Peripheral T-Cell Lymphomas

About the EditorsOwen A. O’Connor, 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, MD, PhD is Professor of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea. Pier Luigi Zinzani, MD, PhD is Professor of Hematology, Director of Lymphoma and CLL Unit, and Chief of Phase I clinical trials, Institute of Hematology, University of Bologna, Italy.

• Contributors xixAbout the Companion Website xxiiiPart I Biological Basis of the Peripheral T-cell Lymphomas 11 The Fundamentals of T-cell Lymphocyte Biology 3Claudio Tripodo and Stefano A. PileriIntroduction 3General View of the Differentiation and Function of T Lymphocytes 3The T-cell System as a Frame for Peripheral T-cell Lymphoma: Taking Plasticity into Account 5Must Reads 7References 72 Mechanisms of T-cell Lymphomagenesis 9François Lemonnier, Philippe Gaulard and Laurence de LevalIntroduction 9Oncogenic Events in the Transformation of T or Natural Killer Cells 9Genetic Lesions 9Deregulated Pathways in Peripheral T-cell Lymphoma Oncogenesis (Figure 2.1, Table 2.1) 10Signaling Pathways 13Cell-cycle Control 14Immune Surveillance 14Role of the Microenvironment in Peripheral T-cell Lymphoma 15The Model of Angio-immunoblastic T-cell Lymphoma and T Follicular Helper-derived Peripheral T-cell Lymphoma 15Specific Microenvironment Components Present in Other Primary Cutaneous T-cell Lymphoma Entities 16Underlying Factors Favoring the Tumor Transformation 18Viruses 18Chronic Antigenic Stimulation 19Other Factors 19Cell of Origin (Table 2.1) 20Conclusion 22Must Reads 22References 223 Epigenetics of T-cell Lymphoma 27H. Miles Prince, Jasmine Zain, Anas Younes, Sean Whittaker, Owen A. O’Connor and Sean HarropIntroduction 27Epigenetic Pathways Altered in T-cell Lymphoma 27Epigenetic Changes Within Specific T-cell Lymphoma Subtypes 31Peripheral T-cell Lymphoma Not Otherwise Specified 32Angioimmunoblastic T-cell Lymphoma and Peripheral T-cell Lymphoma with T Follicular Helper Phenotype 32Anaplastic Large-cell Lymphoma 33Adult T-cell Leukemia/Lymphoma 33Intestinal T-cell Lymphoma 34Hepatosplenic T-cell Lymphomas 34Extranodal Natural Killer/T-cell Lymphoma 34Mycosis Fungoides and Sézary Syndrome 35Established and Emerging Drugs Targeting the T-cell Lymphoma Epigenome 35DNA Methyltransferase Inhibitors 35Isocitrate Dehydrogenase Inhibitors 36EZH2 Inhibitors 37BET Inhibitors 38Protein Arginine Methyltransferases Inhibitors 38Combination Therapies Involving Epigenetic Targeting Agents 38Future Directions 38Must Reads 39References 394 Animal Models of T-cell Lymphoma 47Keiichiro Hattori, Raksha Shrestha, Tatsuhiro Sakamoto, Manabu Kusakabe and Mamiko Sakata-YanagimotoIntroduction 47Angioimmunoblastic T-cell Lymphoma 50The ROQUIN Mouse Model 50The Mouse Models Recapitulating Human Angioimmunoblastic T-cell Lymphoma Genomic Features 50Tet2 Gene Trap Mice 50G17V RHOA Mouse Model 50PDX Models of Angioimmunoblastic T-cell Lymphoma 51Anaplastic Large T-cell Lymphoma 51Viral and Chimeric Models 51Transgenic Models 51CRISPR-Based Models 52PDX Models of Anaplastic Large-Cell Lymphomas 52Human T-cell Lymphotropic Virus Type 1 Adult T-cell Leukemia/Lymphoma 52Mice Expressing HTLV-1 Viral Proteins 52PDX Models of Adult T-cell Leukemia/Lymphoma 52Cutaneous T-cell Lymphoma 53Enteropathy-associated T-cell Lymphoma 53Conclusion 53Must Reads 53References 54Part II Epidemiology and Classification of the PTCL 575 Geographic Distribution of the Peripheral T-cell Lymphomas 59Global EpidemiologyAmulya Yellala, Avyakta Kallam and James O. ArmitageHistorical Perspective 59Epidemiology 60Peripheral T-cell Lymphoma, Not Otherwise Specified 60Angioimmunoblastic T-cell Lymphoma 61Anaplastic Large-cell Lymphoma 61Adult T-cell