The Myelodysplastic Syndromes (eBook)

Preface 6
Contents 8
Contributors 10
Chapter-1 13
The History of the Myelodysplastic Syndromes 13
References 15
Chapter-2 17
Susceptibility to MDS: DNA Repair and Detoxification Genes 17
Introduction 17
Detoxification Pathways 18
Phase I: Cytochrome P450 Enzymes 18
CYP2E1 19
CYP3A4 19
CYP3A5 19
Significant Findings of CYP Variants in t-AML/MDS 19
Phase II: Glutathione S-transferases 20
GSTM1 and GSTT1 20
GSTP1 and GSTPA1 22
Significant Findings of GST Polymorphisms in t-AML/AML 22
NAD(P)H: Quinone Oxidoreductase (NQO1) 23
Significant Findings of NQO1-Pro187Ser in t-AML/MDS 23
DNA Repair 23
Double Strand Break Repair 24
Non-homologous End Joining 24
Homologous Recombination 25
Base Excision Repair: hOGG1 26
Nucleotide Excision Repair 28
Mismatch Repair 28
Discussion 29
Sample Size and Controls for Polymorphism Studies 29
Functional Consequences of Polymorphic Variants 30
Combinations of Polymorphisms 30
Which Polymorphic Genes Confer the Greatest Susceptibility to MDS? 31
References 32
Chapter-3 37
Myelodysplastic Syndromes/Neoplasms: Morphological and Immunohistochemical Features and Standard Evaluation 37
Introduction 37
Materials and Methods 38
Classification System of MDS (WHO 2008) 40
General Considerations 41
Differential Diagnoses 46
Morphology of MDS Subvariants with Special Emphasis on Histopathological Aspects (Subvariants 1.–6. Are Defined by FAB/WHO Criteria) 48
References 52
Chapter-4 54
Diagnostic Criteria and Classification of Myelodysplastic Syndromes 54
Introduction 54
Minimal Diagnostic Criteria 55
ICUS and IDUS: The Diagnostic Interface 56
Important Differential Diagnoses in Patients with Suspected MDS 59
Classification of MDS 59
Prognostic Scoring Systems and Additional Risk Factors 61
Predictive Value of Therapy-Related Scores and Their Use in Treatment Algorithms 61
Concluding Remarks and Future Perspectives 62
References 63
Chapter-5 65
Cytogenetics of MDS 65
Introduction 65
Cytogenetic Features of MDS 65
Distinct Cytogenetic Subgroups 67
5q-Deletions 67
Monosomy 7 67
Trisomy 8 68
Chromosome 17 Abnormalities 69
20q-Deletions 69
Sex Chromosomes Abnomalities 70
Balanced Abnormalities 71
Chromosomal Manifestations of Gene Amplifications 71
Independent Clones 71
Complex Chromosome Abnormalities 73
Karyotype Evolution 74
Cytogenetics in Therapy-Associated MDS 76
FISH-Analyses in MDS 77
Value of FISH as a Supplement to Banding Analyses 77
FISH in cases with a normal banding karyotype 77
Comparison of Metaphase Cytogenetics and Interphase FISH 77
Characterization of Complex Abnormalities 78
FISH-Analysis of Circulating CD34+ cells from Peripheral Blood 78
FISH in MDS—Conclusions 79
Prognostic Meaning of the Karyotype 79
Distinct Frequent Abnormalities 80
Double Abnormalities 82
Complex Abnormalities 83
Cytogenetics Within the IPSS 83
Therapeutic Consequences of Cytogenetics 84
Conclusion 85
References 85
Chapter-6 96
Molecular Changes in Myelodysplastic Syndrome 96
Introduction 96
Conventional Cytogenetics and Fluorescence In Situ Hybridization 97
Alteration of Signal Transduction and Transcription Factors 97
Alteration of the RAS Pathway 97
JAK2 Mutations 97
AML1 Gene 98
EVI1 Gene 98
p53 Gene 99
TET2 Gene 99
Epigenetic Alterations 99
DNA Methylation and Histone Acetylation 99
Array Comparative Genomic Hybridization (aCGH) in MDS 100
