상세정보

Intro -- Contents -- Contributors -- Chapter 1: Epidemiology and Etiology of Childhood ALL -- 1.1 Introduction -- 1.2 General Epidemiology -- 1.3 Natural History -- 1.4 Environmental Risk Factors -- 1.4.1 Infectious Disease and Immune Stimulation -- 1.4.2 Other Risk Factors -- 1.5 Heritability of ALL -- 1.6 High-Penetrance Genetic Predisposition -- 1.6.1 Syndromes Where ALL Is a Dominant Cancer Phenotype -- 1.6.2 Syndromes Where ALL Is Part of a Mixed Cancer Phenotype -- 1.7 Low-Penetrance Genetic Predisposition -- 1.8 Future Directions -- References -- Chapter 2: Clinical Presentation and Prognostic Factors -- 2.1 Clinical Presentation -- 2.1.1 Introduction -- 2.1.2 Symptoms and Signs Related to Bone Marrow Involvement -- 2.1.3 Symptoms and Signs Related to Extensive Bulk Disease -- 2.1.4 Central Nervous System -- 2.1.5 The Eye -- 2.1.6 Genitourinary System -- 2.1.7 Cardiovascular System -- 2.1.8 The Skin -- 2.1.9 Head and Neck -- 2.1.10 Gastrointestinal System -- 2.1.11 Hypercalcaemia -- 2.1.12 Haemophagocytic Lymphohistiocytosis (HLH) -- 2.1.13 Aplastic Presentation -- 2.1.14 Rare Presentations -- 2.1.15 Asymptomatic Pancytopenia -- 2.1.16 The Diagnostic Interval and Pathway -- 2.1.17 Differential Diagnosis -- 2.2 Laboratory Features -- 2.2.1 Haematology -- 2.2.2 Biochemistry -- 2.2.3 Bone Marrow Aspirate -- 2.2.4 Lumbar Puncture -- 2.3 Diagnostic Workup -- 2.4 Prognostic Factors -- 2.5 Individual Prognostic Factors -- 2.5.1 Age -- 2.5.2 White Cell Count -- 2.5.3 NCI Risk Score -- 2.5.4 Gender -- 2.5.5 CNS Disease -- 2.5.6 Disease Bulk -- 2.5.7 Immunophenotype -- 2.5.8 Genetics -- 2.5.9 Response to Treatment -- References -- Chapter 3: Diagnostic Flow Cytometry and Immunophenotypic Classification -- 3.1 Introduction -- 3.2 Immunophenotype of T-Lymphoblastic Leukemia/Lymphoma -- 3.3 Early T-Cell Precursor ALL -- 3.4 Immunophenotype of B-Lymphoblastic Leukemia/Lymphoma -- 3.5 Acute Leukaemia of Ambiguous Lineage -- 3.6 Antigen Expression: Correlation to Prognosis and Cytogenetics -- 3.7 Extended Leukaemia Immunophenotyping -- 3.8 Conclusions and Perspective -- References -- Chapter 4: Cytogenetics and Molecular Genetics -- 4.1 Introduction -- 4.2 Abnormality Detection Methodologies -- 4.3 Chromosomal Abnormalities in BCP-ALL -- 4.3.1 Favourable Risk Abnormalities -- 4.3.1.1 High Hyperdiploidy -- 4.3.1.2 t(12 -- 21)(p13 -- q22)/ETV6-RUNX1 -- 4.3.1.3 t(1 -- 19)(q23 -- p13)/TCF3-PBX1 -- 4.3.2 Poor-Risk Chromosomal Abnormalities -- 4.3.2.1 t(9 -- 22)(q34 -- q11.1)/BCR-ABL1 -- 4.3.2.2 t(17 -- 19)(q22 -- p13)/TCF3-HLF -- 4.3.2.3 11q23/KMT2A Gene Rearrangements -- 4.3.2.4 Near-Haploidy and Low Hypodiploidy -- 4.3.2.5 Intrachromosomal Amplification of Chromosome 21 (iAMP21) -- 4.3.3 B-ALL Lacking Sentinel Chromosomal Rearrangements -- 4.3.3.1 Ph-Like or BCR-ABL1-Like ALL -- 4.3.3.2 CRLF2 Rearrangements and Janus Kinase Mutations in ALL -- 4.3.3.3 DUX4 and ERG-Deregulated ALL -- 4.3.3.4 Translocations Involving the IGH Locus -- 4.3.3.5 PAX5 Rearrangement.
