Diagnosis and Management of Myelodysplastic Syndromes : A Clinical Guide

Myelodysplastic syndromes (MDS) are a group of clonal disorders characterized by pancytopenias and the risk of progression to acute myeloid leukemia. The diagnosis of MDS can be challenging, while the outcomes of MDS patients vary widely. This book provides a concise yet comprehensive overview of MDS. The book begins by reviewing the diagnostic workup of MDS, with a specific focus on the 2016 WHO criteria for MDS diagnosis, and the biology and pathophysiology of the disease. The text then presents the molecular landscape of MDS and its impact on disease diagnosis, prognosis, and treatment decisions. The book continues by profiling different prognostic models of MDS and concludes with a thorough review of treatment algorithms for lower and higher-risk MDS, as well as the use of hematopoietic stem cell transplant to combat the disease. Written by experts in the field, __Diagnosis and Management of Myelodysplastic Syndromes: A Clinical Guide__ is a valuable resource for clinicians, practitioners, and researchers who are interested in MDS. The text also features over 100 illustrations, photographs, and tables. Preface 5 Acknowledgment 7 Contents 8 Contributors 10 Part I: Biology, Pathophysiology, and Clinical Presentation of MDS 12 Chapter 1: Epidemiology, Etiology, and Clinical Presentation of Myelodysplastic Syndromes 13 Introduction 13 Prevalence 17 Clinical Presentation 18 Survival, Cause of Death, and Leukemia Rates 18 Association of MDS with Autoimmune Diseases 19 Risk Factors for MDS 19 Obesity and Lifestyle Factors 20 Benzene 21 Smoking 21 Therapy-Related MDS 22 Summary 23 References 23 Chapter 2: Morphological, Flow Cytometry, and Cytogenetic Diagnosis of MDS 28 Introduction 28 Diagnosis and Classification of MDS 29 Morphology in Peripheral Blood and Bone Marrow 30 Peripheral Blood 30 Bone Marrow 31 Flow Cytometry 37 Cytogenetic Studies 41 MDS Subtypes 43 Myelodysplastic Syndrome with Single Lineage Dysplasia (MDS-SLD) 43 Myelodysplastic Syndrome with Multilineage Dysplasia (MDS-MLD) 43 Myelodysplastic Syndrome with Ring Sideroblasts (MDS-RS) 46 Myelodysplastic Syndrome with Isolated del(5q) (MDS-del5q) 47 Myelodysplastic Syndrome with Excess Blasts (MDS-EB) 47 Myelodysplastic Syndrome, Unclassifiable (MDS-U) 48 Refractory Cytopenia of Childhood (RCC) 48 Therapy-Related MDS (t-MDS) 48 References 48 Chapter 3: Biology and Pathophysiology of MDS with del(5q) 52 Introduction 52 Pathobiology of del(5q) MDS 53 Haploinsufficiency Underlies Hematologic Phenotype 53 Haploinsufficiency Underlies Clonal Expansion 57 Lenalidomide in Del(5q) MDS and Its Mechanism of Action 58 Mechanism of Lenalidomide Resistance in Del(5q) MDS 59 Conclusion 60 References 60 Chapter 4: MDS Stem Cell Biology 64 Introduction 64 Stem Cells, Hematopoiesis, and Energy Metabolism 65 Stem Cell Differentiation and Quiescence 65 Stem Cell Immunophenotypes 66 Leukemic Stem Cell Metabolism 67 Inflammatory Signaling and Cell Death 68 Disordered Innate Immune Signaling 68 Programmed Necrotic Cell Death 69 The Stem Cell Niche 72 Mesenchymal Stroma 72 Immune Microenvironment 74 Conclusion 75 References 76 Chapter 5: Molecular Landscape of MDS 82 Introduction 82 Recurrently Mutated Genes in MDS 83 Molecular Aberrations Contributing to Transcriptional Dysregulation in MDS 83 Epigenetic Regulation 83 DNA Methylation 84 Histone Modifications 85 DNA Looping 87 Transcription Factors (TF) 87 Molecular Aberrations Contributing to Dysregulation of Splicing 88 Molecular Aberrations Contributing to Dysregulation of Signaling 90 Molecular Aberrations Contributing to Dysregulation of the p53 Pathway 90 The Clinical Value of Molecular Genetic Characterization in MDS 91 From Clonal Hematopoiesis to Secondary AML – A Disease Continuum? 