Single Nucleotide Polymorphism (SNP) Analysis in MDS 101
Gene Expression Analysis by Microarrays in MDS 104
Next Generation Sequencing (NGS) 105
Summary 106
References 107
Chapter-7 111
Prognostic Scoring in MDS 111
Introduction 111
Aims and Criteria for Prognostic Factors 112
Prognostic Factors in MDS 113
Morphology 114
Cell Counts 114
Other Laboratory Parameters 114
Cytogenetics 115
Further Genetic Prognostic Factors 116
FACS 118
Transfusion Dependency 118
Patient Related Factors: Age, Gender, Performance Status, Comorbidity 118
Combinations of Prognostic Factors: Prognostic Scores 119
Role of Classifications in Prognostication 119
Prognostic Scoring Systems 120
International Prognostic Scoring System (IPSS) 120
WHO Based Prognostic Scoring System WPSS 122
Ongoing Improvement of Scoring Systems 123
Conclusion: Use of Prognostication for Clinical Decision Making 123
References 124
Chapter-8 129
Flow Cytometry in Myelodysplastic Syndromes 129
Introduction 129
Flow Cytometric Evaluation of Dyspoiesis in MDS 130
Myeloid Progenitors 131
Maturing Myeloid Cells 135
Monocytic Lineage 136
Erythroid and Megakaryocytic Lineage 137
Pitfalls in Flow Cytometry in MDS 139
Role in Diagnosis 141
Role in Prognosis 146
Prediction of Response to Therapy by Flow Cytometry 147
Conclusion 148
References 148
Chapter-9 152
MDS as an Autoimmune Process 152
Introduction 152
Autoimmune Phenomena in MDS 152
Autoimmune Pathogenesis of MDS 154
T cell Clonality and Antigen Specificity 154
CD4+ T cells and MDS 155
Regulatory T cells (Tregs) 156
Th17 Cells 157
Innate Immune Response 157
Bone Marrow Apoptosis 158
Immunosuppressive Therapy 159
Concluding Remarks 161
References 161
Chapter-10 165
The Myelodysplastic Overlap Syndromes 165
Introduction 165
Chronic Myelomonocytic Leukaemia (CMML) 166
Definition and Presenting Features 166
Epidemiology 167
Laboratory Features 167
Genetics 168
Prognosis and Management 170
Atypical Chronic Myeloid Leukaemia (aCML) 171
Definition and Presenting Features 171
Epidemiology 171
Laboratory Features 172
Genetics 172
Prognosis and Management 173
MDS/MPN, Unclassifiable 173
Definition and Presenting Features 173
Epidemiology 173
Laboratory Features 173
Genetics 173
Prognosis and Management 174
Refractory Anaemia with Ring Sideroblasts and Thrombocytosis (RARS-T) 174
MDS with Deletion 5q and JAK2 Positive 175
Concluding Remarks 175
References 176
Chapter-11 180
Iron and Copper Metabolism in the Myelodysplastic Syndromes 180
Introduction 180
Iron (Fe) and Copper (Cu) Metabolism is Closely Related Throughout the Entire Process of Erythropoiesis 180
Copper Deficiency-Related Alterations in Erythropoiesis 182
Different Aspects of Iron Overload Related to MDS 182
Precedent Study Results 183
The Present Study 184
Materials and Methods 184
Results 184
Discussion 185
References 188
Chapter-12 191
Pathogenesis and Management of Iron Overload in MDS 191
Methods for Evaluating Iron Overload in MDS 192
Monitoring Transfusional Burden 192
Monitoring Serum Ferritin 193
Assessment of Hepatic and Myocardial Siderosis 194
Plasma Non-Transferrin Bound Iron Measurements 195
Goals of Iron Chelation in MDS 195
Selection of MDS Patients for Chelation Therapy 195
Choice of Iron Chelators in MDS 197
Deferoxamine 198
Deferiprone 199
Deferasirox 199
Combined Chelation 200
The Impact of ICT on Survival in MDS 200
Effects of ICT on Hemopoiesis in MDS 202
