Pathogenesis and Treatment of Leukemia

Contents
1: Basic Hematopoiesis and Leukemia Stem Cells
	1.1	 Introduction
	1.2	 Hematopoietic Stem and Progenitor Cells
		1.2.1	 Hematopoietic Stem and Progenitor Cell Heterogeneity
		1.2.2	 Lineage Commitment from the Hematopoietic Stem and Progenitor Cell
	1.3	 Hematopoietic Stem and Progenitor Cell Assays
		1.3.1	 Phenotypic Characterization
		1.3.2	 Colony Forming Unit (CFU) and Long-Term Culture-Initiating Cell (LT-CIC) Assays
		1.3.3	 Xenotransplantation Studies
	1.4	 Hematopoietic Stem and Progenitor Cell Expansion
	1.5	 Aging Hematopoiesis, Including Telomeres
		1.5.1	 Influence of Aging on Hematopoiesis
		1.5.2	 Telomeres in Hematopoiesis
	1.6	 Leukemic Stem Cells
	References
2: Modern Classification of Acute and Chronic Leukemias: Integrating Biology, Clinicopathologic Features, and Genomics
	2.1	 Introduction
	2.2	 Myeloproliferative Neoplasms (MPN)
	2.3	 Myeloid/Lymphoid Neoplasms with Eosinophilia and Tyrosine Kinase Gene Fusions (MLN-TK)
	2.4	 Mastocytosis
	2.5	 Myelodysplastic/Myeloproliferative Neoplasms
	2.6	 Myelodysplastic Syndromes or Myelodysplastic Neoplasms (MDS)
	2.7	 Acute Myeloid Leukemia
	References
3: Molecular Techniques in the Diagnosis and Monitoring of Acute and Chronic Leukaemias
	3.1	 Introduction
	3.2	 Short-Read NGS
	3.3	 General Principles of NGS
	3.4	 DNA Sequencing
		3.4.1	 Principles of NGS Assay Design
			3.4.1.1	 Panel Selection
			3.4.1.2	 Gene Selection in Panel Sequencing
			3.4.1.3	 Considerations of Variant Types During Panel Design
		3.4.2	 Bioinformatic Analysis for Variant Detection
			3.4.2.1	 Pre-processing Procedures
			3.4.2.2	 Variant Calling for SNVs and Short Indels
			3.4.2.3	 Variant Annotation
			3.4.2.4	 Variant Calling for Long Indels
			3.4.2.5	 Detection of CNVs at the Gene Level
		3.4.3	 Specific Applications of DNA Sequencing Strategies in Leukaemias
			3.4.3.1	 Molecular Consensus Sequencing for Detection of Subclonal or Rare Variants
			3.4.3.2	 Evaluation of Immunoglobulin/T-Cell Receptor Genes
	3.5	 RNA Sequencing
		3.5.1	 Principles of Assay Design
		3.5.2	 Bioinformatic Considerations for RNA Sequencing
	3.6	 Molecular Monitoring of Measurable Residual Disease
	3.7	 Real-Time Quantitative PCR
		3.7.1	 Principles
		3.7.2	 MRD Monitoring in CML
		3.7.3	 RQ-PCR Monitoring in Other Leukaemias
	3.8	 Digital PCR
		3.8.1	 Principles
		3.8.2	 Considerations on Analytical Sensitivity in DPCR
	3.9	 Gene Expression Profiling
	3.10	 Brief Review of GEP Platforms
	3.11	 Clinical Applications of GEP in Leukaemias
	3.12	 Newer Techniques
		3.12.1	 Long-Read Sequencing
		3.12.2	 Single-Cell Sequencing
		3.12.3	 Optical Mapping
		3.12.4	 Circulating Tumour DNA Testing in Leukaemia
	3.13	 Conclusion
	References
4: Flow Cytometric Techniques in the Diagnosis and Monitoring of Acute Leukaemias
	4.1	 Introduction
	4.2	 Flow Cytometry in the Diagnosis of Acute Leukaemia
	4.3	 Minimal Residual Disease Monitoring
		4.3.1	 Flow Cytometry in ALL MRD
		4.3.2	 Flow Cytometry in AML MRD
		4.3.3	 Technical Considerations in Flow Cytometric MRD
	4.4	 Minimal Residual Disease Studies in Acute Lymphoblastic Leukaemia
		4.4.1	 MRD Assessment in Childhood ALL
		4.4.2	 MRD Assessment in Adult ALL
		4.4.3	 MRD Assessment in Hematopoietic Stem Cell Transplant for ALL
		4.4.4	 MRD Assessment in Relapse ALL
	4.5	 Minimal Residual Disease in Acute Myeloid Leukaemia
		4.5.1	 MRD Assessment in Adult AML
		4.5.2	 MRD Assessment in Paediatric AML
		4.5.3	 MRD Assessment in Hematopoietic Stem Cell Transplant for AML
		4.5.4	 MRD Assessment in Post Remission AML
	4.6	 Conclusion
	References
5: Genomic Landscape and Risk Stratification of Acute Myeloid Leukemia
	5.1	 Classification of AML Changes and Advances in Biological Techniques
	5.2	 Genomic Landscape in AML
	5.3	 Mutations That Lead to Leukemia Cell Survival and Proliferation
		5.3.1	 FLT3 Mutations
		5.3.2	 RAS Mutations
		5.3.3	 KIT Mutations
		5.3.4	 PTPN 11 Mutations
		5.3.5	 JAK2 Mutations
	5.4	 Mutations That Impair Hematopoietic Cell Differentiation
		5.4.1	 CEBPA Mutations
		5.4.2	 AML1/RUNX1 Mutations
	5.5	 Mutations Involving NPM1
		5.5.1	 NPM1 Mutations
	5.6	 Mutations in Tumor Suppressor Genes
		5.6.1	 TP53 Mutations
		5.6.2	 WT1 Mutations
	5.7	 Mutations in Genes Related to DNA Methylation
		5.7.1	 DNMT3A Mutations
		5.7.2	 IDH Mutations
		5.7.3	 TET2 Mutations
	5.8	 Mutations of Genes Related to Histone Modification
		5.8.1	 ASXL1 Mutations
		5.8.2	 KMT2A-Rearrangement
			5.8.2.1	 KMT2A Fusion Protein
			5.8.2.2	 KMT2A/PTD
		5.8.3	 EZH2 Mutations
	5.9	 Mutations Involving Splicing Complex Factor Genes
		5.9.1	 Splicing Factor Mutations
	5.10	 Mutations Involving Cohesin Complex Genes
		5.10.1	 Cohesin Mutations
	5.11	 Conclusion
	References
6: Frontline Management of Acute Myeloid Leukaemia Eligible for Intensive Chemotherapy
