Clinical Management of Acute Lymphoblastic Leukemia: From Bench to Bedside

Description

This book provides a state-of-the-art overview of acute lymphoblastic leukemia (ALL). The first section of the book presents the translational science behind ALL, reviewing molecular pathways and targets in B- and T-cell ALL, as well as techniques and application of minimal residual disease testing. The second section spotlights ALL management strategies for patients across the spectrum, from infants to the elderly. The final section outlines current and new advances in ALL treatment, including new monoclonal antibodies and allogenic and autologous HSCT.  Written by experts in the field, Clinical Management of Acute Lymphoblastic Leukemia: From Bench to Bedside is a valuable resource that will guide patient management, stimulate investigative efforts, and increase understanding of the biologic underpinnings of the disease. Preface Contents Contributors Part I: Translational Science Chapter 1: Molecular Pathways and Targets in B-Cell Progenitor Acute Lymphoblastic Leukemia Introduction Historic Aspects of Genetic and Genomic Classification of B-ALL Heritable Susceptibility to Leukemia Prenatal Origin of Leukemia Aneuploid BCP-ALL: Hyperdiploidy, Hypodiploidy, and Intrachromosomal Amplification of Chromosome 21 ETV6-RUNX1 and ETV6-RUNX1-Like ALL TCF3-PBX1 and TCF3-HLF BCP-ALL KMT2A-Rearranged ALL Kinase-Driven BCP-ALL: BCR-ABL1 ALL and Ph-like ALL DUX4-Rearranged ALL MEF2D-Rearranged ALL ZNF384-Rearranged ALL PAX5-Driven BCP-ALL: PAX5alt and PAX5 P80R Other Subtypes of BCP-ALL Relapsed ALL Summary References Chapter 2: Genetic Mechanisms in T-Cell Acute Lymphoblastic Leukemia T-Cell Lymphoblastic Leukemia: Clinical and Biological Features Oncogenic NOTCH1 in T-ALL Genetic Disruption of Cell Cycle Control T-ALL Transcription Factor Oncogenes Transcription Factor and Epigenetic Tumor Suppressors Mutational Activation of Oncogenic Signaling Pathways Association of Genetic Mutations and Chromosomal Rearrangements with Transcriptional and Biological Groups of T-ALL References Chapter 3: Minimal Residual Disease in Acute Lymphoblastic Leukemia: Techniques and Application Introduction Concept of MRD Techniques for MRD Detection Multiparametric Flow Cytometry Methodological Principles of MRD Detection by Flow Cytometry Flow Cytometry Antibody Panels Real-Time Quantitative PCR High-Throughput Next-Generation Sequencing (HTS) Comparison of Methods for MRD Detection Clinical Application of MRD Prognostic Implication of MRD MRD in Frontline Chemotherapy MRD in Pre- and Post-hematopoietic Cell Transplant MRD In Ph-Positive ALL MRD in Targeted Therapy Therapeutic Implication of MRD Practical Issues Specimen Types for MRD Testing Timing and Methods for MRD Assessment MRD Monitoring Post-remission MRD as a Surrogate Endpoint for Outcomes Summary References Part II: Therapeutics Chapter 4: Treatment of Pediatric B- and T-Cell Acute Lymphoblastic Leukemia Introduction/Epidemiology Biology B-ALL T-ALL Prognostic Factors Disease Management and Treatment Strategy CNS Therapy Adolescents and Young Adults Recurrent Disease Novel Therapies B-ALL T-ALL Late Effects Future Directions References Chapter 5: Treatment of Adult B- and T-Cell Acute Lymphoblastic Leukemia: An Overview of Current Treatments and Novel Advances Clinical Case I Risk Stratification Clinical Case I (Continued) Treatment Induction Chemotherapy Central Nervous System Prophylaxis and/or Treatment Addition of Monoclonal Antibodies for CD20+ ALL Clinical Case I (Continued) Minimal Residual Disease Consolidation/Intensification Chemotherapy Maintenance Chemotherapy Clinical Case I (Continued) Relapsed/Refractory Disease Liposomal Vincristine Clofarabine Blinatumomab Inotuzumab Ozogamicin