development finally results in outgrowth of Tfh-like cells in Tet2gt/gt mice [10]. These results suggest overall that decreased Tet2 function contributes to AITL initiation. Notably, hypermethylation of the corresponding region in BCL6 locus is also found in human PTCL samples with TET2 mutations [12].

G17V RHOA Mouse Model To determine effects of G17V RHOA expression, multiple independent G17V RHOA model mice have been established using either retroviral transduction  [13], knockin  [14], or transgene  [15, 16] approaches. These G17V RHOA model mice did not develop AITL-like lymphomas, although increase of Tfh cell populations [14, 15] and autoimmunity  [15] were observed in some lines of mice. Therefore, the appearance of oncogenic phenotypes may require additional gene mutations. Because the G17V RHOA mutations are almost always accompanied by loss-of-function TET2 mutations in human AITL samples [6], mice expressing the G17V RHOA mutant in Tet2-null background were established by using distinct approaches  [13–16]. Briefly, Zang et  al. transduced Tet2null T cells with retrovirus harboring G17V RHOA, and they performed adoptive transfer of these cells into T-cell receptor (TCR) α-deficient mice  [13]. Cortes et  al. crossed G17V RHOA conditional knock-in (cKI), Tet2 conditional knockout (cKO), and CD4CreERT2 mice, in which tamoxifen induces expression of G17V RHOA mutant and deletion of Tet2 gene in T cells, and then transplanted bone marrow cells of these mice into irradiated C57BL/6 mice, followed by immunization with sheep red blood cells [14]. Ng et  al. crossed G17V RHOA transgenic mice with Tet2 cKO x Vav-Cre mice, lacking Tet2 gene in hematopoietic cells, and OT-II TCR mice, followed by immunization with NP-40-Ovalbumin [15]. Nguyen et al. crossed G17V RHOA transgenic mice with Tet2cKO x Mx1-Cre mice, lacking Tet2 gene in hematopoietic cells with injection of polyinosinic:polycytidylic acid (pI:pC)  [16]. Model mice

­Anaplastic Large T-cell Lymphom  51

established by Zang et al. revealed skewed T-cell differentiation such as increase of TFH cells and decrease of T regulatory cells, and abnormal expansion of CD4+ T cells [13]. Mice established by Cortes et al., Ng et al., and Nguyen et al. developed AITL-like lymphomas after 25, 38, and 48 weeks, respectively [14–16]. Zang et al. also reported that TET2 loss and G17V RHOA expression synergistically inactivates FoxO1: Tet2 loss leads to increase of methylation in FoxO1 promoter that suppress its transcription in CD4+ T cells, whereas the G17V RHOA mutant elevates phosphorylation of FoxO1 and promotes its translocation from the nucleus to the cytosol, where it undergoes proteasomal degradation [13]. This agrees with findings of mTORc1-associated gene expression by Ng et  al. in G17V RHOA-expressing tumor cells, as FoxO1 suppresses mTORc1 signaling  [15]. Likewise, Cortes et al. reported that G17V RHOA activates PI3K-mTORc1 signaling in CD4+ T cells dependent on ICOS-ICOSL signaling [14]. Accordingly, tumor cell proliferation was inhibited by everolimus, a mTOR inhibitor [15] and duvelisib, a PI3K inhibitor  [14], supporting the idea that ICOS-PI3K-mTORc1 signaling drives Tfh cell expansion in mice. Fujisawa et al. reported that hyperactivation of TCR signaling is an essential downstream event of the G17V RHOA mutant in vitro: the G17V RHOA mutant binds to and activates VAV1, a key component of TCR signaling [17]. Nguyen et al. reported that phosphorylation of VAV1 and activation of TCR signaling were also observed in murine tumor cells [16]. Dasatinib, a multikinase inhibitor effectively prolonged the survival of mice through inhibiting the TCR signaling pathway [16].

PDX Models of Angioimmunoblastic T-cell Lymphoma A PDX model was established by inoculating primary AITL tumor cells and microenvironmental reactive cells into NOD/Shi-scid, IL2Rgammanull (NOG) mice  [18]. The immunohistological features of tumors in PDX mice recapitulated those of AITL patients. Additionally, human immunoglobulin G/A/M was detected in the sera of PDX mice, indicating that patient-derived B and plasma cells were activated by AITL tumor cells in mice. Their analysis suggests that the function of TFH cells in AITL cells was reconstituted in the PDX mice.

­Anaplastic Large T-cell Lymphoma Microscopically, anaplastic large-cell lymphoma (ALCL) is commonly marked by large cells with abundant cytoplasm and eccentric, lobulated nuclei  [1]. CD30 is highly

expressed on the surface of ALCL cells  [1]. ALCL is ­classified in two distinct diseases by the expression of ALK: ALCL, ALK positive and ALCL, ALK negative. The translocations involving ALK gene with various partner genes are essential mechanisms in ALK-positive ALC. The most frequent translocation, t(2;5)(p23; q35), fuses a portion of the nucleophosmin (NPM)1 gene on chromosome 5q35 with a portion of ALK on chromosome 2p23 [1]. The NPM1-ALK fusion gives rise to a chimeric protein consisting of the NPM1 N-terminus with the ALK catalytic domain [19].

Viral and Chimeric Models Chimeric models have been created by transplanting bone marrow cells transduced with a retroviral vector carrying NPM1-ALK cDNA into lethally-irradiated mice. The first model was reported by Kuefer et al., who infected 5-fluorouracil-treated murine bone marrow cells with NPM1-ALK cDNA using retrovirus and then injected them into lethally irradiated BALB/cByJ mice [20]. Transplanted mice developed B-lineage large cell lymphomas at four to six months in mesenteric lymph nodes, with metastases clearly associated with aberrant ALK activation  [20]. Miething et  al. later asked whether B-cell phenotypes seen in the Kuefer at al. study were attributable to low infection efficiencies and hence low NPM1-ALK expression. To address this possibility, they compared infection conditions employing low versus high multiplicity of infection and confirmed that lower multiplicity of infection promoted plasmacytomas around 12–16 weeks in mice, while higher multiplicity of infection caused aggressive histiocytic malignancies around 3–4 weeks  [21]. Miething et  al. also developed a murine model of ALCL by employing a Lox-STOP-Lox-NPM1-ALK encoding vector  [22]. They then infected bone marrow cells from two sets of mice: one expressing Cre controlled by the lysozyme M-promotor (lysM-mice), which is active in the myeloid compartment and the other expressing Cre from the granzyme B-promotor (GrzmB-mice), which is mainly active in T cells. Mice transplanted with bone marrow cells from lysM-mice developed histiocytic malignancies around four to six weeks, while those from GrzmB-mice developed a mixed T-cell lymphoma/histiocytic malignancy around four to six weeks [22]. Although these models do not precisely mimic human ALCL in humans, they provide versatile tools to examine NPM1-ALK signaling pathways in vivo.

Transgenic Models Chiarle et al. reported the first transgenic mouse in which NPM1-ALK expression was driven by the Cd4 promoter developed thymic lymphomas and plasmacytomas  [23].

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4  Animal Models of T-cell Lymphoma

They further demonstrated the pathogenic roles of STAT3 in ALCL with NPM1-ALK expression using the mice [24]. Subsequently, Turner et al. generated mice transgenic for a human NPM1-ALK fusion gene regulated by the hematopoietic cell-specific Vav promoter [25]. These mice exhibited development of B-cell lymphomas and plasmacytomas. Similarly, transgenic mice expressing the NPM1-ALK transgene regulated by the T cell-specific Cd2 promoter also developed B-lymphoid malignancies with variable histological features [26].

CRISPR-Based Models In 2019, Rajan et al. used gene editing to establish a mouse model of ALCL, ALK+ after transplantation of hematopoietic stem cells with Npm1-Alk generated by a CRISPR-Cas9 method [27]. The lymphoma cells had a large-cell morphology with CD30 expression accompanied by oligoclonal TCR rearrangements. These features were compatible with those of ALK-positive ALCL. Therefore, this method may replace traditional approaches to modeling of ALCL in mice.

PDX Models of Anaplastic Large-Cell Lymphomas Pfeifer et al. reported a PDX model in which cells from a patient with systemic CD30+ ALCL resistant to chemotherapy were transplanted into severe immunodeficient (SCID) mice  [28]. They showed that human ALCL tumor cells xenografted and then serially passaged into SCID mice maintained the original characteristics of the patient’s tumor. This model was also used to demonstrate antitumor effects of the agonistic anti-human CD30 antibody HeFi-1 on development of CD30+ ALCL tumors in mice.

­ uman T-cell Lymphotropic Virus H Type 1 Adult T-cell Leukemia/ Lymphoma ATLL is caused by persistent infection of the human T-cell lymphotropic virus type 1 (HTLV1). Clinical presentation of ATLL varies from relatively indolent forms to aggressive forms. ATLL develops only a small part of HTLV1 carriers after an incubation period of about 60 years from HTLV1 infection [1]. Additional genetic and epigenetic abnormalities are thought to be required for the onset of ATLL. In addition to gag, pol and env genes, the HTLV1 genome encodes accessory proteins including Tax, a transcriptional activator and HTLV1 basic leucine zipper factor (HBZ), a nuclear protein, both of which play essential roles in ­cellular proliferation, survival, and genetic stability of ATLL cells [29].

Mice Expressing HTLV-1 Viral Proteins Several lines of transgenic mice expressing Tax under the control of viral promoters HTLV1 long terminal repeat have been developed. These mice develop mesenchymal tumors  [30], arthritis  [31], and osteoporosis  [32]. Mesenchymal tumors were observed in the nose, ear, foot, and tail and were characterized by a spindle-cell component and granulocyte infiltration. However, these models do not mimic human ATLL. Other investigators generated Tax transgenic mice using promoters activated in T cells [33, 34]. Among these, transgenic mice expressing Tax from the Cd3-epsilon promoter developed a variety of tumors dependent on the lines, including mesenchymal tumors, and salivary and mammary adenomas  [33]. Transgenic mice expressing Tax in thymocytes under control of the Lck proximal promoter developed thymic T-cell lymphomas  [34]. Moreover, the other transgenic mice expressing Tax using the GrzmB promoter developed large granular lymphocytic leukemia, lymphadenopathy, extranodal disease and hypercalcemia, resembling human ATLL [35, 36]. Transgenic mice expressing HBZ have also been developed [37, 38]. Mice expressing HBZ driven by the Cd4 promoter showed inflammatory lesions of lung and skin, accompanied by increase of effector/memory and regulatory CD4+ T cells  [37]. Approximately 40% of these mice also develop T-cell lymphomas after a long latency, reminiscent of human ATL. HBZ transgenic mice constructed using the GrzmB promoter were also reported  [38] and exhibited lymphoproliferative disease, osteoporosis, splenomegaly, and hypercalcemia, similar to lymphoma-type of ATLL. HBZ/Tax double transgenic mice in which both genes were controlled by the Cd4 promoter showed phenotypes similar to those of HBZ single transgenic mice [39]. Despite this progress, to date a model fully replicating human ATLL disease has not yet been established likely due to the complexity of the human ATLL disease.

PDX Models of Adult T-cell Leukemia/ Lymphoma Xenograft mouse models transplanted with ATLL patientderived cells have been examined  [40]. In these models, immunodeficient SCID and NOD/SCID recipient mice displayed multiple features of human ATLL disease, namely, aberrant lymphocyte infiltration in liver, spleen, lung, peritoneum, and other organs. These models have helped define mechanisms underlying HTLV1 infection, clonal proliferation and the immune response against HTLV1 and have contributed to development of targeted therapies. For example, treatments using the antibody against C─C

Must Reads 

chemokine receptor type 4 and an inhibitor of histone deacetylase have been tested in these models.

result suggests that inhibition of constitutively activated JAK3 may improve treatment outcomes of CTCLs.

­Cutaneous T-cell Lymphoma

­ nteropathy-associated T-cell E Lymphoma

CTCL contains a broad spectrum of diseases: Mycosis fungoides and Sézary syndrome account for more than 60% of CTCL. The tumor cells of Mycosis fungoides and Sézary syndrome represent CD4+ helper T cells. Several CTCL models have been established to define mechanisms underlying CTCL and identify therapeutic targets. Patients with CTCL show high IL-15 protein levels in the skin. Hypermethylation within the IL-15 promoter suppresses binding of the ZEB1 transcriptional repressor to the locus, leading to increase of IL-15 transcription in CD4+ T cells  [41]. Fehniger et  al. reported a transgenic mouse model using the MHC class I promoter to drive IL-15 expression [42]. IL-15 transgenic mice developed fatal leukemia with involvement of multiple organs including skin around 12–30 weeks and have served as a preclinical CTCL model and were useful in the discovery that interruption of IL-15 signaling via an HDAC inhibitor is a promising treatment strategy for CTCL [41, 42]. JAK3-activating mutations are recurrently observed in CTCL  [43]. Human JAK3 shows four mutation hotspots: M511I, R657Q, A572V, and 573V. Cornejo et  al. reported the retroviral transduction of active JAK3A572V mutant cDNA into 5-fluorouracil-treated murine bone marrow cells followed by transplantation into lethally irradiated mice [44]. The recipient mice developed CD8+ lymphoproliferative diseases with skin involvement, mimicking a leukemic form of CTCL [44]. Rivera-Munoz et al. generated a JAK3A572V knock-in mouse model expressing the JAK3A572V mutant from the endogenous Jak3 locus also developed a leukemic form of CTCL  [45]. Phosphorylation of downstream targets of JAK3 was dose dependent: phospho-Stat3 and Stat5 were observed even in thymocytes from heterozygous JAK3A572V mutant mice, while phospho-Akt and Erk1/2 were seen only in those of homozygous. Treatment with tofacitinib, a pan-JAK inhibitor reduced growth of JAK3A572V-positive CD4+ and CD8+ malignant cells. This

EATL is a rare but fatal PTCL arising from the intestinal tract. Genomic alterations in SETD2 gene resulting in SETD2 loss of function, and/or loss of the corresponding 3p.21 locus are found in 31–86% of EATL [46, 47]. SETD2 encodes a non-redundant H3K36-specific tri-methyltransferase that serves as a tumor suppressor. In SETD2-mutated EATL samples, H3K36me3 expression in tumor specimens was either defective or very weak. To further investigate SETD2 function in T-cell development, the Setd2 cKO mice were generated with Lck-Cre transgenic mice  [47]. After comparing the proportion of intraepithelial T cells in Setd2 wild-type versus deficient mice, they observed a significant increase in the population of γδ-positive T cells in Setd2deficient mice. Although these mice do not perfectly recapitulate human EATL, this model may provide a very useful tool for future modeling of this fatal disease and is being evaluated in preclinical studies.

­Conclusion Over the years, murine models have played crucial roles as versatile tools for detailed investigation of T-cell lymphomas. We now have a deeper understanding of the underlying mechanisms, disease pathogenesis and potential therapeutic interventions. Nevertheless, it is essential to understand the limitations of these model systems. Lack of precise simulation of the human disease and the microenvironment in mice are few among many shortcomings that hinder the success of novel drugs in clinical trials. The advent of targeted genetic manipulation using novel technologies may eventually resolve and refine the remaining differences making mouse the ultimate model organism of choice to study human ailments.

Must Reads ●●

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Sakata-Yanagimoto, M., Enami, T., Yoshida, K., et al. (2014). Somatic RHOA mutation in angioimmunoblastic T cell lymphoma. Nat Genet 46 (2): 171–175. Miething, C., Grundler, R., Fend F, et al. (2003). The oncogenic fusion protein nucleophosmin–anaplastic lymphoma kinase (NPM–ALK) induces two distinct

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malignant phenotypes in a murine retroviral transplantation model. Oncogene 22 (30): 4642–4647. Chiarle, R., Gong, J.Z., Guasparri, I. et  al. (2003). NPMALK transgenic mice spontaneously develop T-cell lymphomas and plasma cell tumors. Blood 101 (5): 1919–1927.

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4  Animal Models of T-cell Lymphoma ●●

Kawano, N., Ishikawa, F., Shimoda, K. et  al. (2005). Efficient engraftment of primary adult T-cell leukemia cells in newborn NOD/SCID/beta2-microglobulin(null) mice. Leukemia 19 (8): 1384–1390.

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Cornejo, M.G., Kharas, M.G., Werneck, M.B. et  al. (2009). Constitutive JAK3 activation induces lymphoproliferative syndromes in murine bone marrow transplantation models. Blood 113 (12): 2746–2754.

­References 1 Swerdlow, S., Campo, E., Harris, N. et al. (2017). WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, 4e. Lyon: IARC Press. 2 Crotty, S. (2014). T follicular helper cell differentiation, function, and roles in disease. Immunity 41 (4): 529–542. 3 Yu, D., Tan, A.H., Hu, X. et al. (2007). Roquin represses autoimmunity by limiting inducible T-cell co-stimulator messenger RNA. Nature 450 (7167): 299–303. 4 Ellyard, J.I., Chia, T., Rodriguez-Pinilla, S.M. et al. (2012). Heterozygosity for Roquinsan leads to angioimmunoblastic T-cell lymphoma-like tumors in mice. Blood 120 (4): 812–821. 5 Auguste, T., Travert, M., Tarte, K. et al. (2013). ROQUIN/ RC3H1 alterations are not found in angioimmunoblastic T-cell lymphoma. PLoS One 8 (6): e64536. 6 Sakata-Yanagimoto, M., Enami, T., Yoshida, K. et al. (2014). Somatic RHOA mutation in angioimmunoblastic T cell lymphoma. Nat Genet 46 (2): 171–175. 7 Dobay, M.P., Lemonnier, F., Missiaglia, E. et al. (2017). Integrative clinicopathological and molecular analyses of angioimmunoblastic T-cell lymphoma and other nodal lymphomas of follicular helper T-cell origin. Haematologica 102 (4): e148–e151. 8 Palomero, T., Couronne, L., Khiabanian, H. et al. (2014). Recurrent mutations in epigenetic regulators, RHOA and FYN kinase in peripheral T cell lymphomas. Nat Genet 46 (2): 166–170. 9 Yoo, H.Y., Sung, M.K., Lee, S.H. et al. (2014). A recurrent inactivating mutation in RHOA GTPase in angioimmunoblastic T cell lymphoma. Nat Genet 46 (4): 371–375. 10 Muto, H., Sakata-Yanagimoto, M., Nagae, G. et al. (2014). Reduced TET2 function leads to T-cell lymphoma with follicular helper T-cell-like features in mice. Blood Cancer J 4: e264. 11 Lai, A.Y., Fatemi, M., Dhasarathy, A. et al. (2010). DNA methylation prevents CTCF-mediated silencing of the oncogene BCL6 in B cell lymphomas. J Exp Med 207 (9): 1939–1950. 12 Nishizawa, S., Sakata-Yanagimoto, M., Hattori, K. et al. (2017). BCL6 locus is hypermethylated in angioimmunoblastic T-cell lymphoma. Int J Hematol 105 (4): 465–469.

13 Zang, S., Li, J., Yang, H. et al. (2017). Mutations in 5-methylcytosine oxidase TET2 and RhoA cooperatively disrupt T cell homeostasis. J Clin Invest 127 (8): 2998–3012. 14 Cortes, J.R., Ambesi-Impiombato, A., Couronné, L. et al. (2018). RHOA G17V induces T follicular helper cell specification and promotes lymphomagenesis. Cancer Cell 33 (2): 259–273.e7. 15 Ng, S.Y., Brown, L., Stevenson, K. et al. (2018). RhoA G17V is sufficient to induce autoimmunity and promotes T-cell lymphomagenesis in mice. Blood 132 (9): 935–947. 16 Nguyen, T.B., Sakata-Yanagimoto, M., Fujisawa, M. et al. (2020). Dasatinib is an effective treatment for angioimmunoblastic T-cell lymphoma. Cancer Res 80 (9): 1875–1884. 17 Fujisawa, M., Sakata-Yanagimoto, M., Nishizawa, S. et al. (2018). Activation of RHOA-VAV1 signaling in angioimmunoblastic T-cell lymphoma. Leukemia 32 (3): 694–702. 18 Sato, F., Ishida, T., Ito, A. et al. (2013). Angioimmunoblastic T-cell lymphoma mice model. Leuk Res 37 (1): 21–27. 19 Morris, S.W., Kirstein, M.N., Valentine, M.B. et al. (1995). Fusion of a kinase gene, ALK, to a nucleolar protein gene, NPM, in non-Hodgkin’s lymphoma. Science 267 (5196): 316–317. 20 Kuefer, M.U., Look, A.T., Pulford, K. et al. (1997). Retrovirus-mediated gene transfer of NPM-ALK causes lymphoid malignancy in mice. Blood 90 (8): 2901–2910. 21 Miething, C., Grundler, R., Fend, F. et al. (2003). The oncogenic fusion protein nucleophosmin–anaplastic lymphoma kinase (NPM–ALK) induces two distinct malignant phenotypes in a murine retroviral transplantation model. Oncogene 22 (30): 4642–4647. 22 Miething, C., Grundler, R., Mugler, C. et al. (2004). A new method of retroviral lineage specific expression utilizing the Cre/lox system induces a T-lymphoid malignancy in a mouse model of ALCL. Blood 104 (11): 348. 23 Chiarle, R., Gong, J.Z., Guasparri, I. et al. (2003). NPM-ALK transgenic mice spontaneously develop T-cell lymphomas and plasma cell tumors. Blood 101 (5): 1919–1927. 24 Chiarle, R., Simmons, W.J., Cai, H. et al. (2005). Stat3 is required for ALK-mediated lymphomagenesis and

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provides a possible therapeutic target. Nat Med 11 (6): 623–629. Turner, S.D., Tooze, R., Maclennan, K., and Alexander, D.R. (2003). Vav-promoter regulated oncogenic fusion protein NPM-ALK in transgenic mice causes B-cell lymphomas with hyperactive Jun kinase. Oncogene 22 (49): 7750–7761. Turner, S.D., Merz, H., Yeung, D., and Alexander, D.R. (2006). CD2 promoter regulated nucleophosminanaplastic lymphoma kinase in transgenic mice causes B lymphoid malignancy. Anticancer Res 26 (5A): 3275–3279. Rajan, S.S., Li, L., Kweh, M.F. et al. (2019). CRISPR genome editing of murine hematopoietic stem cells to create Npm1-Alk causes ALK+ lymphoma after transplantation. Blood Adv 3 (12): 1788–1794. Pfeifer, W., Levi, E., Petrogiannis-Haliotis, T. et al. (1999). A murine xenograft model for human CD30+ anaplastic large cell lymphoma. Successful growth inhibition with an anti-CD30 antibody (HeFi-1). Am J Pathol 155 (4): 1353–1359. Bangham, C.R.M. (2018). Human T cell leukemia virus type 1: persistence and pathogenesis. Annu Rev Immunol 36 (1): 43–71. Nerenberg, M., Hinrichs, S.H., Reynolds, R.K. et al. (1987). The tat gene of human T-lymphotropic virus type 1 induces mesenchymal tumors in transgenic mice. Science 237 (4820): 1324–1329. Habu, K., Nakayama-Yamada, J., Asano, M. et al. (1999). The human T cell leukemia virus type I-tax gene is responsible for the development of both inflammatory polyarthropathy resembling rheumatoid arthritis and noninflammatory ankylotic arthropathy in transgenic mice. J Immunol 162 (5): 2956–2963. Ruddle, N.H., Li, C.B., Horne, W.C. et al. (1993). Mice transgenic for HTLV-I LTR-tax exhibit tax expression in bone, skeletal alterations. and high bone turnover. Virology 197 (1): 196–204. Hall, A.P., Irvine, J., Blyth, K. et al. (1998). Tumours derived from HTLV-I tax transgenic mice are characterized by enhanced levels of apoptosis and oncogene expression. J Pathol 186 (2): 209–214. Hasegawa, H., Sawa, H., Lewis, M.J. et al. (2006). Thymus-derived leukemia-lymphoma in mice transgenic for the tax gene of human T-lymphotropic virus type I. Nat Med 12 (4): 466–472. Grossman, W.J., Kimata, J.T., Wong, F.H. et al. (1995). Development of leukemia in mice transgenic for the tax