	6.1	 Intensive Chemotherapy in AML: A Historical Perspective
	6.2	 Intensifying Induction Chemotherapy: Looking beyond ‘DA’
		6.2.1	 Optimising Cytarabine
		6.2.2	 Optimising Anthracyclines
	6.3	 Three Drug Combinations
		6.3.1	 Etoposide
		6.3.2	 Purine Analogues
	6.4	 Gemtuzumab Ozogamicin (GO, GO)
	6.5	 Modulators of Chemotherapy
	6.6	 Post-Remission Strategies in AML: Consolidation and Maintenance
		6.6.1	 Consolidation-Intensity: A Determinant of Outcomes
	6.7	 Identifying the Standard for Intensive Consolidation
		6.7.1	 High-Dose Cytarabine: Studies Defining the ‘Optimal’ Dose in Consolidation
		6.7.2	 Defining the Optimal Drug Combination
		6.7.3	 Defining the Optimal Number of Consolidation Courses
		6.7.4	 Consolidation Therapy in Older patients
		6.7.5	 Maintenance Therapy
		6.7.6	 Risk-Adapting Intensive Therapy in AML
		6.7.7	 Intensive Combinations and ‘Actionable’ Genetic Sub-Types of AML
		6.7.8	 Intensive Drug-Delivery Platforms for Secondary AML
	6.8	 Measurable Residual Disease (MRD)-Adapted Therapy: Genetic-MRD-Based Strategies
	6.9	 Measurable Residual Disease (MRD)-Adapted Therapy: Multi-Parametric Flow-Cytometry (MFC)-MRD-Based Strategies
	6.10	 Too Early to Draft the Obituary for IC?
	References
7: Frontline Management of Elderly Acute Myeloid Leukemia Ineligible for Intensive Treatment
	7.1	 Introduction
	7.2	 Diagnosis and Risk Classification
	7.3	 Definition of “Ineligible”
	7.4	 Frontline Therapeutic Strategies
		7.4.1	 Venetoclax Plus HMAs
		7.4.2	 Venetoclax Plus LDAC
		7.4.3	 Glasdegib Plus LDAC
	7.5	 Therapeutic Strategies in Specific Molecular Subsets
		7.5.1	 AML with NPM1 Mutations
		7.5.2	 AML with FLT3 Mutations
		7.5.3	 AML with IDH Mutation
		7.5.4	 AML with TP53 Mutations
	7.6	 Post-Remission Therapy
	7.7	 Supportive Care
	7.8	 Conclusions and Prospects
	References
8: Management of Acute Myeloid Leukemia with Myelodysplasia-Related Changes and Therapy-Related Acute Myeloid Leukemia
	8.1	 Introduction
	8.2	 Diagnosis of AML-MRC and T-AML
	8.3	 Treatment of AML-MRC and T-AML
		8.3.1	 Intensive Chemotherapy
			8.3.1.1	 CPX-351
			8.3.1.2	 Combination Therapy
		8.3.2	 Treatment Options for Chemotherapy-Ineligible Patients
			8.3.2.1	 Hypomethylating Agent Monotherapy
			8.3.2.2	 Venetoclax-Based Combinations
			8.3.2.3	 Single-Agent Targeted Therapies
			8.3.2.4	 Glasdegib
	8.4	 Future Directions
	8.5	 Conclusion
	References
9: Management of Relapsed or Refractory AML
	9.1	 Young or Fit Patients with Relapsed or Refractory AML with Salvage Chemotherapy
	9.2	 Relapsed or Refractory FLT3-Mutated AML
	9.3	 Relapsed or Refractory IDH1 or IDH2-Muated AML
	9.4	 Nonintensive Approach in Unfit Patients
	9.5	 Relapse After Allogeneic HSCT
	References
10: The Role of BCL-2/MCL-1 Targeting in Acute Myeloid Leukemia
	10.1	 Role of the BCL-2 Family of Proteins in Apoptosis
	10.2	 Role of BCL-2 in AML
		10.2.1	 Oblimersen
		10.2.2	 Obatoclax
		10.2.3	 ABT-737/ABT-263 (Navitoclax)
		10.2.4	 Venetoclax
			10.2.4.1	 Venetoclax Monotherapy in Relapsed/Refractory Patients
