The Peripheral T‐Cell Lymphomas

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Title Page
	Copyright Page
Contents
Contributors
About the Companion Website
Part I Biological Basis of the Peripheral T-cell Lymphomas
	Chapter 1 The Fundamentals of T-cell Lymphocyte Biology
		Introduction
		General View of the Differentiation and Function of T Lymphocytes
		The T-cell System as a Frame for Peripheral T-cell Lymphoma: Taking Plasticity into Account
		Must Reads
		References
	Chapter 2 Mechanisms of T-cell Lymphomagenesis
		Introduction
		Oncogenic Events in the Transformation of T or Natural Killer Cells
			Genetic Lesions
	Deregulated Pathways in Peripheral T-cell Lymphoma Oncogenesis (Figure 2.1, Table 2.1)
				Epigenetic Regulation
				Signaling Pathways
				Cell-cycle Control
				Immune Surveillance
	Role of the Microenvironment in Peripheral T-cell Lymphoma
	The Model of Angio-immunoblastic T-cell Lymphoma and T Follicular Helper-derived Peripheral T-cell Lymphoma
	Crosstalk Between Neoplastic T Follicular Helper Cells and Their Microenvironment in Angioimmunoblastic T-cell Lymphoma
				Genetic Alterations in the Angioimmunoblastic T-cell Lymphoma
	Specific Microenvironment Components Present in Other Primary Cutaneous T-cell Lymphoma Entities
	Underlying Factors Favoring the Tumor Transformation
				Viruses
				Chronic Antigenic Stimulation
				Other Factors
		Conclusion
		Acknowledgement
		Must Reads
		References
	Chapter 3 Epigenetics of T-cell Lymphoma
		Introduction
		Epigenetic Pathways Altered in T-cell Lymphoma
		Epigenetic Changes Within Specific T-cell Lymphoma Subtypes
	Peripheral T-cell Lymphoma Not Otherwise Specified
	Angioimmunoblastic T-cell Lymphoma and Peripheral T-cell Lymphoma with T Follicular Helper Phenotype
			Anaplastic Large-cell Lymphoma
			Adult T-cell Leukemia/Lymphoma
			Intestinal T-cell Lymphoma
			Hepatosplenic T-cell Lymphomas
			Extranodal Natural Killer/T-cell Lymphoma
			Mycosis Fungoides and Sézary Syndrome
		Established and Emerging Drugs Targeting the T-cell Lymphoma Epigenome
			DNA Methyltransferase Inhibitors
			Isocitrate Dehydrogenase Inhibitors
			EZH2 Inhibitors
			Protein Arginine Methyltransferases Inhibitors
		Combination Therapies Involving Epigenetic Targeting Agents
		Future Directions
		Must Reads
		References
	Chapter 4 Animal Models of T-cell Lymphoma
		Introduction
		Angioimmunoblastic T-cell Lymphoma
			The ROQUIN Mouse Model
			The Mouse Models Recapitulating Human Angioimmunoblastic T-cell Lymphoma Genomic Features
			Tet2 Gene Trap Mice
			G17V RHOA Mouse Model
			PDX Models of Angioimmunoblastic T-cell Lymphoma
		Anaplastic Large T-cell Lymphoma
			Viral and Chimeric Models
			Transgenic Models
			CRISPR-Based Models
			PDX Models of Anaplastic Large-Cell Lymphomas
		Human T-cell Lymphotropic Virus Type 1 Adult T-cell Leukemia/Lymphoma
			Mice Expressing HTLV-1 Viral Proteins
			PDX Models of Adult T-cell Leukemia/Lymphoma
		Cutaneous T-cell Lymphoma
		Enteropathy-associated T-cell Lymphoma
		Conclusion
		References
	Part II Epidemiology and Classification of the PTCL
	Chapter 5 Geographic Distribution of the Peripheral T-cell Lymphomas: Global Epidemiology
		Historical Perspective
		Epidemiology
			Peripheral T-cell Lymphoma, Not Otherwise Specified
			Angioimmunoblastic T-cell Lymphoma
			Anaplastic Large-cell Lymphoma
			Adult T-cell Lymphoma/Leukemia(HTLV Associated)
			Extranodal NK/T-cell Lymphomas
			T-cell Prolymphocytic Leukemia
			Large Granular Lymphocytic Leukemia
			Primary Cutaneous Gamma/Delta PTCL
			Enteropathy Associated T-cell Lymphomas and Monomorphic Epitheliotropic Intestinal T-cell lymphoma
			Hepatosplenic T-cell Lymphoma
			The Cutaneous T-cell Lymphomas
		Conclusion
