Childhood Leukemia (eBook)

Gregory H. Reaman, M.D., is Chair of the Children’s Oncology Group (COG) since its inception in 2000 resulting from the merger of four legacy pediatric cancer research organizations, is comprised of over 200 member institutions, dedicated to clinical, translational, and epidemiology research in childhood cancer. Dr. Reaman is a Professor of Pediatrics at The George Washington University School of Medicine and Health Sciences and a member of the Division of Hematology-Oncology at the Children’s National Medical Center in Washington, D.C., which he directed for nearly 18 years, and Executive Director Emeritus of the Center for Cancer and Blood Disorders. Dr. Reaman serves or has served on the Editorial Boards of Leukemia, Journal of Clinical Oncology, Journal of Pediatric Hematology/Oncology, Pediatric Blood and Cancer, The Oncologist, Cancer, and Physicians Data Query (PDQ), National Cancer Institute as well as the ASCO Cancer Foundation’s www.cancer.net. He has served as an Associate Editor of Cancer and Leukemia and Lymphoma. Previously, he served on the Board of Directors of the American Cancer Society and chaired its Task Force on Children and Cancer. Dr. Reaman served on the Board of Directors of the American Society of Clinical Oncology and has served on the ASCO Patient Education Committee, the Education and Program Committees, the Grant Selection Committee, and was the Chair of the ASCO Membership Committee. Also, he was a member of the Food and Drug Administration’s Oncologic Drugs Advisory Committee and continues as a member of its Pediatric Subcommittee. He was a member of the NIH Roadmap Working Group. Additionally, he is a member of the Alliance for Childhood Cancer, a member of the Data Safety Monitoring Board of the National Cancer Institute’s Clinical Oncology Program, and a member of the NCI’s Translational Research Working Group. He is the author of more than 250 peer-reviewed manuscripts resulting from long-standing interests in acute leukemia biology and treatment and development of new drugs for pediatric cancer. Franklin O. Smith, III, M.D., is Vice-Chair of the Children’s Oncology Group (COG). The COG, since its inception in 2000 resulting from the merger of four legacy pediatric cancer research organizations, is comprised of over 200 member institutions, dedicated to clinical, translational, and epidemiology research in childhood cancer. Dr. Smith is the Marjory J. Johnson Professor of Pediatrics at the University of Cincinnati College of Medicine. He has been the Director of the Division of Hematology/Oncology at Cincinnati Children’s Hospital Medical Center (CCHMC) since 2001. He also serves as the Director of the Pediatric Hematology/Oncology Fellowship Training Program at CCHMC. Dr. Smith serves or has served on the Editorial Boards of Blood, the British Journal of Haematology, the Journal of Hematotherapy and Stem Cell Research, and Physicians Data Query (PDQ), National Cancer Institute. He has served as a Section Editor of Cancer Research Therapy and Control, Editor for Medscape General Medicine, Topics in Pediatric Leukemia, and currently serves as Editor of Case Reports in Medicine. Previously, he served on the Board of Directors and as Treasurer of the Foundation for the Accreditation of Cellular Therapies (FACT). Additionally, he is a member of the Sickle Cell Data Safety Monitoring Board of the National Heart, Lung and Blood Institute. He is the author of more than 100 peer-reviewed manuscripts.

