Childhood Leukemia

A Practical Handbook
1. Auflage 2011
ISBN: 978-3-642-13781-5
Verlag: Springer
Format: PDF
Kopierschutz: Adobe DRM (»Systemvoraussetzungen)

E-Book, Englisch, 336 Seiten

This book is a comprehensive and up-to-date compendium on all aspects of childhood leukemia. After introductory chapters on the epidemiology and biology of pediatric leukemia, treatment considerations are extensively reviewed, with emphasis on the use of risk-adjusted treatment approaches. Promising targeted agents are discussed, and strategies for the development of new agents are appraised. The late effects of leukemia and its therapy are then considered in depth, with due attention to management of the psychosocial impact of the disease. Finally, global strategies to improve leukemia care and outcome are reviewed, and future directions discussed. The authors are internationally recognized experts and offer a largely evidence-based consensus on etiology, biology, and treatment. This handbook has far-reaching applicability to the clinical diagnosis and management of pediatric leukemia and will prove invaluable to specialists, generalists, and trainees alike.

Autoren/Hrsg.

Inhaltsverzeichnis

1;Childhood Leukemia;2
1.1;Copyright Page;3
1.2;Preface;4
1.3;Acknowledgments;5
1.4;Contents;6
1.5;Part I:Genetics and the Epidemiologyof Leukemia in Children;8
1.5.1;1: Epidemiology of Acute Childhood Leukemia;9
1.5.1.1;1.1 Classification and Natural History;9
1.5.1.1.1;1.1.1 Classification: Immunophenotype, Morphology;9
1.5.1.1.2;1.1.2 Classification: Molecular and Cytogenetics;10
1.5.1.1.2.1;1.1.2.1 Acute Lymphoid Leukemias;10
1.5.1.1.2.2;1.1.2.2 Acute Myeloid Leukemias;11
1.5.1.1.3;1.1.3 Natural History of Leukemia;12
1.5.1.2;1.2 Incidence, Survival, and Trends;13
1.5.1.2.1;1.2.1 International Incidence Rates;13
1.5.1.2.2;1.2.2 U.S. Incidence Rates and Trends;13
1.5.1.2.3;1.2.3 Survival;16
1.5.1.3;1.3 Risk Factors for Childhood Leukemia;17
1.5.1.3.1;1.3.1 Genetic Syndromes;17
1.5.1.3.2;1.3.2 Environmental and Other Risk Factors for Childhood Leukemia;17
1.5.1.3.2.1;1.3.2.1 Ionizing Radiation;18
1.5.1.3.2.2;1.3.2.2 Prior Chemotherapy;18
1.5.1.3.2.3;1.3.2.3 Reproductive History;18
1.5.1.3.3;1.3.3 Lifestyle Factors;19
1.5.1.3.3.1;1.3.3.1 Cigarette Smoking;19
1.5.1.3.3.2;1.3.3.2 Alcohol Consumption;19
1.5.1.3.3.3;1.3.3.3 Occupational Exposures;19
1.5.1.3.3.4;1.3.3.4 Maternal/Child Diet;19
1.5.1.3.3.5;1.3.3.5 Vitamin Supplementation;20
1.5.1.3.3.6;1.3.3.6 Pesticides;20
1.5.1.3.3.7;1.3.3.7 Infections;20
1.5.1.3.3.8;1.3.3.8 Birth Weight;21
1.5.1.3.4;1.3.4 Genetic Susceptibility;22
1.5.1.4;1.4 Challenges and Future Directions;23
1.5.1.4.1;1.4.1 Improvements in Identification of Cases and Controls for Studiesin the United States;23
