Myeloproliferative Neoplasms (eBook)

Preface 6
References 7
Contents 8
Contributors 10
Chapter 1: Diagnosis and Classification of the BCR-ABL1-Negative Myeloproliferative Neoplasms 12
Introduction 12
General Guidelines for Diagnosis and Classification of Myeloproliferative Neoplasms 15
BCR-ABL1-Negative Myeloproliferative Neoplasms Polycythemia Vera, Primary Myelofibrosis, and Essential Thrombocythemia 17
Polycythemia Vera 17
Diagnosis: Polycythemic Phase 19
Disease Progression Including Post-Polycythemic Myelofibrosis and Acute Leukemia 24
Differential Diagnosis Including Post-Polycy themic Myelofibrosis and Acute Leukemia 25
Primary Myelofibrosis 26
Diagnosis 27
Clinical Findings 27
Laboratory Findings 29
Genetic Studies 31
Disease Progression/Prognosis 31
Differential Diagnosis 32
Essential Thrombocythemia 34
Diagnosis 35
Disease Progression/Prognosis 37
Differential Diagnosis 37
Other BCR-ABL1-Negative Myeloproliferative Neoplasms 38
Chronic Neutrophilic Leukemia 38
Diagnosis 39
Disease Progression 40
Differential Diagnosis 41
Myeloproliferative Neoplasm, Unclassifiable 41
Conclusion 43
References 44
Chapter 2: Genetics of the Myeloproliferative Neoplasms 49
Introduction 49
Somatic Mutations in MPN Pathogenesis 50
Early Evidence for Clonal Disorder 50
JAK2 and MPL Mutations: Constitutive Tyrosine Kinase Activation in MPN Pathogenesis 50
JAK2 Mutations in MPNs 50
TET2 and ASXL1 Mutations in MPNs: Epigenetic Events in MPN Pathogenesis? 57
Evidence for Additional Mutations Beyond JAK2 and MPL 57
Somatic Mutations in TET2 58
Somatic Mutations in ASXL1 63
Genetics of Leukemic Transformation of MPNs 64
The Possibility of Additional Mutated Genes in MPNs 65
Inherited Genetic Events in MPN Pathogenesis 66
Evidence for Germline Mutations in MPN 66
The Germline JAK2 Haplotype 66
Novel Genetic Alterations in MPN: The Possibility of Epigenetic Alterations, Regulatory RNAs, and Post-translational Modifications 68
Conclusion: A Multi-Step Model of MPN Pathogenesis 71
References 73
Chapter 3: Cytogenetic Findings in Classical MPNs 79
Introduction 79
Essential Thrombocythaemia 79
Polycythaemia Vera 81
Primary Myelofibrosis 82
Chronic Neutrophilic Leukaemia 85
Specific Chromosomal Abnormalities 85
Chromosome 1 85
Chromosome 8 86
Chromosome 9 86
Chromosome 13 87
Chromosome 20 88
Karyotype, Haplotype and JAK2-V617F 89
References 90
Chapter 4: Prognostic Factors in Classic Myeloproliferative Neoplasms 94
Introduction 94
Prognosis of PMF 94
Prognostic Factors and Prognostic Classifications of PMF 95
Prognosis of PV and ET 98
Prognostic Factors in PV and ET 99
Prognostic Factors for Thrombosis 99
Prognostic Factors for Transformation to Myelofibrosis and Leukemia 102
Concluding Remarks 102
References 103
Chapter 5: Therapy of Polycythemia Vera and Essential Thrombocythemia 106
Introduction 106
Incidence and Type of Thrombosis 107
Risk Stratification 107
Treatment of “Low-Risk” Patients 110
Phlebotomy 110
Low-Dose Aspirin 110
Treatment of High-Risk Patients 112
Hydroxyurea 112
Interferon Alpha 114
Anagrelide 115
Summary 116
Special Treatment Issues 117
Management of Pregnancy 117
Clinical Epidemiology and Risk Factors 117
Treatment 118
Management of Venous Thrombosis in Unusual Sites 119
Management of Bleeding 120
Management of Surgery 121
References 122