			10.2.4.2	 Venetoclax + Hypomethylating Agents (HMA) in Treatment-Naïve Patients
			10.2.4.3	 Venetoclax + Low Dose Cytarabine in Treatment-Naïve Patients
			10.2.4.4	 Venetoclax + HMA/LDAC in Relapsed/Refractory Patients
	10.3	 Current Clinical Trials of Venetoclax in AML
		10.3.1	 Venetoclax + Intensive Chemotherapy
		10.3.2	 Venetoclax + FLT3 Inhibitors
		10.3.3	 Venetoclax + IDH1/2 Inhibitors
		10.3.4	 Venetoclax + JAK Inhibitors (Ruxolitinib)
		10.3.5	 Venetoclax + MCL-1 Inhibitors
		10.3.6	 Venetoclax + MDM2 Inhibitors
	10.4	 Role of MCL-1 in AML
		10.4.1	 MCL-Inhibitors
	10.5	 Resistance Mechanisms to BCL-2 Inhibitors
		10.5.1	 Increased Expression of MCL-1
		10.5.2	 Dysregulation of Mitochondrial Energy Metabolism
		10.5.3	 Disruption of Mitochondrial Architecture
	10.6	 Conclusion
	References
11: Role of IDH1/IDH2 Inhibitors in AML
	11.1	 IDH Inhibitors
	11.2	 IDH1 Inhibitors
	11.3	 IDH2 Inhibitors
	11.4	 IDH1/2 Inhibitors
	References
12: Next-Generation FLT3 Inhibitors for the Treatment of FLT3-Positive AML
	12.1	 Introduction
	12.2	 First-Generation FLT3 Inhibitors
	12.3	 Second/Next-Generation FLT3 Inhibitors
	12.4	 Other Novel FLT3 Inhibitors
	References
13: Allogeneic Hematopoietic Stem Cell Transplantation for AML
	13.1	 Introduction
	13.2	 The Indication of Allogeneic Stem Cell Transplantation in AML
		13.2.1	 Risk Stratification of AML
			13.2.1.1	 Characteristics at Diagnosis (Pretreatment Factors)
			13.2.1.2	 MRD-Based Risk Stratification (Posttreatment Factors)
		13.2.2	 Evaluation of Risk of Transplant-Related Mortality
		13.2.3	 The Use of Allo-SCT in AML
			13.2.3.1	 AML with Poor-Risk in CR1
			13.2.3.2	 AML with Intermediate Risk in CR1
			13.2.3.3	 AML with Favorable Risk in CR1
			13.2.3.4	 Allo-HSCT in AML with CR2 or Beyond
			13.2.3.5	 Allo-HSCT in Refractory/Relapsed AML
		13.2.4	 Summary of Indication
	13.3	 Transplant-Related Strategies
		13.3.1	 Donor Selection
		13.3.2	 Conditioning Regimen
		13.3.3	 Graft Source
	13.4	 Prevention of Relapse
		13.4.1	 Pretransplantation Strategies
		13.4.2	 Posttransplant Strategies
			13.4.2.1	 Maintenance Therapy (Targeted Drug, HMAs)
			13.4.2.2	 MRD Guided Preemptive Therapy
	13.5	 Conclusion and Perspectives
	References
14: Maintenance Therapy Following Allogeneic Hematopoietic Stem Cell Transplantation in Acute Myeloid Leukemia
	14.1	 Introduction
	14.2	 Targeted Drugs
		14.2.1	 FLT3 Inhibitors
		14.2.2	 Monoclonal Antibodies
	14.3	 Epigenetic Drugs
	14.4	 Checkpoint Inhibitors
		14.4.1	 CTLA-4 Inhibitors
		14.4.2	 PD-1/PD-L1 Inhibitors
	14.5	 Cellular Therapy
		14.5.1	 Donor Lymphocyte Infusion (DLI)
		14.5.2	 NK Cell Infusion
		14.5.3	 γδ T Cells
		14.5.4	 CAR T Cells
		14.5.5	 TCR-T Cells
	14.6	 Perspectives
	References
15: Immunotherapeutic Targeting of AML
	15.1	 Introduction
	15.2	 Mechanisms of Immune Escape
	15.3	 Monoclonal Antibodies
		15.3.1	 Anti-CD33 Monoclonal Antibodies
		15.3.2	 Anti-CD123 Monoclonal Antibodies
		15.3.3	 Other Monoclonal Antibodies Targets