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gene of human T-cell leukemia virus type I. Proc Natl Acad Sci U S A 92 (4): 1057–1061. Gao, L., Deng, H., Zhao, H. et al. (2005). HTLV-1 tax transgenic mice develop spontaneous osteolytic bone metastases prevented by osteoclast inhibition. Blood 106 (13): 4294–4302. Satou, Y., Yasunaga, J.I., Zhao, T. et al. (2011). HTLV-1 bZIP factor induces T-cell lymphoma and systemic inflammation in vivo. PLoS Pathog 7 (2): e1001274. Esser, A.K., Rauch, D.A., Xiang, J. et al. (2017). HTLV-1 viral oncogene HBZ induces osteolytic bone disease in transgenic mice. Oncotarget 8 (41): 69250–69263. Zhao, T., Satou, Y., and Matsuoka, M. (2014). Development of T cell lymphoma in HTLV-1 bZIP factor and tax double transgenic mice. Arch Virol 159 (7): 1849–1856. Kawano, N., Ishikawa, F., Shimoda, K. et al. (2005). Efficient engraftment of primary adult T-cell leukemia cells in newborn NOD/SCID/beta2-microglobulin(null) mice. Leukemia 19 (8): 1384–1390. Mishra, A., La Perle, K., Kwiatkowski, S. et al. (2016). Mechanism, consequences, and therapeutic targeting of abnormal IL15 signaling in cutaneous T-cell lymphoma. Cancer Discov 6 (9): 986–1005. Fehniger, T.A., Suzuki, K., Ponnappan, A. et al. (2001). Fatal leukemia in interleukin 15 transgenic mice follows early expansions in natural killer and memory phenotype CD8+ T cells. J Exp Med 193 (2): 219–231. McGirt, L.Y., Jia, P., Baerenwald, D.A. et al. (2015). Whole-genome sequencing reveals oncogenic mutations in mycosis fungoides. Blood 126 (4): 508–519. Cornejo, M.G., Kharas, M.G., Werneck, M.B. et al. (2009). Constitutive JAK3 activation induces lymphoproliferative syndromes in murine bone marrow transplantation models. Blood 113 (12): 2746–2754. Rivera-Munoz, P., Laurent, A.P., Siret, A. et al. (2018). Partial trisomy 21 contributes to T-cell malignancies induced by JAK3-activating mutations in murine models. Blood Adv 2 (13): 1616–1627. Roberti, A., Dobay, M.P., Bisig, B. et al. (2016). Type II enteropathy-associated T-cell lymphoma features a unique genomic profile with highly recurrent SETD2 alterations. Nat Commun 7 (1): 12602–12613. Moffitt, A.B., Ondrejka, S.L., McKinney, M. et al. (2017). Enteropathy-associated T cell lymphoma subtypes are characterized by loss of function of SETD2. J Exp Med 214 (5): 1371–1386.

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Part II Epidemiology and Classification of the PTCL

59

5 Geographic Distribution of the Peripheral T-cell Lymphomas Global Epidemiology Amulya Yellala, Avyakta Kallam and James O. Armitage Division of Oncology-Hematology, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, USA

TAKE HOME MESSAGES ●●

●●

The T-cell lymphomas are characterized by marked differences in its global patterns of distribution. While the endemic distribution of viruses like human T-cell lymphotropic virus type I (HTLV1) and Epstein–Barr virus may help explain some of the geographic variability, the biological basis for the marked differences in incidence across countries is poorly understood.

­Historical Perspective The epidemiology and classification of non-Hodgkin lymphoma (NHL) has undergone vast transformation over the past few decades. Owing to an increase in incidence of the disease, a number of epidemiological studies were conducted, which led to a better understanding of the risk ­factors and the several subtypes of NHL. Despite these studies, the epidemiological data regarding peripheral T and natural killer (NK)-cell lymphomas is limited, due to the low incidence of this disease when compared with that of B-cell lymphomas. Mycosis fungoides and Sézary syndrome were described as early as 1806  [1] and 1938  [2], respectively. However, they were considered to be a histological subtype in a broad group which includes all lymphomas, distinguished from others based on their growth pattern. The Kiel classification, proposed by Lennert and Luke in 1974, was used to classify the lymphomas, based on the tumor morphological and cytological characteristics  [3]. It was not until mid1970s that they were both recognized to be a spectrum of cutaneous T-cell lymphomas (CTCL) [4], and it was only in the late 1970s that the T-cell lymphomas were proposed as a separate entity from B-cell lymphomas [5].

●●

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T-cell lymphomas like extranodal natural-killer T-cell lymphoma and HTLV1 adult T-cell leukemia/lymphoma have a much higher incidence and prevalence in Asia and the Caribbean, and are considered relative rare in the West. The incidence of peripheral T-cell lymphoma may have increased over the past two decades in the United States, some fraction of which may be due to better diagnosis.

Subsequently, with better understanding and characterization of the immune system, immunohistochemistry, and immunophenotyping were used to identify several subtypes of T-cell lymphomas. This was first incorporated to develop the Revised European–American Classification of Lymphoid Neoplasms classification for NHL based on a consensus list by the International Lymphoma Study Group in 1994  [6]. With improved understanding of the diversity and pathobiology of the disease, several classifications have been developed, such as the World Health Organization (WHO) project, and the European Organization of Research and Treatment of Cancer. These classifications have been further refined, incorporating the genetic, immunophenotypic, and pathobiological advances made in this field. T-cell lymphomas can be divided into those arising from precursor T cells termed as precursor T-lymphoblastic lymphoma and those of more mature T cells, referred to as peripheral or mature T-cell lymphomas (PTCLs). The 2017 WHO classification broadly divides PTCL into three categories based on their location. They are leukemic (disseminated), nodal, and extranodal. These categories are further subdivided based on morphology, immunohistochemistry, and clinical behavior. Examples of these lymphomas include PTCL not

The Peripheral T-Cell Lymphomas, First Edition. Edited by Owen A. O’Connor, Won Seog Kim and Pier Luigi Zinzani. © 2021 John Wiley & Sons Ltd. Published 2021 by John Wiley & Sons Ltd. Companion website: www.wiley.com/go/OConnor/Peripheral_T-cell_Lymphomas

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5  Geographic Distribution of the Peripheral T-cell Lymphomas

otherwise specified (PTCL-NOS), angioimmunoblastic T-cell lymphomas (AITL), anaplastic large-cell lymphoma (ALCL), anaplastic lymphoma kinase positive (ALK+), ALK negative (ALK–) ALCL, intestinal T-cell lymphoma, and breast implant-associated ALCL (BIA-ALCL). Since the 2017 WHO classification, numerous developments have resulted in a better understanding of the genetic basis of ALK+, ALK–, gastrointestinal T-cell and GATA3 subtypes of T-cell lymphomas. These changes will likely be incorporated into the next edition of the WHO classification [7]. The current WHO classification of T-cell lymphomas is presented in Appendix 5.A.

­Epidemiology PTCLs are a usually clinically aggressive, relatively rare, and heterogeneous group of lymphomas. They constitute about 10–15% of all NHL in the Western countries and 15–20% of all NHLs in Asia [8]. They originate from clonal proliferation of mature post-thymic lymphocytes. NK-cell lymphomas are also considered part of the group as NK cells are closely related to T cells. The incidence and prevalence varies in different racial populations and geographical regions [9–11], largely due to host genetic and environmental makeup and prevalence of risk factors, including diseases affecting immunity and virus epidemiology [11]. In an attempt to study the geographical distribution of NHL subtypes, the International NHL Classification Project was conducted in the late 1990s  [8]. A total of 1403 cases diagnosed from 1988 to 1990 were included from eight different geographic regions and nine institutions. Of these, 1378 were confirmed to be NHL and were analyzed; 109 cases of PTCL were included (9.4% of 1378), of which 33 were ALCLs. It was found that there were substantial geographical differences in distribution across different types of NHL. A higher percentage of PTCLs were seen in Hong Kong (10%), Cape Town (8%), and London (8%). The incidence in other geographical locations ranged from 1% to 6%. Non-anaplastic PTCLs (96/129 cases) also revealed geographical variation ranging from 18.3% in Hong Kong to 1.5% in Vancouver. Angiocentric nasal T/NK-cell lymphomas were almost exclusively seen in Hong Kong (8%) [12]. Subsequently, published in 2008 and confirming the results reported by NHL classification project in regards to differences in geographical distribution of various PTCL subtypes, the International T-cell Lymphoma Project reported data on 1314 cases of PTCL/NK-cell lymphomas from 22 centers worldwide with diagnoses between 1990 and 2002. ATLL and NK T-cell lymphomas were more frequent in Asia (25% and 22.4%, respectively) compared with Europe (1% and 4.3%, respectively) and North America (2% and 5.1%, respectively). In Europe and North America,

PTCL-NOS was the most common subtype (34.3% and 34.5%, respectively). AITL and enteropathy-associated T-cell lymphomas (EATL) were more common in Europe compared with North America and Asia, whereas ALK+ ALCLs were most common in North America [10]. In the United States (US), the incidence of T cell lymphomas has been gradually increasing over the past two decades, whereas the incidence of B-cell lymphomas has plateaued. According to a review of US surveillance, epidemiology and end results cancer database, over a 10-year period from 2007 to 2016, the incidence rate of T-cell lymphomas is 2.2 (2.2/1000 patients). Among the T cell lymphomas, PTCLs had the highest incidence (1.2), followed by CTCL (0.6). PTCL-NOS was the most common subtype of PTCL (0.4), followed by ATLL (0.3), ALCL (0.2), and AITL (0.2). The international PTCL project reported the most common subtypes of nodal T-cell lymphoma to be PTCL-NOS (25.9%), AITL (18.5%), ALCL (12%), NK/T-cell lymphoma (10.4%), hepatosplenic T-cell lymphoma (HSTL; 1.4%) and subcutaneous panniculitis-like T-cell lymphoma (0.9%) [13]. In this chapter, we discuss the epidemiological data for each of the individual subtype of PTCL (Table 5.1).

Peripheral T-cell Lymphoma, Not Otherwise Specified PTCL-NOS is a heterogeneous group of predominantly nodal T-cell lymphomas that originate from different types of mature T cells and do not meet the criteria for other specially defined subtypes of PTCL. This is the most prevalent subtype of PTCL seen in Western countries, accounting for approximately 30% of PTCL and approximately 4% of NHLs overall [8, 9, 14–16]. Owing to improved diagnostic methods and awareness of the disease, the incidence of PTCL-NOS has increased in the United States from approximately 0.1 cases per 100 000 population in 1992 to approximately 0.4 cases per 100 000 population in recent years [17]. In the United States, African Americans have a higher incidence, compared with Asian/Pacific Islanders, Hispanic Whites, and Non-Hispanic Whites, with American Indian/ Alaskan natives having the lowest incidence  [18]. As PTCLs account for approximately 15–20% of all NHLs in Asia, the incidence of PTCL-NOS is higher in Asia compared with the Western world [10]. Typically, the median age at diagnosis is 60–65 years [10, 18], and men have a higher incidence than women, with a ratio of approximately two to one [19]. A history of alcohol consumption and allergies is associated with decreased risk, whereas cigarette smoking, a history of psoriasis, and celiac disease are associated with higher risk for the development of PTCL-NOS per the InterLymph study [20]. In African Americans, an inverse relationship between PTCL-NOS and sun exposure was reported in one study [21].

­Epidemiolog 

Table 5.1  Major lymphoma subtypes by geographic region Incidence (%) Subtype

North America

Europe

Asia

PTCL-NOS

34.4

34.3

22.4

Angioimmunoblastic

16.0

28.7

17.9

ALK+ ALCL

16.0

6.4

3.2

ALK– ALCL

7.8

9.4

2.6

NKTCL

5.1

4.3

22.4

ATLL

2.0

1.0

25.0

Enteropathy-type

5.8

9.1

1.9

Hepatosplenic

3.0

2.3

0.2

Primary cutaneous ALCL

5.4

0.8

0.7

Subcutaneous panniculitis-like

1.3

0.5

1.3

Unclassifiable T-cell

2.3

3.3

2.4

Source: Vose et al. [10]. ALCL, anaplastic large-cell lymphoma; ALK, anaplastic lymphoma kinase; ATLL, adult T-cell leukemia/lymphoma; NKTCL, natural killer/T-cell lymphoma; NOS, not otherwise specified; PTCL, peripheral T-cell lymphoma.

Angioimmunoblastic T-cell Lymphoma AITL is thought to arise from follicular helper T cells which correspond to a subset of peripheral CD4 positive T cells [22, 23]. It is the second most commonly seen subtype of PTCL. The highest incidence rates are in Europe, specially Spain, France, Norway, Germany, Italy, and the UK (28.7% of PTCLs), while lower rates are seen in North America (16% of PTCLs) and Asia (17.9% of PTCLs)  [10, 24]. In the United States, the incidence is approximately 0.05 cases per 100 000 person years [25] and it is more frequently seen in Asian/Pacific Islanders and Hispanic Whites, compared with non-Hispanic Whites and African Americans [18]. AITL is not commonly seen in American Indian/Alaskan natives. Typically, the disease affects older adults with a median age at diagnosis of 65 years in France [26] and 69 years in the United States  [27]. It is almost never seen in persons less than 20 years of age, and there is a slight male preponderance seen is some studies  [28–31]. Although Epstein– Barr virus (EBV) infection is associated with pathogenesis of AITL, the exact mechanism remains a topic of debate [32]. Electrical fitters and persons with a family history of hematological malignancies appear to carry an increased risk of developing AITL [33].

Anaplastic Large-cell Lymphoma ALCL accounts for approximately 12% of T-cell lymphomas and approximately 2% of all NHLs  [10, 34]. It is the

third most common PTCL in adults in the United States and has an estimated incidence of 0.25 cases per 100 000 people [25]. The cell of origin is thought to be mature activated cytotoxic T-cells that are CD30+. Based on molecular characterization and clinical features, four distinct forms of ALCL are recognized: (i) primary systemic ALCL, ALK+ ALCL; (ii) primary systemic ALCL, ALK– ALCL; (iii) primary cutaneous ALCL; and (iv) BIA-ALCL. In the international T-cell lymphoma project, which is the largest retrospective study conducted in the disease, approximately 6.6% and 5.5% of cases were classified as ALK+ and ALK– ALCL, respectively [10]. ALCL was the most common PTCL subtype in the United States, accounting for approximately 24% of all cases. In the United States, Asian American are known to have a lower incidence of ALCL than White Americans, American Indians, African Americans, or Asian Pacific Islanders [18, 35]. ALK+ ALCLs have a median age incidence of 33–34 years whereas ALK– ALCLs have a median age of 58 years [10, 36]. In older adults, ALCL is typically ALK–. Male predominance is generally seen, and in young patients with ALK+ ALCL, the male to female ratio may be as high as three to one [37]. People with a history of celiac disease [38], those under 30 years, those with a history of eczema, and those with a history of cigarette smoking, people 30 years and older with a history of psoriasis, occupation as electrical fitter or textile worker, all have an increased risk of the disease [20]. EBV was originally thought to be associated with the development of this disease, but this finding has been subsequently

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reported not to be true [39]. HIV, however, does continue to remain a risk factor particularly for ALK– ALCL [40]. BIA-ALCL was added as a provisional entity in the new WHO classification. The exact incidence is not known. Although earlier or later presentations can be seen, most cases are known to present approximately one decade after implant placement. The median age of onset is approximately 50 years of age [41, 42]. Other implanted medical devices other than breast implants are not known to cause ALCL. Although the absolute risk for development of BIAALCL is low in women with breast implants, there is a high relative risk compared with the general population, as demonstrated in a population-based case–control study from the Netherlands (approximately nine million women) which reported an 18-fold higher rate of ALCL arising in the breast among women with breast implants compared with women who did not have implants [43]. The reason for implant placement (cosmetic versus reconstructive) does not seem to influence the risk of lymphoma [44].

Adult T-cell Lymphoma/Leukemia (HTLV Associated) ATLL is an often aggressive and relatively uncommon PTCL associated with infection by human T-cell lymphotropic virus type 1 (HTLV1). Incidence of ATLL varies by geographical region and population according to the prevalence of HTLV-1 infection [10]. Most affected patients live or originate from those areas where HTLV1 infection is endemic, such as several islands in the Caribbean basin (e.g. Jamaica and Trinidad), southern Japan, western Africa, northeast Iran, Peru, and the southeastern portion of the United States [45–49]. Epidemiologic studies suggest that HTLV-1 is primarily transmitted by breastfeeding, although spread via blood transfusion, sharing of needles, and sexual intercourse also occurs. About 2.5% of people infected with HTLV1 are estimated to be subsequently diagnosed with ATLL  [50, 51]. Patients infected as adults are less likely to develop ATLL compared with those exposed as children [52]. Contrasting evidence in gender distribution was noted with one study reporting equal incidence in males and females [53], whereas a different study noted ATLL to be slightly more predominant in males [52]. In the United States, the incidence of ATLL is approximately 0.05 cases per 100 000 people [54]. It is more commonly seen in African Americans and Asian/Pacific Islanders than White Americans [18]. The median age at diagnosis overall is in the sixth decade  [10, 55] but can vary with geographic location, as reported in a study from Jamaica of 126 patients with ATLL which reported a median age of 43 years [56]. Risk factors associated with

development of ATLL include a family history of ATLL, advanced age, high proviral load [57].

Extranodal NK/T-cell Lymphomas Extranodal NK/T-cell lymphoma (ENKTCL) is most commonly seen in Asia, Central and South America (Peru and Mexico), and Mexico, where it accounts for 5–10% of all NHLs [48, 49, 58, 59]. It is most commonly associated with EBV positivity  [60]. ENKTCL is a rare disorder in the United States, Europe, South Asia, the Middle East, and Africa. In the United States, the incidence is greater in Hispanic Whites and Asian/Pacific Islanders than in African Americans, non-Hispanic Whites, and American Indian/Alaskan natives  [18]. The most common site of presentation is nasal cavity followed by skin. The median age at presentation in Asia is 52 years (ranges from 44 to 54 years) [61] whereas median age at presentation in the United States is relatively older, around 64 years [18]. There is a male predominance with an approximately two to one male to female ratio [61, 62].

T-cell Prolymphocytic Leukemia T-cell prolymphocytic leukemia (T-PLL) is a relatively aggressive and extremely rare disease., Although the name suggests “prolymphocyte,” the cell of origin is actually a post-thymic T cell. T-PLL accounts for approximately 2% of peripheral T-cell lymphomas in adults [63, 64]. It has not been definitively reported in children or young adults. Sporadic T-PLL mainly affects older adults with a mean age at presentation of 63–65 years [65, 66], and there is a slight male predominance with a male to female ratio of 1.33  :  1  [63]. Patients with ataxia telangiectasia have a greatly increased incidence of T-PLL with a different epidemiologic profile [67]. In contrast to patients with sporadic T-PLL, the median age of onset of T-PLL in patients with ataxia telangiectasia is about 30 years, with some cases appearing in adolescence [68].

Large Granular Lymphocytic Leukemia Large granular lymphocytic leukemia (LGLL) constitutes around 6% of the chronic lymphoproliferative disorders in Asia and approximately 2–5% of the chronic lymphoproliferative disorders in the United States [54]. The incidence of LGLL is 0.2 cases per 1 000 000 individuals (range 0.17– 0.23). The incidence among African Americans, American Indians/Alaska Natives or Asian/Pacific Islanders is not significantly different compared with White Americans [69].

­Conclusio 

LGLL is rare in children, and exhibits a median age of onset of 60 years [70]. There is no reported gender difference in incidence. A distinctive feature of LGLL is its known association with autoimmune and hematological disorders. Rheumatoid arthritis is the most common autoimmune disorder which is known to be associated, occurring in approximately 25% of patients with LGLL  [71]. It is also known to coexist with other myeloid and lymphoid malignancies, including monoclonal gammopathy of undetermined significance, follicular lymphoma, Hodgkin lymphoma, chronic lymphocytic leukemia, mantle cell lymphoma, and hairy cell leukemia [72, 73].

Hepatosplenic T-cell Lymphoma HSTL was initially called hepatosplenic gamma–delta T-cell lymphoma, but with identification of the alpha/beta T-cell receptor in the liver, sinusoids of spleen and bone marrow, it was subsequently reclassified as HSTL. It is a very rare neoplasm, which usually has an aggressive course and carries a poor prognosis. HSTL accounts for less than 1% of NHL [9]. Only a few cases are reported in the literature, so the exact incidence is unknown [79]. It appears to have a male predominance with a median age at diagnosis of approximately 35 years [80]. Approximately, 15–20% of patients diagnosed with HSTL are known to be on prolonged immune-suppressive therapy in the setting of solid organ transplantation, and inflammatory bowel disease [81, 82].

Primary Cutaneous Gamma/Delta PTCL Primary cutaneous gamma–delta PTCL was originally classified under cutaneous panniculitis-like T-cell lymphoma [74], however, due to its gamma–delta phenotype and the aggressive nature of disease, it was recognized as a separate entity in the 2008 WHO classification  [9, 75]. It accounts for approximately 1% of CTCLs and because of the rarity of this entity its exact incidence and specific risk factors are not well understood. While males and females are equally affected, the age of incidence ranges from 40 to 60 years [76]. Unlike other types of PTCL, the most common site of origin is oral mucosa, as gamma–delta T-cells are more prevalent at mucosal sites [77].

Enteropathy Associated T-cell Lymphomas and Monomorphic Epitheliotropic Intestinal T-cell lymphoma In combination, EATL and monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL) account for approximately 5% of all T/NK-cell lymphomas [10, 51, 77]. In the past, EATL was classified into two subtypes. Type I is associated with celiac disease and type II is designated by lack of association with celiac disease. Both types originate from intraepithelial T cells of intestinal origin. The most recent 2017 WHO classification recognized type II EATL as a separate entity, now referred to as MEITL, based on its histologic characteristics [9]. EATL is primarily seen in individuals of northern European origin, where there is a higher incidence of celiac disease, whereas MEITL is a relatively aggressive type and is more frequently reported from Asia, but with apparent increase in frequency in individuals of Hispanic origin [78]. Individuals with celiac disease that is not adequately treated or is untreated have a higher incidence of developing EATL.

