Adult Acute Lymphocytic Leukemia (eBook)

Preface 7
Acknowledgement 9
Contents 11
Contributors 13
Chapter 1: A Perspective on the Treatment of Acute Lymphoblastic Leukemia in Adults 17
How Can Results Be Improved in Adults? 18
Focus on Subgroups of Patients 18
What Can Be Learned from Pediatric Protocols and Can This Be Applied to Adults? 18
Future Considerations 20
Why Are Patients with Leukemia Cured? 20
Conclusions 21
References 21
Chapter 2: Acute Lymphocytic Leukemia – Clinical Features and Making the Diagnosis 24
Presentation: Signs, Symptoms and Laboratory Features 1
Superior Vena Cava Syndrome/Mediastinal Mass 24
Neurological Complications 1
Testicular Involvement 25
Other Organ Involvement 26
Hyperleukocytosis and Leukostasis 26
DIC 27
Metabolic Complications 27
Lactic Acidosis 28
Making the Diagnosis 28
Morphologic Assessment 29
Cytochemical Assessment 30
Immunophenotypic Assessment 30
Genetic Analysis 31
Gene Expression Profiling 34
Minimal Residual Disease 34
Differential Diagnosis 35
References 35
Chapter 3: The Biology of Adult Acute Lymphoblastic Leukemia 40
Introduction 40
Epidemiology 40
Biology of ALL 40
The Philadelphia Chromosome, t(9 22)
Ikaros 44
Mixed Lineage Leukemia 44
Chromosomal Changes Affecting Multiple Other Genes Involved with the Cell Cycle 45
MYC in Mature B Cell Leukemia 45
Genome-Wide Expression Analysis 45
T-ALL 46
Recurrent Translocations in T-ALL 46
Deletions, Duplications, and Mutations in T-ALL 47
Gene Expression Changes in T-ALL 48
Aberrant Lymphocyte Development 49
Recombinase Activating Genes (RAG) 49
Oligoclonality and Clonal Evolution 50
Conclusion 52
References 52
Chapter 4: Minimal Residual Disease in Acute Lymphoblastic Leukemia 60
Introduction 60
Techniques for Detecting Minimal Residual Disease 60
PCR Methods 61
PCR for Recurrent Translocations 61
PCR for Antigen Receptor Rearrangements 61
Flow Cytometry Methods 63
Comparing PCR to Flow Cytometry–Based MRD 66
The Prognostic Significance of MRD 67
Efforts to Incorporate MRD into Frontline ALL Trials 69
Applications of MRD Testing in Relapsed ALL 69
Factors Limiting the Use of MRD for Therapeutic Decisions 70
Conclusions 70
References 71
Chapter 5: Cytogenetics 76
Introduction 76
Cytogenetic Techniques and Nomenclature 76
Conventional Cytogenetic Analysis 77
Cytogenetic Terminology 77
Fluorescence In Situ Hybridization 80
Chromosomal Abnormalities in Adult B-Cell Precursor ALL (BCP-ALL) 81
t(9 22)(q34q11.2)/BCR-ABL1/Philadelphia Chromosome81
t(4 11)(q21q23)/MLL-AF4 and Other 11q23/MLL Translocations82
t(1 19)(q23p13)/TCF3-PBX183
High Hyperdiploidy (51–65 Chromosomes) 83
Low Hypodiploidy (30–39 Chromosomes)/Near-Triploidy (60–78 Chromosomes) 84
Complex Karyotype 84
Other Chromosomal Abnormalities 85
Chromosomal Abnormalities in Adult Mature-B ALL 85
Genetic Abnormalities in Adult T-Cell All (T-ALL) 86
Activation of TAL1, TLX1, TLX3, and LMO2 86
Gene Fusions 87
Deletions and Mutations 87
Summary and Future Directions 87
References 88
Chapter 6: Acute Lymphoblastic Leukemia: Epidemiology 91
Demographic Patterns 91
Incidence 91
Survival 91
Mortality 92
Sex Differences 92
Race Differences 92
Age Differences 92
Parental and Birth Characteristics 92
Socioeconomic Status 93
Etiology 93
Biological Factors 94
Genetic Syndromes 94
Acquired Genetic Abnormalities 94
Infectious Etiology 94
Physical Factors 95
Ionizing Radiation 95
Nonionizing Radiation 96
Chemical Factors 96
Hydrocarbons 96
Pesticides 96
Smoking 97
Maternal Pharmaceutical Use 97
Maternal Alcohol Use 97
Outdoor Air Pollution 97
Diet 98
References 98