	15.4	 Adoptive Cellular Therapy
		15.4.1	 Chimeric Antigen Receptor T Cells (CAR T Cells)
		15.4.2	 Antigen-Specific Cytotoxic T Cells
		15.4.3	 Adoptive NK Cell Therapy
	15.5	 Bispecific Antibodies
		15.5.1	 CD33 Targeted Bispecific Antibodies
		15.5.2	 CD123 Targeted Bispecific Antibodies
		15.5.3	 Other Bispecific Antibody Approaches
	15.6	 Checkpoint Inhibitors
	15.7	 Vaccine Therapy for AML
	15.8	 Conclusion
	References
16: In the Pipeline: Emerging Therapy for Acute Myeloid Leukaemia
	16.1	 Introduction
	16.2	 Novel Chemotherapeutic Formulations
		16.2.1	 CPX-351
	16.3	 Targeting Tyrosine Kinases
		16.3.1	 FLT3 Inhibitors
		16.3.2	 c-KIT Inhibitors
		16.3.3	 AXL Inhibitors
		16.3.4	 c-MET Inhibitors
		16.3.5	 SYK Inhibitors
		16.3.6	 BTK Inhibitors
		16.3.7	 SFK Inhibitors
	16.4	 Targeting the Hedgehog Pathway
		16.4.1	 Smo Inhibitors
		16.4.2	 GLI Inhibitors
	16.5	 Targeting Apoptotic Pathways
		16.5.1	 BCL-2 Family Inhibitors
		16.5.2	 Bcl-2 Inhibitors
			16.5.2.1	 Bcl-2/Bcl-xL Dual Inhibitors
			16.5.2.2	 MCL-1 Inhibitors
		16.5.3	 TRAIL Inducers
	16.6	 Targeting the TP53 Pathway
		16.6.1	 Mutant TP53 Inhibitors
		16.6.2	 MDM2 Inhibitors
	16.7	 Targeting the PI3K/AKT/mTOR Pathway
	16.8	 Targeting Metabolic Pathways
		16.8.1	 IDH1/2 Inhibitors
		16.8.2	 Oxidative Phosphorylation Inhibitors
		16.8.3	 Fatty Acid Oxidation Inhibitors
	16.9	 Targeting the Proteasome
		16.9.1	 Proteasome Inhibitors
		16.9.2	 NAE Inhibitors
	16.10	 Targeting Nuclear Transport
		16.10.1	 XPO1 Inhibitors
	16.11	 Targeting Epigenetic Pathways
		16.11.1 Hypomethylating Agents
		16.11.2 HDAC Inhibitors
		16.11.3 LSD1 Inhibitors
		16.11.4 BET Inhibitors
		16.11.5 TET Inhibitors
		16.11.6 Menin-MLL Inhibitors
		16.11.7 DOT1L Inhibitors
		16.11.8 EZH Inhibitors
		16.11.9 PRMT Inhibitors
	16.12	 Targeting DNA Damage Response Pathways
		16.12.1 PARP Inhibitors
		16.12.2 ATR Inhibitors
		16.12.3 ATM Inhibitor
		16.12.4 CHK Inhibitors
		16.12.5 WEE1 Inhibitors
	16.13	 Targeting the Cell Cycle
		16.13.1 CDK Inhibitors
		16.13.2 Aurora Kinase Inhibitors
		16.13.3 PLK Inhibitors
		16.13.4 CDC25 Inhibitors
		16.13.5 RSK Inhibitor
	16.14	 Targeting the Bone Marrow Microenvironment
		16.14.1 SDF1/CXCR4 Inhibitors
		16.14.2 E-Selectin Inhibitors
	16.15	 Immunotherapy
		16.15.1 Antibody-Based Immunotherapies
			16.15.1.1	 Antibody-Drug Conjugates
				Anti-CD33 ADJs
				Anti-CD123 ADJs
			16.15.1.2	 Radioimmunotherapy
		16.15.2 T-Cell-Based Immunotherapies
			16.15.2.1	 Immune-Related Adverse Events
			16.15.2.2	 Immune Checkpoint Inhibitors
				PD-1/PD-L1 Inhibitors
				CTLA-4 Inhibitors
				TIM-3 Inhibitors
				CD47 Inhibitors
			16.15.2.3	 Targeting Co-Stimulatory Pathways
				OX40 Agonists
			16.15.2.4	 Multivalent Antibody Therapies
				Non-IgG like Multivalent Antibodies
					BiTE
					Dart
				IgG-Like Multivalent Antibodies
			16.15.2.5	 Chimeric Antigen Receptor T Cells Therapy
		16.15.3 NK Cell-Based Immunotherapies
			16.15.3.1	 Unconjugated Antibodies
			16.15.3.2	 CAR-NK Cells Therapy
		16.15.4 Vaccination