The Cutaneous T-cell Lymphomas Mycosis fungoides is the most common subtype of CTCL, accounting for approximately 50% of all primary CTCLs [83]. Like other lymphomas, it exhibits a male predominance with a ratio of two to one [84]. It is a disease affecting mostly older white populations, with a median age at diagnosis of 55–60 years [85]. Hispanic and African Americans typically present at a younger age, with most patients diagnosed by 40 years [51, 86]. A personal history of alcohol and tobacco use  [87] and occupations such as carpentry, painting, textile industry, and farming are known to be associated with higher incidence of mycosis fungoides [88]. Sézary syndrome was initially thought to be a leukemic form of mycosis fungoides, but with advancement in histopathologic and genetic technique, is now classified as a separate entity. While the exact incidence is unknown it is thought to accounts for about 2–5% of CTCLs  [85]. The incidence of Sézary syndrome is most common in non-hispanic white populations [89]. Male predominance is noted with a male to female ratio of 2.1 : 1 [90].

­Conclusion The T-cell lymphomas are fairly unique among the NHLs, in that they do exhibit an interesting geographic variation in their distribution, In most cases, we do not yet understand the biological basis for most of this variability, though those cases associated with viruses, like HTLV1 ATLL, do track with the distribution of the infection. The rarity and heterogeneity of the disease demand global collaboration in order to better appreciate the biological factors that may predispose to this geographic variability.

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Must Reads ●●

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Weisenburger, D.D., Savage, K.J., Harris, N.L., et al. (2011). Peripheral T-cell lymphoma, not otherwise specified: a report of 340 cases from the international peripheral T-cell lymphoma project. Blood 117: 3402. Vose, J., Armitage, J., Weisenburger, D. (2008). International peripheral T-cell and natural killer/T-cell lymphoma study: pathology findings and clinical outcomes. J Clin Oncol 26 (25): 4124–4130.

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de Leval, L., Parrens, M., Le Bras, F. et  al. (2015). Angioimmunoblastic T-cell lymphoma is the most common T-cell lymphoma in two distinct French information data sets. Haematologica 100 (9): e361–e364. Chihara, D., Ito, H., Matsuda, T., et al. (2014). Differences in incidence and trends of haematological malignancies in Japan and the United States. Br J Haematol 164: 536.

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5.A 2017 World Health Organization Classification of Mature T- and NK-cell Neoplasms

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lymphomas: a study from the bone marrow pathology group. Am J Clin Pathol 149: 164–171. Dhodapkar, M.V., Li, C.Y., Lust, J.A. et al. (1994). Clinical spectrum of clonal proliferations of T-large granular lymphocytes: a T-cell clonopathy of undetermined significance? Blood 84: 1620–1627. Jaffe, E.S. (2003). Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues. Lyon: International Agency for Research on Cancer Press. Toro, J.R., Liewehr, D.J., Pabby, N. et al. (2003). Gammadelta T-cell phenotypeis associated with significantly decreased survival in cutaneous T-cell lymphoma. Blood 101 (9): 3407–3412. Tripodo, C., Iannitto, E., Florena, A.M. et al. (2009). Gamma-delta T-cell lymphomas. Nat Rev Clin Oncol 6 (12): 707–717. de Baaij, L.R., Berkhof, J., van de Water, J.M.W. et al. (2015). A new and validated clinical prognostic model (EPI) for enteropathy-associated T-cell lymphoma. Clin Cancer Res 21 (13): 3013–3019. Tse, E., Gill, H., Loong, F. et al. (2012). Type II enteropathy-associated T-cell lymphoma: a multicenter analysis from the Asia lymphoma study group. Am J Hematol 87 (7): 663–668. Yabe, M., Miranda, R.N., and Medeiros, L.J. (2018). Hepatosplenic T-cell lymphoma: a review of clinicopathologic features, pathogenesis, and prognostic factors. Hum Pathol 74: 5–16. Belhadj, K., Reyes, F., Farcet, J.P. et al. (2003). Hepatosplenic gammadelta T-cell lymphoma is a rare clinicopathologic entity with poor outcome: report on a series of 21 patients. Blood 102 (13): 4261–4269. Falchook, G.S., Vega, F., Dang, N.H. et al. (2009). Hepatosplenic gamma-delta T-cell lymphoma: clinicopathological features and treatment. Ann Oncol 20: 1080–1085.

82 Ross, C.W., Schnitzer, B., Sheldon, S. et al. (1994). Gamma/delta T-cell posttransplantation lymphoproliferative disorder primarily in the spleen. Am J Clin Pathol 102: 310–315. 83 Burg, G. (2015). Systemic involvement in mycosis fungoides. Clin Dermatol 33 (5): 563–571. 84 Willemze, R. (2006). Primary cutaneous B-cell lymphoma: classification and treatment. Curr Opin Oncol 18 (5): 425–431. 85 Scarisbrick, J.J., Kim, Y.H., Whittaker, S.J. et al. (2014). Prognostic factors, prognostic indices and staging in mycosis fungoides and Sézary syndrome: where are we now? Br J Dermatol 170 (6): 1226–1236. 86 Tan, E.S., Tang, M.B., and Tan, S.H. (2006). Retrospective 5-year review of 131 patients with mycosis fungoides and Sézary syndrome seen at the National Skin Centre, Singapore. Australas J Dermatol 47 (4): 248–252. 87 Morales Suãrez-Varela, M.M., Olsen, J., Kaerlev, L. et al. (2001). Are alcohol intake and smoking associated with mycosis fungoides? A European multicentre case-control study. Eur J Cancer 37 (3): 392–397. 88 Aschebrook-Kilfoy, B., Cocco, P., La Vecchia, C. et al. (2014). Medical history, lifestyle, family history, and occupational risk factors for mycosis fungoides and Sezary syndrome: the InterLymph non-Hodgkin lymphoma subtypes project. J Natl Cancer Inst Monogr 2014 (48): 98–105. 89 Criscione, V.D. and Weinstock, M.A. ((2007). IncidenceofcutaneousT-celllymphoma in the United States, 1973–2002. Arch Dermatol 143 (7): 854–859. 90 Desai, M., Liu, S., and Parker, S. (2015). Clinical characteristics, prognostic factors, and survival of 393 patients with mycosis fungoides and Sezary syndrome in the southeastern United States: a single-institution cohort. J Am Acad Dermatol 72 (2): 276–285.

5.A  2017 World Health Organization Classification of Mature T- and NK-cell Neoplasms T-cell prolymphocytic leukemia T-cell large granular lymphocytic leukemia Chronic lymphoproliferative disorder of natural killer cells Aggressive natural killer (NK) cell leukemia Systemic Epstein–Barr virus-positive T-cell lymphoma of childhood (a) Hydroa vacciniforme-like lymphoproliferative disorder Adult T-cell leukemia/lymphoma Extranodal NK/T-cell lymphoma, nasal type

Intestinal T-cell lymphoma: Enteropathy-associated T-cell lymphoma ●● Monomorphic epitheliotropic intestinal T-cell lymphoma ●● Indolent T-cell lymphoproliferative disorder of the gastrointestinal tract Hepatosplenic T-cell lymphoma Subcutaneous panniculitis-like T-cell lymphoma Mycosis fungoides Sézary syndrome ●●

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Primary cutaneous CD30+ T-cell lymphoproliferative disorders: ●● Lymphomatoid papulosis ●● Primary cutaneous anaplastic large-cell lymphoma Primary cutaneous peripheral T-cell lymphomas, rare subtypes: ●● Primary cutaneous gamma–delta T-cell lymphoma ●● Primary cutaneous CD8+ aggressive epidermotropic cytotoxic T-cell lymphoma ●● Primary cutaneous acral CD8+ T-cell lymphoma ●● Primary cutaneous CD4+ small/medium T-cell lymphoproliferative disorder Peripheral T-cell lymphoma, not otherwise specified Angioimmunoblastic T-cell lymphoma and other nodal lymphomas of T-follicular helper (Tfh) origin:

Angioimmunoblastic T-cell lymphoma ●● Follicular T-cell lymphoma ●● Nodal peripheral T-cell lymphoma with Tfh phenotype Anaplastic lymphoma kinase negative anaplastic large-cell lymphoma Anaplastic lymphoma kinase positive anaplastic large-cell lymphoma Breast implant-associated anaplastic large-cell lymphoma ●●

Provisional entities are listed in italics. Source: Swerdlow et al. [9].

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6 Classification of the Peripheral T-cell Lymphomas Neval Ozkaya and Elaine S. Jaffe Hematopathology Section, Laboratory of Pathology, Center for Cancer Research, NCI, Bethesda, MD, USA

TAKE HOME MESSAGES ●●

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Nodal PTCLs with a T follicular helper phenotype show overlapping features, and often share a common genetic ­ ­profile, with ­mutations in TET2, DNMT3A, and RHOA. Most extranodal T-cell lymphomas have a cytotoxic phenotype and show frequent aberrations affecting the Janus

­Introduction The use of reproducible and clinically relevant disease definitions is critical for a successful classification scheme for lymphomas. Classification schemes can facilitate clinical management and clinical trials, as well as providing a basis for further exploration of lymphoma pathogenesis. The broadly accepted World Health Organization (WHO) classification system has been developed with this purpose. It emphasizes a multiparameter approach, integrating morphologic, immunophenotypic, genetic, and clinical information. Peripheral T-cell lymphomas (PTCLs) are a relatively rare and diverse group of neoplastic disorders, representing 10–15% of all non-Hodgkin lymphomas (NHLs). They originate from mature (post-thymic) T lymphocytes. Because natural killer (NK) cells share many phenotypic and functional properties with T cells, the WHO classification considers neoplasms of both cell types together. The classification system takes into account the physiological complexity of the various cell types, as well as the impact of their tissue distribution, which impacts cellular function. Progress to decipher the genomic basis of PTCL has lagged behind that of the B-cell lymphomas, in part due to their relative rarity and heterogeneity of the cellular composition. This latter aspect impacts the ability to obtain and characterize highly purified tumor cells. Nevertheless, in

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kinase–signal transducers and activators of transcription pathway. Anaplastic lymphoma kinase-negative anaplastic large-cell lymphoma is genetically heterogeneous, with significant ­variability in the clinical outcome.

the past decade, the advent of genomic characterization technologies has shed light on the molecular mechanisms and related phenotypes of PTCL. The revised fourth edition of the WHO classification delineates more than 30 different subtypes of mature T- and NK-cell neoplasms (see Appendix 5.1) [1].

­Angioimmunoblastic T-cell Lymphoma and Other Nodal Lymphomas of T follicular Helper Cell Origin Angioimmunoblastic T-cell lymphoma (AITL) has been recognized for many years as exhibiting a T follicular helper (Tfh) phenotype, similar to that of normal germinal center-derived T cells  [2–4]. Recent studies have shown that a proportion of PTCLs not otherwise specified (PTCLNOS) share similar biology and genomic profile with AITL. These observations have led to the recognition of two other PTCL entities related to AITL: nodal PTCL with a Tfh phenotype (PTCL-Tfh) and follicular T-cell lymphoma (FTCL)  [5, 6]. These diseases are grouped together with AITL under a common heading in the WHO classification, and are distinguished from other tumors within the category of PTCL-NOS [1].

The Peripheral T-Cell Lymphomas, First Edition. Edited by Owen A. O’Connor, Won Seog Kim and Pier Luigi Zinzani. © 2021 John Wiley & Sons Ltd. Published 2021 by John Wiley & Sons Ltd. Companion website: www.wiley.com/go/OConnor/Peripheral_T-cell_Lymphomas

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Angioimmunoblastic T-cell Lymphoma AITL is a systemic lymphoproliferative disorder (LPD) characterized by unique clinical presentation with prominent constitutional symptoms. Most patients manifest ­generalized lymphadenopathy and hepatosplenomegaly, but skin rash and polyclonal hypergammaglobulinemia associated with autoimmune phenomena are also frequently observed. AITL affects adults but has not been described in children [1]. Initially, AITL was recognized as an abnormal immune reaction morphologically characterized as atypical lymphoid hyperplasia with high risk of progression to malignant lymphoma  [7]. Subsequent studies have identified clonal T-cell receptor (TCR) gene rearrangements and clonal cytogenetic abnormalities in the majority of cases and established the neoplastic nature of the disease [8]. Histologically, the normal architecture of the lymph node is partially or entirely effaced. A characteristic feature of the disease is the prominent proliferation of high endothelial venules (HEVs) with arborization. There is a diffuse proliferation of follicular dendritic cells around HEVs, usually along with disappearance of follicles and germinal centers. The neoplastic T cells have clear cytoplasm and form small clusters, generally around the HEVs with a polymorphous inflammatory background (Figure 6.1).

Initially, the absence of hyperplastic B-cell follicles was thought to be a characteristic feature of the disease. Afterwards, it is accepted that there are three overlapping patterns with transition from pattern 1 to pattern 3. In pattern 1, the neoplastic cells surround hyperplastic follicles in a perifollicular distribution. In pattern 2, germinal centers are regressed, and the neoplastic cells are readily identifiable in the expanded paracortex. In pattern 3, there is diffuse effacement of the normal nodal architecture by the expanded paracortex with few regressed follicles [9]. Phenotypically, the neoplastic T-cells of AITL have a characteristic Tfh phenotype expressing Tfh markers include CD10, PD-1, CXCL13, ICOS, CXCR5, and BCL6 [2– 4, 9]. Although the relationship between AITL and Tfh was first proved by histopathological studies, it was further supported by the subsequent gene expression profiling [10]. Secondary expansion of B cells and plasma cells is a common feature of AITL, which likely reflects the Tfh function of the neoplastic T cells. These B-cell expansions are often oligoor monoclonal. Increased Epstein–Barr virus (EBV)-positive B cells are nearly always present, but the clonality of the B-cell expansion appears independent of EBV. The strong association with EBV infection suggests that the virus may be implicated in development of AITL. The clonal B-cell proliferations histologically may suggest coexistent B-cell lymphoma [11, 12],

H&E

CD3

PD1

CD21

Figure 6.1  Angioimmunoblastic T-cell lymphoma. Lymph node contains a polymorphous infiltrate with prominent high endothelial venules (HEV). Immunohistochemical (hematoxylin and eosin, H&E) stain for CD3 highlights the cytologic atypia. PD1 stain is strongly positive in the neoplastic cells. CD21 highlights a marked expansion of follicular dendritic cells around the HEV. Source: Neval Ozkaya, Elaine Jaffe.

­Peripheral T-cell Lymphoma Not Otherwise Specifie  71

but for the most part, this component is viewed as a manifestation of the primary disease, and not a secondary process, a finding suggested by recent genomic studies [13]. Recurrent TET2 mutations have been identified in 30–80% of the AITLs. Interestingly, TET2 mutations were also identified in some of the monocytes, CD34+ hematopoietic stem/precursor cells, and B cells of patients with AITL, indicating that AITL may be a disease of multiple lineages, at least in part  [14]. Other recurrently mutated genes are IDH2, DNMT3A, RHOA, and CD28 [1].

Follicular T-cell Lymphoma FTCL is an uncommon lymph node-based neoplasm of Tfh cells with characteristic morphologic features [15]. Clinical presentation of FTCL may overlap with AITL but it more often presents with lesser systemic symptoms and localized disease [15]. Two morphologic types have been described: follicular lymphoma-like FTCL (Figure 6.2) in which the Tfh cells are arranged in well-defined nodules, and a second pattern wherein the Tfh cells are arranged in well-defined aggregates surrounded by small immunoglobulin D+ naïve B cells that mimic progressive transformation of germinal centers [15]. The interfollicular areas lack the background histologic findings of AITL, including polymorphous infiltrate, significant vasculature proliferation, and extrafollicular expansion of follicular dendritic cell meshworks  [15]. Scattered B immunoblasts and, in a subset of cases, Hodgkin and Reed–Sternberg (HRS)-like cells often surrounded by neoplastic T cells are present [16]. In rare cases, sequential biopsies have demonstrated a switch in morphology from FTCL to typical AITL or vice versa, suggesting that these H&E

two entities may reflect different morphological stages of the same biological process [15]. However, significant clinical and pathological differences remain, so that both diagnoses are retained in the 2017 WHO classification  [1]. Approximately 20% of FTCL and rare cases of AITL carry a t(5;9)(q33;q22) leading to ITK–SYK fusion  [15, 17]. This translocation has not been reported in other subtypes of PTCLs. A recent study described novel protein tyrosine kinase genes rearrangements, namely FER and FES fusions in cases lacking ITK-SYK fusion [18]. Similarly, some of the mutations seen in AITL can occur in FTCL.

Nodal Peripheral T-cell Lymphoma with T-follicular Helper Phenotype PTCL-Tfh is a lymph node-based neoplasm of Tfh cells without distinctive morphologic features. It often shows a diffuse infiltration pattern without the characteristic histologic findings of AITL. In a subset of cases, a “T-zone pattern” may be seen [19]. In addition to Tfh phenotype, these cases also display some genetic alterations seen in AITL [20, 21]. Although relationship of these features to AITL is perceived, currently it is recommended that these cases be classified as PTCL-Tfh [1].

­ eripheral T-cell Lymphoma Not P Otherwise Specified PTCL-NOS is a wastebasket category to encompass heterogeneous diseases that do not correspond to any of the “otherwise specified” subtypes of T-cell lymphoma. PTCL-NOS is primarily seen in adults (median age 60 years) with male

PD1

Figure 6.2  Follicular T-cell lymphoma. The low-power view of the lymph node shows a vaguely nodular lymphoproliferation. A stain for PD1 shows neoplastic T cells infiltrating the lymphoid follicles. H&E, hematoxylin and eosin. Source: Neval Ozkaya, Elaine Jaffe.

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predominance and account for nearly one-third of PTCLs in Western countries. A broad spectrum of clinical presentations may be encountered but most patients present with generalized lymphadenopathy and B symptoms. Involvement of the spleen, liver, bone marrow, and other extranodal tissues may be seen in advanced-stage disease [22]. Rarely, primary cutaneous, central nervous system, and pulmonary diseases have been reported [23–25]. Although little biologic insight was obtained by immunophenotypic studies, recent gene expression profiling identified at least two major subgroups of PTCL-NOS that are categorized by high expression of either GATA3 or TBX21 (T-bet). These genes are transcription factors that regulate gene expression profiles in T helper cells and have an essential role in differentiation into Th2 and Th1 pathways, respectively. The GATA3 group was associated with distinctly worse prognosis. However, the TBX21 subgroup may be heterogeneous since a subset of the cases with a cytotoxic gene signature showed poor clinical outcomes [26]. A recent study generated an algorithm to identify these two molecular subtypes in paraffin tissue by immunohistochemistry using antibodies to key transcriptional factors (GATA3 and TBX21) and their target proteins (CCR4 and CXCR3). This algorithm resulted in a high sensitivity detection rate (85%) of the molecular subgroups, which needs to be confirmed in other studies [27]. CD30 expression is variable and usually does not have the strong intensity seen in ALCL [28]. However, there are rare cases with uniformly strong CD30 expression and an absence of characteristic cytologic features of ALCL  [28, 29]. For these cases, the differential diagnosis between anaplastic lymphoma kinase negative (ALK–) ALCL and CD30+ PTCL-NOS is controversial, and well-defined criteria have not been delineated. Some cases may also express CD15 and this finding is associated with an adverse prognosis  [29]. Aberrant expression of a single B-cell marker (CD20, CD19, CD79a, PAX5) has been documented in rare cases of PTCL-NOS, but the detection of more than one B-cell marker in an individual case is exceptional [30, 31]. The lymphoepithelioid variant, also known as “Lennert lymphoma,” is considered as a histologic variant of PTCLNOS and is characterized by numerous clusters of epithelioid histiocytes. In most cases, the neoplastic cells are CD8+ and have a cytotoxic phenotype [22, 32]. Primary EBV-positive nodal T/NK-cell lymphoma is a rare entity, which is characterized by a monomorphic infiltrate and absence of the angiodestruction and necrosis seen in extranodal NK/T-cell lymphomas. EBV expression in the majority of the neoplastic cells is a constant feature [17]. It is more common in the elderly or in the setting of immune deficiency. Currently, these cases are classified as a variant of PTCL-NOS [1].

­Anaplastic Large-cell Lymphomas ALCLs consist of several distinct clinicopathologic entities that are unified by the presence of characteristic “hallmark” cells and uniformly strong CD30 expression [1].

Anaplastic Large-cell Lymphoma, ALK-Positive ALK+ ALCL is a malignant neoplasm that differs from most other PTCLs in that it affects predominantly children and young adults. Although mostly nodal, extranodal involvement is frequent including bone, soft tissue, skin, and liver. Overall, ALK+ ALCL has a favorable prognosis superior to that of ALK– ALCL and most other systemic PTCLs [1, 33, 34]. In the lymph node, the neoplastic cells typically show a sheet-like infiltrate that sometimes spare residual lymphoid follicles and tend to invade lymphoid sinuses (Figure  6.3). The characteristic cell type is large with abundant cytoplasm, which contains a nucleus that is horseshoe shaped, folded, or lobated, and surrounds a prominent central Golgi zone socalled hallmark cell. It is called a common variant when the predominant population is composed of large cells. Two other histologic variants, namely small cell and lymphohistiocytic variants, have been recognized and are associated with a more aggressive clinical course [35]. Other cases with sarcomatous features, and rare cases with a hypocellular or myxoid background, have also been described [1]. Phenotypically, the neoplastic cells express an ALK fusion protein derived from an ALK rearrangement, and also express CD30  [1]. In most cases, neoplastic cells exhibit an aberrant phenotype with loss of many T-cellassociated antigens. Among T-cell antigens, CD2 and CD4 are most commonly expressed; while CD3, CD5, and CD8 are usually negative. Cytotoxic-associated antigen expression (TIA1, granzyme B, and perforin) are often encountered. A great majority of the cases show clonal TCR gene rearrangement. Although it does not pose a diagnostic challenge in most cases given the immunohistochemical detection of ALK, cases with variant morphological patterns may be harder to recognize, especially the small-cell variant, which is often misdiagnosed as PTCL-NOS. In ALK-positive ALCL, it has been shown that most changes leading to cell transformation are induced by transcription factors including STAT3/5 [36].

Anaplastic Large-cell Lymphoma, ALK-Negative By definition, ALK– ALCL is a CD30-positive T-cell neoplasm that is histologically similar to ALK-positive ALCL but lacks ALK protein [1]. The differences in epidemiology

­Anaplastic Large-cell Lymphoma  73 H&E

CD30

H&E

DUSP22 BA

Figure 6.3  Anaplastic large-cell lymphoma, anaplastic lymphoma kinase-negative. Hematoxylin and eosin (H&E) stain shows characteristic sinusoidal involvement by cohesive sheets of large cells. The neoplastic cells are strongly positive for CD30, which also highlights sinusoidal distribution. High-power view cells with the features of so-called “hallmark cells” (arrow). Fluorescence in situ hybridization using DUSP22/IRF4 break-apart probe shows rearrangement. Source: Neval Ozkaya, Elaine Jaffe.

and clinical outcomes between ALK– ALCL and either ALK+ ALCL or other CD30+ PTCLs have supported the concept of ALK– ALCL as a distinct entity [33]. In contrast to the ALK-positive ALCL, ALK– ALCL typically affects adults, although it may occur at any age. Patients typically present with adenopathy, but extranodal involvement is less common than in ALK+ ALCL [33]. The molecular pathogenesis of ALK– ALCL is heterogeneous. Two variants exhibited rearrangements of DUSP22 and TP63, which respectively had different clinical outcomes [37]. DUSP22-rearranged cases usually show a monomorphic population of hallmark cells and lack cytotoxic marker expression  [37, 38] (Figure  6.3). They lack expression of genes associated with the Janus-associated kinase–signal transducers and activators of transcription (JAK–STAT) signaling pathway, which contributes to growth in the majority of ALCLs including both the ALK-positive and ALK– types [39]. Moreover, they associate with a novel MSCE116K mutation likely involved in the CD30-IRF4-MYC axis, driving cellcycle progression, which is very rare in ALCLs without DUSP22 rearrangements  [40]. Although the initial studies showed a favorable prognosis in DUSP22-rearranged cases, recent reports show greater clinical variation [37, 41].