1.5.1.4.1.1;1.4.1.1 Cases;23
1.5.1.4.1.2;1.4.1.2 Controls;24
1.5.1.4.2;1.4.2 Opportunities for Validation;24
1.5.1.4.2.1;1.4.2.1 Neonatal Blood Spots;24
1.5.1.4.2.2;1.4.2.2 Maternal-Fetal Cohort Studies;25
1.5.1.4.3;1.4.3 Comprehensive Use of Animal Models to Assess Exposure/Cancer Relationships;25
1.5.1.5;1.5 Conclusion;26
1.5.1.6;References;27
1.6;Part II:Biology of Pediatric Leukemia;33
1.6.1; 2: The Biology of Acute Lymphoblastic Leukemia;34
1.6.1.1;2.1 Introduction;34
1.6.1.2;2.2 The Cellular Biology of Acute Lymphoblastic Leukemia (ALL);35
1.6.1.2.1;2.2.1 Lymphoid Development and Immunophenotype of Acute Lymphoblastic Leukemia;35
1.6.1.2.1.1;2.2.1.1 Lymphoid Development;35
1.6.1.2.1.2;2.2.1.2 B-Cell Development;36
1.6.1.2.1.3;2.2.1.3 T-Cell Development;36
1.6.1.2.1.4;2.2.1.4 Immunophenotype of Acute Leukemia;37
1.6.1.2.2;2.2.2 Antigen Receptor Genes and Clonality;38
1.6.1.2.2.1;2.2.2.1 Immunoglobulin (Ig) and T-Cell Receptor (TCR) Gene Rearrangements in ALL;38
1.6.1.2.2.2;2.2.2.2 Assessment of Clonality by PCR Amplification;39
1.6.1.2.2.3;2.2.2.3 Use of Ig and TCR Gene Rearrangements for the Detection of MRD;39
1.6.1.2.3;2.2.3 Leukemia-Initiating Cells in ALL;40
1.6.1.3;2.3 The Molecular Biology of ALL;41
1.6.1.3.1;2.3.1 Introduction to Cancer Genomics and New Technology;41
1.6.1.3.2;2.3.2 Host Susceptibility to ALL;42
1.6.1.3.2.1;2.3.2.1 Genetic Syndromes and Down Syndrome ALL;42
1.6.1.3.2.2;2.3.2.2 Germline Genetic Variation and ALL;43
1.6.1.3.3;2.3.3 Somatic Genetic Changes in ALL;43
1.6.1.3.3.1;2.3.3.1 Chromosomal Lesions and Karyotype;43
1.6.1.3.3.2;2.3.3.2 Copy Number Abnormalities;45
1.6.1.3.3.3;2.3.3.3 Gene Expression Profiling;48
1.6.1.3.3.4;2.3.3.4 Discovery of Novel Therapeutic Targets Through DNA Sequencing and Genomic Studies;51
1.6.1.3.3.5;2.3.3.5 Epigenetic Modifications and Posttranscriptional Regulation by microRNAs;53
1.6.1.4;2.4 Signaling Pathways in Childhood ALL;55
1.6.1.4.1;2.4.1 BCR-ABL Tyrosine Kinase;55
1.6.1.4.2;2.4.2 FLT-3 Receptor Tyrosine Kinase;55
1.6.1.4.3;2.4.3 JAK Tyrosine Kinase;56
1.6.1.4.4;2.4.4 Pre-B Cell Receptor;56
1.6.1.4.5;2.4.5 RAS Pathway;56
1.6.1.4.6;2.4.6 NOTCH1 Pathway;57
1.6.1.4.7;2.4.7 Therapy Targeted to Signaling Pathways;57
1.6.1.5;2.5 The Apoptotic Pathway and ALL;57
1.6.1.6;2.6 The Biology of Relapsed ALL;59
1.6.1.7;2.7 Summary;62
1.6.1.8;References;62
1.6.2;3: Biology of Acute Myeloid Leukemia;67
1.6.2.1;3.1 Introduction;67
1.6.2.2;3.2 Cytogenetic Alterations;69
1.6.2.2.1;3.2.1 t(15;17) Translocation69
1.6.2.2.2;3.2.2 CBF AML;70
1.6.2.2.3;3.2.3 t(8;21); AML1/ETO;70
1.6.2.2.4;3.2.4 Inv(16);71
1.6.2.2.5;3.2.5 AML with MLL Rearrangement;71
1.6.2.2.6;3.2.6 Sub-karyotypic (Cryptic) Chromosomal Abnormalities;72