	16.16	 Conclusion
	References
17: Frontline Management of Acute Promyelocytic Leukemia
	17.1	 Introduction
	17.2	 Early Deaths in Newly Diagnosed APL: The Major Predictor of Outcome in APL
	17.3	 Principles of Initial Management and Supportive Care for APL
	17.4	 Arsenic Trioxide (Intravenous or Oral) Plus All-Trans Retinoic Acid: The Preferred Frontline Induction Regimen for All Patients with Newly Diagnosed APL
	References
18: Management of Relapsed Acute Promyelocytic Leukemia and the Role of Hematopoietic Stem Cell Transplantation
	18.1	 Introduction
	18.2	 HSCT for APL in the Pre-ATO and Post-ATO Era
	18.3	 Oral Arsenic Trioxide-based Consolidation and Remission of CR2 Instead of HSCT
	References
19: Genomic Landscape of Acute Lymphoblastic Leukemia (ALL): Insights to Leukemogenesis, Prognostications, and Treatment
	19.1	 Introduction
	19.2	 World Health Organization (WHO) Classification of ALL
		19.2.1 Aneuploidy
		19.2.2 Intrachromosomal Amplification of Chromosome 21 (iAMP21)
		19.2.3 Gene Translocation
	19.3	 Ph-Like ALL
		19.3.1 Role of Lymphoid Transcription Factor IKAROS in Ph-Like ALL
		19.3.2 CRLF2 Rearrangement
		19.3.3 ABL Gene Rearrangement
		19.3.4 Rearrangement of JAK2 and EPOR
		19.3.5 Other Kinase Fusion
		19.3.6 Diagnostic Approach of Ph-Like ALL
	19.4	 Other New Subtypes of B-ALL
		19.4.1 ETV6-RUNX1-Like ALL
		19.4.2 DUX4-Rearranged ALL
		19.4.3 Alterations in Transcription Factors
		19.4.4 TCF-HLF Fusion
		19.4.5 B-Other ALL
			19.4.5.1	 IGH Rearrangement
			19.4.5.2	 NUTM1 Rearrangement
			19.4.5.3	 PAX5-Driven Subtypes
	19.5	 Genomic Landscape of T Lymphoblastic Leukemia (T-ALL)
		19.5.1 Oncogenic NOTCH1 Signaling Pathway
		19.5.2 Cell Cycle Regulator Mutations
		19.5.3 Aberrations in Transcription Factor Genes
			19.5.3.1	 bHLH and LMO Transcription Factors
			19.5.3.2	 HOX Transcription Factor
			19.5.3.3	 Other Transcription Factors Aberrations
		19.5.4 Aberrations in Epigenetic Regulators
			19.5.4.1	 PHF6
			19.5.4.2	 Other Epigenetic Regulators
		19.5.5 Aberrations in Oncogenic Signaling Pathway
		19.5.6 Mutations of Genes of Ribosomal Proteins
		19.5.7 Genomic Landscape of ETP-ALL
		19.5.8 Genetic Aberrations in Transcription Factors in ETP-ALL
		19.5.9 Molecular Mechanism of Gene Arrangement in Leukemogenesis of ETP-ALL
		19.5.10 Activating Mutations in IL7R in ETP-ALL
		19.5.11 Mutations in Epigenetic Regulators and Leukemogenesis of ETP-ALL
		19.5.12 Challenges and Future Perspectives
	References
20: Management of Adolescent and Young Adults with Acute Lymphoblastic Leukaemia
	20.1	 Introduction
	20.2	 Genetic Subtypes of ALL in AYA
	20.3	 Immunophenotyping of ALL in AYA
	20.4	 Risk Stratification in ALL
	20.5	 Reports of Traditional Adult ALL Protocols and Paediatric-Inspired ALL Protocols
	20.6	 Ph-Positive ALL
	20.7	 Relapsed ALL in AYA
	20.8	 New Treatment
	20.9	 Management Issues in AYA Patients Receiving Paediatric-Inspired Protocols
	References
21: Management of Older Patients with Acute Lymphoblastic Leukemia
	21.1	 Introduction