Childhood Leukemia 2
Copyright Page 3
Preface 4
Acknowledgments 5
Contents 6
Part I:Genetics and the Epidemiologyof Leukemia in Children 8
1: Epidemiology of Acute Childhood Leukemia 9
1.1 Classification and Natural History 9
1.1.1 Classification: Immunophenotype, Morphology 9
1.1.2 Classification: Molecular and Cytogenetics 10
1.1.2.1 Acute Lymphoid Leukemias 10
1.1.2.2 Acute Myeloid Leukemias 11
1.1.3 Natural History of Leukemia 12
1.2 Incidence, Survival, and Trends 13
1.2.1 International Incidence Rates 13
1.2.2 U.S. Incidence Rates and Trends 13
1.2.3 Survival 16
1.3 Risk Factors for Childhood Leukemia 17
1.3.1 Genetic Syndromes 17
1.3.2 Environmental and Other Risk Factors for Childhood Leukemia 17
1.3.2.1 Ionizing Radiation 18
1.3.2.2 Prior Chemotherapy 18
1.3.2.3 Reproductive History 18
1.3.3 Lifestyle Factors 19
1.3.3.1 Cigarette Smoking 19
1.3.3.2 Alcohol Consumption 19
1.3.3.3 Occupational Exposures 19
1.3.3.4 Maternal/Child Diet 19
1.3.3.5 Vitamin Supplementation 20
1.3.3.6 Pesticides 20
1.3.3.7 Infections 20
1.3.3.8 Birth Weight 21
1.3.4 Genetic Susceptibility 22
1.4 Challenges and Future Directions 23
1.4.1 Improvements in Identification of Cases and Controls for Studiesin the United States 23
1.4.1.1 Cases 23
1.4.1.2 Controls 24
1.4.2 Opportunities for Validation 24
1.4.2.1 Neonatal Blood Spots 24
1.4.2.2 Maternal-Fetal Cohort Studies 25
1.4.3 Comprehensive Use of Animal Models to Assess Exposure/Cancer Relationships 25
1.5 Conclusion 26
References 27
Part II:Biology of Pediatric Leukemia 33
2: The Biology of Acute Lymphoblastic Leukemia 34
2.1 Introduction 34
2.2 The Cellular Biology of Acute Lymphoblastic Leukemia (ALL) 35
2.2.1 Lymphoid Development and Immunophenotype of Acute Lymphoblastic Leukemia 35
2.2.1.1 Lymphoid Development 35
2.2.1.2 B-Cell Development 36
2.2.1.3 T-Cell Development 36
2.2.1.4 Immunophenotype of Acute Leukemia 37
2.2.2 Antigen Receptor Genes and Clonality 38
2.2.2.1 Immunoglobulin (Ig) and T-Cell Receptor (TCR) Gene Rearrangements in ALL 38
2.2.2.2 Assessment of Clonality by PCR Amplification 39
2.2.2.3 Use of Ig and TCR Gene Rearrangements for the Detection of MRD 39
2.2.3 Leukemia-Initiating Cells in ALL 40
2.3 The Molecular Biology of ALL 41
2.3.1 Introduction to Cancer Genomics and New Technology 41
2.3.2 Host Susceptibility to ALL 42
2.3.2.1 Genetic Syndromes and Down Syndrome ALL 42
2.3.2.2 Germline Genetic Variation and ALL 43
2.3.3 Somatic Genetic Changes in ALL 43
2.3.3.1 Chromosomal Lesions and Karyotype 43
2.3.3.2 Copy Number Abnormalities 45
2.3.3.3 Gene Expression Profiling 48
2.3.3.4 Discovery of Novel Therapeutic Targets Through DNA Sequencing and Genomic Studies 51
2.3.3.5 Epigenetic Modifications and Posttranscriptional Regulation by microRNAs 53
2.4 Signaling Pathways in Childhood ALL 55
2.4.1 BCR-ABL Tyrosine Kinase 55
2.4.2 FLT-3 Receptor Tyrosine Kinase 55
2.4.3 JAK Tyrosine Kinase 56
2.4.4 Pre-B Cell Receptor 56
2.4.5 RAS Pathway 56
2.4.6 NOTCH1 Pathway 57
2.4.7 Therapy Targeted to Signaling Pathways 57
2.5 The Apoptotic Pathway and ALL 57
2.6 The Biology of Relapsed ALL 59
2.7 Summary 62
References 62
3: Biology of Acute Myeloid Leukemia 67
3.1 Introduction 67
3.2 Cytogenetic Alterations 69
3.2.1 t(15 17) Translocation69
3.2.2 CBF AML 70
3.2.3 t(8 21)
3.2.4 Inv(16) 71
3.2.5 AML with MLL Rearrangement 71
3.2.6 Sub-karyotypic (Cryptic) Chromosomal Abnormalities 72