1.6.2.3;3.3 Disease Associated Mutations in Signal Transduction Pathways;72
1.6.2.3.1;3.3.1 FLT3 Mutations;73
1.6.2.3.2;3.3.2 FLT3 Internal Tandem Duplications (FLT3/ITD);73
1.6.2.3.3;3.3.3 FLT3 Activation Loop Mutation (FLT3/ALM);74
1.6.2.3.4;3.3.4 c-KIT Mutations;74
1.6.2.3.5;3.3.5 Other Receptor Tyrosine Kinase Mutations;74
1.6.2.4;3.4 Other Frequent Mutations in AML;74
1.6.2.4.1;3.4.1 RAS Mutations;74
1.6.2.4.2;3.4.2 Nucleophosmin (NPM1) Mutations;75
1.6.2.4.3;3.4.3 CEBPA Mutations;75
1.6.2.4.4;3.4.4 Wilms Tumor-1 (WT1) Gene Expression and Mutation;76
1.6.2.4.5;3.4.5 TET2 Mutations;76
1.6.2.5;3.5 Epigenetic Dysregulation in Myeloid Leukemogenesis;76
1.6.2.5.1;3.5.1 Altered Methylation Pattern in AML;77
1.6.2.5.2;3.5.2 MicroRNA Dysregulation in AML;77
1.6.2.6;3.6 Conclusions;77
1.6.2.7;References;78
1.7;Part III:Treatment Considerationsin Childhood Leukemia;81
1.7.1;4: Classification and Treatment of Acute Lymphoblastic Leukemia;82
1.7.1.1;4.1 Introduction and Overview;83
1.7.1.2;4.2 Historical Development of Treatment Regimens for Newly Diagnosed Childhood ALL;83
1.7.1.2.1;4.2.1 Early Events Leading to First Cures of Childhood ALL;83
1.7.1.2.2;4.2.2 Phases of Multi-agent Chemotherapy;84
1.7.1.2.3;4.2.3 Evolution of BFM Therapy;85
1.7.1.2.4;4.2.4 COG Adaptation and Modification of BFM-Based Therapy;86
1.7.1.2.5;4.2.5 Development and Evolution of DFCI Consortium ALL Regimens;88
1.7.1.2.6;4.2.6 Development and Evolution of SJCRH ALL Regimens;88
1.7.1.2.7;4.2.7 Treatments Used by Other ALL Cooperative Groups;88
1.7.1.3;4.3 Unique Subsets of ALL;89
1.7.1.3.1;4.3.1 Infants;89
1.7.1.3.2;4.3.2 Young Adults;89
1.7.1.3.3;4.3.3 Philadelphia Chromosome-Positive ALL;90
1.7.1.3.4;4.3.4 Down Syndrome;91
1.7.1.4;4.4 Treatment Controversies and Critical Questions in Childhood ALL;91
1.7.1.4.1;4.4.1 The Role of Cranial Radiotherapy;91
1.7.1.4.2;4.4.2 Pulses of Steroids and Vincristine During Maintenance Therapy;92
1.7.1.4.3;4.4.3 Identification of the Optimum Corticosteroid for Induction Therapy;92
1.7.1.4.4;4.4.4 Identification and Treatment of Low-Risk Subsets of Childhood ALL;92
1.7.1.4.5;4.4.5 The Role of Hematopoietic Stem Cell Transplant in First Remission;93
1.7.1.5;4.5 Prognostic Factors and Risk Stratification Approaches;94
1.7.1.5.1;4.5.1 Clinical Features;94
1.7.1.5.2;4.5.2 Blast Immunophenotype and Genotype;95
1.7.1.5.3;4.5.3 Early Treatment Response;96
1.7.1.6;4.6 Relapsed ALL;97
1.7.1.6.1;4.6.1 Overview;97
1.7.1.6.2;4.6.2 Diagnostic Procedures at Relapse;98
1.7.1.6.3;4.6.3 Risk Factors in Relapsed ALL;98
1.7.1.6.3.1;4.6.3.1 Time to Relapse;98
1.7.1.6.3.2;4.6.3.2 Site of Relapse;99
1.7.1.6.3.3;4.6.3.3 Immunophenotype;100
1.7.1.6.3.4;4.6.3.4 Genotype;101
1.7.1.6.3.5;4.6.3.5 Summary of Risk Factors in Relapsed ALL;101