Lymphoma/Leukemia (HTLV Associated) 62Extranodal NK/T-cell Lymphomas 62T-cell Prolymphocytic Leukemia 62Large Granular Lymphocytic Leukemia 62Primary Cutaneous Gamma/Delta PTCL 63Enteropathy Associated T-cell Lymphomas and Monomorphic Epitheliotropic Intestinal T-cell lymphoma 63Hepatosplenic T-cell Lymphoma 63The Cutaneous T-cell Lymphomas 63Conclusion 63Must Reads 64References 646 Classification of the Peripheral T-cell Lymphomas 69Neval Ozkaya and Elaine S. JaffeIntroduction 69Angioimmunoblastic T-cell Lymphoma and Other Nodal Lymphomas of T follicular Helper Cell Origin 69Angioimmunoblastic T-cell Lymphoma 70Follicular T-cell Lymphoma 71Nodal Peripheral T-cell Lymphoma with T-follicular Helper Phenotype 71Peripheral T-cell Lymphoma Not Otherwise Specified 71Anaplastic Large-cell Lymphomas 72Anaplastic Large-cell Lymphoma, ALK-Positive 72Anaplastic Large-cell Lymphoma, ALK-Negative 72Breast Implant-associated Anaplastic Large-cell Lymphoma (Provisional) 73Adult T-cell Leukemia/Lymphoma 74Intestinal T-cell Lymphomas 74Enteropathy-associated T-Cell Lymphoma 75Monomorphic Epitheliotropic Intestinal T-cell Lymphoma 76Intestinal T-cell ymphoma, Not Otherwise Specified 76Indolent T-cell Lymphoproliferative Disorder of the Gastrointestinal Tract (Provisional) 77NK-Cell Enteropathy 78Hepatosplenic T-cell Lymphoma 78Mycosis Fungoides 78Sézary Syndrome 79Primary Cutaneous CD30-positive T-cell Lymphoproliferative Disorders 79Lymphomatoid Papulosis 79Primary Cutaneous Anaplastic Large-cell Lymphoma 80Subcutaneous Panniculitis-like T-cell Lymphoma 80Primary Cutaneous Gamma–Delta T-cell Lymphoma 80Primary Cutaneous CD8+ Aggressive Epidermotropic Cytotoxic T-cell Lymphoma (Provisional) 81PrimaryCutaneous CD4+ Small/Medium T-Cell Lymphoproliferative Disorder (Provisional) 81Primary Cutaneous Acral CD8+ T-cell Lymphoma (Provisional) 82Large Granular Lymphocytic Leukemia 82T-cell Large Granular Lymphocytic Leukemia 82Chronic Lymphoproliferative Disorder of NK Cells (Provisional) 82T-cell Prolymphocytic Leukemia 82NK-cell Lymphomas 83Extranodal NK/T-cell Lymphoma, Nasal Type 83Aggressive NK-cell Leukemia 83EBV-positive T-cell and NK-cell Lymphoproliferative Diseases of Childhood 83Must Reads 84References 847 Molecular Classification of the Peripheral T-cell Lymphomas 91Tyler A. Herek and Javeed IqbalIntroduction 91T-cell Development and Activation: An Overview 92T-cell Receptor Signaling 92Derivation of Diagnostic Signatures for Molecular Classification of Peripheral T-cell Lymphomas 95Angioimmunoblastic T-cell Lymphoma and Other T Follicular Helper-derived Malignancies 95Recurrent Genetic Features 96Anaplastic Large-cell Lymphomas 96Recurrent Genetic Features 96Adult T-cell Leukemia/Lymphoma 97Recurrent Genetic Features 97Peripheral T-cell Lymphoma Not Otherwise Specified 97Recurrent Genetic Features in Two Novel Subgroups 98Hepatosplenic T-cell Lymphoma 98Recurrent Genetic Features 98Extranodal natural killer/T-cell Lymphoma 98Recurrent Genetic Features 99Cutaneous T-cell Lymphomas 99Conclusion 99Must Reads 99References 99Part III Discrete Clinical Subtypes of PTCL (Unique Epidemiology, Therapy and Management) 1058 Peripheral T-cell Lymphoma Not Otherwise Specified 107N. Nora Bennani and Stephen M. AnsellIntroduction 107Epidemiology, Risk Factors, and Clinical Characteristics 107Basic Principles of Disease Biology 108Prognostic Tools 109Frontline Therapy 110Management of Relapsed or Refractory Disease 111Future Directions 112Must Reads 112References 1129 Angioimmunoblastic T-cell Lymphoma 115Jehan Dupuis and Franck MorschhauserIntroduction 115Clinical and Biological Presentation 115Epidemiology and Risk Factors, Disease Incidence and Prevalence 117Basic Principles of Disease Biology 