		Must Reads
		References
		5.A 2017 World Health Organization Classification of Mature T- and NK-cell Neoplasms
	Chapter 6 Classification of the Peripheral T-cell Lymphomas
		Introduction
		Angioimmunoblastic T-cell Lymphoma and Other Nodal Lymphomas of T follicular Helper Cell Origin
			Angioimmunoblastic T-cell Lymphoma
			Follicular T-cell Lymphoma
			Nodal Peripheral T-cell Lymphoma with T-follicular Helper Phenotype
		Peripheral T-cell Lymphoma Not Otherwise Specified
		Anaplastic Large-cell Lymphomas
			Anaplastic Large-cell Lymphoma, ALK-Positive
			Anaplastic Large-cell Lymphoma, ALK-Negative
			Breast Implant-associated AnaplasticLarge-cell Lymphoma (Provisional)
		Adult T-cell Leukemia/Lymphoma
		Intestinal T-cell Lymphomas
			Enteropathy-associated T-Cell Lymphoma
			Monomorphic Epitheliotropic Intestinal T-cell Lymphoma
			Intestinal T-cell ymphoma, Not Otherwise Specified
			Indolent T-cell Lymphoproliferative Disorder of the Gastrointestinal Tract (Provisional)
			NK-Cell Enteropathy
		Hepatosplenic T-cell Lymphoma
		Mycosis Fungoides
		Sézary Syndrome
		Primary Cutaneous CD30-positive T-cell Lymphoproliferative Disorders
			Lymphomatoid Papulosis
			Primary Cutaneous Anaplastic Large-cell Lymphoma
			Subcutaneous Panniculitis-like T-cell Lymphoma
		Primary Cutaneous Gamma–Delta T-cell Lymphoma
		Primary Cutaneous CD8+ Aggressive Epidermotropic Cytotoxic T-cell Lymphoma (Provisional)
		Primary Cutaneous CD4+ Small/Medium T-Cell Lymphoproliferative Disorder (Provisional)
		Primary Cutaneous Acral CD8+ T-cell Lymphoma (Provisional)
		Large Granular Lymphocytic Leukemia
			T-cell Large Granular Lymphocytic Leukemia
			Chronic Lymphoproliferative Disorder of NK Cells (Provisional)
		T-cell Prolymphocytic Leukemia
		NK-cell Lymphomas
			Extranodal NK/T-cell Lymphoma, Nasal Type
			Aggressive NK-cell Leukemia
			EBV-positive T-cell and NK-cell Lymphoproliferative Diseases of Childhood
		Must Reads
		References
	Chapter 7 Molecular Classification of the Peripheral T-cell Lymphomas
		Introduction
		T-cell Development and Activation: An Overview
		T-cell Receptor Signaling
		Derivation of Diagnostic Signatures for Molecular Classification of Peripheral T-cell Lymphomas
		Angioimmunoblastic T-cell Lymphoma and Other T Follicular Helper-derived Malignancies
			Recurrent Genetic Features
		Anaplastic Large-cell Lymphomas
			Recurrent Genetic Features
		Adult T-cell Leukemia/Lymphoma
			Recurrent Genetic Features
		Peripheral T-cell Lymphoma Not Otherwise Specified
			Recurrent Genetic Features in Two Novel Subgroups
		Hepatosplenic T-cell Lymphoma
			Recurrent Genetic Features
		Extranodal natural killer/T-cell Lymphoma
			Recurrent Genetic Features
		Cutaneous T-cell Lymphomas
		Must Reads
		Conclusion
		References
Part III Discrete Clinical Subtypes of PTCL (Unique Epidemiology, Therapy and Management)
	Chapter 8 Peripheral T-cell Lymphoma Not Otherwise Specified
		Introduction
		Epidemiology, Risk Factors, and Clinical Characteristics
		Basic Principles of Disease Biology
		Prognostic Tools
		Frontline Therapy
		Management of Relapsed or Refractory Disease
		Future Directions
		Must Reads
		References
	Chapter 9 Angioimmunoblastic T-cell Lymphoma
		Introduction
		Clinical and Biological Presentation
		Epidemiology and Risk Factors, Disease Incidence and Prevalence
		Basic Principles of Disease Biology
			TET2 Mutations
			IDH2 Mutations
			DNMT3A Mutations
			Rho A Mutations
			CD28 Alterations
			Other Mutations Affecting the T-cell Lymphoma Pathway
		Management of Disease in the Front Line
		Management of Relapsed or Refractory Disease
			Conventional Chemotherapy Agents
			Romidepsin
			Newer Targeted Therapy Approaches
		Future Directions
		Must Reads
		References