Chapter 7: Prognostic Factors in Adult Acute Lymphoblastic Leukemia (ALL) 102
Introduction 102
“Classic” Clinical Diagnostic Prognostic Factors 102
Presenting White Blood Count (WBC) 102
Age 103
Impact of Therapy Received on Age-Related Prognosis 103
Immunophenotype 104
T Cell Versus B Cell ALL 104
Other Immunophenotypic Markers 104
Specific Clinical Features 105
CNS Disease at Diagnosis 105
Cytogenetics 105
Response to Therapy 105
Time to CR 105
Minimal Residual Disease (MRD) 106
Pharmacogenetics 106
Genomics 107
Prognosis of Relapsed ALL 107
Conclusions 108
References 108
Chapter 8: The Generalized Care of the Patient with Acute Lymphoblastic Leukemia 110
Introduction 110
Metabolic and Hematologic Complications 110
Tumor Lysis Syndrome 110
Hyperleukocytosis 112
Disseminated Intravascular Coagulation (DIC) 114
Cytopenias and Transfusion Support 115
Infectious Complications 115
Febrile Neutropenia 115
Sepsis 117
Invasive Fungal Infections 118
Herpes Family Viral Infections 119
Respiratory Syncytial Virus (RSV) 119
Pneumocystis jiroveci 120
Issues Related to Specific Antileukemic Agents 120
Conclusions 121
References 123
Chapter 9: Treatment of Acute Lymphoblastic Leukemia in Middle-Age and Older Adults 128
Introduction 128
Recent Clinical Trials 129
ALL in Older Adults 131
Clinical Trial Data 135
Co-morbidities and Complications 136
Summary 137
References 137
Chapter 10: Pharmacology of Acute Lymphoblastic Leukemia Therapy 140
Introduction 140
Glucocorticoids 141
Mechanism of Action 141
Clinical Pharmacology and Pharmacokinetics 141
Adverse Effects 141
Drug Interactions 141
Methotrexate 142
Mechanism of Action 142
Clinical Pharmacology and Pharmacokinetics 142
Adverse Effects 143
Drug Interactions 143
6-Mercaptopurine and 6-Thioguanine 143
Mechanism of Action 143
Clinical Pharmacology and Pharmacokinetics 144
Adverse Effects 144
Drug Interactions 144
Cytarabine 144
Mechanism of Action 144
Clinical Pharmacology and Pharmacokinetics 144
Adverse Effects 145
Drug Interactions 145
Anthracyclines 145
Mechanism of Action 145
Clinical Pharmacology and Pharmacokinetics 146
Adverse Effects 146
Drug Interactions 146
Vincristine 147
Mechanism of Action 147
Clinical Pharmacology and Pharmacokinetics 147
Adverse Effects 147
Drug Interactions 147
Cyclophosphamide 148
Mechanism of Action 148
Clinical Pharmacology and Pharmacokinetics 148
Adverse Effects 148
Drug Interactions 149
Asparaginase 149
Mechanism of Action 149
Clinical Pharmacology and Pharmacokinetics 149
Adverse Effects 149
Drug Interactions 150
Nelarabine, Clofarabine, and Forodesine 150
Mechanism of Action 150
Clinical Pharmacology and Pharmacokinetics 150
Adverse Effects 151
Drug Interactions 151
Imatinib, Nilotinib, Dasatinib 151
Mechanism of Action 151
Clinical Pharmacology and Pharmacokinetics 152
Adverse Effects 152
Drug Interactions 152
References 153
Chapter 11: Assessment of Response to Treatment 158
Introduction 158
Clinical Response Assessment 159
Hematologic/Morphologic 159
Central Nervous System Involvement 160
Minimal Residual Disease 160
Definitions of Response 161
Clinical Significance of MRD 162
MRD: Redefining Remission? 164
Cautions of MRD Interpretation 164
How to Respond to MRD Data – Therapeutic Decisions 164
MRD-Based Early Treatment Response 164
MRD Monitoring During Follow-Up to Detect Early Relapse 165
MRD-Based Post-Consolidation Therapy and SCT 165
Emerging Indicators for Response Assessment 166
Pharmacological 166
Epigenetics 166
Conclusions 166
References 167
Chapter 12: T-Cell Acute Lymphoblastic Leukemia 170
Introduction 170
T-ALL Classification 170