118TET2 Mutations 119IDH2 Mutations 120DNMT3A Mutations 120Rho A Mutations 121CD28 Alterations 121Other Mutations Affecting the T-cell Lymphoma Pathway 121Management of Disease in the Front Line 122Management of Relapsed or Refractory Disease 122Conventional Chemotherapy Agents 123Bendamustine 123Pralatrexate 123Romidepsin 124Belinostat 124Newer Targeted Therapy Approaches 125Future Directions 125Must Reads 126References 12610 The Spectrum of Anaplastic Large-cell Lymphoma 129Jianping Kong and Andrew L. FeldmanIntroduction 129Epidemiology and Risk Factors 129Disease Incidence and Prevalence 131Basic Principles of Disease Biology 133Management of Disease in the Front Line 134Management of the Relapsed or Refractory Patient 137Future Directions 138Acknowledgement 140Must Reads 140References 14011 Human T-cell Lymphotropic Virus Type 1 Positive Adult T-cell Leukemia/Lymphoma 145Wataru Munakata and Kensei TobinaiEpidemiology and Disease Incidence 145Basic Principles of Disease Biology 145CCR4 and Adult T-cell Leukemia/Lymphoma 146Clinical Features of Adult T-cell Leukemia/Lymphoma 146Prognosis and Prognostic Index of ATLL 147Front-line Management of Aggressive Adult T-cell Leukemia/Lymphoma 149Chemotherapy and Hematopoietic Stem-cell Transplantation 149Mogamulizumab with Dose-intensified Chemotherapy 150Interferon alpha and Antiretroviral Agents 151Chemotherapy in Transplant-ineligible Patients with Aggressive Adult T-cell Leukemia/Lymphoma 151Front-line Management of Indolent ATLL 152Management of Relapsed or Refractory Patients 152Mogamulizumab Monotherapy 152Lenalidomide Monotherapy 153Other Treatments for Relapsed or Refractory Adult T-cell Leukemia/Lymphoma 153Future Directions 154Must Reads 154References 15412 Natural Killer/T-cell Lymphomas 159Seok Jin Kim, Ritsuro Suzuki, Arnaud Jaccard, Soon Thye Lim and Wong Seog KimIntroduction 159Epidemiology and Risk Factors 161Disease Incidence and Prevalence 161Basic Principles of Disease Biology 161Genetic Susceptibility to NK/T-Cell Lymphoma 161Molecular Pathogenesis 162JAK–STAT and Associated Pathways 162Nuclear Factor Kappa B and Other Deregulated Pathways 163The Programmed Cell Death 1/Programmed Death Ligand 1 Pathway 163Management of Newly Diagnosed Treatment-naïve Patients 163Diagnosis and Initial Assessment 164Monitoring the Response 165Treatment Strategies 165Localized Disease 165Disseminated Disease 167Consolidation Treatment with Hematopoietic Stem-cell Transplantation 167Management of Relapsed or Refractory Disease 167Treatment of Localized Nasal Relapse 167Treatment of a Systemic Relapse 167Novel Agents for Relapsed or Refractory ENKTL 168Future Directions 168Must Reads 168References 16913 T-Prolymphocytic Leukemia 175Dima El-Sharkawi and Claire DeardenIntroduction 175Incidence 175Clinical Features 175Laboratory Findings 175Treatment 176Stem-cell Transplantation 178Treatment for Relapsed/Refractory Disease 178Future Directions 178Must Reads 179References 17914 Large Granular Lymphocyte Leukemia 183Karolina H. Dziewulska, Katharine B. Moosic, HeeJin Cheon, Kristine C. Olson, David J. Feith and Thomas P. Loughran, JrIntroduction 183Epidemiology and Risk Factors 183Prevalence of Concomitant Disorders 184Autoimmune Diseases 184Hematological Disorders 184Basic Principles of Disease Biology 185Biology 185STAT3 Dysregulation 185STAT3 and Common Cytopenias 186JAK–STAT Pathway 187Other Mutated and Dysregulated Pathways 187Chronic Activation and Large Granular Lymphocyte Clonal Malignancy 188STAT3 and Clonality 188Antigenic Stimulation 188Immune System Dysregulation 189Cytotoxic Killer Cells and Autoimmunity 189Humoral Abnormalities 189Abnormal Bone Marrow 190Neutropenia and Rheumatoid Arthritis 190Spleen Pathology 