Breast Implant-associated Anaplastic Large-cell Lymphoma (Provisional) Breast implant-associated ALCL (BIA-ALCL) was incorporated in the 2017 WHO classification  [1]. It is a peculiar form of ALK– ALCL, first described in 1997, arising primarily in association with breast implants, where chronic antigenic stimulation is believed to promote activation and proliferation of cells [42, 43]. BIA-ALCL has morphologic and immunophenotypic features indistinguishable from ALK– ALCL, but distinctively indolent clinical behavior if the neoplastic cells are localized to the seroma cavity without capsular invasion [44–48]. In that setting, the disease can be managed conservatively, with removal of the implant and associated capsule, but without additional chemotherapy or radiation  [48]. The risk of developing BIA-ALCL is confined to those with textured implants [49]. The median time interval between implant placement and lymphoma diagnosis is eight to nine years. In cases with capsular invasion or extension to regional or distant nodes, the prognosis is less favorable [45, 47]. The diagnosis of BIA-ALCL is best made in cytological samples obtained by fine-needle aspiration of seroma fluid.

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In capsulectomy specimens, the tumor cells are embedded within a proteinaceous matrix and adherent to the capsule with varying degrees of capsular infiltration  [44, 46]. Similar to other forms of ALK– ALCL, cases show activating mutations of the JAK–STAT pathway, and new data show mutations in epigenetic modifiers [38, 50].

­Adult T-cell Leukemia/Lymphoma Adult T-cell leukemia/lymphoma (ATLL) is etiologically linked to the infection with an RNA retrovirus, the human T-cell lymphotropic virus type 1 (HTLV1, 51]. Approximately 2–7% of people infected with HTLV1 develop ATLL, where the incidence of the disease correlates with prevalence of HTLV1 infection in the population  [52]. ATLL is the first human neoplasm proved to be caused by a virus, although because of its unique clinicopathologic features, it was recognized as a disease entity in 1970s before HTLV1 was identified as a causal factor [51, 53]. HTLV1 infection has a long latency, as affected individuals are usually exposed to the virus very early in life, with ATLL occurring at an average age of 58 [52]. Morphologically, the spectrum of ATLL is diverse, though some cytologic features are typical including the presence of “flower cells” that demonstrate markedly polylobated nuclei, which are best seen in peripheral blood smears. The cells have hyperchromatic nuclei and basophilic cytoplasm, features that help in the distinction from Sézary syndrome [54, 55]. Lymph nodes show architectural effacement with a diffuse neoplastic infiltrate, morphologically resembling other forms of nodal PTCLs (Figure  6.4). Occasionally, a leukemic pattern of involvement with preserved or dilated sinuses can be seen. Lymph nodes in some patients in an early phase of ATLL may exhibit a Hodgkin lymphomalike histology including interspersed EBV+ B-lymphocytes with HRS-like features, which may be secondary to the underlying immunodeficiency seen in patients with ATLL [54, 55]. A broad spectrum of cutaneous lesions are encountered in ATLL, from erythematous rashes to large nodules, which may be ulcerated. The skin lesions often show epidermotropism with Pautrier-like microabscesses resembling mycosis fungoides [54, 55]. Phenotypically, as recent studies suggested, the cells of ATLL may be the equivalent of regulatory T cells. Therefore, regardless of the cytologic subtype, the neoplastic cells are CD4+ T cells that strongly express CD25 in nearly all cases and also express FOXP3 in at least subset of the cases (Figure  6.4). The neoplastic cells also express pan-T-cell antigens including CD2, CD3, and CD5, but usually lack

CD7 [56]. Strong and diffuse PD1 expression can be seen in ATLL and may potentially lead to diagnostic confusion with AITL, albeit expression of other Tfh markers is not seen [57]. CD52 and CCR4 can be positive, findings of clinical relevance for the use of anti-CD52 humanized antibody (alemtuzumab) and anti-CCR4 monoclonal antibody (mogamulizumab), respectively for treatment purposes [58]. Nonetheless, the hallmark for the diagnosis of ATLL is the demonstration of HTLV1 infection. A recent study of an integrated molecular analysis of Japanese patients has identified alterations of NF-nuclear factor kappa B (NF-κB) signaling. Other notable features include a predominance of activating mutations (PLCG1, PRKCB, CARD11, VAV1, IRF4, FYN, CCR4, CCR7) and gene fusions (CTLA4-CD28 and ICOS-CD28). Frequent intragenic deletions involving IKZF2, CARD11, and TP73 and mutations in GATA3, HNRNPA2B1, GPR183, CSNK2A1, CSNK2B, and CSNK1A1 were also observed  [59]. Interestingly, these findings were not seen in the North American ATLL cohort, which has a distinct genomic landscape that is characterized by frequent epigenetic mutations [60].

­Intestinal T-cell Lymphomas Intestinal T-cells normally found within the lamina propria and epithelial compartments are heterogenous with different phenotypes and functions  [61, 62]. Primary intestinal T-cell lymphomas are presumed to arise from those T cells, which can be of either alpha–beta or gamma–delta derivations. In the 2017 WHO classification, intestinal T-cell lymphomas are classified into four subcategories: enteropathy-associated T-cell lymphoma (EATL), monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL), intestinal T-cell lymphoma not otherwise specified, and indolent T-cell LPD of the gastrointestinal tract [1]. The former category of EATL type I is now renamed as EATL and is closely linked to celiac disease, whereas EATL type II is now renamed as MEITL and shows only rare association with celiac disease. Both have similar clinical presentation with abdominal pain, diarrhea, weight loss, gastrointestinal bleeding, and obstruction or perforation, as well as having a poor prognosis with a suboptimal response to chemotherapy. There remains rare cases of intestinal T-cell lymphomas that do not correspond to either EATL or MEITL category, which should be designated as intestinal T-cell lymphoma not otherwise specified. Recognition of a heterogenous group of clonal T-cell LPDs with indolent clinical course and characteristic morphologic features led to the inclusion of “indolent T-cell lymphoproliferative disorder of the gastrointestinal tract” which was classified as a new provisional entity. Aside

­Intestinal T-cell Lymphoma  75 H&E

CD3

CD25

FOXP3

Figure 6.4  Adult T-cell leukemia/lymphoma. Neoplastic lymphoid cells have pleomorphic and irregular nuclei. The neoplastic cells are positive for CD3, CD4 (not shown), CD25, and FOXP3. Positivity for HTLV1 was confirmed by polymerase chain reaction studies (not shown). H&E, hematoxylin and eosin. Source: Neval Ozkaya, Elaine Jaffe.

from the intestinal T-cell lymphomas, the gastrointestinal tract can be the site of primary or secondary extranodal NK/T-cell lymphoma. EBV is consistently negative in the all subtypes of intestinal T-cell lymphomas, unlike extranodal NK/T-cell lymphomas, but EBV expression may sometimes be seen in background reactive B cells [1].

Enteropathy-associated T-Cell Lymphoma EATL, formerly type I EATL, is a neoplasm of intraepithelial T cells that is associated with clinical or subclinical celiac disease and is closely linked to the prevalence of celiac disease in the population [63–65]. It is the most common primary intestinal T-cell lymphoma in Western countries, which occurs in adults between 50 and 60 years of age  [66]. Accompanying hemophagocytic syndrome has been reported in up to 40% of cases [67]. The most common sites of involvement are jejunum and ileum, seen in over 90% of cases [66]. A small fraction of the cases shows multifocal involvement  [67]. The tumor

mostly presents as strictures or ulcerating nodules and rarely as an exophytic mass. Spread to intraabdominal lymph nodes is seen in 30% of cases and a secondary involvement of bone marrow, skin, spleen, liver, and even central nervous system, can occur [66–68]. Morphologically, the neoplastic cells show a range in cell size and morphology, both between cases and within a single case, in contrast to the monomorphism appreciated in MEITL  [67]. Admixed inflammatory cells, particularly eosinophils, can be numerous and can mask tumor cells. Tumor necrosis is common, along with transmural invasion leading to perforation. The adjacent mucosa often shows intraepithelial spread of tumor cells. The nontumoral intestinal mucosa often shows changes of celiac disease, especially in the jejunum [69] (Figure 6.5). In most cases of EATL, the tumor cells express CD3, CD7, CD103 as well as cytotoxic markers such as TIA1, granzyme B, and perforin (Figure 6.5), while lacking CD5 and CD56 expression. Although they are usually double negative for CD4 and CD8, a CD8+ subset is also present  [67, 69].

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6  Classification of the Peripheral T-cell Lymphomas H&E

CD3

H&E

CD103

Figure 6.5  Enteropathy-associated T-cell lymphoma. CD3 stain shows increased intraepithelial lymphocytes in mucosa adjacent to tumor. Tumor cells infiltrate the intestinal wall and are strongly positive for CD103. H&E, hematoxylin and eosin. Source: Neval Ozkaya, Elaine Jaffe.

Variable CD30 expression can be seen; especially those cases with large-cell morphology are usually CD30+ and may resemble ALCL [67]. Gains of 9q34 region or deletions of 16q12 (these changes may also be seen in MEITL) as well as gains of chromosomes 1q and 5q (seen less frequently in MEITL) are detected in most of the cases [70, 71]. Recurrent mutations in the JAK–STAT signaling pathway have been described by recent studies  [72]. JAK1 and STAT3 mutations have also been detected in refractory celiac disease supports that the deregulation of JAK–STAT signaling to be an early event in disease pathogenesis [73].

Monomorphic Epitheliotropic Intestinal T-cell Lymphoma MEITL, formerly type II EATL, is a primary intestinal T-cell lymphoma derived from intraepithelial lymphocytes shows no clear association with celiac disease  [58]. The tumor often presents as a mass lesion with or without ulceration in the jejunum and ileum with involvement of the mesenteric lymph nodes. The neoplastic cells show monomorphic features with round nuclei, finely dispersed chromatin, and ample pale cytoplasm  [58, 69]. Prominent epitheliotropism with dis-

tortion of the adjacent villi is seen (Figure 6.6). An inflammatory background and necrosis are uncommon features in contrast to EATL [58]. MEITL has a distinctive phenotype with expression of CD3, CD8, and CD56 (Figure  6.6), and lack of CD5 and CD103 in the large subset of the cases [69]. Most cases are of gamma–delta T-cell derivation but some cases are of alpha– beta type, whereas others are TCR silent [58]. Approximately, 20% of cases show aberrant expression of CD20, a feature that can potentially lead to diagnostic confusion with B-cell lymphomas [74]. Gains of 9q34 region and extra signals at 8q24 (MYC) are commonly detected [75]. However, gains chromosomes 1q and 5q are far less frequent in comparison to EATL [76]. The most commonly mutated gene is SETD2 seen in up to 90% of cases [77]. STAT5B mutations have been reported in up to 63% of cases including those of both gamma–delta and alpha–beta derivations, which causes significant overlap with EATL [76].

Intestinal T-cell ymphoma, Not Otherwise Specified Intestinal T-cell lymphoma, not otherwise specified is not a specific entity but a provisional designation for cases that

­Intestinal T-cell Lymphoma  77 H&E

H&E

CD56

Perforin

Figure 6.6  Monomorphic epitheliotropic intestinal T-cell lymphoma. Monotonous medium-sized cells diffusely infiltrate the mucosa. The cells are positive for CD56 and cytotoxic markers including perforin. H&E, hematoxylin and eosin. Source: Neval Ozkaya, Elaine Jaffe.

arise in the gastrointestinal tract and do not fit either the EATL or the MEITL category  [1]. In the literature, most cases assigned to this category involved the colon and showed heterogeneous histopathologic features often with cytotoxic marker expression  [17]. Some cases appear to have widespread disease, so the intestine may not have been the primary site. They seem to be clinically aggressive.

Indolent T-cell Lymphoproliferative Disorder of the Gastrointestinal Tract (Provisional) The first case of indolent T-cell LPD of the gastrointestinal tract composed of CD4+ T cells widely distributed throughout the lamina propria of the intestinal mucosa without a transmural involvement – an unusual feature for intestinal T-cell lymphomas – was described in 1994 [78]. Since then, sporadic case reports and limited series have provided greater insight in to the clinicopathologic spectrum of these low-grade LPDs [79–82]. This has led to the inclusion of “indolent T-cell lymphoproliferative disorder of the gastrointestinal tract” as a provisional entity in the 2017 WHO classification [1]. These clonal T-cell proliferations involve the mucosa and can present throughout the gastrointestinal tract. They are most commonly seen in the small intestine and colon.

Most patients are adults, with a male predominance. Involvement is generally multifocal. Common presenting signs are abdominal pain, diarrhea, vomiting, dyspepsia, and weight loss [79–82]. The etiology of these disorders is unknown, with no ethnic or genetic factors having been identified, although some patients may have a history of autoimmune or infectious disease [79]. Microscopically, a characteristic feature is a variably dense, monotonous infiltrate composed of small lymphoid cells with little or no atypia, expanding the lamina propria. Focal infiltration of the muscularis mucosa and submucosa may be seen. Although the mucosal epithelium may be displaced by the lymphoid infiltrate, destruction, villous atrophy or crypt hyperplasia is typically not seen. No angiocentricity or angiodestructive pattern of growth or necrosis has been reported. Admixed inflammatory cells such as plasma cells, neutrophils, and eosinophils can be seen. The proliferative index is generally low [1, 79]. The atypical lymphoid cells show a mature T-cell phenotype characterized by expression of CD2, CD3, CD5, and variable expression of CD7. A greater proportion of cases are positive for CD4 compared with CD8. In rare instances, they may have either double negative or double positive phenotype by CD4 and CD8. CD8+ cases may display TIA1 expression but generally lack expression of granzyme B, and some cases show downregulation or loss of CD5 and/

78

6  Classification of the Peripheral T-cell Lymphomas

or CD7. Tfh markers (PD1, CD10, and BCL6) and EBV are consistently negative, although rare cases only with PD1 expression have been described [79, 83]. All reported cases thus far have expressed TCR alpha–beta and have had clonal rearrangements of TCR genes. Recent sequencing studies identified recurrent STAT3-JAK2 fusions and IL2 rearrangements exclusively in CD4+ and CD8+ subtypes, respectively suggesting that the molecular pathogenesis of gastrointestinal T-LPD may vary based on cell of origin. Another recurrently mutated gene is STAT3, which was found in CD4+, CD4/CD8++, and CD4/CD8 double negative cases but not in the CD8+ cases [83, 84].

NK-Cell Enteropathy NK-cell enteropathy is an indolent disease that shares many features with indolent T-LPD of the gastrointestinal tract, but as the term implies it is derived from NK cells. Although its nature as clonal compared with inflammatory non-clonal condition has been debated, a recent study identified recurrent JAK3 mutations, indicating a neoplastic nature of the process, at least for subset of the cases [85]. It is characterized by expression of CD2, CD3 (cytoplasmic), CD7, CD56, and cytotoxic markers including TIA1 and granzyme B but negative for TCR (beta, gamma, or delta)  [85, 86]. Polymerase chain reaction studies show polyclonal gene rearrangement pattern for TCR beta and TCR gamma genes, supporting an NK-cell origin.

­Hepatosplenic T-cell Lymphoma Hepatosplenic T-cell lymphoma (HSTCL) is a rare and c­linically aggressive type of extranodal T-cell lymphoma H&E

c­haracterized by a liver- and spleen-based disease without lymphadenopathy. It commonly affects adolescents and young adults with a male predominance. A proportion of HSTCL (around 20%) has been reported in association with long-term immunosuppressive therapy or prolonged antigenic stimulation  [87, 88]. Bone marrow involvement is almost always present at the time of diagnosis and accompanied by cytopenias [88]. Morphologically, the neoplastic cells are generally medium in size with pale cytoplasm, inconspicuous nucleoli and characteristically show a sinusoidal infiltration pattern in the spleen, liver (Figure  6.7) as well as bone marrow [1]. Most cases have a gamma–delta T-cell phenotype. Tumor cells are positive for CD2, CD3, CD7, TCR gamma–delta, and CD56; while negative for CD5 and CD57. The cells are usually double negative for CD4 and CD8 and display a non-activated cytotoxic T-cell phenotype, a helpful feature for the differentiation from T-large granular lymphocyte (T-LGL), with the expression of TIA1 but lack of granzyme B and perforin [37, 89]. A minority of cases may be of the alpha–beta type, though they appear to have a similar gene expression profile as the gamma–delta type [87, 90]. Isochromosome 7q and trisomy 8 are present in subset of the cases. Missense mutations involving STAT5B and STAT3 have been found in 40% of cases, as well as mutations in chromatin modifying genes, particularly SETD2 [91–93].

­Mycosis Fungoides Mycosis fungoides is the most common type of cutaneous T-cell lymphoma (CTCL) and comprises approximately 50% of all primary cutaneous lymphomas. CD3

Figure 6.7  Hepatosplenic T-cell lymphoma. Liver biopsy shows intrasinusoidal involvement by medium-sized lymphoid cells, highlighted by CD3. Cells were positive for TIA1 and TCR delta, but negative for granzyme B (not shown). H&E, hematoxylin and eosin. Source: Neval Ozkaya, Elaine Jaffe.

­Primary Cutaneous CD30-positive T-cell Lymphoproliferative Disorder  79

Three clinical stages have been recognized: early patch lesions, plaque lesions, and tumor stage [1]. Histologic features of the infiltrate vary with the clinical stage. Early patch lesions show a superficial band-like infiltrate with a linear distribution along the basal layer composed of small to medium-sized neoplastic cells which demonstrate characteristic cerebriform nuclei with clumped chromatin, inconspicuous nucleoli, and scant cytoplasm. Plaque lesions show more prominent epidermotropism  [94]. Progression to tumor stage is characterized by a diffuse dermal infiltrate composed of the variable-sized cells with pleomorphic nuclei. Transformation is defined by the presence of large neoplastic cells comprising more than 25% of the neoplastic infiltrate. The transformed large cells may show strong CD30 expression and resemble primary cutaneous ALCL (PCALCL). Epidermotropism with intraepidermal collections of tumor cells so-called “Pautrier microabscesses” are a hallmark for mycosis fungoides but are often absent in early plaque lesions and in tumor stage [95]. There are some histologic variants of mycosis fungoides, including folliculotropic, pagetoid reticulosis, and granulomatous slack skin [96]. Classic mycosis fungoides has mostly intact pan-T-cell markers and expresses CD4 with an alpha–beta phenotype [94]. CD7 is typically lost. There are rare cases with a cytotoxic phenotype expressing CD8 and/or TCR gamma– delta with a similar clinical behavior and prognosis as CD4+ cases  [94]. A CD8+ phenotype is mostly seen in pediatric patients. Clonal TCR gene rearrangements are usually detected, which can be helpful to rule out a reactive process when comparing multiple sites of involvement. Histologic assessment of clinically abnormal lymph nodes (>1.5 cm) is part of the staging system for mycosis fungoides. The morphologic appearance of the lymph node can be divided into three groups: N1, lymph nodes may only show reactive changes such as dermatopathic changes with no involvement; N2, lymph nodes may show an early involvement without architectural effacement; N3, lymph nodes may show overt involvement with either partial or complete effacement [97].

­Sézary Syndrome Sézary syndrome is an erythrodermic CTCL with a leukemic component, and is characterized by erythroderma, lymphadenopathy, and the presence of atypical circulating lymphocytes, so called “Sézary cells,” in the peripheral blood, skin, and lymph node [96]. Peripheral blood involvement requires demonstration of a clonal TCR gene rearrangement along with a total Sézary cell count   1000/μl, CD4 : CD8 ratio of  10, or an expanded

CD4+ T-cell population with abnormal phenotype including loss of CD7 or CD26. Overall histologic features of Sézary syndrome may resemble mycosis fungoides. However, the neoplastic infiltrate in Sézary syndrome is often more monotonous, and epidermotropism may sometimes be absent  [98]. Lymph node involvement, when present, shows effacement of the nodal architecture with a dense monotonous infiltrate. The neoplastic cells express CD3, CD4, PD1, and lack CD7, CD26, and CD8 [1]. Recurrent gain of function mutations affecting genes involved in TCR signaling including PLCG1, CD28, and TNFRSF1B, which may explain the constitutive activation of NF-κB pathway in Sézary syndrome. Other notable features include frequent TP53 inactivation mutations, loss of function aberrations in ARID1A as well as RHOA and DNMT3A mutations [1].

­ rimary Cutaneous CD30-positive P T-cell Lymphoproliferative Disorders The primary cutaneous CD30+ T-LPDs are the second most common group of cutaneous lymphomas, accounting for 10% of all cutaneous lymphomas and one third of CTCLs, characterized by chronic and indolent clinical behavior. This category includes three subtypes in the 2017 WHO classification: PCALCL, lymphomatoid papulosis, and borderline lesions. The clinical features are essential to make an accurate diagnosis. The hallmark pathological feature is the presence of atypical T-lymphocytes that strongly express CD30 on a lesional skin biopsy. Any age can be affected, including children, though the incidence overall increases with age and show a male predominance. Any region of the skin can be affected, including mucosal surfaces. Importantly, primary cutaneous CD30+ T-LPD must be distinguished from secondary involvement by systemic ALCL and transformed MF [1].

Lymphomatoid Papulosis Lymphomatoid papulosis occurs as recurring outbreaks of papulonodular lesions, often multiple and centrally necrotic, up to 2 cm in diameter. The lesions may regress spontaneously, usually in four to six weeks, leaving a hyper- or hypopigmented scar [1]. The histologic picture of lymphomatoid papulosis is heterogenous and mainly comprises six WHO-recognized histologic subtypes. Type A, the most common subtype (> 80%), may resemble Hodgkin lymphoma because of the presence of large HRS-like cells admixed with inflammatory cells. Type B lesions ( North America (7.8%) > Asia (2.6%)

LN, extranodal (skin, soft tissue, liver, lung, and bone; rarely CNS or GI tract)

Lymphadenopathy, B symptoms

30–49a

pcALCL

61

Mostly adults

Slight M > F (1.5–2:1)

Mostly white

North America (5.4%) > Europe (0.8%) > Asia (0.7%)

Skin; no dissemination but regional LN involved in 5–10%

Uni- or multifocal cutaneous nodules with or without erythema, ulceration

90–95

BIA-ALCL

53

Mostly adults

Nearly all F

Mostly white

Predominantly North America and Europe

Seroma and or capsule surrounding breast implant; may be bilateral; occasional regional LN

Peri-implant effusion or breast enlargement; may form mass; occasional lymphadenopathy, B symptoms

89

 Varies by tumor genetics (DUSP22 rearrangement, 90%; TP63 rearrangement, 17%; triple-negative, 42%) [1]. ALCL, anaplastic large-cell lymphoma; ALK, anaplastic lymphoma kinase; CNS, central nervous system; F, female; GI, gastrointestinal; LN, lymph node; M, male; OS, overall survival.

