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.
Author(s): Mark R. Litzow, Elizabeth A. Raetz
Publisher: Springer
Year: 2021
Language: English
Pages: 448
City: Cham
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