1.7.1.6.4;4.6.4 Treatment of Relapsed ALL;103
1.7.1.6.4.1;4.6.4.1 Remission Induction Chemotherapy;103
1.7.1.6.4.2;4.6.4.2 Post-remission Therapy;104
1.7.1.6.5;4.6.5 Treatment of Extramedullary Relapses;105
1.7.1.6.5.1;4.6.5.1 CNS Relapse;105
1.7.1.6.5.2;4.6.5.2 Testicular Relapse;106
1.7.1.6.6;4.6.6 Role of Allogeneic Stem Cell Transplantation;106
1.7.1.6.7;4.6.7 Study of New Agents in Relapsed ALL;108
1.7.1.6.8;4.6.8 Summary and Perspectives on Relapsed ALL;109
1.7.1.7;4.7 Clinical Trial Design Considerations and Endpoints;109
1.7.1.7.1;4.7.1 Trial Design;109
1.7.1.7.2;4.7.2 Endpoints for Clinical Trials;111
1.7.1.7.3;4.7.3 Surrogate Endpoints: Principles;112
1.7.1.7.4;4.7.4 Primary Endpoint in ALL Trials: EFS or Survival?;113
1.7.1.8;4.8 Summary and Future Directions;115
1.7.1.9;References;115
1.7.2;5: Treatment of Acute Myeloid Leukemia;124
1.7.2.1;5.1 Acute Myeloid Leukemia in Children: Overview;124
1.7.2.2;5.2 Acute Myeloid Leukemia: Diagnosis and Classification;125
1.7.2.2.1;5.2.1 Diagnosis: Clinical Manifestations;125
1.7.2.2.2;5.2.2 Overview of Laboratory Diagnostic Studies;126
1.7.2.2.3;5.2.3 Clinical Diagnosis: Morphologic Classification Schemes;126
1.7.2.2.4;5.2.4 Clinical Diagnosis: Immunophenotyping;127
1.7.2.2.5;5.2.5 Clinical Diagnosis: Conventional and Molecular Cytogenetics;127
1.7.2.2.6;5.2.6 Clinical Diagnosis: Molecular Genetic Analyses;128
1.7.2.2.7;5.2.7 World Health Organization Classification System;128
1.7.2.3;5.3 Overview of Risk-Stratified Approaches;129
1.7.2.3.1;5.3.1 Overview;129
1.7.2.3.2;5.3.2 Age and White Blood Cell Count at Presentation;129
1.7.2.3.3;5.3.3 FAB Classification;129
1.7.2.3.4;5.3.4 Acute Promyelocytic Leukemia and Down Syndrome AML;129
1.7.2.3.5;5.3.5 Cytogenetic Abnormalities;130
1.7.2.3.6;5.3.6 Molecular Mutations;131
1.7.2.3.6.1;5.3.6.1 Fms-Like Tyrosine Kinase 3: FLT3 Mutations;132
1.7.2.3.6.2;5.3.6.2 Nucleophosmin: NPM1 Mutations;132
1.7.2.3.6.3;5.3.6.3 CCAAT/Enhancer Binding Protein Alpha: CEBPA Mutations;132
1.7.2.3.6.4;5.3.6.4 c-kit Mutations;132
1.7.2.3.6.5;5.3.6.5 MLL-PTD Mutations;133
1.7.2.3.6.6;5.3.6.6 BAALC (Brain and Acute Leukemia Cytoplasmic Protein), EVI1 and ERG;133
1.7.2.3.6.7;5.3.6.7 RAS and WT1 Mutations;133
1.7.2.3.7;5.3.7 Correlation of Prognostic Signature with Clinical Data;133
1.7.2.3.8;5.3.8 Initial Response to Treatment;133
1.7.2.3.9;5.3.9 Minimal Residual Disease Assays and Markers;134
1.7.2.3.10;5.3.10 Minimal Residual Disease Studies;134
1.7.2.3.11;5.3.11 Summary;135
1.7.2.4;5.4 Treatment of Pediatric AML;135
1.7.2.4.1;5.4.1 Overview;135
1.7.2.4.2;5.4.2 Childhood AML Therapy: MRC Experience;136
1.7.2.4.2.1;5.4.2.1 Induction Therapy;136
1.7.2.4.2.2;5.4.2.2 Consolidation/Post-remission Therapy;136