Claims for Protection from Other Harmful Effects of Iron in MDS 202
Conclusions 204
References 204
Chapter-13 209
Cytokines in MDS: Abnormalities and Treatment 209
Erythroid Series 209
Erythropoietin (Erythroid Stimulating Agents) 209
The Myeloid Lineage 213
Granulopoietic Agents: G/GM-CSF 213
The Megakaryocytic Lineage 214
Thrombopoietic Agents 214
References 216
Chapter-14 223
Therapeutic Modalities and New Molecular Targets in MDS 223
Introduction 223
Standard Treatment of Patients with Lower Risk MDS 224
Identification of Patients with Lower Risk Disease but Poor Prognosis: Can We Treat Earlier? 224
“Supportive Care” Measures in Lower Risk MDS 226
What Is the Role of Iron Chelation? 226
The Role of Lenalidomide in Patients with Alteration of Chromosome 5 227
The Role of Lenalidomide in Patients Without Alteration of Chromosome 5 or with Higher Risk Disease 228
Use of Hypomethylating Agents in Lower Risk MDS 229
Immune Modulation in MDS 230
Standard Treatment of Patients with Higher Risk MDS 230
Decitabine 231
5-azacitidine 232
Does Intensive Chemotherapy Still Have a Role in the Treatment of Higher Risk MDS? 233
New Targets and New Drugs in MDS: Investigational Approaches 234
Nucleoside Analogues: Clofarabine and Sapacitabine 235
Oral Formulation of 5-azacitidine 235
Histone Deacetylase (HDAC) Inhibitors 235
Combination Strategies 236
Phase I Trials in MDS 236
Therapy for Patients that Have Been Exposed to Hypomethylating Based Therapy 237
A Treatment Algorithm for Patients with MDS 238
References 238
Chapter-15 243
Haematopoietic Stem Cell Transplantation in MDS for Adults 243
Introduction 243
Indication and Timing of Haematopoietic Stem Cell Transplantation 244
Patient Age, Co-Morbidities and Conditioning Regimen 245
Stem Cell Sources—Bone Marrow (BM) Versus Peripheral Blood (PBSC)—for HSCT in MDS 247
Autologous Transplantation 247
Allogenic Transplantation 248
Allogeneic Transplantation with Family Donor 248
Allogeneic Transplantation with Matched Unrelated Donor 249
Allogeneic Transplantation with Cord Blood 250
Conclusions and Future Directions 253
References 253
Chapter-16 257
JMML and Myelodysplastic Syndrome in Children 257
Introduction 257
Myelodysplastic Syndrome (MDS) 258
Classification 258
Primary and Secondary MDS 259
Epidemiology 259
Incidence, Sex, Age and Subtype Distribution 259
Associated Abnormalities 260
Inherited Bone Marrow Failure 260
Acquired Aplastic Anemia 261
Familial MDS 261
Pathophysiology 262
Clinical and Laboratory Features 262
Bone Marrow Features 262
Cytogenetics 263
Immunophenotype 263
Differential Diagnosis 264
Refractory Cytopenia Versus Aplastic Anemia 264
MDS Versus Non-Clonal Disorders 264
Separating MDS from AML 265
Prognosis and Natural Course 265
Treatment 266
AML Type Chemotherapy 266
Hematopoietic Allogeneic Stem Cell Transplantation 267
Myeloid Leukemia and Down Syndrome 267
Transient Abnormal Myelopoiesis 268
Myeloid Leukemia of Down syndrome 268
Pathobiology 268
Epidemiology 269
Clinical and Laboratory Features 269
Cytogenetics 270
Treatment 270
Juvenile Myelomonocytic Leukemia (JMML) 270
Epidemiology 270
Clinical and Laboratory Features 271
Cytogenetics 272
Differential Diagnoses 272
Pathophysiology 272
Natural Course and Prognostic Factors 273
Treatment 274
References 275
Appendix 283
PB Alterations 283
BM Alterations 285
Index 289