­Basic Principles of Disease Biolog  133

Table 10.2  Pathological and molecular features of anaplastic large-cell lymphomas. Subtype

Morphological features

Phenotype

Genetics

ALK+ALCL

Presence of hallmark cells; usually sheet-like growth with sinusoidal involvement (common pattern); variant patterns recognized (smallcell, lymphohistiocytic, Hodgkin-like)

ALK+, CD30+, CD25+, CD43+, cytotoxic proteins+, CD2+/−, CD4+/−, CD56+/−, clusterin+/−, EMA+/−, CD3−/+, CD5 −/+, CD7−/+, CD15−/+; rare: PAX5, keratins, CD13, CD33

Rearrangements of ALK on 2p23 with NPM1 (70%) or alternate fusion partner

ALK−ALCL

Presence of hallmark cells; usually sheet-like growth with sinusoidal involvement; variant patterns not formally recognized; DUSP22 rearrangement associated with doughnut cells, few large pleomorphic cells

ALK−, CD30+, CD25+, CD43+, CD45+/−, CD2+/−, CD3+/−, CD4+/−, EMA+/−, clusterin+/−, CD7−/+; rare: PAX5

Rearrangements of DUSP22 on 6p25.3 in 30% and TP63 on 3q28 in 8%; JAK–STAT pathway activation associated with mutations of JAK1, JAK3, STAT3 or rearrangements of ROS1, TYK2

pcALCL

Presence of hallmark cells; sheet-like growth in dermis; may extend into subcutaneous tissue; no significant epidermotropism

ALK−, CD30+, CD25+, CD43+, CD45+/−, CD2+/−, CD3+/−, CD4+/−, EMA+/−, clusterin+/−, CD7−/+

Rearrangements of DUSP22 or TP63 in subset

BIA-ALCL

Presence of hallmark cells; tumor cells in seroma fluid or on luminal side of fibrotic capsule; may show capsular invasion, mass formation, and/or lymph node involvement

ALK−, CD30+, IRF4+, pSTAT3+, CD3−/+

Mutations of DNMT3A, TP53, JAK1 and/or STAT3; no rearrangements of ALK, DUSP22, or TP63;

ALCL, anaplastic large cell lymphoma; ALK, anaplastic lymphoma kinase; BIA-ALCL, breast implant-associated ALCL; JAK–STAT, Janusassociated kinase– signal transducers and activators of transcription; pcALCL, primary cutaneous ALCL.

­Basic Principles of Disease Biology The cell of origin of ALCL has been controversial, although all subtypes are considered PTCLs, which are of post-thymic T-cell origin by definition  [31]. Gene expression profiling analysis supports derivation from activated T cells rather than from resting T, natural killer (NK) or NKT cells, but origin from a specific T-cell subset has been difficult to establish  [32]. One study suggested that ALK+ ALCL may be induced by the NPM-ALK fusion protein in early thymocytes before T-cell receptor (TCR) beta rearrangement, but that transient expression of a functional TCR is needed to enable thymic emigration of primed T lymphocytes to the periphery. Children with ALCL might thus harbor thymic lymphoma initiating cells capable of seeding relapse after chemotherapy [31, 33]. Genome-wide methylation studies have shown that ALK+ and ALK– ALCL share common DNA methylation changes in genes involved in T-cell differentiation and immune response. In addition, there is a close relationship between global ALCL DNA methylation patterns and those in distinct thymic developmental stages, with tumor-specific DNA hypomethylation in regulatory regions enriched for conserved transcription factor binding motifs [34].

Cutaneous T-cell lymphomas have been postulated to originate from skin-homing memory CD4+/CD45RO+ T cells [35]. Genome-wide analyses of sequential cutaneous CD30+ lymphoproliferative disorders, including lymphomatoid papulosis and PCALCL with and without lymph node involvement, have suggested a continuous spectrum of clonal evolution, supporting a common cell of origin among primary cutaneous cases [36]. Thus, PCALCL and systemic ALCL might have different cellular origins despite the finding that few genes are differentially expressed between systemic and PCALCL [32]. Because of the relatively recent recognition of BIA-ALCL as a clinical entity and its relative rarity, knowledge of its pathobiology is limited. The disease first presents as a periimplant seroma, a capsular mass, regional adenopathy, or an incidental finding during revision surgery. The clinical course varies widely from apparent spontaneous resolution to disseminated treatment-resistant disease and death [29]. The cell of origin has been difficult to decipher due to varying antigenic stimuli, proliferation drivers, host factors including host genetics, and shaping by the acquisition of oncogenic driver mutations. Cytokine expression profiling of BIA-ALCL cell lines and clinical specimens has revealed

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10  The Spectrum of Anaplastic Large-cell Lymphoma

a predominantly type 17 helper T cell (Th)/Th1 signature within an inflammatory microenvironment characterized by the presence of interleukin 13 and infiltration of eosinophils and mast cells [37]. While ALCL subtypes have distinct molecular abnormalities, which might drive malignant transformation and enhance tumor cell proliferation, all express CD30 by definition  [38, 39]. CD30 is a type I transmembrane protein belonging to the tumor necrosis factor receptor superfamily and encoded by the TNFRSF8 gene [40]. CD30 expression is constitutively induced in ALCL through the CD30/extracellular-regulated kinase (ERK) 1/2 mitogenactivated protein kinase (MAPK)/Ets-1/JunB/activator protein-1 (AP-1) signaling cascade, which regulates the CD30 promoter  [41–43]. CD30 stimulation triggers two competing effects in ALCL cells: caspase activation and nuclear factor kappa B (NF-κB)-mediated survival  [44]. Interferon regulatory factor 4 (IRF4) also transcriptionally regulates CD30 expression, which promotes NF-κB p52 and RelB activity that in turn augments IRF4 expression in a positive feedback loop [45]. In NPM-ALK+ ALCL, CD30 and NPM-ALK fusion protein collaborate to activate the MAPK pathway, including ERK, Jun N-terminal kinase, and p38 [46]. The ALK gene expressed in ALK+ ALCLs is consistently fused with one of multiple partner genes. ALK was first identified as the fusion partner of the nucleophosmin (NPM1) gene in recurrent t(2;5)(p23;q35) translocations and NPM1-ALK is the most common fusion in ALK+ ALCL (70–80%), followed by TPM3-ALK (12–18%), and fusions of ALK with less common partners [38]. The resulting fusion proteins are self-associating and constitutively active, influencing a number of downstream effectors including phospholipase C-gamma [47], phosphoinositide 3′-kinase/AKT  [48], Ras/ERK, Janus-associated kinase (JAK) 3–signal transducers and activators of transcription (STAT) 3 [49, 50], and the Sonic hedgehog signaling pathways [51], all of which support malignant transformation of lymphoma cells [52, 53]. Constitutive activation of STAT3 is detected in 93% of ALK+ ALCLs, 57% of ALK– ALCLs [54], and 90% of BIAALCLs [55]. The pleiotropic effects of STAT3 are due to the regulation of multiple sets of genes, including BCL2L1, TNFRSF8, and IL2RA. STAT3 regulates crucial functions that contribute to oncogenesis, such as cell cycle, apoptosis, motility, immune response, metabolism, and angiogenesis. In ALK+ ALCL, STAT3 constitutively activated by JAK3 is required for the maintenance of the neoplastic phenotype, and JAK inhibitor sensitivity has been correlated to the STAT3 phosphorylation status independently of JAK1 or STAT3 mutations [56]. IRF4 also regulates STAT3 signaling and its inhibition might represent a promising avenue for

the design of combination therapies in ALCL  [57]. Some ALK– ALCLs bear a spectrum of genetic events not involving ALK that also lead to STAT3 activation, including fusions involving ROS1 or TYK2 and mutations of JAK1, JAK3, or STAT3 itself [58]. These mutations have also been observed in BIA-ALCL. Chromosomal rearrangements of dual-specificity phosphatase-22 (DUSP22) and the TP53 homolog TP63 have been identified in 30% and 8% of ALK– ALCLs, respectively  [1, 59, 60]. ALCLs with DUSP22 rearrangements have unique morphological and molecular characteristics and decreased DUSP22 expression associated with disruption of the DUSP22 gene. These events have been observed in both systemic ALK– ALCL and PCALCL, but not BIAALCL  [61]. Systemic ALK– ALCLs with DUSP22 rearrangements have favorable outcomes, with a five-year overall survival rate of 90% that is similar to ALK+ ALCL (85%); in contrast, the five-year overall survival rate is only 17% in TP63-rearranged cases and 42% in in the remaining (“triple negative”) cases [1, 60].

­ anagement of Disease M in the Front Line Patients diagnosed with ALCL require pretreatment evaluation. CD30 and ALK are required for accurate diagnosis and subclassification, and also serve as therapeutic targets in ALCL. Rearrangements of DUSP22 and TP63 can be assessed by fluorescence in situ hybridization to provide prognostic information and potentially guide management decisions. Disease stage, performance status, and the International Prognostic Index score should be determined. Clinical staging is of utmost importance before rendering a diagnosis of PCALCL, since systemic ALCL may involve the skin secondarily. Front-line therapy for ALCL traditionally has consisted of combination chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP; Table 10.3). A retrospective analysis of 40 patients with systemic ALCL, of whom the majority received CHOP, reported a three-year overall survival rate of 100% for ALK+ ALCL compared with 66% for ALK– ALCL [62, 63]. A series from the International Peripheral T-cell Lymphoma Project reported overall response rates to primary treatment of 88% and 76% in ALK+ and ALK– ALCL, respectively  [11]. The German High-Grade Non-Hodgkin Lymphoma Study Group reported that the addition of etoposide to CHOP regimens (CHOEP) improved overall response rates and provided superior event-free survival rates in younger patients with ALK+ ALCL and normal LDH (three-year event-free survival rates of 91% and 57%

Table 10.3  Current treatment of anaplastic large-cell lymphoma. Setting

Regimen

Front line

BV-CHP

Response rates

Major toxicities

ORR, 100%; CR, 84%

Peripheral neuropathy, neutropenia, PML, pancreatitis, pulmonary toxicity, skin and subcutaneous tissue disorders, diarrhea, hyperglycemia

 60 years or unfit, CHOEP if  60 years) for six cycles followed by carmustine, etoposide, cytarabine, and melphalan, or cyclophosphamide/ASCT in responding patients. Outcomes in ALK– ALCL have been superior to other subtypes of PTCL with five-year progression-free and overall survival rates of 61% and 70%, respectively  [72]. Because most patients with ALK– ALCL with DUSP22 rearrangements have overall survival rates similar to those of ALK+ ALCL, ASCT may not provide additional benefit in these patients and could potentially be avoided, except in high-risk patients  [73]. Given new treatment recommendations for brentuximab vedotin in the front-line setting, the role of ASCT in first remission will require reevaluation in this context. Radiation therapy is used widely in PCALCL but has a limited role in patients with systemic ALCL. If patients

­Management of the Relapsed or Refractory Patien  137

with limited stage (I/II) ALCL are unable to tolerate extensive chemotherapy or have significant comorbidities, three to four cycles of chemotherapy followed by localized radiation therapy may be recommended. For patients with limited stage BIA-ALCL, surgical removal of the implant and capsule with negative margins is recommended. These patients have no need for adjunctive chemotherapy or radiotherapy, and surgery is associated with excellent outcomes (three-year overall survival of 100%) [74]. Patients with advanced BIA-ALCL presenting with a mass, capsular extension and/or lymphadenopathy may have a more aggressive course. Among these patients, implant removal followed by adjunctive chemotherapy (CHOP, EPOCH, or brentuximab vedotin for first-line therapy) is required, although there is no consensus on the type of chemotherapy to administer. For patients with bilateral implants, removal of the contralateral implant should be considered since cases may present or recur with contralateral disease. For patients with proven disseminated disease or who recur after surgical therapy alone, anthracyclinebased chemotherapy is recommended. The role of radiation therapy in the management of BIA-ALCL is unclear.

­ anagement of the Relapsed or M Refractory Patient Although overall response rates to combination therapy in ALCL are generally favorable, relapse after first-line therapy is common with the exception of low-risk ALK+ ALCL, and five-year overall survival rates in relapsed patients are only 10–30% [75]. After initial therapy, patients should be monitored at routine intervals for treatmentrelated complications and progression. Progressive disease includes any new lesion, enlargement of previously identified lesions, or new involvement of the bone marrow. With suspected relapse, biopsy of the corresponding lymph node or other site is recommended. If relapse is confirmed, the patient should undergo restaging with physical examination and imaging studies. There is no standard therapy for patients with relapsed or refractory ALCL, although a number of new single agents have been approved which include this entity. In most cases, a salvage combination chemotherapy regimen is commonly used because of higher response rates and the possibility of long-term survival following hematopoietic cell transplantation (HCT) in those who achieve complete response. Patients with relapsed or refractory ALCL are also likely to benefit from second- or third-line therapies or may be enrolled in a clinical trial [76]. Brentuximab vedotin has been approved by the FDA for the treatment of relapsed ALCL after failure of prior

chemotherapy regimens. Response rates to brentuximab vedotin in patients with relapsed/refractory ALCL have exceeded 80% with frequent complete responses and a median duration of response greater than one year. In a phase II clinical trial, brentuximab vedotin at a dose of 1.8 mg/kg administered every three weeks induced objective responses in 86% of 58 patients (57% complete response, 29% partial response) with recurrent systemic ALCL (median duration of overall response, 12.6 months)  [77]. However, long-term treatment with brentuximab vedotin for advanced ALCL may be hindered by side effects, particularly incremental neurotoxicity. Brentuximab vedotin is sometimes used as a bridge to stem-cell transplant [71, 76]. Both autologous and allogeneic HCT have been shown to have efficacy in relapsed ALCL  [78]. High-dose chemotherapy followed by autologous HCT is often used in relapsed/refractory ALCL because of relatively good response rates and a higher complete response rate than other modalities. Although some studies have reported that autologous HCT in first remission can improve overall survival, a consistent benefit has not been confirmed in randomized trials. In 1999, Fanin et al. reported that 47% of 64 patients with relapsed ALCL achieved complete response after high-dose chemotherapy and ASCT [79]. In prospective trials of ASCT with high-dose chemotherapy in patients with relapsed PTCL of whom 57% had ALCL, 39% achieved complete response [80]. However, long-term survival is relatively poor and approximately two-thirds of patients with relapsed or refractory ALCL are not transplant candidates. ALK+ ALCL is associated with the best event-free survival after high-dose chemotherapy and ASCT in the relapsed setting [80]. There has been limited experience with allogeneic HCT for relapsed/refractory PTCL in general, including ALCL. Allogeneic HCT is associated with a lower relapse rate but a higher non-relapse mortality, resulting in overall survival rates similar to those for ASCT [81]. Myeloablative allogeneic HCT can lead to durable remissions in 30–50% of patients with PTCL; however, the transplant-related mortality rate is approximately 30%. Crizotinib is an oral first-generation ALK inhibitor that is FDA-approved for ALK-positive advanced non-small-cell lung cancer (NSCLC). It blocks ALK-triggered pathways such as PI3K/AKT/mTOR indispensable for survival of ALK-driven tumors. Crizotinib has therapeutic activity in relapsed and refractory ALK+ ALCL. In a phase I doseescalation trial that included nine pediatric patients with ALK+ ALCL, there was an overall response rate of 88% with seven complete responses and one partial response [82]. However, ALK gene mutations can induce resistance to ALK inhibitors. Strategies to overcome resistance include

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10  The Spectrum of Anaplastic Large-cell Lymphoma

the design of second-generation drugs and the use of combined therapies that simultaneously target multiple signaling nodes essential for cell survival. Brigatinib is a second-generation ALK and enhanced green fluorescent protein inhibitor with activity against a broad spectrum of ALK mutants resistant to other agents, and is approved as a second-line treatment for NSCLC. Lorlatinib is a third-generation ALK and ROS1 inhibitor approved by the FDA for NSCLC [83]. It is a macrocyclic TKI specifically designed to overcome TKI-resistant ALK mutations and to penetrate the blood–brain barrier. Lorlatinib has breakthrough therapy designation for use in patients with ALK+ unresectable advanced and/or recurrent NSCLC who have previously received one or more ALK inhibitors and orphan drug status for first- and second-line treatment in ALK+ NSCLC in the United States [84]. Histone deacetylases (HDACs) play multiple roles in cancer pathogenesis, regulating cancer cell differentiation, proliferation, migration, and survival. HDAC inhibitors are pleiotropic drugs that simultaneously target multiple signaling pathways essential for tumor-cell survival. Romidepsin is a class I selective histone deacetylase inhibitor approved by the FDA for patients with cutaneous T-cell lymphoma or PTCL treated with at least one prior systemic therapy  [85]. In the pivotal phase II trial in 130 patients with relapsed/refractory PTCL with a median follow-up of 13.4 months, romidepsin led to an overall response rate of 25% and a median progression-free survival of four months [86]. The efficacy was similar in ALK– ALCL with an overall response rate of 24%. Belinostat, approved by the FDA in 2014, is a hydroxamic acid-derived pan-HDAC inhibitor acting on all zinc-dependent HDAC enzymes. It is indicated for the treatment of relapsed PTCL following at least one line of therapy. Belinostat has been shown to be well tolerated across malignancies (n = 512) and was effective in a subpopulation of 144 patients with relapsed/ refractory PTCLs including 12.4% ALCLs. An overall response rate of around 25% and complete response rates of 8–23% have been reported. Safety analysis demonstrated common adverse effects including fatigue, nausea and vomiting, but low rates of grade 3/4 hematologic toxicity (6.4%) [87]. Pralatrexate is a dihydrofolate reductase (DHFR) inhibitor with high affinity for the reduced folate carrier type-1 oncoprotein and is an efficient substrate for polyglutamylation by the enzyme folylpolyglutamate synthetase, resulting in extensive internalization and accumulation within tumor cells. DHFR inhibition results in disruption of DNA synthesis and subsequent tumor cell death [88]. Pralatrexate was the first drug approved by the FDA for relapsed/refractory PTCL [89] and has higher potency than methotrexate

or edatrexate [90]. A phase II study of cyclophosphamide, etoposide, vincristine, and prednisone, alternating with pralatrexate as front-line therapy for 33 patients with stage II–IV PTCL included four with ALCL (12%), all of whom achieved a complete or partial response. The two-year progression-free and overall survival rates were 50% and 75%, respectively [91]. A detailed discussion on the data and role of these drugs across the spectrum of PTCL is provided in other chapters.

­Future Directions Strategies to improve outcomes in ALCL include the design of next generation drugs and the use of combined therapies that simultaneously target multiple nodes essential for cell survival (Table 10.4). Immune checkpoint inhibitors work by blocking checkpoint proteins from binding with their partner proteins and have been approved by the FDA for a variety of cancer types. PD1/PD-L1 blockade is one of the most successful immunotherapies that enhances T-cell immune responses against tumor cells. PD-L1 is highly expressed in ALK+ ALCL and many ALK– ALCLs, particularly those without DUSP22 rearrangements  [95], and has been associated with inferior outcomes in ALK– ALCL  [96]. PD1/PD-L1 blockade is currently being examined in multiple NHL subtypes, including T-cell lymphoma. Anecdotal reports have indicated that patients with refractory ALK-positive ALCL can achieve dramatic responses after anti-PD1 therapy  [97, 98]. However, recent experimental data indicate PD1 is a tumor suppressor in T cells  [99], and reports of rapid progression of T-cell lymphomas after anti-PD1 therapy have suggested that other approaches to checkpoint blockade should be explored in these patients [100]. Inhibition of the JAK–STAT pathway inhibits cell growth in a variety of cancers. In ALCL cells, the JAK3 inhibitors AG490, WHI-P131 and WHI-P154 induced apoptosis with activation of caspase-3, decreased BCL-xL and BCL-2, and induced cell cycle arrest attributed to cyclin D3 downregulation and p21waf1 upregulation  [92]. Another group found that exogenous cytokine-independent ALCL cells responded to JAK inhibition regardless of JAK mutation status, with sensitivity correlated to STAT3 phosphorylation status. Ruxolitinib, a JAK1/2 inhibitor, was effective in an ALK-ALCL xenograft model  [101]. Therefore, JAK inhibitor therapy might benefit patients with ALK- ALCL expressing phosphorylated STAT3 [58]. Dual phosphatidylinositol-3-kinase (PI3K)/mTOR inhibition represents another potential therapeutic strategy, particularly in ALK+ ALCL given direct activation of this pathway by NPM-ALK signaling  [102]. The dual

­Future Direction 

Table 10.4  Future directions for treatment of anaplastic large-cell lymphoma. Approach

Possible agents

Target

Current status

Immune checkpoint blockade

Nivolumab

PD-1

Phase II (NCT03703050)

Kinase inhibition

AG490

JAK3

Preclinical [92]

WHI-P131/ WHI-P154

JAK3

Preclinical [50, 92]

Ruxolitinib

JAK1/2

Phase I (NCT02613598)

BGT226

PI3K

Preclinical [93]

MLN8237

Aurora kinase A

Phase III (NCT01466881/ NCT01567709)

Chidamide

HDAC

Phase II [94]

Benzamide

HDAC

Phase II (NCT04233294)

5-aza-2′deoxycytidine (5-aza-CdR)

DNA methylation

Phase I (NCT00002980)

ATLCAR.CD30

CD30 (CAR-T)

Phase I (NCT03602157)

ATLCAR. CD30.CCR4

CD30/CCR4 (CAR-T)

Phase I (NCT03602157)

AFM13

CD30/CD16A (tandem Ab)

Phase I (NCT04074746)

Epigenetic therapies

Antibody-based therapies

PI3K/mTOR inhibitor BGT226 induced cell-cycle arrest in ALK+ ALCL cells in vitro and in vivo, and activity could be monitored with fluorodeoxyglucose (FDG)positron emission tomography (PET) and FLT-PET during therapy [93]. A 2016 study combined ALK inhibitors with the mTOR inhibitor temsirolimus in ALK+ ALCL cells, resulting in increased inhibition of mTOR effectors, cell-cycle arrest, apoptosis, and complete regression of tumors in a xenograft model [103]. Aurora A kinase represents another potential target; a phase II trial of the aurora kinase inhibitor alisertib demonstrated antitumor activity in relapsed/refractory PTCL, though relatively few patients with ALCL were enrolled [104]. As indicated by FDA approval of multiple HDAC inhibitors for PTCLs, new epigenetic approaches to therapy offer considerable promise  [105]. Because response rates are modest, however, new agents, combination approaches, and biomarkers to select patients for therapy all need to be explored. A phase II trial of the novel oral benzamide HDAC inhibitor chidamide was conducted in 17 patients with ALCL  [106]. Patients who were ALK– had an overall response rate of 45% and a complete response rate of 36% with a duration of response of 19.1 months. DNA methylation is an epigenetic mechanism inducing long-term gene silencing during development and cell commitment, which is maintained in subsequent cell generations. Aberrant DNA methylation is found at gene promoters in most cancers and

can lead to silencing of tumor suppressor genes. The DNA methyltransferase inhibitor 5-aza-2′-deoxycytidine (5-azaCdR) is able to reactivate genes silenced by DNA methylation and has potent activity in several hematological malignancies. Low-dose treatment of ALCL cells with 5-azaCdR has been shown to induce apoptosis and cell cycle arrest in vitro and in xenograft models [107]. CAR-T cells combine the specificity of an antibody with the cytotoxic function of T cells to harness anti-tumor T-cell activity independent of HLA. Currently there are five ongoing clinical trials using CAR-T therapy in ALCL. Ramos et al. have reported a phase 1 dose escalation study using CAR-T cells expressing a chimeric anti-CD30 antibody. One of two patients with ALCL had a complete response persisting nine months after the fourth dose [108]. The chemokine receptor CCR4 represents another candidate target for CAR-T cell therapy. CCR4-directed CAR-T cells have shown antigen-dependent efficacy against patient derived ALCL cell lines  [109]. An additional approach is to engineer anti-CD30 CAR-T cells to express more CCR4 to enhance localization of the CAR-T cells to areas of tumor [110]. Finally, a phase I/II trial is evaluating a novel fourth generation anti-CD30 CAR-T engineered with a self-withdrawal mechanism (FKBP-iCasp9) for both efficacy and safety evaluation in 20 relapsed/refractory patients with CD30-positive lymphomas including ALCL. AFM13 is a bispecific, tetravalent chimeric antibody that

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recruits NK cells by binding to CD16A and engages them to eliminate CD30-positive lymphoma cells via an anti-CD30 antibody. A phase I study of 28 patients with heavily pretreated relapsed/refractory Hodgkin lymphoma reported an overall response rate of 23%; [111] further phase 1 and 2 studies are underway (NCT02321592, NCT04074746) [112].