Molecular Genetics and Pathogenesis 171
Factors Predicting Clinical Outcomes in T-ALL 175
Treatment Outcomes in T-ALL 177
Novel and Investigational Therapies 180
T-ALL: Future Directions 181
References 182
Chapter 13: Burkitt Lymphoma and Leukemia 188
Introduction 188
Epidemiology 188
Pathogenesis 189
Role of c-myc 189
Role of Epstein-Barr Virus (EBV) 190
The Germinal Center 191
Diagnosis of Burkitt Lymphoma and Burkitt Leukemia 191
B-Cell Lymphoma, Unclassifiable, with Features Intermediate Between Diffuse Large B-Cell Lymphoma and Burkitt Lymphoma 197
Clinical Presentation of Burkitt Lymphoma and Leukemia 198
Burkitt Lymphoma 198
Burkitt Leukemia 199
Staging Systems 199
Treatment: Newly-Diagnosed Disease 200
Pediatric Studies 201
Adult Trials 203
Role of Rituximab 211
Therapy of HIV-Related Burkitt Lymphoma/Leukemia 212
Tumor Lysis Syndrome 215
Relapsed/Refractory Disease and the Role of Stem Cell Transplant 216
Novel Therapies 217
Conclusion 217
References 217
Chapter 14: Treatment of Acute Lymphoblastic Leukemia in Young Adults 224
Introduction 224
Adolescents with ALL : Young Adults or Old Children? 226
Adolescent ALL Characteristics 226
Dose Intensity 226
Allogeneic Transplantation (ASCT) 230
Adherence to Treatment 230
Outcome of AYA in Adult Protocols 231
Prognostic Factors and Risk Assessment 231
Remission Induction 235
Post-remission Therapy 235
Allogeneic Stem Cell Transplantation (ASCT) 236
Autologous Stem Cell Transplantation (autoSCT) 236
Current Therapeutic Options for ALL in AYA 237
Treating AYA in “Hybrid” Protocols 237
Treating AYA According to Pediatric Trials 237
Long-Term Toxicity 238
Conclusion 239
References 239
Chapter 15: Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia 245
Biology of Philadelphia Positive ALL 245
Historical Outcomes with Chemotherapy for Ph-Positive ALL 246
Historical Outcomes with Stem Cell Transplant for Ph-Positive ALL 246
Imatinib Mesylate for Previously Treated Ph-Positive ALL 247
Imatinib-Based Chemotherapy Regimens for De Novo Ph-Positive ALL 248
Imatinib-Based Chemotherapy Regimens for Younger De Novo Ph Positive ALL 248
Perspectives on Allogeneic Stem Cell Transplant in the TKI-Era 252
Role of Imatinib Post Allogeneic Stem Cell Transplantation 253
Treatment of Elderly Patients with Ph-Positive ALL 253
Mechanisms of Resistance to Tyrosine Kinase Inhibitors 254
ABL Kinase Domain Mutations 254
Other Mechanisms of Resistance to Imatinib 256
Second Generation Tyrosine Kinase Inhibitors for Ph-Positive ALL 257
Dasatinib 257
Nilotinib 259
Later Generation ABL Tyrosine Kinase Inhibitors 259
Targeting the T315I ABL Kinase Domain Mutation 259
Role of Monoclonal Antibodies in Ph-Positive ALL 259
Future Directions 260
Conclusions 260
References 261
Chapter 16: Molecular Therapies 268
Introduction 268
Epigenetic Therapy 269
Methylation 269
Histone Acetylation 270
Molecular Targets 271
Mammalian Target of Rapamycin (mTOR) 271
Angiogenesis 272
Hedgehog Signaling 273
Survivin 273
NOTCH1 Signaling 274
Toll-like Receptor Signaling 275
Other Pathways and Targets 275
Monoclonal Antibodies 276
Conclusions 278
References 278
Chapter 17: Treatment of Relapsed Acute Lymphoblastic Leukemia 287
Introduction 287
Strategies for the Treatment of Patients with Relapsed ALL 288
Salvage Chemotherapy 289
Stem-Cell Transplantation 291
Prognostic Factors 292
Biologic Features 293
Clonal Evolution of Relapsed Leukemia 293
CNS Relapse 293
Testicular Relapse 294
Nucleoside Analogues 294
Clofarabine 294
Nelarabine 295
Asparaginase Preparations 296
Methotrexate Analogues 296
Monoclonal Antibodies 297