	Chapter 10 The Spectrum of Anaplastic Large-cell Lymphoma
		Introduction
		Epidemiology and Risk Factors
		Disease Incidence and Prevalence
		Basic Principles of Disease Biology
		Management of Disease in the Front Line
		Management of the Relapsed or Refractory Patient
		Future Directions
		Must Reads
		Acknowledgement
		References
	Chapter 11 Human T-cell Lymphotropic Virus Type 1 Positive Adult T-cell Leukemia/Lymphoma
		Epidemiology and Disease Incidence
		Basic Principles of Disease Biology
		CCR4 and Adult T-cell Leukemia/Lymphoma
		Clinical Features of Adult T-cell Leukemia/Lymphoma
		Prognosis and Prognostic Index of ATLL
		Front-line Management of Aggressive Adult T-cell Leukemia/Lymphoma
			Chemotherapy and Hematopoietic Stem-cell Transplantation
			Mogamulizumab with Dose-intensified Chemotherapy
			Interferon alpha and Antiretroviral Agents
			Chemotherapy in Transplant-ineligible Patients with Aggressive Adult T-cell Leukemia/Lymphoma
		Front-line Management of Indolent ATLL
		Management of Relapsed or Refractory Patients
			Mogamulizumab Monotherapy
			Lenalidomide Monotherapy
			Other Treatments for Relapsed or Refractory Adult T-cell Leukemia/Lymphoma
		Future Directions
		Must Reads
		References
	Chapter 12 Natural Killer/T-cell Lymphomas
		Introduction
			Epidemiology and Risk Factors
			Disease Incidence and Prevalence
			Basic Principles of Disease Biology
			Genetic Susceptibility to NK/T-Cell Lymphoma
			Molecular Pathogenesis
			JAK–STAT and Associated Pathways
			Nuclear Factor Kappa B and Other Deregulated Pathways
			The Programmed Cell Death 1/Programmed Death Ligand 1 Pathway
		Management of Newly Diagnosed Treatment-naïve Patients
			Diagnosis and Initial Assessment
			Monitoring the Response
			Treatment Strategies
			Localized Disease
			Disseminated Disease
		Consolidation Treatment with Hematopoietic Stem-cell Transplantation
		Management of Relapsed or Refractory Disease
			Treatment of Localized Nasal Relapse
			Treatment of a Systemic Relapse
			Novel Agents for Relapsed or Refractory ENKTL
		Future Directions
		Must Reads
		References
	Chapter 13 T-Prolymphocytic Leukemia
		Introduction
			Incidence
			Clinical Features
			Laboratory Findings
			Treatment
			Stem-cell Transplantation
			Treatment for Relapsed/Refractory Disease
			Future Directions
		Must Reads
		References
	Chapter 14 Large Granular Lymphocyte Leukemia
		Introduction
		Epidemiology and Risk Factors
		Prevalence of Concomitant Disorders
			Autoimmune Diseases
			Hematological Disorders
		Basic Principles of Disease Biology
			Biology
			STAT3 Dysregulation
			STAT3 and Common Cytopenias
			JAK–STAT Pathway
			Other Mutated and Dysregulated Pathways
			Chronic Activation and Large Granular Lymphocyte Clonal Malignancy
			Immune System Dysregulation
		Management of Disease in the Front Line
			Diagnosis
			Prognosis
			Current Treatments
		Management of Relapsed or Refractory Disease
		Future Directions
			JAK–STAT Pathway Targeting
			Natural Compounds
			Other Candidate Agents
		Funding
			Disclosures
		Must Reads
		References
	Chapter 15 Gamma–Delta T-cell Lymphomas
		Introduction
		Epidemiology and Risk Factors
		Biology of Primary Cutaneous Gamma–Delta T-cell Lymphoma
			Management of Disease in the Front Line
			Management of Relapsed/Refractory Disease
		Must Reads
		References
	Chapter 16 Enteropathy-Associated and Monomorphic Epitheliotropic Intestinal T-cell Lymphomas
		Introduction
		Enteropathy-associated T-cell Lymphoma
			Epidemiology and Risk Factors
			Disease Incidence and Prevalence
			Basic Principles of Disease Biology
			Management of Patients in the Front Line
			Management of the Relapsed or Refractory Patient
			Future Directions