3.3 Disease Associated Mutations in Signal Transduction Pathways 72
3.3.1 FLT3 Mutations 73
3.3.2 FLT3 Internal Tandem Duplications (FLT3/ITD) 73
3.3.3 FLT3 Activation Loop Mutation (FLT3/ALM) 74
3.3.4 c-KIT Mutations 74
3.3.5 Other Receptor Tyrosine Kinase Mutations 74
3.4 Other Frequent Mutations in AML 74
3.4.1 RAS Mutations 74
3.4.2 Nucleophosmin (NPM1) Mutations 75
3.4.3 CEBPA Mutations 75
3.4.4 Wilms Tumor-1 (WT1) Gene Expression and Mutation 76
3.4.5 TET2 Mutations 76
3.5 Epigenetic Dysregulation in Myeloid Leukemogenesis 76
3.5.1 Altered Methylation Pattern in AML 77
3.5.2 MicroRNA Dysregulation in AML 77
3.6 Conclusions 77
References 78
Part III:Treatment Considerationsin Childhood Leukemia 81
4: Classification and Treatment of Acute Lymphoblastic Leukemia 82
4.1 Introduction and Overview 83
4.2 Historical Development of Treatment Regimens for Newly Diagnosed Childhood ALL 83
4.2.1 Early Events Leading to First Cures of Childhood ALL 83
4.2.2 Phases of Multi-agent Chemotherapy 84
4.2.3 Evolution of BFM Therapy 85
4.2.4 COG Adaptation and Modification of BFM-Based Therapy 86
4.2.5 Development and Evolution of DFCI Consortium ALL Regimens 88
4.2.6 Development and Evolution of SJCRH ALL Regimens 88
4.2.7 Treatments Used by Other ALL Cooperative Groups 88
4.3 Unique Subsets of ALL 89
4.3.1 Infants 89
4.3.2 Young Adults 89
4.3.3 Philadelphia Chromosome-Positive ALL 90
4.3.4 Down Syndrome 91
4.4 Treatment Controversies and Critical Questions in Childhood ALL 91
4.4.1 The Role of Cranial Radiotherapy 91
4.4.2 Pulses of Steroids and Vincristine During Maintenance Therapy 92
4.4.3 Identification of the Optimum Corticosteroid for Induction Therapy 92
4.4.4 Identification and Treatment of Low-Risk Subsets of Childhood ALL 92
4.4.5 The Role of Hematopoietic Stem Cell Transplant in First Remission 93
4.5 Prognostic Factors and Risk Stratification Approaches 94
4.5.1 Clinical Features 94
4.5.2 Blast Immunophenotype and Genotype 95
4.5.3 Early Treatment Response 96
4.6 Relapsed ALL 97
4.6.1 Overview 97
4.6.2 Diagnostic Procedures at Relapse 98
4.6.3 Risk Factors in Relapsed ALL 98
4.6.3.1 Time to Relapse 98
4.6.3.2 Site of Relapse 99
4.6.3.3 Immunophenotype 100
4.6.3.4 Genotype 101
4.6.3.5 Summary of Risk Factors in Relapsed ALL 101
4.6.4 Treatment of Relapsed ALL 103
4.6.4.1 Remission Induction Chemotherapy 103
4.6.4.2 Post-remission Therapy 104
4.6.5 Treatment of Extramedullary Relapses 105
4.6.5.1 CNS Relapse 105
4.6.5.2 Testicular Relapse 106
4.6.6 Role of Allogeneic Stem Cell Transplantation 106
4.6.7 Study of New Agents in Relapsed ALL 108
4.6.8 Summary and Perspectives on Relapsed ALL 109
4.7 Clinical Trial Design Considerations and Endpoints 109
4.7.1 Trial Design 109
4.7.2 Endpoints for Clinical Trials 111
4.7.3 Surrogate Endpoints: Principles 112
4.7.4 Primary Endpoint in ALL Trials: EFS or Survival? 113
4.8 Summary and Future Directions 115
References 115
5: Treatment of Acute Myeloid Leukemia 124
5.1 Acute Myeloid Leukemia in Children: Overview 124
5.2 Acute Myeloid Leukemia: Diagnosis and Classification 125
5.2.1 Diagnosis: Clinical Manifestations 125
5.2.2 Overview of Laboratory Diagnostic Studies 126
5.2.3 Clinical Diagnosis: Morphologic Classification Schemes 126
5.2.4 Clinical Diagnosis: Immunophenotyping 127
5.2.5 Clinical Diagnosis: Conventional and Molecular Cytogenetics 127