s -- MEF2D and ZNF384 Gene Fusions -- ETV6-RUNX1-Like -- 4.3.4 Secondary Genetic Alterations in BCP-ALL -- 4.4 Genetic Rearrangements in T-Lineage ALL -- 4.4.1 TAL1/LMO2 Rearranged T-ALL -- 4.4.2 TLX1/TLX3 Rearranged T-ALL -- 4.4.3 Early T-Cell Precursor ALL -- 4.4.4 Other T-ALL Genetic Subtypes: KMT2A Rearranged and PICALM-MLLT10 -- 4.5 Relapsed ALL -- 4.6 Inherited Genetic Variation and ALL Risk -- 4.7 Future Strategies/Conclusions -- References -- Chapter 5: Pharmacokinetics, Pharmacodynamics and Pharmacogenetics of Antileukemic Drugs -- 5.1 Introduction -- 5.2 Pharmacokinetics and Pharmacodynamics -- 5.3 Pharmacogenetics -- 5.4 Glucocorticosteroid -- 5.5 Vincristine -- 5.6 Anthracyclines -- 5.7 Asparaginase -- 5.8 Thiopurines -- 5.9 Methotrexate -- 5.10 Cytosine Arabinoside -- 5.11 Cyclophosphamide and Ifosfamide -- 5.12 Epipodophyllotoxins -- 5.13 Intrathecal Chemotherapy and Central Nervous System Leukemia -- 5.14 Patient Adherence and Physician Compliance -- 5.15 Treatment of Infants -- 5.16 Treatment of Adolescents -- 5.17 Treatment of Obese Patients -- 5.18 ALL Predisposition Syndromes and Chemotherapy -- 5.19 Conclusions and Future Perspectives -- References -- Chapter 6: Minimal Residual Disease (MRD) Diagnostics: Methodology and Prognostic Significance -- 6.1 Introduction -- 6.2 Standard MRD Methods -- 6.2.1 Quantitative PCR of Immunoglobulin and T Cell Receptor Gene Re-arrangement (IG-TR) Targets (DNA Level) -- 6.2.2 Classical Multicolor (4–6-Color) Flow-MRD -- 6.2.3 Real-Time Quantitative Reverse Transcriptase (RQ-RT)-PCR of Fusion Gene Transcripts -- 6.3 Sample Requirements -- 6.3.1 Monitoring of Bone Marrow Samples, Not Blood Samples -- 6.3.2 Homogeneous Distribution of ALL Cells over BM During Treatment -- 6.3.3 Always Use the First Pull Aspirate for Obtaining Reliable MRD Measurements -- 6.4 Prognostic Value of MRD Diagnostics -- 6.4.1 Frontline Treatment -- 6.4.2 Treatment Reduction in MRD-Based Low-Risk Patients? -- 6.4.3 Stem Cell Transplantation, Relapse Treatment, and Innovative Drugs -- 6.4.4 Continuous Monitoring After Induction Treatment? -- 6.5 New High Throughput MRD Technologies -- 6.5.1 EuroFlow-Based (≥8-Color) Next Generation Flow-­MRD (NGF-MRD) -- 6.5.2 High-Throughput Sequencing (HTS) of IG-TCR Targets (DNA Level) -- 6.6 Conclusions -- References -- Chapter 7: First Line Treatment: Current Approach -- 7.1 Introduction -- 7.1.1 Drugs and Protocols -- 7.1.2 Historical Background -- 7.1.2.1 Intensification Therapy -- 7.1.2.2 CNS Directed Therapy: Is Cranial Radiotherapy Essential? -- 7.1.2.3 Intravenous Methotrexate -- 7.1.2.4 Steroid, Asparaginase and Thiopurine Formulation -- 7.1.2.5 Purine Analogues and Proteasome Inhibitors -- 7.1.2.6 Haemopoietic Stem Cell Transplant (HSCT) -- 7.1.3 Current UK Strategy -- 7.1.3.1 Risk Stratification -- 7.1.3.2 Treatment -- 7.1.3.3 Induction and Consolidation -- 7.1.3.4 Interim Maintenance and Delayed Intensification -- 7.1.3.5 Continuation Therapy -- 7.1.3.6 Steroid and Asparag.