1.7.2.4.2.3;5.4.2.3 Hematopoietic Stem Cell Transplantation;137
1.7.2.4.3;5.4.3 Childhood AML Therapy: European and Japanese Experience;137
1.7.2.4.3.1;5.4.3.1 Induction Therapy;137
1.7.2.4.3.2;5.4.3.2 Consolidation/Post-remission Therapy;138
1.7.2.4.3.3;5.4.3.3 Hematopoietic Stem Cell Transplantation;139
1.7.2.4.3.4;5.4.3.4 Maintenance Therapy;139
1.7.2.4.4;5.4.4 Childhood AML Therapy: North American Experience;140
1.7.2.4.4.1;5.4.4.1 Induction Therapy;140
1.7.2.4.4.2;5.4.4.2 Consolidation/Post-remission Therapy;141
1.7.2.4.4.3;5.4.4.3 Hematopoietic Stem Cell Transplantation;141
1.7.2.4.4.4;5.4.4.4 Current Areas of Investigation;142
1.7.2.4.4.5;5.4.4.5 Summary;142
1.7.2.4.5;5.4.5 Extramedullary and CNS-Directed Therapy;143
1.7.2.4.6;5.4.6 Hematopoietic Stem Cell Transplantation;143
1.7.2.5;5.5 Treatment Strategies in Special Subgroups;144
1.7.2.5.1;5.5.1 Acute Promyelocytic Leukemia;144
1.7.2.5.1.1;5.5.1.1 Introduction;144
1.7.2.5.1.2;5.5.1.2 Demographic Features;144
1.7.2.5.1.3;5.5.1.3 Pathogenesis;144
1.7.2.5.1.4;5.5.1.4 Diagnosis;145
1.7.2.5.1.5;5.5.1.5 Prognostic Factors;145
1.7.2.5.1.6;5.5.1.6 Treatment;145
1.7.2.5.1.7;5.5.1.7 Refractory or Relapsed Disease;147
1.7.2.5.1.8;5.5.1.8 New Drugs;148
1.7.2.5.1.9;5.5.1.9 Conclusions;148
1.7.2.5.2;5.5.2 Down Syndrome Transient Myeloproliferative Disorder and Myeloid Leukemia;148
1.7.2.5.2.1;5.5.2.1 Epidemiology and Incidence;148
1.7.2.5.2.2;5.5.2.2 Biology of TMD and AML in Children with Down Syndrome;149
1.7.2.5.2.3;5.5.2.3 Clinical Features and Management of TMD in Children with Down Syndrome;150
1.7.2.5.2.4;5.5.2.4 Clinical Features and Management of AML in Children with Down Syndrome;151
1.7.2.6;5.6 Refractory and Relapsed AML;154
1.7.2.7;5.7 New/Recent Approaches to Therapy;154
1.7.2.7.1;5.7.1 Approaches to MRD;154
1.7.2.7.2;5.7.2 Targeted Therapy Approaches;155
1.7.2.8;5.8 Summary: Advances in Therapies for Pediatric Acute Myeloid Leukemia;155
1.7.2.9;References;156
1.8;Part IV:The Impact of Pharmacogeneticsand Pharmacogenomicson Childhood Leukemia;164
1.8.1; 6: Pharmacogenetic and Pharmacogenomic Considerations in the Biology and Treatment of Childhood Leukemia;165
1.8.1.1;6.1 Concept of Pharmacogenetics and Pharmacogenomics;165
1.8.1.1.1;6.1.1 Types of Genetic Variations;165
1.8.1.1.2;6.1.2 Phenotype–Genotype Relationships and Goals of Pharmacogenetics and Pharmacogenomics;166
1.8.1.2;6.2 Acute Lymphoblastic Leukemia;167
1.8.1.2.1;6.2.1 Genetic Variations Related to Drug Efficacy;167
1.8.1.2.1.1;6.2.1.1 Genetic Aberrations in Tumor Affecting Anti-leukemic Drugs;168
1.8.1.2.1.2;6.2.1.2 Genetic Variations in the Host Affecting Anti-leukemic Drugs;170
1.8.1.2.2;6.2.2 Genetic Variations Related to Drug Toxicity;174
1.8.1.3;6.3 Acute Myeloid Leukemia;177