5.2.6 Clinical Diagnosis: Molecular Genetic Analyses 128
5.2.7 World Health Organization Classification System 128
5.3 Overview of Risk-Stratified Approaches 129
5.3.1 Overview 129
5.3.2 Age and White Blood Cell Count at Presentation 129
5.3.3 FAB Classification 129
5.3.4 Acute Promyelocytic Leukemia and Down Syndrome AML 129
5.3.5 Cytogenetic Abnormalities 130
5.3.6 Molecular Mutations 131
5.3.6.1 Fms-Like Tyrosine Kinase 3: FLT3 Mutations 132
5.3.6.2 Nucleophosmin: NPM1 Mutations 132
5.3.6.3 CCAAT/Enhancer Binding Protein Alpha: CEBPA Mutations 132
5.3.6.4 c-kit Mutations 132
5.3.6.5 MLL-PTD Mutations 133
5.3.6.6 BAALC (Brain and Acute Leukemia Cytoplasmic Protein), EVI1 and ERG 133
5.3.6.7 RAS and WT1 Mutations 133
5.3.7 Correlation of Prognostic Signature with Clinical Data 133
5.3.8 Initial Response to Treatment 133
5.3.9 Minimal Residual Disease Assays and Markers 134
5.3.10 Minimal Residual Disease Studies 134
5.3.11 Summary 135
5.4 Treatment of Pediatric AML 135
5.4.1 Overview 135
5.4.2 Childhood AML Therapy: MRC Experience 136
5.4.2.1 Induction Therapy 136
5.4.2.2 Consolidation/Post-remission Therapy 136
5.4.2.3 Hematopoietic Stem Cell Transplantation 137
5.4.3 Childhood AML Therapy: European and Japanese Experience 137
5.4.3.1 Induction Therapy 137
5.4.3.2 Consolidation/Post-remission Therapy 138
5.4.3.3 Hematopoietic Stem Cell Transplantation 139
5.4.3.4 Maintenance Therapy 139
5.4.4 Childhood AML Therapy: North American Experience 140
5.4.4.1 Induction Therapy 140
5.4.4.2 Consolidation/Post-remission Therapy 141
5.4.4.3 Hematopoietic Stem Cell Transplantation 141
5.4.4.4 Current Areas of Investigation 142
5.4.4.5 Summary 142
5.4.5 Extramedullary and CNS-Directed Therapy 143
5.4.6 Hematopoietic Stem Cell Transplantation 143
5.5 Treatment Strategies in Special Subgroups 144
5.5.1 Acute Promyelocytic Leukemia 144
5.5.1.1 Introduction 144
5.5.1.2 Demographic Features 144
5.5.1.3 Pathogenesis 144
5.5.1.4 Diagnosis 145
5.5.1.5 Prognostic Factors 145
5.5.1.6 Treatment 145
5.5.1.7 Refractory or Relapsed Disease 147
5.5.1.8 New Drugs 148
5.5.1.9 Conclusions 148
5.5.2 Down Syndrome Transient Myeloproliferative Disorder and Myeloid Leukemia 148
5.5.2.1 Epidemiology and Incidence 148
5.5.2.2 Biology of TMD and AML in Children with Down Syndrome 149
5.5.2.3 Clinical Features and Management of TMD in Children with Down Syndrome 150
5.5.2.4 Clinical Features and Management of AML in Children with Down Syndrome 151
5.6 Refractory and Relapsed AML 154
5.7 New/Recent Approaches to Therapy 154
5.7.1 Approaches to MRD 154
5.7.2 Targeted Therapy Approaches 155
5.8 Summary: Advances in Therapies for Pediatric Acute Myeloid Leukemia 155
References 156
Part IV:The Impact of Pharmacogeneticsand Pharmacogenomicson Childhood Leukemia 164
6: Pharmacogenetic and Pharmacogenomic Considerations in the Biology and Treatment of Childhood Leukemia 165
6.1 Concept of Pharmacogenetics and Pharmacogenomics 165
6.1.1 Types of Genetic Variations 165
6.1.2 Phenotype–Genotype Relationships and Goals of Pharmacogenetics and Pharmacogenomics 166
6.2 Acute Lymphoblastic Leukemia 167
6.2.1 Genetic Variations Related to Drug Efficacy 167
6.2.1.1 Genetic Aberrations in Tumor Affecting Anti-leukemic Drugs 168
6.2.1.2 Genetic Variations in the Host Affecting Anti-leukemic Drugs 170
6.2.2 Genetic Variations Related to Drug Toxicity 174
6.3 Acute Myeloid Leukemia 177