­Acknowledgement Supported in part by award number T32 GM008685 from the National Institute of General Medical Sciences.

Must Reads ●●

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Horwitz, S., O’Connor, O.A., Pro, B. et  al. (2019). Brentuximab vedotin with chemotherapy for CD30positive peripheral T-cell lymphoma (ECHELON-2): a global, double-blind, randomised, phase 3 trial. Lancet 393 (10168): 229–240. Bennani-Baiti, N., Ansell, S., and Feldman, A.L. (2016). Adult systemic anaplastic large-cell lymphoma:

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Group for Blood and Marrow Transplantation (EBMT). Bone Marrow Transplant 23 (5): 437–442. Jagasia, M., Morgan, D., Goodman, S. et al. (2004). Histology impacts the outcome of peripheral T-cell lymphomas after high dose chemotherapy and stem cell transplant. Leuk Lymphoma 45 (11): 2261–2267. Reimer, P. (2010). Impact of autologous and allogeneic stem cell transplantation in peripheral T-cell lymphomas. Adv Hematol 2010: 320624. Mosse, Y.P., Lim, M.S., Voss, S.D. et al. ((2013). Safety and activity of crizotinib for paediatric patients with refractory solid tumours or anaplastic large-cell lymphoma: a Children’s Oncology Group phase 1 consortium study. Lancet Oncol 14 (6): 472–480. Syed, Y.Y. (2019). Lorlatinib: first global approval. Drugs 79 (1): 93–98. Yang, J. and Gong, W. (2019). Lorlatinib for the treatment of anaplastic lymphoma kinase-positive non-small cell lung cancer. Expert Rev Clin Pharmacol 12 (3): 173–178. Shimony, S., Horowitz, N., Ribakovsky, E. et al. (2019). Romidepsin treatment for relapsed or refractory peripheral and cutaneous T-cell lymphoma – real-life data from a national multicenter observational study. Hematol Oncol 37 (5): 569–577. Coiffier, B., Pro, B., Prince, H.M. et al. (2012). Results from a pivotal, open-label, phase II study of romidepsin in relapsed or refractory peripheral T-cell lymphoma after prior systemic therapy. J Clin Oncol 30 (6): 631–636. Allen, P.B. and Lechowicz, M.J. (2018). Hematologic toxicity is rare in relapsed patients treated with belinostat: a systematic review of belinostat toxicity and safety in peripheral T-cell lymphomas. Cancer Manag Res 10: 6731–6742. Horwitz, S.M., Kim, Y.H., Foss, F. et al. (2012). Identification of an active, well-tolerated dose of pralatrexate in patients with relapsed or refractory cutaneous T-cell lymphoma. Blood 119 (18): 4115–4122. O’Connor, O.A., Pro, B., Pinter-Brown, L. et al. (2011). Pralatrexate in patients with relapsed or refractory peripheral T-cell lymphoma: results from the pivotal PROPEL study. J Clin Oncol 29 (9): 1182–1189. Hui, J., Przespo, E., and Elefante, A. (2012). Pralatrexate: a novel synthetic antifolate for relapsed or refractory peripheral T-cell lymphoma and other potential uses. J Oncol Pharm Pract 18 (2): 275–283. Advani, R.H., Ansell, S.M., Lechowicz, M.J. et al. (2016). A phase II study of cyclophosphamide, etoposide, vincristine and prednisone (CEOP) alternating with Pralatrexate (P) as front line therapy for patients with peripheral T-cell lymphoma (PTCL): final results from the T- cell consortium trial. Br J Haematol 172 (4): 535–544.

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92 Amin, H.M., Medeiros, L.J., Ma, Y. et al. (2003). Inhibition of JAK3 induces apoptosis and decreases anaplastic lymphoma kinase activity in anaplastic large cell lymphoma. Oncogene 22 (35): 5399–5407. 93 Graf, N., Li, Z., Herrmann, K. et al. (2014). Positron emission tomographic monitoring of dual phosphatidylinositol-3kinase and mTOR inhibition in anaplastic large cell lymphoma. Onco Targets Ther 7: 789–798. 94 Chan, T.S., Tse, E., and Kwong, Y.L. (2017). Chidamide in the treatment of peripheral T-cell lymphoma. Onco Targets Ther 10: 347–352. 95 Luchtel, R.A., Dasari, S., Oishi, N. et al. (2018). Molecular profiling reveals immunogenic cues in anaplastic large cell lymphomas with DUSP22 rearrangements. Blood 132 (13): 1386–1398. 96 Kong, J., Dasari, S., and Feldman, A.L. (2020). PD-L1 expression in anaplastic large cell lymphoma. Mod Pathol 33 (6): 1232–1233. 97 Hebart, H., Lang, P., and Woessmann, W. (2016). Nivolumab for refractory anaplastic large cell lymphoma: a case report. Ann Intern Med 165 (8): 607–608. 98 Rigaud, C., Abbou, S., Minard-Colin, V. et al. (2018). Efficacy of nivolumab in a patient with systemic refractory ALK+ anaplastic large cell lymphoma. Pediatr Blood Cancer 65 (4) https://doi.org/10.1002/ pbc.26902. 99 Wartewig, T., Kurgyis, Z., Keppler, S. et al. (2017). PD-1 is a haploinsufficient suppressor of T cell lymphomagenesis. Nature 552: 121. 100 Ratner, L., Waldmann, T.A., Janakiram, M., and Brammer, J.E. (2018). Rapid progression of adult T-cell leukemia-lymphoma after PD-1 inhibitor therapy. N Engl J Med 378 (20): 1947–1948. 101 Chen, J., Zhang, Y., Petrus, M.N. et al. (2017). Cytokine receptor signaling is required for the survival of ALKanaplastic large cell lymphoma, even in the presence of JAK1/STAT3 mutations. Proc Natl Acad Sci U S A 114 (15): 3975–3980. 102 Amin, H.M. and Lai, R. (2007). Pathobiology of ALK+ anaplastic large-cell lymphoma. Blood 110 (7): 2259–2267.

103 Redaelli, S., Ceccon, M., Antolini, L. et al. (2016). Synergistic activity of ALK and mTOR inhibitors for the treatment of NPM-ALK positive lymphoma. Oncotarget 7 (45): 72886–72897. 104 Barr, P.M., Li, H., Spier, C. et al. (2015). Phase II intergroup trial of alisertib in relapsed and refractory peripheral T-cell lymphoma and transformed mycosis fungoides: SWOG 1108. J Clin Oncol 33 (21): 2399–2404. 105 Ahmed, N. and Feldman, A.L. (2020). Targeting epigenetic regulators in the treatment of T-cell lymphoma. Expert Rev Hematol 13 (2): 127–139. 106 Shi, Y., Dong, M., Hong, X. et al. (2015). Results from a multicenter, open-label, pivotal phase II study of chidamide in relapsed or refractory peripheral T-cell lymphoma. Ann Oncol 26 (8): 1766–1771. 107 Hassler, M.R., Klisaroska, A., Kollmann, K. et al. (2012). Antineoplastic activity of the DNA methyltransferase inhibitor 5-aza-2’-deoxycytidine in anaplastic large cell lymphoma. Biochimie 94 (11): 2297–2307. 108 Ramos, C.A., Ballard, B., Zhang, H. et al. (2017). Clinical and immunological responses after CD30-specific chimeric antigen receptor-redirected lymphocytes. J Clin Invest 127 (9): 3462–3471. 109 Perera, L.P., Zhang, M., Nakagawa, M. et al. (2017). Chimeric antigen receptor modified T cells that target chemokine receptor CCR4 as a therapeutic modality for T-cell malignancies. Am J Hematol 92 (9): 892–901. 110 Di Stasi, A., De Angelis, B., Rooney, C.M. et al. (2009). T lymphocytes coexpressing CCR4 and a chimeric antigen receptor targeting CD30 have improved homing and antitumor activity in a Hodgkin tumor model. Blood 113 (25): 6392–6402. 111 Rothe, A., Sasse, S., Topp, M.S. et al. (2015). A phase 1 study of the bispecific anti-CD30/CD16A antibody construct AFM13 in patients with relapsed or refractory Hodgkin lymphoma. Blood 125 (26): 4024–4031. 112 Wu, J., Fu, J., Zhang, M., and Liu, D. (2015). AFM13: a first-in-class tetravalent bispecific anti-CD30/CD16A antibody for NK cell-mediated immunotherapy. J Hematol Oncol 8: 96.

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11 Human T-cell Lymphotropic Virus Type 1 Positive Adult T-cell Leukemia/ Lymphoma Wataru Munakata and Kensei Tobinai Department of Hematology, National Cancer Center Hospital, Tokyo, Japan

TAKE HOME MESSAGES ●●

●●

Adult T-cell leukemia-lymphoma (ATLL) is a peripheral T-lymphocytic malignancy caused by the RNA retrovirus human T-cell leukemia virus type 1 (HTLV1). ATLL is clinically classified into four disease types (acute, lymphoma, chronic, and smoldering); the acute type, lymphoma type, and chronic type showing unfavorable prognostic factors are regarded as aggressive ATLL subtypes that require urgent treatment.

­Epidemiology and Disease Incidence Adult T-cell leukemia/lymphoma (ATLL) is a distinct subtype of peripheral T-cell lymphoma (PTCL) caused by the RNA retrovirus human T-cell leukemia virus type 1 (HTLV1)  [1]. Compared with most other types of nonHodgkin’s lymphoma, its prognosis is extremely poor. ATLL is relatively common in southwestern Japan, West Africa, the Caribbean islands, and Brazil, which are HTLV1-endemic areas  [2, 3]. Approximately 1.08 million individuals are presumed to be carriers of HTLV1 in Japan [4], and the total number of HTLV1 carriers globally is estimated to be between 5 and 20 million [5]; however, the latter figure is probably an underestimate because of the lack of epidemiological information in developing countries. Epidemiological studies have suggested that HTLV1 is primarily transmitted by breastfeeding, although its spread via blood transfusion and sexual intercourse have also been reported. The majority of HTLV1 carriers remain asymptomatic during their lifetime. On the other hand, it is estimated that the annual incidence of ATLL among HTLV1 carriers is approximately 60 per 100 000 carriers, with a lifetime risk of approximately 5% for men and 3% for women in Japan  [6]. The reported risk factors for the

●●

●●

●●

Dose-intensified multiagent chemotherapy, such as the VCAPAMP-VECP regimen, followed by allogeneic hematopoietic stem-cell transplantation is considered the most effective treatment for younger patients with aggressive ATLL. The efficacy of mogamulizumab, an anti-CCR4 monoclonal antibody, in patients with ATLL has been confirmed. Recent studies have revealed the genetic and molecular mechanisms through which ATLL develops in HTLV1-infected cells.

d­evelopment of ATLL among HTLV1 carriers include HTLV1 infection early in life, increased age, male sex, and a higher proviral load [7]. The mean age of ATLL onset differs based on the geographic area: the mean age at diagnosis was reported to be around 40 years in Central and South America [8, 9]. On the other hand, according to the latest national survey in Japan, the mean age at ATLL diagnosis was 67.5 years  [10]. These differences in the age at ATLL onset in different regions of the world suggest that both environmental and genetic factors play a role in the onset of the disease. However, because of the lack of large-scale studies, the mechanisms responsible for ATLL onset remain to be elucidated. In addition, the Japanese national survey showed a significant shift toward older age at diagnosis of ATLL in Japan [10].

­Basic Principles of Disease Biology The HTLV1 genome encodes three structural proteins: Gag, Pol, and Env. It also encodes complex regulatory proteins such as Tax, which not only activate viral replication, but also induce the expression of several cellular genes that are important for promoting proliferation and preventing apoptosis in ATLL cells, including nuclear factor kappa B (NF-κB)  [11]. The expression of these cellular proteins

The Peripheral T-Cell Lymphomas, First Edition. Edited by Owen A. O’Connor, Won Seog Kim and Pier Luigi Zinzani. © 2021 John Wiley & Sons Ltd. Published 2021 by John Wiley & Sons Ltd. Companion website: www.wiley.com/go/OConnor/Peripheral_T-cell_Lymphomas

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11  Human T-cell Lymphotropic Virus Type 1 Positive Adult T-cell Leukemia/Lymphoma

potentially enhances the multistep carcinogenic process involved in ATLL, whereas the expression of the abovementioned viral proteins in vivo is suppressed by cytotoxic T cells. HTLV1 basic Zip factor (HBZ), which is encoded by a minus mRNA strand, may play a role in viral replication and T-cell proliferation because it is steadily expressed in most HTLV1-infected cells, especially ATLL cells, whereas Tax is not [12]. In addition, RNAi screening of ATLL cell lines revealed that the BATF3/IRF4 transcriptional complex is a master regulator of ATLL gene expression and proliferation, and that HBZ directly transactivates BATF3 by binding its super enhancer, thereby contributing to ATLL proliferation  [13]. The polycomb-mediated epigenetic silencing of miR31 was reported to be implicated in the aberrant and constitutive activation of NF-κB signaling in ATLL cells [14]. An integrated genomic analysis of ATLL revealed that genomic alterations are highly concentrated in genes associated with T-cell receptor-NF-κB signaling, such as phospholipase C gamma 1 (PLCG1), protein kinase C beta (PRKCB), and caspase recruitment domain family member 11 (CARD11), and gain-of-function mutations were found in C─C motif chemokine receptor 4 (CCR4) and CCR7  [15]. Furthermore, a study investigating structural variations revealed that the 3′-UTR of the programmed cell death 1 ligand (PD-L1) gene was disrupted by structural variations in 27% of ATLL cases [16]. These structural variations invariably led to a markedly elevated number of aberrant PD-L1 transcripts, which were stabilized by the truncation of the 3′-UTR. This is a unique genetic mechanism of immune escape caused by structural variations. In addition, according to a recent comprehensive study of the polycomb-dependent epigenetic landscape of ATLL cells, high levels of enhancer zeste homolog 2 (EZH2) expression were observed in both HTLV1-infected cells and ATLL cells [17]. Thus, there may be a compensatory mechanism involving EZH1 and EZH2 that contributes to the oncogenesis and progression of ATLL.

­ CR4 and Adult T-cell Leukemia/ C Lymphoma Chemokines, a small family of cytokines, act as signaling molecules during the migration and tissue homing of v­arious leukocytes. Among them, thymus and activationregulated chemokine and monocyte-derived chemokine (MDC) are known to induce the selective recruitment of distinct subsets of T cells by triggering the chemokine receptor CCR4. CCR4 is a seven-transmembrane G-proteincoupled receptor used as a marker of type 2 helper T cells (Th2) and regulatory T cells (Tregs) [18, 19]. Although the expression of CCR4 on healthy cells, such as Th2 cells, is partially ­regulated by its ligands [20], especially MDC, the

mechanism involved in the ligand-based regulation of CCR expression in tumor cells has not yet been fully elucidated. Ishida et al. [21] examined ATLL cells obtained from 103 patients and found that tumor cells from approximately 90% of the patients were positive for CCR4. They also showed that patients with CCR4-positive ATLL were more likely to experience skin infiltration and worse clinical outcomes than those with CCR4-negative ATLL, indicating that CCR4 plays an important pathogenetic role in ATLL. CCR4 is also expressed on tumor cells in approximately 30–65% of patients with other types of PTCL [22, 23]. An analysis of 50 patients with PTCL not otherwise specified revealed that patients with CCR4-positive disease had significantly shorter survival times than those with CCR4negative disease. Furthermore, CCR4 expression increased with advancing disease stage in patients with mycosis fungoides or Sézary syndrome  [24]. Gain-of-function mutations in CCR4 are frequently observed in patients with ATLL, as mentioned above [15]. Such mutations lead to the increased cell surface expression of CCR4 and could result in enhanced ligand-induced chemotaxis and the activation of the phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) pathway [15, 25]. Although the roles of CCR4 in the tumorigenesis and progression of ATLL and PTCL have not been fully elucidated, CCR4 was considered a promising target molecule for treatments against ATLL and PTCL. Mogamulizumab, a defucosylated, humanized anti-CCR4 monoclonal antibody, was developed using a novel glycoengineering technique [26, 27].

­ linical Features of Adult T-cell C Leukemia/Lymphoma The clinical features of ATLL include generalized lymphadenopathy, skin lesions and hepatosplenomegaly, leukocytosis involving increased numbers of abnormal lymphocytes exhibiting cerebriform or flower-like nuclei (Figure 11.1), or increased numbers of neutrophils, hypercalcemia, and frequent opportunistic infections by Pneumocystis jiroveci, Candida species, cytomegalovirus, and other pathogens. ATLL cells characteristically express CD3, CD4, CD25, CCR4, and forkhead box P3 (FOXP3) on their surfaces, and the monoclonal integration of HTLV1 proviral DNA is detectable by Southern blotting. The clinical course of ATLL is highly heterogeneous. Most patients with ATLL are resistant to conventional chemotherapeutic agents, and limited treatment options for the condition currently exist. ATLL is clinically classified into four disease subtypes (acute, lymphoma, chronic, and smoldering) based on its clinical features, which include the presence/absence of leukemic changes, high lactate dehydrogenase (LDH) levels,

­Prognosis and Prognostic Index of ATL 

Figure 11.1  Peripheral blood films of adult T-cell leukemia/lymphoma. These cells are medium-to-large lymphoid cells with cerebriform or flower-like nuclei and basophilic cytoplasm. Source: Wataru Munakata, Kensei Tobinai.

hypercalcemia, and organ infiltration [28]. Chronic-type ATLL can be further divided into favorable and unfavorable types based on the presence/absence of abnormally high LDH, abnormally high blood urea nitrogen concentrations, or abnormally low albumin concentrations. This system, known as the Shimoyama classification, has been widely used to establish therapeutic strategies for ATLL (Figure 11.2). It was reported that the median survival time for patients with ATLL varies according to the disease type: acute type, 6 months; lymphoma type, 10 months; chronic type, 24 months; and smoldering type, 3 years or more. It is recommended that the treatment strategy for ATLL should be selected according to the disease subtype. In Japan, the acute type, lymphoma type, and chronic type involving unfavorable prognostic factors are regarded as aggressive ATLL subtypes that require immediate treatment. On the other hand, the chronic type with no unfavorable prognostic factors, and the smoldering type, are considered to be indolent ATLL subtypes. Among the various major subtypes of PTCL,

patients with aggressive ATLL subtypes have the worst prognosis, with five-year overall survival and failure-free survival rates of 14% and 12%, respectively  [29]. According to the latest national survey in Japan [10], the prevalence of each diagnosed subtype showed that acute type was most prevalent (49.5%), followed by lymphoma type (25.7%), chronic type (14.2%), and smoldering type (10.6%). Furthermore, the same survey revealed that the proportion of lymphoma type increased from 21.4% in 1992–1993 to 34.7% in 2006–2007, and then decreased to 25.7% in 2010–2011.

­Prognosis and Prognostic Index of ATLL In a retrospective analysis of 1594 patients with ATLL diagnosed and treated in Japan between 2000 and 2009, the median overall survival time for each disease subtype was as follows: acute, 8.3 months (95% confidence interval [CI] 7.5–8.9 months); lymphoma, 10.6 months (95% CI

147

ATL suspected in HTLV-1 infected individuals

Number of lymphoid cells (normal and abnormal in morphology) in peripheral blood ≥4000/ Yes No Serum LDH >2 x ULN and/or corrected serum Ca ≥11.0 mg/dL? Yes Abnormal lymphocytes in PB ≥5%? Yes No Histologically proven ATL lesion(s) in any sites ? Yes

Histologically proven lymphadenopathy involved by ATL ? Yes No

No ATL lesion(s) in either the CNS, bone, pleural effusion, ascites, or gastrointestinal tract ? Yes No

Abnormal lymphocytes in PB >1% ? Yes No

ATL lesion(s) in either the CNS, bone, pleural effusion, ascites, gastrointestinal tract, liver, or spleen ? Yes No Serum LDH >1.5 × ULN and/or corrected serum Ca ≥11.0 mg/dL ? Yes No

Abnormal lymphocytes in PB ≥5% ? Yes

No

No

Abnormal lymphocytes in PB ≥5% ?

ATL lesion(s) in either the liver, spleen, skin, lung, or LN ? Yes No

Yes No

Abnormal lymphocytes in PB ≥5% ? Yes

No

Not ATL

Serum LDH >ULN, serum BUN >ULN, serum albumin 70 years), and serum levels of albumin ( 20 000 u/ml) were identified as independent prognostic factors. Then, a simplified ATLL prognostic index was established as follows: prognostic score = 2 (at stage III or IV) + 1 (at performance status > 1) + 1 (at age > 70 years) + 1 (at serum albumin  20 000 u/ml). Scores of 0–2, 3–4, and 5–6 were categorized as low risk, intermediate risk, and high risk, respectively. The median overall survival times were 4.6 months (95% CI 2.6–5.4 months), 7.0 months (95% CI 6.3–8.6 months), and 16.2 months (95% CI 13.4–23.2 months), and the two-year overall survival rates were 6% (95% CI 2–12%), 17% (95% CI 12–23%), and 37% (95% CI 25–49%) for patients at high, intermediate, and low risk, respectively. The ATLL prognostic index was found to be a better predictor of risk than the International Prognostic Index. On the other hand, the Lymphoma Study Group  of  the Japan Clinical Oncology Group (JCOG-LSG) performed a

Management of Aggressive Adult T-cell Leukemia/Lymphom  149

combined analysis of all patients with ATLL enrolled in previous JCOG studies to develop a new prognostic index for the disease  [32]. The corrected calcium level (≥ 2.75 mmol/l) and performance status (2–4) were identified as independent prognostic factors. The median overall survival time and five-year overall survival rate were 14 months and 18% in the moderate-risk group (with a calcium level of  2 mmol/l) is considered imperative before administering these agents. Monitoring electrolytes while receiving romidepsin, and avoiding antiemetics associated with QTc prolongation nullifies the bulk of this risk. In addition, life-threatening EBV reactivation has been described with romidepsin in patients with relapsed/ refractory EBV-driven ENKTL, leading to discontinuation of the trial and a black-box warning in this subpopulation [53]. This is an extremely important consideration that requires attention prior to administering these drugs in this patient population. Another unusual feature of the HDAC inhibitors relates to their possible enhanced activity in AITL. While data extracted from HDAC inhibitor studies are pulled on a post-hoc fashion, and were not planned, nor are the number of AITL patients significant to justify dogmatic conclusions, caution needs to be exercised before we proclaim this benefit. Nonetheless, several lines of data support the consideration that HDAC inhibitors might exhibit better activity in AITL compared with other PTCL subtypes. For example, subset analysis of patients with AITL in the phase

294

21  Approved Agents in the Relapsed or Refractory Setting, Excluding Brentuximab Vedotin

II trial of romidepsin in relapsed/refractory PTCL showed an overall response rate of 33% (9/27) compared with 25% (33/130) in the overall population  [54]. Belinostat produced clinical benefit very similar to that observed with romidepsin, including improved outcomes in patients with AITL in a subset analyses [55, 56].