1.8.1.3.1;6.3.1 Genetic Variations in the Host Affecting Antileukemic Drugs;178
1.8.1.3.1.1;6.3.1.1 Race and Ethnicity;178
1.8.1.3.1.2;6.3.1.2 Pharmacogenetic Variation in Metabolism of Cytarabine;178
1.8.1.3.2;6.3.2 X-Ray Repair Cross-complementing – 3 (XRCC3);179
1.8.1.3.3;6.3.3 Glutathione S-Transferase Polymorphisms;180
1.8.1.3.4;6.3.4 CD33: Coding Region Polymorphisms;181
1.8.1.3.5;6.3.5 XPD;181
1.8.1.3.6;6.3.6 P-Glycoprotein Polymorphism and Outcome of AML;182
1.8.1.4;6.4 Pharmacogenetics and Leukemia Survivors;183
1.8.1.5;6.5 Conclusion;184
1.8.1.6;References;184
1.9;Part V:The Potential Role of Biologically TargetedTherapy for Childhood Leukemia;192
1.9.1;7: Promising Targeted Agents;193
1.9.1.1;7.1 Introduction;193
1.9.1.1.1;7.1.1 Overview;193
1.9.1.1.2;7.1.2 Molecular Pathogenesis of Leukemia: The Basis of Targeted Therapy;194
1.9.1.2;7.2 Monoclonal Antibodies and Immunoconjugates;196
1.9.1.2.1;7.2.1 Differentiation Antigens as a Potential Target for Immunotherapy Approaches;196
1.9.1.2.2;7.2.2 Anti-CD33 (Gemtuzumab Ozogamicin);196
1.9.1.2.3;7.2.3 Anti-CD22 (Epratuzumab);197
1.9.1.2.4;7.2.4 Anti-CD19;197
1.9.1.3;7.3 Tyrosine Kinase Inhibitors (TKI);198
1.9.1.3.1;7.3.1 BCR-ABL: Imatinib, Dasatinib;198
1.9.1.3.2;7.3.2 FLT3: Lestaurtinib, Sorafenib, AC220, Midostaurin;199
1.9.1.4;7.4 Proteasome Inhibitors;201
1.9.1.5;7.5 mTOR Inhibitors Sirolimus, Temsirolimus;202
1.9.1.6;7.6 NOTCH Pathway Inhibitors;203
1.9.1.7;7.7 Epigenetic Modulators;204
1.9.1.7.1;7.7.1 Overview;204
1.9.1.7.2;7.7.2 DNA Methyltransferase Inhibitors;205
1.9.1.7.3;7.7.3 Histone Deacetylase Inhibitors;207
1.9.1.8;7.8 Targeting Apoptosis Pathways: BCL2 Family Inhibitors, XIAP Inhibitors;207
1.9.1.8.1;7.8.1 Overview;207
1.9.1.8.2;7.8.2 BCL2 Family Inhibitors;207
1.9.1.8.3;7.8.3 XIAP Inhibitors;208
1.9.1.9;7.9 Conclusions;208
1.9.1.10;References;209
1.9.2;8: Strategies for New Agent Development and Clinical Trial Considerations;215
1.9.2.1;8.1 Introduction;215
1.9.2.2;8.2 Role of Preclinical Testing;216
1.9.2.2.1;8.2.1 Description of Ability to Establish Direct Transplant Leukemia Xenografts;216
1.9.2.2.2;8.2.2 Overview of In vivo Testing Procedures;217
1.9.2.2.3;8.2.3 Examples of Activity Signals;219
1.9.2.2.3.1;8.2.3.1 The Aurora A Kinase Inhibitor MLN8237;219
1.9.2.2.3.2;8.2.3.2 The Bcl-2 Inhibitor ABT-263;220
1.9.2.2.3.3;8.2.3.3 The Anti-CD19-DM4 Conjugated Antibody SAR3419;221
1.9.2.2.4;8.2.4 Preclinical Combination Testing;221
1.9.2.2.5;8.2.5 Future Directions;222
1.9.2.3;8.3 Phase I and Dose-Finding Studies in Children with Leukemia;222
1.9.2.4;8.4 Phase II Studies;224
1.9.2.5;8.5 Phase III Studies;227
1.9.2.5.1;8.5.1 Rationale for Randomized Trials;227
1.9.2.5.2;8.5.2 Design;229
1.9.2.5.2.1;8.5.2.1 Eligibility;229
1.9.2.5.2.2;8.5.2.2 Endpoints;229