6.3.1 Genetic Variations in the Host Affecting Antileukemic Drugs 178
6.3.1.1 Race and Ethnicity 178
6.3.1.2 Pharmacogenetic Variation in Metabolism of Cytarabine 178
6.3.2 X-Ray Repair Cross-complementing – 3 (XRCC3) 179
6.3.3 Glutathione S-Transferase Polymorphisms 180
6.3.4 CD33: Coding Region Polymorphisms 181
6.3.5 XPD 181
6.3.6 P-Glycoprotein Polymorphism and Outcome of AML 182
6.4 Pharmacogenetics and Leukemia Survivors 183
6.5 Conclusion 184
References 184
Part V:The Potential Role of Biologically TargetedTherapy for Childhood Leukemia 192
7: Promising Targeted Agents 193
7.1 Introduction 193
7.1.1 Overview 193
7.1.2 Molecular Pathogenesis of Leukemia: The Basis of Targeted Therapy 194
7.2 Monoclonal Antibodies and Immunoconjugates 196
7.2.1 Differentiation Antigens as a Potential Target for Immunotherapy Approaches 196
7.2.2 Anti-CD33 (Gemtuzumab Ozogamicin) 196
7.2.3 Anti-CD22 (Epratuzumab) 197
7.2.4 Anti-CD19 197
7.3 Tyrosine Kinase Inhibitors (TKI) 198
7.3.1 BCR-ABL: Imatinib, Dasatinib 198
7.3.2 FLT3: Lestaurtinib, Sorafenib, AC220, Midostaurin 199
7.4 Proteasome Inhibitors 201
7.5 mTOR Inhibitors Sirolimus, Temsirolimus 202
7.6 NOTCH Pathway Inhibitors 203
7.7 Epigenetic Modulators 204
7.7.1 Overview 204
7.7.2 DNA Methyltransferase Inhibitors 205
7.7.3 Histone Deacetylase Inhibitors 207
7.8 Targeting Apoptosis Pathways: BCL2 Family Inhibitors, XIAP Inhibitors 207
7.8.1 Overview 207
7.8.2 BCL2 Family Inhibitors 207
7.8.3 XIAP Inhibitors 208
7.9 Conclusions 208
References 209
8: Strategies for New Agent Development and Clinical Trial Considerations 215
8.1 Introduction 215
8.2 Role of Preclinical Testing 216
8.2.1 Description of Ability to Establish Direct Transplant Leukemia Xenografts 216
8.2.2 Overview of In vivo Testing Procedures 217
8.2.3 Examples of Activity Signals 219
8.2.3.1 The Aurora A Kinase Inhibitor MLN8237 219
8.2.3.2 The Bcl-2 Inhibitor ABT-263 220
8.2.3.3 The Anti-CD19-DM4 Conjugated Antibody SAR3419 221
8.2.4 Preclinical Combination Testing 221
8.2.5 Future Directions 222
8.3 Phase I and Dose-Finding Studies in Children with Leukemia 222
8.4 Phase II Studies 224
8.5 Phase III Studies 227
8.5.1 Rationale for Randomized Trials 227
8.5.2 Design 229
8.5.2.1 Eligibility 229
8.5.2.2 Endpoints 229
8.5.2.3 Sample Size Calculation 231
8.5.2.4 Accrual 232
8.5.2.5 Single-Arm Trials 232
8.5.2.6 Randomization 233
8.5.2.7 Factorial Designs 233
8.5.2.8 Correlative Studies 234
8.5.3 Analysis 234
8.5.3.1 Intention-to-Treat 234
8.5.3.2 Statistical Tests 234
8.5.3.3 Interim Analysis 235
8.5.3.4 Subgroup Analyses 235
8.5.4 Reporting of Results 235
8.5.5 Meta-analysis 235
8.6 Summary 236
References 236
Part VI:Late Effects of Leukemiaand Its Therapy 242
9: Late Sequelae in Children with Acute Lymphoblastic Leukemia: Impact on Long-Term Survival and Quality of Life 243
9.1 Introduction 243
9.2 Burden of Morbidity 245
9.3 Cardiotoxicity 245
9.3.1 Recommended Screening and Follow-Up 246
9.4 Neurocognitive Effects 246
9.4.1 Radiation 246
9.4.2 Chemotherapy 246
9.4.3 Recommended Screening and Follow-Up 247
9.5 Endocrine Late-Effects 248
9.5.1 Growth 248
9.5.2 Thyroid Function 248
9.5.3 Gonadal Function 249
9.5.4 Obesity/Metabolic Syndrome 249
9.6 Bone Health 250
9.7 Hepatotoxicity 251
9.8 Second Malignant Neoplasms 252
9.8.1 Therapy-Related Myelodysplasia and Acute Myeloid Leukemia 252
9.8.1.1 Alkylating Agent-Related t-MDS/AML 252