92 References 94 Chapter 6: MDS Mimics Including CHIP, ICUS, and CCUS 100 Introduction 100 MDS Diagnostic Criteria and Non-neoplastic Mimics 101 Congenital Syndromes with Predisposition to MDS 102 Conditions at the Diagnostic Border of MDS 104 Aplastic Anemia 104 Clonal Hematopoiesis in Individuals with Clinically Normal Hematopoiesis 105 Clonal and Idiopathic Cytopenias of Undetermined Significance (CCUS vs ICUS) 108 MDS Can Sometimes Be Considered an AML Mimic 110 Summary 110 References 111 Part II: Prognosis 115 Chapter 7: Prognostic Models in Myelodysplastic Syndromes 116 Introduction 116 Established Scoring Systems 117 Scoring Systems Dedicated to Specific Patient Populations and Clinical Circumstances 121 Therapy-Related and Secondary MDS 121 Prediction Rules for the Response to Hypomethylating Agents and for Prognostication in HMA-Refractory Patients 123 Scores in Patients with Lower-Risk MDS 124 Hypocellular MDS 125 A New Era: Risk Stratification Tools Including Somatic Mutations 126 Future Directions and Conclusion 128 References 129 Part III: Treatment 135 Chapter 8: Treatment Algorithms for Lower-Risk Myelodysplastic Syndrome 136 Definition and Limits of Lower-Risk MDS 136 Proposed Algorithms for the Treatment of Lower-Risk (LR) MDS 138 Watchful Observation 138 Treatment of Anemia 139 Erythropoiesis-Stimulating Agents (ESAs) 139 Treatment of Anemia of LR-MDS with del 5q 140 Second-line Treatment of Anemia in Non-del 5q MDS 140 Lenalidomide 140 Immunosuppressive Agents 141 Hypomethylating Agents (HMAs) 141 Iron Chelation 141 Allogeneic Hematopoietic S tem Cell Transplantation (Allo-HCT) 142 New Treatments for Anemia in Low-Risk MDS 142 Treatment of Neutropenia and Thrombocytopenia 143 Neutropenia 143 Thrombocytopenia 144 References 145 Chapter 9: Treatment Algorithms for Higher-Risk Disease 151 Introduction 151 Initial Steps 152 Hypomethylating Agent Selection 153 Hypomethylating Agent Dosing Schedule 154 Combination Therapy with Hypomethylating Agents 154 Initial Intensive Chemotherapy 155 Applying Molecular Data to the Therapeutic Paradigm 155 Assessing Response to Initial Therapy in Higher-Risk Patients 156 Therapy After Hypomethylating Agent Failure 157 Targeted Therapy in Higher Risk Disease 158 Upfront Treatment Considerations in Patients Planned for HSCT 160 Supportive Care 161 Infections and Prophylactic Antimicrobials 161 Growth Factors in Combination with Chemotherapy 161 Transfusions 162 Summary 162 References 163 Chapter 10: Hematopoietic Cell Transplantation for MDS Patients 168 Introduction 168 Indication and Timing for Allogeneic Hematopoietic Stem Cell Transplantation 169 Risk Factors Influencing Outcome After Allogeneic Hematopoietic Cell Transplantation 170 Cytoreductive Treatment Prior to Allogeneic Hematopoietic Stem Cell Transplantation 171 Conditioning Intensity Prior to Allogeneic Hematopoietic Stem Cell Transplantation 172 Post-transplantation Strategies 172 Conclusion 173 References 173 Index 177 Front Matter ....Pages i-xii Front Matter ....Pages 1-1 Epidemiology, Etiology, and Clinical Presentation of Myelodysplastic Syndromes (Rena Buckstein)....Pages 3-17 Morphological, Flow Cytometry, and Cytogenetic Diagnosis of MDS (Shalini Goel, Robert P. Hasserjian)....Pages 19-42 Biology and Pathophysiology of MDS with del(5q) (Onyee Chan, Chetasi Talati, David Sallman, Alan List)....Pages 43-54 MDS Stem Cell Biology (Matthew T. Villaume, P. Brent Ferrell, Michael R. Savona)....Pages 55-72 Molecular Landscape of MDS (Torsten Haferlach, Ines Schmidts)....Pages 73-90 MDS Mimics Including CHIP, ICUS, and CCUS (Rafael Bejar)....Pages 91-105 Front Matter ....Pages 107-107 Prognostic Models in Myelodysplastic Syndromes (Jan Philipp Bewersdorf, Amer M. Zeidan)....Pages 109-127 Front Matter ....Pages 129-129 Treatment Algorithms for Lower-Risk Myelodysplastic Syndrome (Pierre Fenaux, Lionel Adès)....Pages 131-145 Treatment Algorithms for Higher-Risk Disease (Bryan C. Hambley, Amy E. DeZern)....Pages 147-163 Hematopoietic Cell Transplantation for MDS Patients (Anne Sophie Kubasch, Uwe Platzbecker)....Pages 165-173 Back Matter ....Pages 175-179