	21.2	 Philadelphia Chromosome (Ph) Negative ALL
	21.3	 Ph-positive ALL
	21.4	 Allogeneic Transplantation
	21.5	 Targeted Therapies
	21.6	 Closing Remarks
	References
22: Management of Philadelphia Chromosome-positive Acute Lymphoblastic Leukaemia
	22.1	 Introduction
		22.1.1	 Definition, Background, and Incidence
		22.1.2	 Molecular Biology
		22.1.3	 Chronic Myeloid Leukaemia with Lymphoid Blast Crisis
	22.2	 Diagnosis, Monitoring, and Minimal Residual Disease
		22.2.1	 Diagnosis
		22.2.2	 Monitoring Response and Minimal Residual Disease
	22.3	 Therapy for Newly Diagnosed Disease
		22.3.1	 Tyrosine Kinase Inhibitor Overview
			22.3.1.1	 Which Tyrosine Kinase Inhibitor Is Preferred in Frontline Treatment?
			22.3.1.2	 Tyrosine Kinase Inhibitor Resistance, BCR-ABL1 Mutations, and Mutation Analysis
			22.3.1.3	 Central Nervous System Penetration of Tyrosine Kinase Inhibitors
		22.3.2	 Chemotherapy + Tyrosine Kinase Inhibitor Regimens
			22.3.2.1	 Paediatrics
			22.3.2.2	 Adults
			22.3.2.3	 Older Adults
		22.3.3	 Stem Cell Transplantation
			22.3.3.1	 Who Needs Stem Cell Transplantation?
			22.3.3.2	 Optimisation of Disease Prior to SCT
			22.3.3.3	 Role of TKI Post-SCT?
	22.4	 Therapy for Relapsed/Refractory Disease
		22.4.1	 Ponatinib
		22.4.2	 Asciminib
		22.4.3	 Blinatumomab
		22.4.4	 Inotuzumab Ozogamicin
	22.5	 Future Directions and the Unknown
	References
23: Management of Philadelphia Chromosome-Like Acute Lymphoblastic Leukemia (Ph-Like ALL)
	23.1	 Definition of Ph-Like ALL
	23.2	 Biology and Genomic Landscape of Ph-Like ALL
		23.2.1	 JAK/STAT Pathway Gene Alterations
		23.2.2	 ABL Class Alterations
		23.2.3	 Ras Pathway Mutations
		23.2.4	 Rare Kinase Fusions
	23.3	 Epidemiology and Clinical Picture of Ph-like ALL
	23.4	 Diagnostic Modalities and Clinical Workflow Algorithms for Ph-Like ALL
	23.5	 Precision Medicine Trials in Ph-Like ALL
		23.5.1	 Targeted Therapies
		23.5.2	 Hematopoietic Stem Cell Transplantation
		23.5.3	 Antibody-Based and Cellular Immunotherapy
	23.6	 Conclusions and Future Perspectives
	References
24: Allogeneic Hematopoietic Stem Cell Transplantation for Acute Lymphoblastic Leukemia
	24.1	 Introduction
	24.2	 Indication of Allo-HSCT for ALL
		24.2.1	 High-Risk ALL in First Complete Remission
		24.2.2	 Standard-Risk Ph-Negative ALL in First Complete Remission
		24.2.3	 Minimal Residual Diseases for Transplant Decision
		24.2.4	 Pediatric ALL in First Complete Remission
		24.2.5	 ALL Beyond CR1
	24.3	 Donor Selection
		24.3.1	 Matched Sibling Donors (MSDs) and Unrelated Donors (URDs) in ALL
		24.3.2	 Haploidentical Donor in ALL
	24.4	 Outcomes of ALL Following Allo-HSCT
		24.4.1	 MRD Before Transplant
		24.4.2	 Conditioning Regimen
		24.4.3	 Risk Assessment for Patients Undergoing Allo-HSCT
	24.5	 Prophylaxis and Prevention of Relapse Post-Transplant
		24.5.1	 Maintenance with Target Drugs
		24.5.2	 MRD-Guided Pre-Emptive Therapy
		24.5.3	 Therapy Post-Relapse
	24.6	 Impact of New Immunotherapeutic Agents on Allo-HSCT