9.8.1.2 Topoisomerase II Inhibitor-Related t-MDS/AML 252
9.8.2 Therapy-Related Solid Second Malignancies 253
9.8.2.1 Second Brain Tumors 253
9.8.2.2 Second Thyroid Cancers 253
9.8.2.3 Soft Tissue Sarcomas 253
9.8.3 Pathogenesis of Second Malignancies 254
9.9 Late Mortality 254
9.10 Quality of Life 254
9.10.1 Challenges with Delivering Survivorship Care 255
9.11 Cancer Survivorship: Future Research Opportunities 255
References 257
10: Acute Toxicities, Late Sequelae, and Quality of Survivorship in Children with Acute Myeloid Leukemia: The Impact of Allo 262
10.1 Introduction 262
10.2 Timing and Appropriateness of Transplant in Pediatric AML 263
10.3 Hematopoietic Stem Cell Sources and Donor Types 266
10.4 Conditioning Regimens 266
10.5 Graft vs. Host Disease Prophylaxis 267
10.6 Transplant-Related Morbidity and Mortality 268
10.7 Quality of Life During the Peritransplant Period 269
10.8 Late Graft vs. Host Disease 269
10.9 Late Deaths 269
10.10 Second Cancers 270
10.11 Cardiopulmonary Toxicity 271
10.12 Fertility and Offspring After BMT for AML 272
10.13 Other Organ Toxicities 273
10.14 Quality of Life and Neuropsychometric Outcomes 274
10.15 Conclusion 275
References 275
Part VII:Psychosocial Implications of AcuteLeukemia Diagnosis and Treatmentfor Children and Families 280
11: Appreciation and the Interdisciplinary Management of the Psychosocial Impact of Leukemia on Children and Their Families 281
11.1 Models of Psychosocial Health Services 281
11.2 Communication of Diagnosis 284
11.3 Social Impact of the Child–School Issue 285
11.4 Discussion of the Treatment Plan and Informed Consent 286
11.5 Family Distress and Resilience in the Face of a Childhood Cancer Diagnosis 286
11.5.1 A Framework for Understanding Distress 286
11.5.2 Mothers 287
11.5.3 Fathers 288
11.5.4 Siblings 289
11.6 Diagnosis of Depressive or Anxiety Disorders and Serotonin Reuptake Inhibitor Prescription Practices 289
11.7 Issues Around the Death of a Child 292
11.8 Issues Related to Survivorship 293
References 294
Part VIII:Global Strategies to Improve LeukemiaCare and Outcome for Children 298
12: Improved Outcome for Children with Acute Leukemia: How to Address Global Disparities 299
12.1 Introduction 300
12.2 Globalization of the International Society of Pediatric Oncology (SIOP) 301
12.3 The “La Mascota” Twinning Program Between Monza (Italy) and Managua (Nicaragua): A 23-year Experience 303
12.3.1 Long-Term Impact of La Mascota Program 306
12.3.2 Conclusions 306
12.4 Twinning: The VU-Netherlands-UGM-Indonesia Experience – Staff Education, Protocol Development, and Research 307
12.5 Strategies to Improve Pediatric Cancer Care in Low- and Mid-Income Countries: The Experience of the St. Jude Internation 309
12.5.1 The Status of Pediatric Oncology Worldwide 309
12.5.2 Implementing Pediatric Cancer Care in Low- and Mid-Income Countries 310
12.5.3 Components of Pediatric Cancer Care in Low- and Mid-Income Countries 312
12.5.4 Outcome Measures 312
12.5.5 Program Sustainability 313
12.5.6 Conclusions 313
12.6 International Clinical Trials for Children with Cancer – Hurdles and Solutions: The Children’s Oncology Group (COG) App 314
12.7 Summary and Conclusions 315
References 315
Part IX:Perspectives and Future Direction 317
13: Future Challenges and Opportunities to Improve Outcomes for Children with Leukemia 318
References 323
Index 324