191Management of Disease in the Front Line 191Diagnosis 191Prognosis 191Current Treatments 192Indications for Treatment 192Evaluation of Treatment Response 192Therapeutic Approach 192Canonical Immunosuppressive Treatments 192Non-canonical Immunosuppressive Treatments 193Supportive Therapy 194Summary of Therapeutic Recommendations 194Management of Relapsed or Refractory Disease 194Future Directions 194JAK–STAT Pathway Targeting 194Natural Compounds 196Other Candidate Agents 196Funding 196Disclosures 197Must Reads 197References 19715 Gamma–Delta T-cell Lymphomas 203Francine Foss, Aadil Ahmed and Mina XuIntroduction 203Epidemiology and Risk Factors 203Biology of Primary Cutaneous Gamma–Delta T-cell Lymphoma 204Management of Disease in the Front Line 206Management of Relapsed/Refractory Disease 208Must Reads 209References 20916 Enteropathy-Associated and Monomorphic Epitheliotropic Intestinal T-cell Lymphomas 211Craig R. Soderquist, Jennifer Shingleton, Sandeep Dave and Govind BhagatIntroduction 211Enteropathy-associated T-cell Lymphoma 211Epidemiology and Risk Factors 211Disease Incidence and Prevalence 212Basic Principles of Disease Biology 212Morphology and Immunophenotype 212Molecular and Genetic Alterations 212Management of Patients in the Front Line 213Management of the Relapsed or Refractory Patient 214Future Directions 214Refractory Celiac Disease 214Disease Definition, Risk Factors, Incidence, and Prevalence 214Basic Principles of Disease Biology 214Morphology and Immunophenotype 214Molecular and Genetic Alterations 215Management of Patients in the Front-Line 216Management of the Relapsed or Refractory Patient 216Future Directions 216Monomorphic Epitheliotropic Intestinal T-Cell Lymphoma 216Disease Risk Factors, Incidence, and Prevalence 216Basic Principles of Disease Biology 216Morphology and Immunophenotype 216Molecular and Genetic Alterations 218Management of Disease in the Front Line 218Management of Relapsed or Refractory Disease 218Future Directions 218Must Reads 218References 21917 Hepatosplenic T-cell Lymphomas 225Robert N. Stuver, Mwanasha Merrill and Salvia JainEpidemiology and Disease Incidence 225Basic Principles of Disease Biology 227Clinical Features 227Management of Disease in the Front Line 228Management of the Relapsed or Refractory Disease 229Splenectomy 230Future Directions 230Funding 231Must Reads 231References 23118 Cutaneous T-cell Lymphoma 235Alejandro A. Gru, Bethanie Rooke, Kevin Molloy and Julia ScarisbrickIntroduction 35Epidemiology and Risk Factors 236Basic Principles of Disease Biology 237Clinical, Pathologic, and Immunophenotypic Findings 240Management of Front-Line Mycosis Fungoides/Sézary Syndrome 247Early-stage Disease (Stages IA–IIA) 248Late-stage Disease (Stage IIB–IVA2) 250Stage IIB (Tumor-stage Disease) 250Stage III–IVA1 Disease (Erythrodermic Disease and Sézary) 250Stage IVA2–IVB Disease 250Management of Relapsed or Refractory Disease with Mycosis Fungoides/Sézary Syndrome 250Early-stage Disease (Stage IA–IIA) 250Late-stage Disease (IIB–IVA2) 251Stage IIB (Tumor-stage Disease) 251Stage III–IVA1 (Erythrodermic Disease) 251Stage IVA2–IVB Disease 252Front-Line Management of Non-mycosis Fungoides Cutaneous T-cell Lymphomas 252Management of Relapsed or Refractory Non-mycosis Fungoides Cutaneous T-cell Lymphomas 252Future Directions 252Must Reads 253References 25319 Other Rare Subtypes of Peripheral T-cell Lymphoma 259Pier Paolo PiccalugaIntroduction 259Chronic Lymphoproliferative Disorders of Natural Killer Cells 259Epidemiology and Risk Factors 259Disease Incidence and Prevalence 259Basic Principles of Disease Biology 260Management of Front-line Disease 260Epstein–Barr Virus-associated T-cell and NK-cell Lymphoproliferative