		24.6.1	 CAR-T May Broaden the Indications of Allo-HSCT in R/R ALL Patients
		24.6.2	 CAR-T in Relapse Post-Allo-HSCT
		24.6.3	 CAR-T Therapy Challenges to Allo-HSCT Indications
	24.7	 Conclusion and Perspectives
	References
25: Immunotherapy for ALL
	25.1	 Overview
	25.2	 CAR-T Therapy
		25.2.1	 Overview of CAR-T Cell Therapy
		25.2.2	 Current Status of CAR-T Cell Therapy in ALL
		25.2.3	 Modification of CAR-T Cell Therapy
		25.2.4	 Application of Allogeneic CAR-T Cell Therapy
		25.2.5	 Challenges of CAR-T Cell Therapy
	25.3	 Bispecific T-Cell-Engaging (BiTE) Antibody
	25.4	 Antibody–Drug Conjugate (ADC)
	25.5	 Natural Killer (NK) Cells
	25.6	 Donor Leukocyte Infusion (DLI)
	25.7	 Summary
	References
26: In the Pipeline—Emerging Therapy for ALL
	26.1	 Introduction
	26.2	 Targeting the PI3K/Akt/mTOR Pathway
		26.2.1 PI3K Inhibitors
		26.2.2 Akt Inhibitors
		26.2.3 mTOR Inhibitors
		26.2.4 Dual Inhibitors
	26.3	 Targeting the BCR-ABL1 Fusion
	26.4	 Targeting the JAK/STAT Pathway
	26.5	 Targeting the NOTCH Signaling Pathway
	26.6	 Targeting Cell Cycle Regulation
		26.6.1 Targeting Cell Cycle Promoters
		26.6.2 Targeting the Mitotic Regulators
	26.7	 Targeting the DNA Damage Response (DDR) Pathway
		26.7.1 Chk Inhibitor
		26.7.2 WEE Inhibitors
		26.7.3 Combination of Chk Inhibitors and WEE Inhibitors
	26.8	 Targeting the p53-MDM2 Pathway
	26.9	 Targeting the SYK Pathway
	26.10	 Targeting the FLT3 Signaling Pathway
	26.11	 Targeting the Wnt/β-Catenin Signaling Pathway
	26.12	 Targeting the RAS/RAF/MEK/ERK (MAPK) Pathway
	26.13	 Targeting the Autophagy Pathway
	26.14	 Targeting the Ubiquitin–Proteasome System
	26.15	 Targeting the NEDD8 Conjugation Pathway
	26.16	 Targeting the Epigenetic Regulation
		26.16.1 Histone Methylation
		26.16.2 DNA Methylation: Hypomethylating Agents (HMAs)
		26.16.3 Histone Acetylation
	26.17	 Targeting the BET Protein
	26.18	 Targeting the Mitochondrial Pathway of Apoptosis
		26.18.1 Targeting BCL-2 Family Proteins
	26.19	 Targeting Bone Marrow Microenvironment (BMM)
		26.19.1 Targeting the CXCL12/CXCR4 Axis
	26.20	 Immunotherapy
	26.21	 Naked Monoclonal Antibodies
		26.21.1 Anti-CD20 Monoclonal Antibodies
		26.21.2 Anti-CD22 Monoclonal Antibodies
		26.21.3 Anti-CD38 Monoclonal Antibodies
		26.21.4 Anti-CD52 Monoclonal Antibodies
	26.22	 Antibody–Drug Conjugates (ADCs)
		26.22.1 Anti-CD22 ADCs
		26.22.2 Anti-CD19 ADCs
		26.22.3 Anti-CD25 ADC
	26.23	 Bispecific T-Cell Engager (BiTE)
	26.24	 Chimeric Antigen Receptors (CARs)
		26.24.1 CD19 CAR-T Cells
		26.24.2 CAR-T Therapy in T-ALL
	26.25	 Immune Checkpoint Inhibitors
	26.26	 Conclusion
	References
27: Inherited/Genetic Predisposition to MDS and AML
	27.1	 Introduction
	27.2	 Germline Predisposition to Myelodysplastic Syndrome (MDS)
		27.2.1	 Deleterious Germline SAMD9 Variants (OMIM 610456, 617053, and 619041) [12, 14, 16, 17]
		27.2.2	 Deleterious Germline SAMD9L Variants (OMIM 611170, 159550, and 252270) [11, 14, 16–18]
		27.2.3	 “Adaptation by Aneuploidy” Seen in Germline SAMD9/SAMD9L Mutation Carriers (OMIM 619041) [12, 14]