1.9.2.5.2.3;8.5.2.3 Sample Size Calculation;231
1.9.2.5.2.4;8.5.2.4 Accrual;232
1.9.2.5.2.5;8.5.2.5 Single-Arm Trials;232
1.9.2.5.2.6;8.5.2.6 Randomization;233
1.9.2.5.2.7;8.5.2.7 Factorial Designs;233
1.9.2.5.2.8;8.5.2.8 Correlative Studies;234
1.9.2.5.3;8.5.3 Analysis;234
1.9.2.5.3.1;8.5.3.1 Intention-to-Treat;234
1.9.2.5.3.2;8.5.3.2 Statistical Tests;234
1.9.2.5.3.3;8.5.3.3 Interim Analysis;235
1.9.2.5.3.4;8.5.3.4 Subgroup Analyses;235
1.9.2.5.4;8.5.4 Reporting of Results;235
1.9.2.5.5;8.5.5 Meta-analysis;235
1.9.2.6;8.6 Summary;236
1.9.2.7;References;236
1.10;Part VI:Late Effects of Leukemiaand Its Therapy;242
1.10.1; 9: Late Sequelae in Children with Acute Lymphoblastic Leukemia: Impact on Long-Term Survival and Quality of Life;243
1.10.1.1;9.1 Introduction;243
1.10.1.2;9.2 Burden of Morbidity;245
1.10.1.3;9.3 Cardiotoxicity;245
1.10.1.3.1;9.3.1 Recommended Screening and Follow-Up;246
1.10.1.4;9.4 Neurocognitive Effects;246
1.10.1.4.1;9.4.1 Radiation;246
1.10.1.4.2;9.4.2 Chemotherapy;246
1.10.1.4.3;9.4.3 Recommended Screening and Follow-Up;247
1.10.1.5;9.5 Endocrine Late-Effects;248
1.10.1.5.1;9.5.1 Growth;248
1.10.1.5.2;9.5.2 Thyroid Function;248
1.10.1.5.3;9.5.3 Gonadal Function;249
1.10.1.5.4;9.5.4 Obesity/Metabolic Syndrome;249
1.10.1.6;9.6 Bone Health;250
1.10.1.7;9.7 Hepatotoxicity;251
1.10.1.8;9.8 Second Malignant Neoplasms;252
1.10.1.8.1;9.8.1 Therapy-Related Myelodysplasia and Acute Myeloid Leukemia;252
1.10.1.8.1.1;9.8.1.1 Alkylating Agent-Related t-MDS/AML;252
1.10.1.8.1.2;9.8.1.2 Topoisomerase II Inhibitor-Related t-MDS/AML;252
1.10.1.8.2;9.8.2 Therapy-Related Solid Second Malignancies;253
1.10.1.8.2.1;9.8.2.1 Second Brain Tumors;253
1.10.1.8.2.2;9.8.2.2 Second Thyroid Cancers;253
1.10.1.8.2.3;9.8.2.3 Soft Tissue Sarcomas;253
1.10.1.8.3;9.8.3 Pathogenesis of Second Malignancies;254
1.10.1.9;9.9 Late Mortality;254
1.10.1.10;9.10 Quality of Life;254
1.10.1.10.1;9.10.1 Challenges with Delivering Survivorship Care;255
1.10.1.11;9.11 Cancer Survivorship: Future Research Opportunities;255
1.10.1.12;References;257
1.10.2; 10: Acute Toxicities, Late Sequelae, and Quality of Survivorship in Children with Acute Myeloid Leukemia: The Impact of Allo;262
1.10.2.1;10.1 Introduction;262
1.10.2.2;10.2 Timing and Appropriateness of Transplant in Pediatric AML;263
1.10.2.3;10.3 Hematopoietic Stem Cell Sources and Donor Types;266
1.10.2.4;10.4 Conditioning Regimens;266
1.10.2.5;10.5 Graft vs. Host Disease Prophylaxis;267
1.10.2.6;10.6 Transplant-Related Morbidity and Mortality;268
1.10.2.7;10.7 Quality of Life During the Peritransplant Period;269
1.10.2.8;10.8 Late Graft vs. Host Disease;269
1.10.2.9;10.9 Late Deaths;269
1.10.2.10;10.10 Second Cancers;270
1.10.2.11;10.11 Cardiopulmonary Toxicity;271