CAR-T (Tisagenlecleucel) Venetoclax/Navitoclax Clinical Case II Approach to a Young Adult Risk Stratification Clinical Case II (Continued) Treatment Clinical Case II (Continued) Hematopoietic Stem Cell Transplant Psychosocial Support Clinical Case III Risk Stratification Upfront Treatment Relapsed/Refractory Treatment Investigational Agents Conclusion References Chapter 6: Acute Lymphoblastic Leukemia in Infants: A Distinctive, High-Risk Subtype of Childhood Acute Lymphoblastic Leukemia Introduction Biological Features Treatment Future Directions Conclusion References Chapter 7: Treatment of Elderly Patients with Acute Lymphoblastic Leukemia Introduction Epidemiology and Outcomes in Older ALL Biology of ALL in Older Adults Treatment of Ph-Negative ALL in Older Adults Treatment of Ph-Positive ALL in Older Adults Relapsed or Refractory ALL in Older Adults Allogeneic HCT for Older Adults with ALL Future Directions in the Management of Older Adults with ALL References Chapter 8: Treatment of Childhood Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia Introduction Treatment of Newly Diagnosed Pediatric Philadelphia-Positive Acute Lymphoblastic Leukemia Treatment in the Pre-Tyrosine Kinase Era Imatinib Combined with Chemotherapy Dasatinib Combined with Chemotherapy Other TKIs HSCT in First Complete Remission Prognostic Factors in Pediatric Ph+ ALL Age and Presenting Leukocyte Count Early Morphologic Response Minimal Residual Disease (MRD) IKZF1 Deletions Treatment of Relapsed Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia Summary References Chapter 9: Treatment of Adult Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia Introduction Clinical Features and Diagnosis Conventional and Genetic Risk Factors Standard Treatment for Newly Diagnosed Ph+ ALL Induction Therapy Postremission Therapy Stem Cell Transplantation Autologous SCT TKI as Post-Transplant Maintenance Minimal Residual Disease Kinase Domain Mutations Selecting the Best TKI Combining TKI with Immunooncology Agents Salvage Therapy Summary and Conclusions References Chapter 10: Treatment of Ph-Like Acute Lymphoblastic Leukemia Definition of Ph-Like ALL Biology and Genomic Landscape of Ph-Like ALL JAK-STAT Pathway Gene Alterations ABL Class Alterations Ras Pathway Mutations Rare Kinase Fusions Epidemiology and Clinical Picture of Ph-Like ALL Diagnostic Modalities and Clinical Workflow Algorithms for Ph-Like ALL Precision Medicine Trials in Ph-Like ALL Targeted Therapies Hematopoietic Stem Cell Transplantation Antibody-Based and Cellular Immunotherapy Conclusions and Future Perspectives References Chapter 11: Prophylaxis and Treatment of Central Nervous System (CNS) Acute Lymphoblastic Leukemia Introduction Diagnosis of CNS Disease in Patients with ALL Risk-Stratified Treatment of CNS Disease Methods of Initial CNS Prophylaxis and Treatment Cranial Radiation Therapy Systemic Chemotherapy Corticosteroids High-Dose Methotrexate and/or High-Dose Cytarabine Intensive Asparaginase Thiopurines Ifosfamide Nelarabine Intrathecal Chemotherapy Refractory CNS Disease and CNS Relapse New Therapeutic Approaches and Potential for CNS Treatment Conclusion References Chapter 12: Late Effects of Therapy of Acute Lymphoblastic Leukemia Introduction The Toxicity Scenario Pattern of Late Effects Severe Toxicity Free Survival Late Deaths Second Malignant Neoplasm The Overall Burden of Antileukemic Therapy Endocrine Late Effects Growth Thyroid Dysfunction Metabolic Syndrome Puberty and Fertility Male Females Bone Morbidity Osteoporosis Osteonecrosis Teeth Neurotoxicity Neurocognitive Effects Peripheral Neuropathy Cardiovascular Late Effects Pulmonary Late Effects Immune Reconstitution Cellular Aging Leukemia Predisposition Common Germline DNA Variants Patient