		Refractory Celiac Disease
			Disease Definition, Risk Factors, Incidence, and Prevalence
			Basic Principles of Disease Biology
			Molecular and Genetic Alterations
			Management of Patients in the Front-Line
			Management of the Relapsed or Refractory Patient
			Future Directions
		Monomorphic Epitheliotropic Intestinal T-Cell Lymphoma
			Disease Risk Factors, Incidence, and Prevalence
			Basic Principles of Disease Biology
			Management of Disease in the Front Line
			Management of Relapsed or Refractory Disease
			Future Directions
		Must Reads
		References
	Chapter 17 Hepatosplenic T-cell Lymphomas
		Epidemiology and Disease Incidence
		Basic Principles of Disease Biology
		Clinical Features
		Management of Disease in the Front Line
		Management of the Relapsed or Refractory Disease
		Splenectomy
		Future Directions
		Funding
		Must Reads
		References
	Chapter 18 Cutaneous T-cell Lymphoma
		Introduction
		Epidemiology and Risk Factors
		Basic Principles of Disease Biology
		Clinical, Pathologic, and Immunophenotypic Findings
		Management of Front-Line Mycosis Fungoides/Sézary Syndrome
			Early-stage Disease (Stages IA–IIA)
			Late-stage Disease (Stage IIB–IVA2)
		Management of Relapsed or Refractory Disease with Mycosis Fungoides/Sézary Syndrome
			Early-stage Disease (Stage IA–IIA)
			Late-stage Disease (IIB–IVA2)
		Front-Line Management of Non-mycosis Fungoides Cutaneous T-cell Lymphomas
		Management of Relapsed or Refractory Non-mycosis Fungoides Cutaneous T-cell Lymphomas
		Future Directions
		Must Reads
		References
	Chapter 19 Other Rare Subtypes of Peripheral T-cell Lymphoma
		Introduction
		Chronic Lymphoproliferative Disorders of Natural Killer Cells
			Epidemiology and Risk Factors
			Disease Incidence and Prevalence
			Basic Principles of Disease Biology
			Management of Front-line Disease
		Epstein–Barr Virus-associated T-cell and NK-cell Lymphoproliferative Disorders of Childhood
			Systemic Epstein–Barr Virus-positive T-cell Lymphoma of Childhood
			Chronic Active Epstein–Barr Virus Infection of T- and NK-cell Type, Systemic Form
			Chronic Active Epstein–Barr Virus Infection of T- and NK-cell Type, Cutaneous Form
			Severe Mosquito Bite Allergy
		Future Directions
		Must Reads
		References
Part IV Treatment of the PTCL
	Chapter 20 Standard Front-line Therapies
		Introduction
		Initial Workup and Risk Stratification
		Front-line Therapy
			Front-line Treatment Approaches for Common Subtypes
			Systemic Anaplastic Large-cell Lymphomas
			Breast Implant-associated AnaplasticLarge-cell Lymphomas
			Enteropathy-associated T-cell Lymphoma and Monomorphic Epitheliotropic Intestinal T-cell Lymphoma
			Hepatosplenic T-cell Lymphoma
			Extranodal natural killer/T-cell Lymphoma, Nasal Type
			T-cell Prolymphocytic Leukemia
			Adult T-Cell Leukemia/Lymphoma
		Must Reads
		References
	Chapter 21 Approved Agents in the Relapsed or Refractory Setting, Excluding Brentuximab Vedotin
		Introduction
		Challenges in Developing New Drugs in Peripheral T-cell Lymphomas
		Drugs Approved by the US Food and Drug Administration with an Indication in Relapsed/Refractory Peripheral T-cell Lymphoma
			Pralatrexate
			Histone Deacetylase Inhibitors (Including Romidepsin and Belinostat)
		Drugs Approved by the US Food and Drug Administration But Without An Indication in Relapsed/Refractory Peripheral T-cell Lymphoma
			Etoposide
			Bortezomib
			Bendamustine
			Gemcitabine
		Drugs Approved by International Regulatory Agencies, Not Including the United States, that Carry an Indication in Relapsed/Refractory Peripheral T-cell Lymphoma
			Chidamide
			Forodesine
		Conclusion
		Must Reads
		References
	Chapter 22 The Role of Autologous Stem-cell Transplantation in Peripheral T-cell Lymphomas