Chapter 6: Conventional and Investigational Therapy for Primary Myelofibrosis 125
Background 125
Medical Needs 126
Conventional Therapeutic Strategies 128
Treatment of Anemia 129
Androgens 129
Erythropoiesis-Stimulating Agents 130
Thalidomide 131
Treatment Strategy for Anemia 132
Treatment of Transfusional Iron Overload 132
Treatment of Splenomegaly 133
Medical Therapies 133
Splenic Radiotherapy 135
Splenectomy 135
Treatment Strategy for Splenomegaly 137
Treatment of Extramedullary Nonhepato-splenic Hematopoiesis 138
Treatment of Pulmonary Hypertension 138
Management of Leukemic Transformation 139
Experimental Therapies 139
Interferon in the Early Phase of the Disease 139
Testing More Potent Immunomodulators: Lenalidomide and Pomalidomide 140
Addressing Nonspecific Molecular Targets: Antifarnesyl Transferase and Antiproteasome Agents 141
Targeting Neoangiogenesis 142
Targeting Epigenetics 142
Concluding Remarks 143
References 143
Chapter 7: Hematopoietic Cell Transplantation for Myelofibrosis 147
Introduction 147
Autologous HCT 148
Allogeneic HCT 148
High-Dose (Conventional) Conditioning HCT for Patients with Myelofibrosis 148
Reduced Intensity Conditioning HCT for Myelofibrosis 152
What to Consider When Advising Patients with Myelofibrosis on Transplantation 154
Prognostic Score Models 154
The Role of JAK2 Mutations 154
Conclusions 154
References 156
Chapter 8: JAK2 Inhibitors for Therapy of Myeloproliferative Neoplasms 159
Introduction 159
The JAK Family of Tyrosine Kinases 160
The JAK2 V617F Mutation 162
Rationale for Targeting JAK2 in Myeloproliferative Neoplasms 163
Clinical Trials with JAK2 Inhibitors 164
CEP-701 164
INCB018424 166
SB1518 168
TG101348 169
XL019 170
Future Perspectives 171
References 171
Chapter 9: Blastic Transformation of Classic Myeloproliferative Neoplasms 176
The BCR-ABL Negative MPNs 176
Phenotype of Leukemic Transformation in the MPNs 176
Pathogenesis of Blastic Transformation in MPNs 178
Defining Blastic Transformation from the MPNs 178
WHO Definition of Acute Leukemia 178
Assessing the Importance of Peripheral Blast Percentage 179
Risk Factors for Blastic Transformation 179
Risk Factors at Presentation 179
Influence of Therapy upon Development of MPN-BP 180
Clinical Course and Therapy of MPN-BP 181
Conclusions 183
References 184
Chapter 10: Eosinophilic Disorders: Differential Diagnosis and Management 188
Introduction 188
Classification 188
Secondary Eosinophilia 191
“Primary” or “Clonal” Eosinophilia 191
Myeloid and Lymphoid Neoplasms with Eosinophilia and Abnormalities of PDGFRA, PDGFRB, or FGFR1 192
Clinical Presentations of FIP1L1-PDGFRA-Positive Disease 193
Lymphocyte-Variant Hypereosinophilia 195
Diagnostic Algorithm for Evaluation and Treatment of Hypereosinophilia 196
Therapy 196
Molecularly Defined Eosinophilias 196
Safety Profile of Imatinib in FIP1L1-PDGFRA Positive Disease 199
Resistance to Imatinib in FIP1L1-PDGFRA Positive Disease 199
Treatment of Idiopathic Hypereosinophilic Syndrome and Non-Molecularly Defined Eosinophilia 200
Conclusion 202
References 202
Chapter 11: Pathogenesis, Diagnosis, Classification, and Management of Systemic Mastocytosis 211
Introduction 211
Pathogenesis 211
KIT Mutations 211
TET2 Mutations 213
FIP1L1-PDGFRA Mutation 213
Diagnosis and Classification 214
Treatment 220
Conflicts of Interest 222
References 223
Index 228