Disorders of Childhood 260Systemic Epstein–Barr Virus-positive T-cell Lymphoma of Childhood 260Epidemiology and Risk Factors 260Basic Principles of Disease Biology 260Management of Front-Line Disease 261Chronic Active Epstein–Barr Virus Infection of T- and NK-cell Type, Systemic Form 261Epidemiology and Risk Factors 261Basic Principles of Disease Biology 261Management of Front-Line Disease 262Chronic Active Epstein–Barr Virus Infection of T- and NK-cell Type, Cutaneous Form 264Hydroa Vacciniforme-like Lymphoproliferative Disorder 264Basic Principles of Disease Biology 264Management of Disease in the Front Line 264Severe Mosquito Bite Allergy 265Epidemiology and Risk Factors 265Basic Principles of Disease Biology 265Management of Disease in the Front-Line 265Future Directions 265Must Reads 265References 266Part IV Treatment of the PTCL 26920 Standard Front-line Therapies 271Raphael Koch and Lorenz TruempeIntroduction 271Initial Workup and Risk Stratification 271Front-line Therapy 274Front-line Treatment Approaches for Common Subtypes 274Systemic Anaplastic Large-cell Lymphomas 276Breast Implant-associated Anaplastic Large-cell Lymphomas 277Enteropathy-associated T-cell Lymphoma and Monomorphic Epitheliotropic Intestinal T-cell Lymphoma 277Hepatosplenic T-cell Lymphoma 278Extranodal natural killer/T-cell Lymphoma, Nasal Type 279T-cell Prolymphocytic Leukemia 280Adult T-Cell Leukemia/Lymphoma 280Must Reads 281References 28121 Approved Agents in the Relapsed or Refractory Setting, Excluding Brentuximab Vedotin 287Helen Ma and Owen A. O’ConnorIntroduction 287Challenges in Developing New Drugs in Peripheral T-cell Lymphomas 288Drugs Approved by the US Food and Drug Administration with an Indication in Relapsed/Refractory Peripheral T-cell Lymphoma 288Pralatrexate 289Pharmacology 289Early-phase Data 289Pivotal Data 289Recent Developments 291Histone Deacetylase Inhibitors (Including Romidepsin and Belinostat) 291Pharmacology 291Early Phase Data 292Pivotal Data 292Recent Developments 293Drugs Approved by the US Food and Drug Administration But Without An Indication in Relapsed/Refractory Peripheral T-cell Lymphoma 294Etoposide 294Pharmacology 294Clinical Experiences in Peripheral T-cell Lymphoma 294Summary 294Bortezomib 294Pharmacology 294Clinical Experiences in Peripheral T-cell Lymphoma 296Recent Developments 296Bendamustine 296Pharmacology 296Clinical Experience in Peripheral T-cell Lymphoma 296Recent Developments 296Gemcitabine 296Pharmacology 296Clinical Data 297Recent Developments 297Drugs Approved by International Regulatory Agencies, Not Including the United States, that Carry an Indication in Relapsed/Refractory Peripheral T-cell Lymphoma 297Chidamide 297Pharmacology 297Early Phase Data 297Pivotal Data 297Recent Developments 297Forodesine 297Pharmacology 297Early Phase Data 297Pivotal Data 298Recent Developments 298Considerations in the Selection of Therapy 298Treatment Goals 298Aggressive Versus Indolent Disease 299Transplant Eligible or Ineligible 299Suitability for Chemotherapy 299Conclusion 299Must Reads 299References 30022 The Role of Autologous Stem-cell Transplantation in Peripheral T-cell Lymphomas 305Juan Alejandro Ospina-Idárraga, Rolando Humberto Martinez-Cordero, Leonardo José Enciso-Olivera and Henry Idrobo-QuinteroIntroduction 305Autologous Stem-cell Transplantation in First Complete Remission 306Autologous Stem-cell Transplantation in Relapsed/Refractory Disease 307Interpretation of Available Literature 307Identifying the Most Relevant Determinants for Survival among Patients with Peripheral T-cell Lymphoma Undergoing Autologous Stem-cell Transplantation 308Status of Response Prior to Autologous Stem-cell Transplantation 309Risk of Stage 310Number of