Liposomal Conjugates 297
Targeted Therapy 298
Other Agents 299
Conclusion 300
References 301
Chapter 18: Allogeneic Stem Cell Transplantation for Acute Lymphoblastic Leukaemia in Adults 307
Introduction 307
Rationale and the Graft Versus Leukaemia Effect 307
Conditioning Regimens 308
Sibling Allografting in First Remission 308
Unrelated Donor (UD) SCT in First Remission 309
The Role of RIC Allografting 310
Allografting for Relapsed Disease 310
Donor Lymphocyte Infusions 311
Allografting for Refractory Disease 311
Haploidentical and Cord Blood Transplantation for High-Risk ALL 311
Other Issues and Supportive Care 312
Central Nervous System (CNS) Disease 312
Palifermin 312
The Future 312
References 313
Chapter 19: Hematopoietic Stem Cell Transplantation in Philadelphia-Positive Acute Lymphoblastic Leukemia 315
Introduction 315
Historical Perspective 315
Allogeneic Stem Cell Transplant 316
“Donor” Versus “No Donor” 316
Umbilical Cord Blood Transplants 317
Graft Versus Leukemia Effect 317
Reduced-Intensity Conditioning Regimens 317
Autologous Stem Cell Transplant 318
Myeloablative Preparative Regimens 318
Tyrosine Kinase Inhibitors (TKIs) 319
Conclusion 320
References 321
Chapter 20: Special Challenges: Genetic Polymorphisms and Therapy 324
Thiopurines 324
Methotrexate 327
Methylene Tetrahydrofolate Reductase 328
Thymidylate Synthase 328
Cyclin D1 (CCND1) 329
Reduced Folate Carrier 329
Multidrug-Resistance Protein and Multidrug-Resistance-Associated Proteins 330
Corticosteroids 330
Genes of CS Action Pathways 330
Genes Coding for Xenobiotic Metabolizing Enzymes 331
Disease-Associated Genes 331
Other Genes Modulating the Therapeutic Response in Acute Lymphoblastic Leukemia 333
Hematopoietic Stem Cell Transplantation 333
Conclusion 334
References 334
Chapter 21: Late Consequences of Therapy of Acute Lymphoblastic Leukemia 340
Introduction 340
Cohort Studies 340
Neurologic 343
Endocrine 343
Height and Weight 343
Thyroid 344
Fertility and Sterility 344
Bone 345
Cardiac 346
Respiratory 347
Hepatic 347
Genitourinary 347
Ophthalmologic 348
Dental 348
Second Malignancies 348
Psychosocial 349
Blood and Marrow Transplantation 350
Follow-up Care 352
Conclusion 353
References 353
Chapter 22: Immunotherapy for Acute Lymphocytic Leukemia 359
Introduction 359
Allogeneic Transplantation as Cellular Immunotherapy 359
Reduced Intensity Conditioning 361
Donor Lymphocyte Infusion 361
Augmenting Alloreactive Immunity 362
Role of NK Cells 362
Generation of Leukemia Specific Immunity 363
Leukemia-Associated Targets for Antibody-Mediated Immunotherapy 363
T Cells Expressing Chimeric Antigen Receptors: Combined Humoral and Adoptive Immunotherapy 364
Targeting Known Tumor-Associated Antigens 365
Enhancement of Antigen Presentation Using Dendritic Cells 365
Conversion of ALL Cells into Antigen Presenting Cells 366
Cytokine Therapy as Immune Adjuvants 367
Summary 367
References 367
Chapter 23: Unique Subtypes in Acute Lymphoblastic Leukemia 372
Myeloid Antigen Expression in ALL 373
My Agpos Genetic Subtypes 375
BCR/ABLpos ALL 376
CD117pos ALL with or Without FLT3 Gene Mutations 376
NOTCH1-Mutated T-ALL with Myeloid Features 379
T-ALL with HOX11/TLX1 Overexpression 379
TEL/AML1pos ALL 380
MLL/AF4pos ALL 380
Genotypes with Unique Antigenic Features Other Than My Ags 381
CALM/AF10pos T-ALL and Gd-T-Cell Receptor Expression 381
E2A/PBX1pos B-Lineage ALL 381
TCRb-HOXA Rearranged T-ALL 382
Unique ALL Subtypes without Invariably Apparent Genetic Correlates 382
CD56pos ALL 382
CD2pos B-Lineage ALL 383
Comments for the Future 383
References 384
Index 389