inase Formulations, Doses and Schedules -- 7.1.3.7 Central Nervous System (CNS) Directed Therapy -- 7.1.3.8 Allogeneic Haemopoietic Stem Cell Transplantation (HSCT) -- 7.2 Current Outcomes -- 7.3 Treatment of Distinct Sub-groups -- 7.3.1 Young People (Age 16–25 Years) -- 7.3.2 Infants -- 7.3.3 Down Syndrome -- 7.4 Future Strategies and Conclusions -- References -- Chapter 8: Targeted Therapy and Precision Medicine -- 8.1 Introduction -- 8.2 Precision Medicine for B-ALL -- 8.2.1 Kinase Inhibition for BCR-ABL1-Rearranged (Ph+) ALL -- 8.2.2 Kinase Inhibition for BCR-ABL1-Like (Ph-Like) ALL -- 8.2.3 FLT3 Receptor Kinase Inhibition for KMT2A (MLL)-Rearranged ALL -- 8.2.4 MAP Kinase Inhibition for RAS Pathway-Mutant ALL -- 8.3 Precision Medicine for T-ALL -- 8.3.1 Kinase Inhibition for T-ALL -- 8.3.2 Gamma Secretase Inhibition for Notch1-Mutant T-ALL -- 8.4 Future Strategies/Conclusions -- References -- Chapter 9: Monoclonal Antibodies in Pediatric Acute Lymphoblastic Leukemia -- 9.1 Monoclonal Antibodies -- 9.1.1 Introduction -- 9.1.2 Structure of Monoclonal Antibodies (moAbs) -- 9.1.3 Clinical Use of moAbs -- 9.2 Target Antigens in Acute Lymphoblastic Leukemia -- 9.3 Naked moAbs -- 9.3.1 CD52 -- 9.3.1.1 Alemtuzumab -- 9.3.2 CD20 -- 9.3.2.1 Rituximab -- 9.3.2.2 Ofatumomab -- 9.3.2.3 Other Anti-CD20 moAbs -- 9.3.3 CD22 -- 9.3.3.1 Epratuzumab -- 9.4 MoAb-Drug Conjugates -- 9.4.1 CD22 -- 9.4.1.1 Moxetumomab -- 9.4.1.2 Inotuzumab Ozogamicin -- 9.4.2 CD19 -- 9.4.2.1 SAR3419 -- 9.4.3 CD19/CD22 -- 9.4.3.1 Combotox -- 9.4.3.2 DT2219 -- 9.5 Radioimmunotherapy -- 9.5.1 CD20 -- 9.5.2 CD22 -- 9.6 T Cell Engaging Antibodies/MoAb T Cell Conjugates -- 9.6.1 CD19 -- 9.6.1.1 Blinatumomab -- 9.6.2 CD20 -- 9.7 T Cell Targets -- 9.7.1 CD7 -- 9.7.2 CD5 -- 9.7.3 CD2 -- 9.8 Inhibitory T Cell Pathways -- 9.8.1 CTLA-4 -- 9.8.1.1 Ipilimumab -- 9.8.2 PD-1 Inhibitors -- 9.8.2.1 Nivolumab -- 9.8.2.2 Pembrolizumab -- 9.8.2.3 Pidilizumab -- 9.8.3 PD-L1 Inhibitors -- 9.8.3.1 AMP-224 -- 9.8.3.2 MPDL3280A -- 9.8.4 CD137 -- 9.8.5 CCR4 -- 9.9 Future Strategies/Conclusions -- References -- Chapter 10: Cellular Therapy -- 10.1 Introduction -- 10.2 Non-gene Engineered Cellular Therapies -- 10.2.1 Donor Leucocyte Infusions -- 10.2.2 Cytokine Induced Killer Cells -- 10.3 CAR-Engineered Cellular Therapies -- 10.3.1 Basic Principles -- 10.3.2 CD19 as a Target Antigen for CAR Therapy -- 10.3.3 T Cell Populations for CD19 CAR Transduction -- 10.3.4 CD19 CAR T Cell Therapy in B-ALL -- 10.3.5 Lessons Learnt from ALL Studies -- 10.3.5.1 Clinical Outcomes in Relation to CD19 CAR Design -- 10.3.5.2 Factors Associated with Improved Outcomes Following CD19CAR Therapy -- 10.3.5.3 Toxicity -- B Cell Aplasia -- Cytokine Release Syndrome (CRS) -- Neurotoxicity -- 10.4 Other CAR T Cell Targets in ALL -- 10.5 Future Directions -- References -- Chapter 11: Relapsed Acute Lymphoblastic Leukemia of Childhood -- 11.1 Introduction -- 11.2 Pathogenesis of Relapsed ALL -- 11.2.1 CNS Relapses -- 11.2.2 Bone Marrow R.