Prior Therapies and Refractory Disease 311Autologous Stem-cell Transplantation on Specific Subtypes of Peripheral T-cell Lymphoma 311Peripheral T-cell Lymphomas Not Otherwise Specified 311Angioimmunoblastic T Cell Lymphoma 312Anaplastic T Large-cell Lymphoma 312Extranodal Natural Killer/T-cell Lymphoma, Nasal Type 313The Role of Autologous Stem-cell Transplantation in Cutaneous T-cell Lymphomas 314Must Reads 314References 31523 Allogeneic Stem-cell Transplantation 319Anna Dodero and Paolo CorradiniIntroduction 319Allogeneic Stem-cell Transplantation for Relapsed andRefractory Disease (Focus on Nodal Hystotypes) 320Allogeneic Stem-cell Transplantation as Consolidation of First Remission 322Allogeneic Stem-cell Transplantation in Specific Subtypes 322Cutaneous T-cell Lymphomas 322Hepatosplenic T-cell Lymphomas 324Extranodal Natural Killer/T-cell Lymphomas, Nasal Type 324Adult T-cell Leukemia/Lymphoma 324Future Directions 325Must Reads 325References 32524 Emerging Immunotherapy Approaches in Peripheral T-cell Lymphomas 329Barbara Pro and Andrei ShustovIntroduction 329Monoclonal Antibody Therapy 329Alemtuzumab 330Mogamulizumab 330Immunoconjugate-Based Therapy for Peripheral T-Cell Lymphoma 331Brentuximab Vedotin 332Cell-Mediated or Cellular Immunotherapy in Peripheral T-Cell Lymphoma 333PD1–PD-L1 Checkpoint Inhibition 334AFM13 – Targeted Natural Killer Cell Immunotherapy Facilitator 335TTI-621 – Targeted Macrophage Immunotherapy Facilitator 3354-1BB – Enabled Adoptive Therapy of Epstein–Barr Virus-Positive Malignancies 335IPH4102 (Anti-KIR3DL2 Monoclonal Antibody) 336Chimeric Antigen Receptor T-cell Therapy for Peripheral T-cell Lymphoma 336Challenges and Future Directions 336Must Reads 337References 33825 Emerging New Small Molecules in Peripheral T-cell Lymphomas 343Alessandro Broccoli and Pier Luigi ZinzaniIntroduction 343Demethylating Agents 344Janus-associated Kinase–Signal Transducers and Activators of Transcription and Spleen Tyrosine Kinase Inhibitors 345Phosphatidylinositol 3-Kinase Inhibitors 345Miscellaneous 347Pro-apoptotic Small Molecules 347Farnesyltransferase Inhibitors 347Aurora Kinase Inhibitors 347Conclusion 348Must Reads 348References 348Part V Future Directions 35126 The Value and Relevance of T-cell Lymphoma Registries 353Tetiana Skrypets, Martina Manni, Monica Civallero, Iryna Kriachok and Massimo FedericoIntroduction 353Population-based Cancer Registries 353Retrospective Studies 355T-cell Lymphoma Registries 360T-cell Project 1.0 360COMPLETE 363T-cell Project 2.0 363Future Directions 364Disclosures 364Must Reads 364References 36527 Innovative Chemotherapy-free Approaches for the Treatment of Peripheral T-Cell Lymphoma 367Enrica Marchi, Ahmed Sawas, Helen Ma, Luigi Scotto and Francesca MontanariIntroduction 367Targeting the Peripheral T-cell Lymphoma Epigenome 369Romidepsin Plus Pralatrexate 370Preclinical Rationale 370Clinical Experience 370Romidepsin Plus 5-Azacytidine 371Preclinical Rationale 371Clinical Experience 371Romidepsin Plus Duvelisib 372Preclinical Rationale 372Clinical Experience 372Romidepsin Plus Lenalidomide 373Preclinical Rationale 373Clinical Experience 373Panobinostat and Bortezomib 373Preclinical Rationale 373Clinical Experience 374A Glance at the Future: Building on the Active Doublets 374Must Reads 375References 37528 Global Collaborations 379Dejan Radjeski, Eliza Hawke, Owen A. O’Connor, Pier Luigi Zinzani, Won Seog Kim and Enrica MarchiIntroduction 379The Global T-cell Lymphoma Consortium 380The Mission 380Structure 380Organizational Features 380Submission of Trial Concepts 381Budget Negotiations 382Institutional Review Board 383Publications 383Conclusion 384Index 385

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