and Society Quality of Life (QoL) Conclusion and Future Research References Part III: New and Existing Modalities of Therapy Chapter 13: Monoclonal Antibody-Based Treatment and Other New Agents for B-Lineage Acute Lymphoblastic Leukemia Introduction Monoclonal Antibody-Based Treatment CD19-Directed Therapy Blinatumomab Mechanism of Action Treatment-Specific Adverse Effects Administration Clinical Trial Results Mechanisms of Resistance Future Directions Additional CD19 Targeted Approaches CD22-Directed Therapy Inotuzumab Ozogamicin Mechanism of Action Treatment-Specific Adverse Effects Administration Clinical Results Mechanisms of Resistance Future Directions Additional CD22 Targeted Approaches CD20-Directed Therapy Other Pre-B-ALL Monoclonal Targets New Cytotoxic and Non-immunomodulatory Agents for B-Lineage ALL (Fig. 13.3) Cytotoxic Epigenetic Modifiers Other Targetable Pathways Conclusion: The Future of B-ALL Therapy References Chapter 14: New Agents for the Treatment of T-Cell Acute Lymphoblastic Leukemia Introduction and Overview of the Treatment of T-Cell Acute Lymphoblastic Leukemia Overview of the Biology of T-ALL Review of Novel Agents by Type/Class Notch Jak/Stat MAPK/Ras PI3K/AKT/mTOR D-Type Cyclins and Cyclin-Dependent Kinases Ubiquitin-Proteasome Pathway BCL-2 Apoptotic Machinery Epigenetic Targeting BRD4/MYC Tyrosine Kinase Inhibitors Immunotherapy Nelarabine Other Agents Conclusion References Chapter 15: The Development and Management of Treatment with Chimeric Antigen Receptor T Cell (CAR T) Introduction to CAR T Cell Therapy Validated Targets in B-ALL Clinical Trial Insights Approaches to Overcoming Barriers to Therapeutic Efficacy Universal Products Advances in Manufacturing Platforms Identification of Risk Factors for Lack of Response Overcoming Antigen Loss Promoting Long-Term Persistence CAR T Cell Therapy Indications and Role of Consolidation Therapy Toxicity and Management of Toxicity Cytokine Release Syndrome Neurotoxicity Infectious Complications Conclusions References Chapter 16: Hematopoietic Stem Cell Transplantation in Adults with Acute Lymphoblastic Leukemia Introduction Current Indications for HSCT in ALL HSCT Outcomes in Adults with ALL Transplantation Versus Chemotherapy Transplantation in CR1 Transplantation After Pediatric-Inspired Chemotherapy Transplantation in CR2 HSCT for Refractory Disease Philadelphia Chromosome-Positive ALL T-Cell ALL Factors Impacting Outcomes of HSCT for ALL Preparative Regimen Conditioning Intensity Donor Source Matched Sibling Donor vs Unrelated Donor Alternative Donor Sources Umbilical Cord Blood Haplo-Identical Related Donor KIR Typing Minimal Residual Disease Pre-Transplant Consolidation Strategy Post-Transplant Prophylaxis Ph-Positive ALL Ph-Negative ALL CNS Prophylaxis HSCT and the Use of Novel Therapies for ALL Blinatumomab CAR T-Cell Therapy Inotuzumab Ozogamicin Future of HSCT for ALL References Chapter 17: Hematopoietic Stem Cell Transplantation in Pediatric Acute Lymphoblastic Leukemia History of HSCT in Pediatric ALL Current Indication for HSCT in Pediatric ALL Criteria for HSCT in Pediatric ALL in CR1 MRD-Positive ALL-CR1 Philadelphia Chromosome-Positive (Ph+) ALL BCR-ABL-Like ALL Hypodiploid ALL Infant ALL Mixed-Phenotype Acute Leukemia (MPAL) Induction Failure Criteria for HSCT in Pediatric ALL in CR ≥2 The Role of HSCT in Treatment of Relapsed T-ALL The Role of HSCT in Treatment of Extramedullary Relapse The Role of Second HSCT for Relapsed ALL Factors Impacting Outcomes of HSCT in ALL Preparative Regimen Donor Type and Graft Source The Impact of Pre-HSCT MRD on HSCT in ALL GvHD and GVL Effect Post-Transplant Prophylaxis CNS Prophylaxis Long-Term Outcomes of HSCT HSCT in Era of CAR-T Cell Therapy Future of HSCT in ALL References Index