­ rugs Approved by the US Food D and Drug Administration But Without An Indication in Relapsed/Refractory Peripheral T-cell Lymphoma While the past decade has seen a number of new drugs approved for the indication of relapsed/refractory PTCL, there are also a number of FDA-approved drugs with activity in the disease, though they do not carry an indication in PTCL (Table 21.2). It is important to recognize that data in support of those drugs that carry an indication are considered far more robust, as these data are conducted under the rigor of FDA guidance, have central radiology and response review, have central pathology review, are conducted in a multicenter fashion, and, most importantly, typically accrue well over 100 patients per study. In contrast, many of the experiences with the drugs that do not carry an indication are based on small numbers, with no central review of response of pathology, and often are based on extremely small numbers of patients. Another important consideration relates to the fundamental differences in the type of drug being considered and its associated toxicities. The approved drugs without an i­ndication are typically conventional cytotoxic drugs, commonly associated with myelosuppression, and thus can only be given for brief periods of time. While it would be beyond the scope of this chapter to discuss every anti-neoplastic drug and its role in PTCL, there are drugs that are more c­ommonly prescribed than others, and it is those drugs we have focused on herein. These drugs include: (i) etoposide, a topoisomerase II inhibitor approved in 1983 for the treatment of testicular and small cell lung cancer; (ii) bortezomib, a proteasome inhibitor approved in 2003 for the treatment of multiple myeloma and mantle cell lymphoma; (iii) bendamustine, a DNA alkylator approved in 2008 for the t­reatment of B-cell lymphomas; and (iv) gemcitabine, an inhibitor of DNA s­ynthesis approved in 2011 for the treatment of various solid malignancies [66–69].

Etoposide Pharmacology

Etoposide, a natural product extracted from Podophyllum species [66], was developed in 1966 as a synthetic analogue

of 4′-demethylepipodophyllin benzylidene. Although FDA-approved in 1983, the mechanism of action was only elucidated in 1984, when laboratories characterized the protein-associated breaks in treated cells due to inhibition of topoisomerase II [67]. Etoposide is used in combination as first-line therapy for many lymphomas, including PTCL (CHOEP), but is only approved in combination with other chemotherapy drugs for refractory testicular tumors and small-cell lung cancer  [70]. The drug can be given as an intravenous infusion or as an oral pill, the latter making it an ideal drug for the palliative control of malignant diseases. The major toxicities of the drug include myelosuppression, most notably neutropenia, secondary leukemias, hypersensitivity reactions, and embryo/fetal toxicity. Clinical Experiences in Peripheral T-cell Lymphoma

As early as 1982, a phase II trial using etoposide in the treatment of relapsed lymphomas reported an overall response rate of 30% (complete 0%, partial 30%) using a dose of 120 mg/m2 intravenously daily for 5 days, or orally for 7–10 days, in nine patients with NHL [57]. Oral etoposide was studied in patients who had relapsed/refractory lymphomas and achieved an overall response rate of 50–62% (complete 12%, partial 50%) with adverse events consisting of hematologic or gastrointestinal toxicities [58, 59]. In Japan, 29 elderly patients with relapsed/refractory NHL, including two patients who had ATLL, were treated with low-dose oral etoposide at a dose of 50 mg daily until progression of disease [60]. Of the two patients with ATLL, both responded, achieving a partial response. Adverse events mostly consisted of myelosuppression. Summary

Clearly, while etoposide has widespread use in PTCL, there is an absolute paucity of data regarding its clinical benefit in PTCL. The experiences are largely pulled from studies focused on other diseases, where PTCL was included as one subtype of NHL. In general, when not integrated into standard chemotherapy combinations for the disease (as in CHOEP or ICE), etoposide is reserved as a means to achieve palliative control usually through oral administration, with careful monitoring the blood counts and dose/schedule adjustments so patients only achieve modest neutropenia or leukopenia.

Bortezomib Pharmacology

The ubiquitin proteasome pathway is the major pathway responsible for regulating intracellular protein, and is important in maintaining intracellular protein homeostasis  [68]. Proteasome inhibitors block the 26S proteasome, leading

Table 21.2 

Clinical activity of US Federal Drug Administration-approved single agents without indication in primary cutaneous T-cell lymphoma. Response rate

Drug

Method of administration

Clinical trial (location)

Patients (n)

Overall (%)

Complete (%)

Median PFS, months (range)

Median DOR, months (range)

Refs.

Etoposide

Topoisomerase II inhibitor

Relapsed lymphomas

9–29 with NHL

30–65.5 (95% CI 42–80)

0–20.7

NA

NA

[57–60]

Bortezomib

Proteasome inhibitor

Phase II trial (Italy)

2 with PTCL

1/2

1/2

10

10

[61]

Bendamustine

Alkylating agent

LYSA retrospective study (France)

138

32.6

24.6

3.1 (0.2–46)

3.3 (1–39)

[62]

Retrospective study (Italy)

20

55 (95% CI 31–78)

10 (95% CI 4–24)

3 (1–18+)

6 (1–18) NR after median follow-up

[63]

Gemcitabine

Nucleoside analogue

Phase II study (Italy)

20

55

30

NA

34 (15–60)

[64]

Phase III LUMIERE

30

35

22

1.9

134 days

[65]

CI, confidence interval; DOR, duration of response; LYSA, French Lymphoma Study Association; NHL, non-Hodgkin lymphoma; NR, not reached; PFS, progression-free survival; PTCL, primary cutaneous T-cell lymphoma.

296

21  Approved Agents in the Relapsed or Refractory Setting, Excluding Brentuximab Vedotin

to an accumulation of protein, including unfolded proteins, leading to cell death. Bortezomib is a reversible inhibitor of the proteasome, and is FDA approved for the treatment of multiple myeloma and mantle cell lymphoma  [71]. A host of trials have clarified its activity across the larger spectrum of lymphoid malignancies, including most forms of indolent and aggressive lymphoma, including PTCL [72, 73]. Overall, the drug is very well tolerated, though is associated with sensory neuropathy. Giving the drug via the subcutaneous route, or on a weekly schedule, has been found to mitigate much of the neurotoxic effect, although the efficacy of these route and schedules has not been validated in NHL. Clinical Experiences in Peripheral T-cell Lymphoma

In a phase II trial, Zinzani et  al. administered bortezomib (at a dose of 1.3 mg/m2 intravenously on days 1, 4, 8, 11, every 21 days for six cycles) to treat 12 patients with relapsed or refractory T-cell lymphomas, including 10 patients with CTCL and 2 patients with PTCLNOS  [61]. In patients with PTCL, 1 of 2 patients responded (complete response). Among the patients with CTCL, 7 of 10 responded (1 complete and 6 partial). Overall, there were no grade 4 toxicities, though the most common grade 3 toxicities included neutropenia (n = 2), thrombocytopenia (n = 2), and sensory neuropathy (n = 2). Recent Developments

New formulations of bortezomib have been developed, although there are no real experiences with these drugs in PTCL. In addition, second-generation proteasome inhibitors like carfilzomib have been developed, and have been approved for patients with multiple myeloma. Again, there are no data with second-generation proteasome inhibitors in this setting. Finally, some recent preclinical data have established potent synergy between bortezomib plus proteasome inhibitors or pralatrexate [74–76], which are discussed in detail in other chapters.

Bendamustine Pharmacology

Bendamustine is a bifunctional mechlorethamine derivative containing a purine-like benzimidazole ring that forms covalent bonds, and crosslinks with DNA leading to cell death [66]. Since 2008, the drug has been FDA approved for the treatment of chronic lymphocytic leukemia and indolent B-cell lymphomas that are relapsed or refractory to a rituximab-containing regimen  [77]. An experience dedicated to PTCL has been reported based in the BENTLY study [78].

Clinical Experience in Peripheral T-cell Lymphoma

Bendamustine has been studied in patients with relapsed/ refractory PTCL at a dose of 120 mg/m2 on days 1 and 2 every three weeks for six cycles in the BENTLY study [78]. This study treated 60 patients with relapsed/refractory T-cell lymphomas. The study reported an overall response rate of 50% (complete 28%, partial 22%) with a median duration of response of 3.5 months (range, 1–20.7 months). The most frequent grade 3 or 4-adverse events were neutropenia (30%), thrombocytopenia (24%), and infections (20%). In another reported retrospective series, Zaja et al. from Italy and the French Lymphoma Study Association reported that 20 and 138 patients with PTCL, respectively, who were treated with bendamustine, exhibited an overall response rate of 32.6–55% (complete 10–24.6%, partial 7.2–45%) with duration of response of 3.3 months (range, 1–39 months) in their real-world experiences [62, 63]. Overall, these studies demonstrated a reasonable response rate, similar to that seen with other chemotherapy drugs in this setting, the duration of benefit was deemed too short to be of any practical value in PTCL management. Recent Developments

Based on the promising activity of bendamustine plus brentuximab vedotin in patients with classical Hodgkin lymphoma, a number of centers are exploring the activity of this combination in PTCL [79]. Albeit early, anecdotal reports affirming durable high response rates are emerging, and we await the presentation of formal datasets in the near future.

Gemcitabine Pharmacology

Gemcitabine (2′,2′-difluorodeoxycytidine) is a nucleoside analogue of deoxycytidine that exerts its antitumor effect on cells undergoing DNA synthesis in the S phase and blocks the progression of cells through the G1/S-phase checkpoint  [69]. Incorporation of the drug into DNA induces death because DNA polymerases are halted and unable to proceed. Gemcitabine has been FDA-approved as a single agent in pancreatic cancer and in combination with other chemotherapy agents in ovarian, breast, and NSCLC as early as 2011 [80]. The major toxicity of the drug is, like bendamustine and etoposide, myelosuppression. This particular toxicity can be challenging in a patient population that often has received many lines of conventional cytotoxic therapy, leading to comparatively impaired hematopoiesis.

Drugs Approved by International Regulatory Agencies, Not Including the United States  297

Clinical Data

A phase II study in 39 patients with relapsed/refactory T-cell lymphomas, including 20 patients with PTCL-NOS, was completed with gemcitabine 1200 mg/m2 on days 1, 8, and 15 of a 28-day cycle [64, 81]. Of the 20 patients with PTCL, the overall response rate was 55% (complete 30%, partial 25%), and adverse events included grade 1 or 2 neutropenia (38.5%), thrombocytopenia (46%), and hepatic toxicity (36%). Among those who achieved a complete response, the median duration of response was 34 months (range, 15–120 months). In another phase II study in patients with relapsed/refractory PTCL using the same dose and schedule, 6 of 10 patients responded (complete n = 2, partial n = 4), with a toxicity profile very similar to that reported by Zinzani et al., albeit that dose reductions were common [82]. Recent Developments

The randomized phase III LUMIERE trial in patients with R/R PTCL compared alisertib with investigator’s choice of pralatrexate, romidepsin, and gemcitabine. A total of 30 patients were treated with gemcitabine 1000 mg/m2 on days 1, 8, and 15 of a 28-day cycle, resulting in an overall response rate of 35% (complete 22%, partial 11%) with a median progression-free survival of 1.9 months and median duration of response of 134 days [65]. While the study was not powered to evaluate the merits of one investigator’s choice compared with any other drug, the only drug that alisertib appeared to be superior to was gemcitabine. This suggests that at least in this patient population, pralatrexate (overall response rate 40%, complete response 25%, median progression-free survival 3.4 months) and romidepsin (overall response rate 59%, complete response 29%, median progression-free survival 8 months) outperformed both alisertib and gemcitabine. The Lumiere study was the first randomized study ever conducted in patients with relapsed/refractory PTCL, and alisertib, although better than gemcitabine, was not found to be statistically superior to the investigator’s choice.

­ rugs Approved by International D Regulatory Agencies, Not Including the United States, that Carry an Indication in Relapsed/Refractory Peripheral T-cell Lymphoma Chidamide Pharmacology

Chidamide (also known as tucidinostat) is a synthetic benzamide HDAC inhibitor and is recognized as a pan class I and II inhibitor with a wide therapeutic index [83].

In preclinical models in hematologic malignancy, the drug induced G1 arrest at low concentrations, differentiation at moderate doses, and caspase-dependent apoptosis at high concentrations [84]. Early Phase Data

In China, chidamide was studied in 31 patients with advanced solid and hematologic malignancies  [85]. The drug led to a PR in four of six patients with T-cell lymphomas. Dose-limiting toxicities were grade 3 diarrhea and vomiting in two patients who received chidamide 50 mg orally twice per week. Pivotal Data

In 2014, chidamide was approved in China based on phase II data in 79 patients with relapsed/refractory PTCL, producing an overall response rate of 29% with a median duration of response of 9.9 months (Table 21.3) [86]. At a dose of 30 mg orally twice weekly, the median progression-free survival was 2.1 months (range, 1 day to 44.9 months) and the median overall survival was 21.4 months (range, 0.3–50.1 months. The most common grade 3/4 adverse events were thrombocytopenia (22%), leukopenia (13%), and neutropenia (11%), usually occurring within the first six weeks of treatment. Recent Developments

Real-world data of chidamide  [88] in 383 patients with relapsed/refractory PTCL revealed an overall response rate of 39% with a median progression-free survival of 129 days. In the community, there were similar grade 3/4 adverse events, including, thrombocytopenia (18%), neutropenia (12.6%), and anemia (7.1%). In addition, chidamide was recently studied in combination with CHOEP in China [89].

Forodesine Pharmacology

Forodesine (1-(9-deazahypoxanthin)-1,4-dideoxy-1,4-imino-D-ribitol hydrochloride) is a PNP inhibitor that selectively inhibits T-lymphocyte proliferation  [90]. PNP is an enzyme that catalyzes the phosphorolysis of 2-deoxyguanosine to guanine and 2-deoxyribose-1-phosphate. In the presence of forodesine, PNP is blocked and 2-deoxyguanosine accumulates and is also intracellularly converted to deoxyguanosine triphosphate, leading to inhibition of ribonucleotide reductase (which is required for cell replication) and eventual apoptosis. Early Phase Data

Intravenous forodesine, in a phase I/II trial, was studied in 13 patients with relapsed/refractory CTCL where the overall

298

21  Approved Agents in the Relapsed or Refractory Setting, Excluding Brentuximab Vedotin

Table 21.3  Clinical activity of US Federal Drug Administration-approved single agents in primary cutaneous T-cell lymphoma outside the United States. Response rate Patients (n)

Overall (%)

Complete (%)

Median PFS, months

Median DOR, months

Phase II trial (China)

79

28

14

2.1 (range, 1 day – 44.9 months)

9.9s (range 1.1–40.8)

[86]

Phase I/II trial (Japan)

41

22 (90% CI 12–35%)

10

1.9 (95% CI, 1.8–4.6)

10.4 (95% CI 5.9–16)

[87]

Method of administration

Clinical trial (location)

Chidamidea

HDAC inhibitor

Forodesine

PNP inhibitor

Drug

Refs.

a

 Approved in China. CI, confidence interval; DOR, duration of response; HDAC, histone deacetylase; PFS, progression-free survival; PNP, purine nucleoside phosphorylase.

response rate was 3/13 (complete 1/13, partial 2/13)  [91]. Hyperuricemia was the dose-limiting toxicity in one patient. Two years later, a phase I/II study reported a study of 37 patients with relapsed/refractory CTCL with stage IB or greater using oral forodesine 40–320 mg/m2 every day for four weeks [92]. The maximum tolerated dose was never reached because there were no dose-limiting toxicities but, based on pharmacokinetic studies, 80 mg/m2 daily was deemed the optimal biologic dose at which 28 patients were treated. The overall response rate was 53.6% (complete 2/28, partial 13/28) and 67.9% (complete 1/19, partial 9/19) overall, and in patients with stage IIB or greater, respectively. The only grade 3/4 adverse event was lymphopenia, which occurred in two patients. Long-term follow-up revealed that the overall response rate was 27% overall in 64 patients and 39% in 36 patients treated with 80 mg/m2 (complete 6%, partial 33%) with grade 3 lymphopenia in 8 of 9 patients [93]. Grade 3/4 adverse events included renal failure, peripheral edema, B-cell lymphoma, diarrhea, and cellulitis. Results of the phase II study were reported for 144 patients, in which oral forodesine 200 mg daily was given and resulted in no complete responses, 11% partial responses, and common adverse events such as peripheral edema, fatigue, insomnia, pruritus, diarrhea, headache, and nausea [87]. Of note, five patients died of sepsis or infections, one of esophageal cancer, one of disease progression, and one of liver failure. Pivotal Data

In Japan, a multicenter phase I/II study in patients with relapsed/refractory PTCL was completed without any dose limiting toxicities. The phase II study enrolled and treated 41 patients with forodesine 300 mg orally twice daily (Table 21.3) [94]. The overall response rate was 25% (90% CI 14–38%) and the compete response rate was 10%, leading to a median progression-free survival of 1.9 months and overall survival of 15.6 months. The most common grade 3/4 adverse events were lymphopenia (96%), leukopenia (42%), and neutropenia (35%). Five patients who achieved

remission developed B-cell lymphoma, which was thought to be due to immune dysregulation from lymphoma. Twenty-two patients experienced serious adverse events, and one patient died from disseminated intravascular coagulation, thought to be due to disease progression. The drug obtained regulatory approval in Japan in 2017. Recent Developments

Clinical development of the drug for relapsed/refractory PTCL was discontinued in the United States and Europe because development of the drug was considered not sufficiently active to warrant an indication in PTCL. [95]. Considerations in the Selection of Therapy

The selection of therapy is dependent on multiple factors, including: (i) patient and tumor characteristics; (ii) efficacy of the drug and (iii) tolerability of administration. Due to the wide variation of the subtypes and the small numbers in clinical trials, choosing treatment for patients can be very nuanced because the patient populations in studies are almost always very different (for example, aggressive vs. indolent disease, heavily treated patients vs. recently relapsed after first line, and older and frail patients compared with younger and healthier ones). Treatment Goals

First, after a patient presents with relapsed or refractory disease, deciding the treatment goals is the most important discussion. Combination chemotherapy and bridging to autologous stem-cell transplant may be curative after first relapse but will decrease quality of life during a defined course of treatment. Some patients may not be eligible for transplant, and undergoing such toxic treatment with chemotherapy may not prolong their survival while exposing them to significant morbidity, mortality, and possible quality of life-related issues. Single-agent therapies may improve quality of life but may be associated with fewer responses and a prolonged treatment course. With these

Must Reads 

more palliative agents, patients should understand that therapy will generally continue until disease progression or unacceptable toxicities, as there is little guidance and no standard on the duration of these treatments. Aggressive Versus Indolent Disease

The type of disease can also dictate the type of treatment. Aggressive disease warrants more high-intensity treatment since it is life threatening. “Indolent” diseases, to the extent that some PTCL may exhibit such behavior, may need therapy if symptomatic or impairing organ function, but there are situations, such as localized cutaneous disease, for which patients can be monitored after undergoing a complete workup. Of course, most PTCL are aggressive, though at times more indolent versions of some subtypes can be seen. Transplant Eligible or Ineligible

After first relapse, patients should be evaluated for transplant eligibility with bone-marrow transplant specialists, since transplant is considered the only curative option. If the patients are older and/or have important comorbidities, autologous stem-cell transplant may not be an option, and combination chemotherapy may not be indicated if they will not be undergoing curative consolidation. Patients often have the best outcomes if they can achieve a complete remission, so choosing treatments associated with high response rates (even if they do not have prolonged duration of response) should be prioritized. Allogeneic transplant is indicated if patient relapses after autologous transplant and they should be evaluated for a donor as soon as the patient is deemed a candidate. Suitability for Chemotherapy

As for transplantation, patients should be evaluated for appropriateness in receiving combination or single-agent chemotherapy. Their age, organ function, genetic polymorphisms, and other comorbidities will dictate which chemotherapy regimens are appropriate. In addition, if patients are heavily pretreated, their bone-marrow reserve may be less robust and may not tolerate myelosuppressive

chemotherapy. These factors will be important to consider when deciding the next treatment option.

­Conclusion The treatment of PTCL has been challenging because of the rare and heterogeneous nature of these diseases. The key issues and difficulties in treating patients with PTCL include: (i) the poor understanding of the underlying diseases, limiting identification of targeted therapies; (ii) the short durations of responses in those who respond to conventional therapy, and (iii) the growing heterogeneity and paucity of patients with the disease. Presently, we have evidence that epigenetic-based combinations are uniquely effective in PTCL, even if the underlying mechanism of action is still poorly understood. It is likely that, given the enormous genetic and histologic heterogeneity of these diseases, the optimal treatment will need to be tailored not merely to the histology, but rather to the unique genetic landscape of the particular subtype of disease. One potentially important path forward is to think about logical combinations of epigenetic-based therapies with the many newer immunotherapies available for patients with cancer. Preclinical studies conducted by our group and others have confirmed that the HDAC inhibitors exhibit potent synergy in combination with a host of other drugs known as “active” in PTCL, including hypomethylating agents, pralatrexate, proteasome inhibitors, and aurora A kinase inhibitors, and can serve as a cornerstone for platform development [36, 74, 75, 96–99]. Novel scientific discoveries in the pathophysiology of PTCL, coupled with the emergence of drugs that have substantial single-agent activity, are charting new paths for the treatment of PTCL. These collective findings have led to the development of novel drug combinations with lineage selective activity in T-cell malignancies that is unprecedented. These developments have allowed us to start tailoring treatments in a fashion that respects and therapeutically exploits the underlying biology.

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Marchi, E., O’Connor, O.A. (2019). The rapidly changing  landscape in mature T-cell lymphoma (MTCL) biology and management. CA Cancer J Clin 70 (1): 47–70. O’Connor, O.A., Marchi, E., Volinn, W. et al. (2018). Strategy for assessing new drug value in orphan diseases: an international case match control analysis of the PROPEL Study. JNCI Cancer Spectr 2(4): pky038. doi: https://doi. org/10.1093/jncics/pky038.