1.10.2.12;10.12 Fertility and Offspring After BMT for AML;272
1.10.2.13;10.13 Other Organ Toxicities;273
1.10.2.14;10.14 Quality of Life and Neuropsychometric Outcomes;274
1.10.2.15;10.15 Conclusion;275
1.10.2.16;References;275
1.11;Part VII:Psychosocial Implications of AcuteLeukemia Diagnosis and Treatmentfor Children and Families;280
1.11.1;11: Appreciation and the Interdisciplinary Management of the Psychosocial Impact of Leukemia on Children and Their Families;281
1.11.1.1;11.1 Models of Psychosocial Health Services;281
1.11.1.2;11.2 Communication of Diagnosis;284
1.11.1.3;11.3 Social Impact of the Child–School Issue;285
1.11.1.4;11.4 Discussion of the Treatment Plan and Informed Consent;286
1.11.1.5;11.5 Family Distress and Resilience in the Face of a Childhood Cancer Diagnosis;286
1.11.1.5.1;11.5.1 A Framework for Understanding Distress;286
1.11.1.5.2;11.5.2 Mothers;287
1.11.1.5.3;11.5.3 Fathers;288
1.11.1.5.4;11.5.4 Siblings;289
1.11.1.6;11.6 Diagnosis of Depressive or Anxiety Disorders and Serotonin Reuptake Inhibitor Prescription Practices;289
1.11.1.7;11.7 Issues Around the Death of a Child;292
1.11.1.8;11.8 Issues Related to Survivorship;293
1.11.1.9;References;294
1.12;Part VIII:Global Strategies to Improve LeukemiaCare and Outcome for Children;298
1.12.1;12: Improved Outcome for Children with Acute Leukemia: How to Address Global Disparities;299
1.12.1.1;12.1 Introduction;300
1.12.1.2;12.2 Globalization of the International Society of Pediatric Oncology (SIOP);301
1.12.1.3;12.3 The “La Mascota” Twinning Program Between Monza (Italy) and Managua (Nicaragua): A 23-year Experience;303
1.12.1.3.1;12.3.1 Long-Term Impact of La Mascota Program;306
1.12.1.3.2;12.3.2 Conclusions;306
1.12.1.4;12.4 Twinning: The VU-Netherlands-UGM-Indonesia Experience – Staff Education, Protocol Development, and Research;307
1.12.1.5;12.5 Strategies to Improve Pediatric Cancer Care in Low- and Mid-Income Countries: The Experience of the St. Jude Internation;309
1.12.1.5.1;12.5.1 The Status of Pediatric Oncology Worldwide;309
1.12.1.5.2;12.5.2 Implementing Pediatric Cancer Care in Low- and Mid-Income Countries;310
1.12.1.5.3;12.5.3 Components of Pediatric Cancer Care in Low- and Mid-Income Countries;312
1.12.1.5.4;12.5.4 Outcome Measures;312
1.12.1.5.5;12.5.5 Program Sustainability;313
1.12.1.5.6;12.5.6 Conclusions;313
1.12.1.6;12.6 International Clinical Trials for Children with Cancer – Hurdles and Solutions: The Children’s Oncology Group (COG) App;314
1.12.1.7;12.7 Summary and Conclusions;315
1.12.1.8;References;315
1.13;Part IX:Perspectives and Future Direction;317
1.13.1; 13: Future Challenges and Opportunities to Improve Outcomes for Children with Leukemia;318
1.13.1.1;References;323
1.13.2;Index;324