		Introduction
		Autologous Stem-cell Transplantation in First Complete Remission
		Autologous Stem-cell Transplantation in Relapsed/Refractory Disease
		Interpretation of Available Literature
		Identifying the Most Relevant Determinants for Survival among Patients with Peripheral T-cell Lymphoma Undergoing Autologous Stem-cell Transplantation
		Status of Response Prior to Autologous Stem-cell Transplantation
		Risk of Stage
		Number of Prior Therapies and Refractory Disease
		Autologous Stem-cell Transplantation on Specific Subtypes of Peripheral T-cell Lymphoma
			Peripheral T-cell Lymphomas Not Otherwise Specified
			Angioimmunoblastic T Cell Lymphoma
			Anaplastic T Large-cell Lymphoma
			Extranodal Natural Killer/T-cell Lymphoma, Nasal Type
			The Role of Autologous Stem-cell Transplantation in Cutaneous T-cell Lymphomas
		Must reads
		References
	Chapter 23 Allogeneic Stem-cell Transplantation
		Introduction
		Allogeneic Stem-cell Transplantation for Relapsed and Refractory Disease (Focus on Nodal Hystotypes)
		Allogeneic Stem-cell Transplantation as Consolidation of First Remission
		Allogeneic Stem-cell Transplantation in Specific Subtypes
			Cutaneous T-cell Lymphomas
			Hepatosplenic T-cell Lymphomas
			Extranodal Natural Killer/T-cell Lymphomas, Nasal Type
			Adult T-cell Leukemia/Lymphoma
		Future Directions
		Must Reads
		References
	Chapter 24 Emerging Immunotherapy Approaches in Peripheral T-cell Lymphomas
		Introduction
		Monoclonal Antibody Therapy
			Alemtuzumab
			Mogamulizumab
		Immunoconjugate-Based Therapy for Peripheral T-Cell Lymphoma
			Brentuximab Vedotin
		Cell-Mediated or Cellular Immunotherapy in Peripheral T-Cell Lymphoma
			PD1–PD-L1 Checkpoint Inhibition
			AFM13 – Targeted Natural Killer Cell Immunotherapy Facilitator
			TTI-621 – Targeted Macrophage Immunotherapy Facilitator
			4-1BB – Enabled Adoptive Therapy of Epstein–Barr Virus-Positive Malignancies
			IPH4102 (Anti-KIR3DL2 Monoclonal Antibody)
			Chimeric Antigen Receptor T-cell Therapy for Peripheral T-cell Lymphoma
		Challenges and Future Directions
		Must Reads
		References
	Chapter 25 Emerging New Small Molecules in Peripheral T-cell Lymphomas
		Introduction
		Demethylating Agents
		Janus-associated Kinase–Signal Transducers and Activators of Transcription and Spleen Tyrosine Kinase Inhibitors
		Phosphatidylinositol 3-Kinase Inhibitors
		Miscellaneous
			Pro-apoptotic Small Molecules
			Farnesyltransferase Inhibitors
			Aurora Kinase Inhibitors
		Conclusion
		Must Reads
		References
Part V Future Directions
	Chapter 26 The Value and Relevance of T-cell Lymphoma Registries
		Introduction
		Population-based Cancer Registries
		Retrospective Studies
		T-cell Lymphoma Registries
			T-cell Project 1.0
			COMPLETE
			T-cell Project 2.0
		Future Directions
		Must Reads
		Disclosures
	Chapter 27 Innovative Chemotherapy-free Approaches for the Treatment of Peripheral T-Cell Lymphoma
		Introduction
		Targeting the Peripheral T-cell Lymphoma Epigenome
		Romidepsin Plus Pralatrexate
			Preclinical Rationale
			Clinical Experience
		Romidepsin Plus 5-Azacytidine
			Preclinical Rationale
			Clinical Experience
		Romidepsin Plus Duvelisib
			Preclinical Rationale
			Clinical Experience
		Romidepsin Plus Lenalidomide
			Preclinical Rationale
			Clinical Experience
		Panobinostat and Bortezomib
			Preclinical Rationale
			Clinical Experience
		A Glance at the Future: Building on the Active Doublets
		Must Reads
		References
	Chapter 28 Global Collaborations
		Introduction
		The Global T-cell Lymphoma Consortium
			The Mission
			Structure
			Organizational Features
			Submission of Trial Concepts
			Budget Negotiations
			Institutional Review Board
			Publications
		Conclusion
Index
EULA