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Coiffier, B., Pro, B., Prince, H.M. et al. (2014). Romidepsin for the treatment of relapsed/refractory peripheral T-cell lymphoma: pivotal study update demonstrates durable responses. J Hematol Onco. 7: 11. doi: https://doi. org/10.1186/1756-8722-7-11. Prince, H.M., Bishton, M.J., and Harrison, S.J. (2009). Clinical studies of histone deacetylase inhibitors. Clin. Cancer Res. 15 (12): 3958–3969. doi: https://doi. org/10.1158/1078-0432.CCR-08-2785.

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61 Zinzani, P.L., Musuraca, G., Tani, M. et al. (2007). Phase II trial of proteasome inhibitor bortezomib in patients with relapsed or refractory cutaneous T-cell lymphoma. J Clin Oncol 25 (27): 4293–4297. 62 Reboursiere, E., Le Bras, F., Herbaux, C. et al. (2016). Bendamustine for the treatment of relapsed or refractory peripheral T cell lymphomas: a French retrospective multicenter study. Oncotarget 7 (51): 85573–85583. 63 Zaja, F., Baldini, L., Ferreri, A.J. et al. (2013). Bendamustine salvage therapy for T cell neoplasms. Ann Hematol 92 (9): 1249–1254. 64 Zinzani, P.L., Venturini, F., Stefoni, V. et al. (2010). Gemcitabine as single agent in pretreated T-cell lymphoma patients: evaluation of the long-term outcome. Ann Oncol 21 (4): 860–863. 65 O’Connor, O.A., Ozcan, M., Jacobsen, E.D. et al. (2019). Randomized phase III study of alisertib or investigator’s choice (selected single agent) in patients with relapsed or refractory peripheral T-cell lymphoma. J Clin Oncol 37 (8): 613–623. 66 Gandhi, V. (2002). Metabolism and mechanisms of action of bendamustine: rationales for combination therapies. Semin. Oncol 29 (4 Suppl 13): 4–11. 67 Hande, K.R. (1998). Etoposide: four decades of development of a topoisomerase II inhibitor. Eur J Cancer 34 (10): 1514–1521. 68 LeBlanc, R., Catley, L.P., Hideshima, T. et al. (2002). Proteasome inhibitor PS-341 inhibits human myeloma cell growth in vivo and prolongs survival in a murine model. Cancer Res 62 (17): 4996–5000. 69 Plunkett, W., Huang, P., Xu, Y.Z. et al. (1995). Gemcitabine: metabolism, mechanisms of action, and self-potentiation. Semin Oncol 22 (4 Suppl 11): 3–10. 70 US Food and Drug Administration. FDA approves atezolizumab for extensive-stage small cell lung cancer. March 19, 29019. www.fda.gov/drugs/drug-approvalsand-databases/fda-approves-atezolizumab-extensivestage-small-cell-lung-cancer (accessed 4 August 2020). 71 US Food and Drug Administration. FDA-Approved Drugs: New Drug Application (NDA): 206927. https:// www.accessdata.fda.gov/scripts/cder/daf/index. cfm?event=overview.process&ApplNo=206927 (accessed 4 August 2020). 72 O’Connor, O.A., Moskowitz, C., Portlock, C. et al. (2009). Patients with chemotherapy-refractory mantle cell lymphoma experience high response rates and identical progression-free survivals compared with patients with relapsed disease following treatment with single agent bortezomib: results of a multicentre Phase 2 clinical trial. Br J Haematol 145 (1): 34–39. 73 Orlowski, R.Z., Stinchcombe, T.E., Mitchell, B.S. et al. (2002). Phase I trial of the proteasome inhibitor PS-341 in

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22 The Role of Autologous Stem-cell Transplantation in Peripheral T-cell Lymphomas Juan Alejandro Ospina-Idárraga1, Rolando Humberto Martinez-Cordero2, Leonardo José Enciso-Olivera3 and Henry Idrobo-Quintero4 1

 Los Cobos Medical Center, Instituto Nacional de Cancerología, Universidad El Bosque, Bogotá, Colombia  Instituto Nacional de Cancerología, Universidad El Bosque, Bogotá, Colombia 3  Programa de Investigación e Innovación en Leucemias Agudas y Crónicas (PILAC), Instituto Nacional de Cancerología, Bogotá, Colombia 4  Grupo Latinoamericano de estudio de Linfoproliferativos (GELL), Hospital Universitario del Valle, Grupo Ospedale, Universidad del Valle, Universidad Libre, Cali, Colombia 2

TAKE HOME MESSAGES ●●

●●

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Status of response is the most relevant variable for overall and progression-free survival after first-line therapy. Primary induction failure is related to poor prognosis and low survival rates independently of performing autologous stem cell transplant (ASCT). Given the available information, there is no support to practice ASCT in patients who have a complete response (either a first complete response or complete response after rescue therapy).

­Introduction The principles of cancer medicine are based on treatment paradigms that seek to identify the best possible state of objective response, and then to try to diminish the risk of disease recurrence and improve overall survival. In the case of autologous stem-cell transplant (ASCT), strategies that may influence outcome are varied, and include the nature or timing of induction, consolidation or use of maintenance therapies. In the case of the peripheral T-cell lymphomas (PTCLs), ASCT has been explored from first remission to the relapsed setting, and of course is confounded by the diversity of histology, and different degrees of chemotherapy sensitivity for different subtypes. At this time, we still have no randomized prospective data to determine the benefit, or not, of ASCT in first remission. However, the opportunities to potentially improve on the outcome of ASCT in PTCL are expanding, given our deepening knowledge of the disease, and the development of many new treatment prospects. Collectively, these new and

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All patients with peripheral T-cell lymphomas should be included in registries and/or clinical trials with an urgent need for quality prospective data about ASCT. Clinicians should use the best possible treatment with novel directed therapies reaching complete response with perhaps no difference between observation or consolidation with ASCT.

emerging resources are providing clinicians with new ways to improve upon the potential merits of ASCT in PTCL, while also trying to diminish toxicity of long-term adverse events of the transplant [1]. Historically, the care of patients with PTCL has been predicated on the application of treatment paradigms developed for the B-cell malignancies, which have been suboptimal in achieving high rates of complete remission and durable responses, compared at least with the outcomes achieved for diffuse large B-cell lymphoma. For decades, front-line PTCL treatments have been based on conventional chemotherapy regimens (i.e. CHOP-like [cyclophosphamide, doxorubicin, vincristine, and prednisone])  [2], which have achieved mixed results across a heterogenous disease, with complete response rates (in most studies this is not confirmed, often not even specifying the method of evaluation or use of positron emission tomography [PET]) in the 17–70% range. However, almost two-thirds of patients experience a relapse or early progression, with a five-year overall survival rate of approximately

The Peripheral T-Cell Lymphomas, First Edition. Edited by Owen A. O’Connor, Won Seog Kim and Pier Luigi Zinzani. © 2021 John Wiley & Sons Ltd. Published 2021 by John Wiley & Sons Ltd. Companion website: www.wiley.com/go/OConnor/Peripheral_T-cell_Lymphomas

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22  The Role of Autologous Stem-cell Transplantation in Peripheral T-cell Lymphomas

25–30%, which itself is dependent on disease subtype and its prognostic risk index [3]. In general, only two subtypes of PTCL are recognized as having a favorable prognosis: anaplastic lymphoma kinase-positive (ALK+) anaplastic large-cell lymphoma (ALCL), and strictly localized presentations of extranodal nasal-type natural killer (NK)/T-cell lymphomas (ENKTL-NT) without primary tumor invasion  [4]. Most others, irrespective of their international prognostic index, have very poor long-term outcomes. Once the patient develops relapsed or refractory disease, the outlook becomes even more grave, where overall response rates with conventional chemotherapy typically do not exceed 20%, and overall survival rates of less than six months [5]. Given these poor prognostic features of the disease, efforts are constantly being made to identify better management alternatives for these patients, including everything from changing the chemotherapy drugs in various regimens to exploring the timing of ASCT, and even including evaluation of the benefit of allogeneic stem-cell transplant (STC) in the front line [6]. To date, there are no data that any of these approaches has improved outcome. The usual paradigm of treatment for patients with any form of lymphoma has been to consider the potential role of ASCT in those patients who attain an objective complete response, either in the front-line setting or in subsequent relapsed states with salvage therapy. This approach has been recommended in different guidelines and international consensus documents  [7], as the “best strategy” to reduce the risk of relapse and obtain responses that remain stable over time, despite the absence of randomized data. The role of SCT has been highly debated for patients with PTCL, especially now that there appear to be more emerging drugs and drug combinations that could be an alternative to the toxicity and uncertain outcomes associated with SCT. Many of these more innovative approaches are producing sustained duration of response in first or subsequent lines of treatment  [8]. Evidence for a role of ASCT in PTCL is limited, as it often carries multiple biases and is frequently difficult to interpret given the incredible heterogeneity of the study populations, and an often unclear status of response prior to ASCT, which is a critical factor influencing outcome [9]. Currently, there are retrospective studies in which the usefulness of performing ASCT compared with observation have been evaluated in those patients who reach complete response, establishing, with all the caveats acknowledged, that there does not seem to be a statistically significant difference on survival rates between the two groups [10]. Despite the limited results available on the optimal treatment of PTCL, there have been significant advances over the past decade on the immunophenotypic, molecular, and epigenetic characteristics of these diseases, deepening our

understanding of the epidemiological behavior of this complex group of neoplasms [11]. As we refine our understanding of these many details, we anticpate significantly improving the natural history of the disease on a global sale, and more clearly defining the role of ASCT in the care of specific PTCL populations. In this chapter we review the available literature, including national registries, and discuss the major questions to consider regarding the role of ASCT in different subtypes of PTCL.

­ utologous Stem-cell Transplantation A in First Complete Remission Registries and trials have demonstrated that conventional chemotherapy regimens typically fail to induce stable and long-term remissions in most patients with PTCL, which has formed the basis for consolidation with ASCT being considered in fit patients who achieve remission with chemotherapy [12]. Several retrospective studies and comprehensive systematic reviews of ASCT for consolidation or treatment for patients that relapse or are refractory have been presented in the literature [13]. These results must be interpreted with extreme caution (as would be the case for most of lymphoproliferative disorders), given that the only patients who could proceed to ASCT, as opposed to all patients for whom ASCT might be considered in general, are included in most analyses  [14–17]. This important nuance has been verified in prospective phase II/III studies, which have repeatedly demonstrated that up to 40% of “candidates” cannot move on to ASCT because of failure to achieve a meaningful response, with many national registries or real-life experiences suggesting that only 15–25% of patients undergo transplant because of early progression or relapse [18]. There are data from prospective phase II studies on the role of front-line ASCT for patients with PTCL that have been reported by the Spanish Groups (Grupo Español de Linfomas/Traplaute Autólogo de Médula Ósea  [19] and Grup per l’Estudi dels Limfomes de Catalunya i Balears [20]), a German consortium [14], and the Nordic Lymphoma Group [15]. In the Nordic study, for example, the five- year overall and progression-free survival rates were 51% and 44%, respectively. Patients with PTCL-not otherwise specified (NOS) had an overall survival rate of 47% and progression-free survival rate of 38%, while the overall and progression-free survival rates for patients with angioimmunoblastic T-cell lymphoma (AITL) was a little higher at 52% and 49%, respectively. The German study reported on 111 patients with extended follow-up, recording a five-year overall and progression-free survival rates of

­Interpretation of Available Literatur  307

44% and 39%, respectively, without entity-specific differences in survival rates  [21]. Specifically for patients with AITL, there are two trials from the European Group for Blood and Marrow Transplantation (EBMT) [22, 23], one of which reported overall survival rates of 50% and 44% at four and five years, respectively (n = 146). A comprehensive analysis of the available literature suggests that 40–50% of fit patients who undergo ASCT with chemosensitive disease (primarily comprising those in complete remission after conventional chemotherapy), have improved overall and progression-free survival rates. Patients who do not achieve complet remission (or PET negativity) after conventional chemotherapy (with few exceptions) typically do not benefit from ASCT [24]. In practice, approximately one-third of patients progress or relapse before considering consolidation, and are unable to reach ASCT in the majority of cases. It is clear that patients with PTCL who receive ASCT represent a highly selective group likely to have a better prognosis than patients with PTCL in general, especially since they almost always represent those patients who have achieved complete or a very good partial response. This point is underscored in a retrospective report by Abramson et al., who tracked the survival of patients who achieved a complete response, including those who transitioned to ASCT and those who were followed by observation alone with no consolidative therapy. These data, surprisingly, demonstrated that both populations experienced precisely the same overall survival, suggesting that perhaps it is those patients who achieve a complete response with conventional chemotherapy who may be the ones who do not need to ASCT to begin with [25]. By broadening our repertoire of tools to include drugs specifically active in PTCL, such as pralatrexate, the histone deacetylase inhibitors (HDACi) and brentuximab vedotin, a host of new innovative strategies can be conceived for patients with PTCL in both the front-line ­scenario and beyond. Such approaches, if associated with deepening of the response or increasing the number of complete responses, may help those patients not achieving a complete response with chemotherapy alone. Ultimately however, these approaches will need to be vetted in a randomized controlled clinical trial.

­ utologous Stem-cell Transplantation A in Relapsed/Refractory Disease ASCT is usually considered as a fundamental part of the treatment program for patients who have relapsed/refractory PTCL, following administration of high-dose chemotherapy. Two case series from the EBMT (n = 484) [23] and Center for International Blood and Marrow Transplant

Research (CIBMTR; n  = 115)  [26], which reported on all PTCL entities, had a favorable outcome in patients with chemosensitive disease who reached complete response status prior to ASCT (three-year progression-free survival 47%) and also demonstrated that ASCT is much less effective in patients with refractory disease (three-year progression-free survival 15%). There are no prospective clinical trials or cohort studies around the role of ASCT in the relapse setting, only descriptive series, including available meta-analysis of the literature [27], which do not incorporate intent-to-treat analyses. They are typically based on the inclusion of patients who underwent ASCT and were in complete or at least a good partial response prior to SCT. In summary, for patients with relapsed/refractory PTCL, only those who reach a complete response (PET negative confirmed) have an opportunity for long-term survival after ASCT. Perhaps, for all those patients without a complete response after high-dose therapy (as a rescue after first line of treatment) better results can be obtained by using novel therapies or, in selected fit and heavily treated patients, allogeneic SCT rather than ASCT [28].

­Interpretation of Available Literature Considering the poor results of conventional chemotherapy for patients with PTCL, high-dose chemotherapy followed by ASCT has been widely employed as a consolidation strategy for patients in first complete response or for patients who have relapsed/refractory disease despite the absence of prospective trial evidence to support this therapy [29]. Nevertheless, there are several systematic reviews of the literature that include prospective studies regarding ASCT in patients with PTCL. When using the Cochrane assessment of bias tool to assess for selection bias, performance bias, attrition bias, detection bias and selective reporting of outcomes, and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses checklist, the results are even more than disappointing  [9]. Most of the studies did not include a valid comparator and were not able to harmonize the substantial heterogeneity associated with the varied conditioning regimens (Table 22.1). Considering the extensive methodological limitations associated with the study of ASCT in the literature, there is an enormous need for prospective trials, and the generation of consensus recommendations regarding the details of the ASCT in patients with PTCL. A better understanding of the population likely to experience the greatest ­benefit is mandatory, as the medical community continues to struggle defining the terms of its recommendations regarding ASCT.

22  The Role of Autologous Stem-cell Transplantation in Peripheral T-cell Lymphomas

Table 22.1  Risk of bias summary: review authors’ judgments of each risk of bias item for each included study. Randomsequence generationa

Allocation biasa

Binding of participants and personnelb

Binding of outcome assessmentc

Incomplete outcome datad

Selective biase

Corradini et al (2006)

–

–

–

–

+

+

d’Amore et al. (2012)

–

–

–

–

+

+

Dupuis et al. (2015)

–

–

–

–

+

+

Mercadal et al. (2008)

–

–

–

–

+

+

Reimer et al. (2004)

–

–

–

–

+

+

Rodriguez et al. (2007)

–

–

–

–

+

+

Study

Other bias

a

 Selection bias.  Performance bias. c  Detection bias. d  Attrition bias. e  Reporting bias. Created using RevMan version 5.3. +  , low risk of bias; –  , high risk of bias. Source: Jethwa et al. [9]. b

1.0

Censored

0.8 Survival Probability

308

0.6 After 2009

0.4 2009 and earlier

0.2

0.0 0

5

10

15

Time (years)

Figure 22.1  The impact of time. Survival curves of patients based on time period of diagnosis. Survival curves of 219 patients based on diagnosis ≤ 2009 (n = 114): median overall survival 1.71 years (range 0.82–2.34 years) and ≥ 2010 (n = 105): median overall survival 4.29 years (range 2.62 years–not reached; P = .0017. Source: Ma et al. figure 2 [30].

I­ dentifying the Most Relevant Determinants for Survival among Patients with Peripheral T-cell Lymphoma Undergoing Autologous Stem-cell Transplantation Virtually all treatment paradigms for patients with PTCL have considered consolidation therapy after achieving objective responses with conventional chemotherapy. Over

time, with the knowledge of the pathophysiology of the diseases and the publication of prospective series and registries around the world, this paradigm is changing, as new more specific, effective, and less toxic alternatives emerge for the treatment of PTCL. Remarkably, it seems that patients diagnosed with PTCL a decade ago (when SCT was available), had significantly worst outcomes compared with those diagnosed after 2010, which may reflect improvements in new treatments and in our ability to risk stratify to select patients for treatment (Figures 22.1 and  22.2). The

­Status of Response Prior to Autologous Stem-cell Transplantatio  309 1.0

Censored

Survival Probability

0.8 0.6 Novel Single Agent

0.4 0.2

No Novel Single Agent

0.0 0

5

10 Time (years)

15

Figure 22.2  Survival curve of patients who received novel therapies compared with patients who did not. Survival curves of patients (n = 219) based on exposure to the following: US Federal Drugs Administration-approved single agents: pralatrexate, histone deacetylase inhibitors, brentuximab vedotin in patients who are CD30-positive compared with no approved single agents (P = 0.003). Source: Ma et al. [30].

use of s­pecifically targeted drug treatment strategies instead of using conventional chemotherapy may improve the depth and duration of clinical responses over time, possibly allowing the clinician to have a lower degree of urgency to pursue consolidation or rescue therapies in routine practice (Figure 22.3) [30]. Prior to ASCT, patients are first characterized as fit or not, and whether they are candidates to receive the therapy. As discussed above, transplant may be considered either as a strategy for consolidation, or as part of a treatment program for patients with relapsed or refractory disease. Most critical in the determination as to whether to proceed with transplant or not is the status of response to cytoreductive therapy. Several analyses have identified the status of response as the most relevant issue, but other factors like stage, lactate dehydrogenase, number of prior

­ tatus of Response Prior to Autologous S Stem-cell Transplantation As discussed, one of the most relevant determinants of benefit in ASCT in PTCL is the status of response reached prior to ASCT, whether it be in the front-line or relapsed/ refractory setting, where platinum-based chemotherapy is the most commonly employed cytoreductive approach, and a major factor in predicting survival. [32]. Progression Free Survival

1.00

Active Observation Survival Probability

Figure 22.3  Progression-free survival stratified by consolidative strategy. Kaplan–Meier progression-free survival plots for patients who underwent a consolidative autologous stem-cell transplant (dashed line) compared with patients who underwent active observation (solid line) in first complete response following CHOP-like induction chemotherapy (log rank, P = 0,79). Source: Yam et al. [10].

therapies, and whether the patient has refractory disease are also important considerations [24]. For the two subtypes of PTCL which carry a favorable prognosis (ALK+ ALCL and the strictly localized without primary tumor invasion presentations of ENKTL [4, 31]), there is little or no rationale for considering consolidation with SCT in the front-line setting, because of the low rate of relapses and the sustained clinical responses seen with front-line therapy. In the case of relapse of these entities, ASCT is thus far the standard of care, albeit with limited evidence. For ALCL, integration of brentuximab vedotin, either as a single agent or in combination, is prudent. As a single agent, brentuximab vedotin is associated with high response rates and prolonged duration of benefit (complete response rate of 66%, an estimated five-year overall survival rate of 79% (95% confidence interval [CI], 65–92%), with median overall survival not reached (endpoints of 95% CI not estimable)  [32]. However, given the positive results of the ECHELON 2 study, it is likely that most patients will be exposed to brentuximab vedotin in the front-line setting, making its role in relapsed disease uncertain in the future. For localized ENKTL, protocols for relapsed disease tend to adopt those used for patients with advanced stages of the disease (See ahead ASCT for Extranodal Nk/T cell lymphomas).

ASCT

0.75

0.50

0.25

0.00 0

12

24

36

48 60 72 84 96 Months from Diagnosis

108

120

132

144

310

22  The Role of Autologous Stem-cell Transplantation in Peripheral T-cell Lymphomas

Retrospective analyses of patients with PTCL who achieved a primary complete response following CHOPlike induction chemotherapy from case series or national registries have demonstrated that patients who underwent consolidative ASCT did not have a reduced risk of relapse or experience a statistically significant improvement in progression-free or overall survival compared with patients who underwent active observation  [10]. It has been reported that the benefit of ASCT disappears in multivariate analysis when adjusting for initial treatment response, suggesting that the most dominant factor predictive of a favorable overall survival rate is achievement of complete response to initial chemotherapy [25]. In a large retrospective case match control analysis reported by the French Lymphoma Study Association, 134 patients were allocated to ASCT in an intention to treat analysis, while 135 were not. Neither the Cox multivariate model (hazard ratio [HR] 1.02, 95% CI 0.69–1.50 for progression-free survival, and HR 1.08, 95% CI 0.68–1.69 for overall survival), nor the propensity score analysis after stringent matching for potential confounding factors (logrank P = 0.90 and 0.66 for progression-free and overall survival, respectively) found a survival advantage in favor of ASCT as a consolidation procedure for patients in response after induction. Subgroup analyses did not reveal any further difference for patients according to response status, stage disease, or risk category [12]. Similar results have been reported in observational studies that performed a comparison with historical cohorts. In a study by Kitahara et al. [33], 78 patients were included and assessable for response, which reported no difference between the regimens used in front-line therapy (CHOPlike) with an overall response rate of 74% (58/78), including 53 patients (68%) achieving a complete response. A total of 26 of 39 patients aged 65 years or younger achieved complete response after CHOP/CHOP-like therapy. No patient underwent high-dose chemotherapy/ASCT at first complete response. The median relapse-free survival was 21 months, and the two-, three-, and five-year relapse free survival was 46%, 45%, and 36%, respectively. Although these results revealed an unfavorable outcome for PTCL as a whole, those who achieved a complete response following CHOP/CHOP-like chemotherapy did not always have a poor outcome without the consolidation of high-dose chemotherapy/ASCT. In fact, 45% of the 65 years or younger patients were alive and without relapse after five years of evaluation. Primary induction failure is the lack of effectiveness to reach a complete response after front-line chemotherapy, and is now identified as one of the most important independent factors influencing PTCL survival, which makes sense given the import of disease status prior to ASCT [34].

A large retrospective analysis by Yamasaki et al. sought to define risk factors for outcomes of 570 patients with PTCL, including PTCL-NOS) and AITL, who received ASCT as front-line consolidation (n  = 98 and 75, respectively) or alternative therapies after either relapse (n = 112 and 75) or primary induction failure (n  = 127 and 83) between 2000 and 2015. Statistically significant risk factors for overall survival after upfront ASCT included a primary induction failure score of 2 or more (P