		27.2.4	 Deleterious Germline GATA2 Variants (OMIM 137295, 601626, 614286, 614038, and 614172) [13, 14, 19–21]
		27.2.5	 MDS in Young Adults
	27.3	 Germline Predisposition to AML
		27.3.1	 Deleterious Germline DDX41 Variants (OMIM 608170) [1, 2, 4, 30, 31]
		27.3.2	 Deleterious Germline RUNX1 Mutations/Familial Platelet Disorder (FPD) (OMIM 151385 and 601399) [35–37]
		27.3.3	 Deleterious Germline GATA2 Variants (OMIM 137295, 601626, 614286, 614038, and 614172) [19–21, 24, 46, 47]
		27.3.4	 Deleterious Germline CEBPA Variants (OMIM 116897) [52]
	27.4	 Key Aspects of Germline Testing
		27.4.1	 Who Should Be Tested?
		27.4.2	 When Will Be Testing All Patients with a Myeloid Malignancy and Their Allogeneic Stem Cell Donors?
		27.4.3	 Use of True Germline DNA
			27.4.3.1	 Why Is It Critical to Use True Germline DNA?
			27.4.3.2	 How Do You Obtain True Germline DNA?
		27.4.4	 Use Testing That Is Comprehensive
		27.4.5	 Carefully Interpret Molecular Profiling Data from Leukemia Cells in Patients Without Significant Personal/Family Histories
	27.5	 Conclusions
	References
28: Clonal Hematopoiesis and Its Functional Implications in MDS/AML
	28.1	 Introduction
	28.2	 Clonal Hematopoiesis and Hematological Malignancies
	28.3	 Clonal Hematopoiesis and Non-hematological Diseases
	28.4	 Impact of Clonal Hematopoiesis on Cellular Therapy
	References
29: Therapy-Related MDS/AML and the Role of Environmental Factors
	29.1	 Introduction
	29.2	 Epidemiology
	29.3	 Pathogenesis
		29.3.1	 Cytotoxic Therapy
		29.3.2	 Inherited Risk Factors
			29.3.2.1	 Single-Nucleotide Polymorphisms (SNP)
			29.3.2.2	 Germline Single-Nucleotide Variants (SNV)
			29.3.2.3	 Clonal Hematopoiesis of Indeterminate Potential (CHIP)
		29.3.3	 Bone Marrow Niche: Focus on the Mesenchymal Stem Cells
	29.4	 Genetic and Cytogenetic Profile of t-MN
	29.5	 Environmental Factors
	29.6	 Clinical Characteristics and Treatment
		29.6.1	 Prognosis
		29.6.2	 Treatment
	References
30: Prognostic Indicators in MDS and CMML
	30.1	 Myelodysplastic Syndrome
		30.1.1 Introduction
		30.1.2 Classification and Prognostication of MDS (Table 30.1)
		30.1.3 Prognostic Scoring Systems in MDS
		30.1.4 International Prognostic Scoring System (IPSS)
		30.1.5 WHO Classification-Based Prognostic Scoring System (WPSS)
		30.1.6 MD Anderson General Risk Model (MDAS)
		30.1.7 MD Anderson Low-Risk Prognostic Scoring System (MDA LR-PSS)
		30.1.8 Revised International Prognostic Scoring System (IPSS-R)
		30.1.9 Prognostic Values of Different Prognostic Scoring System
		30.1.10 Limitations of Current Prognostic Scoring System
		30.1.11 The Molecular Genetics of MDS
		30.1.12 New Scoring System with Molecular Integration
	30.2	 Chronic Myelomonocytic Leukemia (CMML)
		30.2.1 Introduction
		30.2.2 Prognostic Scoring Systems in CMML
		30.2.3 Incorporation of Gene Mutations into Prognostic Models in CMML
		30.2.4 Predictive Ability of Different Prognostic Models in CMML
		30.2.5 Impact of Risk Stratification on Treatment Decision
	30.3	 Conclusion
	References
31: Treatment Algorithm of Myelodysplastic Syndromes
	31.1	 Introduction
	31.2	 Summary of Current Available Treatment Options
		31.2.1	 Treatment Options for Patients with Lower-Risk MDS
			31.2.1.1	 Erythropoiesis-Stimulating and Maturing Agents (ESAs and EMAs)
			31.2.1.2	 Lenalidomide
		31.2.2	 Treatment Options for Patients with Higher-Risk MDS
			31.2.2.1	 Hypomethylating Agents (HMAs)
		31.2.3	 Treatment Options for Patients with Hypoplastic MDS
	31.3	 Summary
	References
32: Treatment Algorithm of CMML and Other Adult MDS/MPN Subtypes
	32.1	 Introduction
	32.2	 Chronic Myelomonocytic Leukemias
		32.2.1	 Epidemiology
		32.2.2	 Presentation and Diagnosis
			32.2.2.1	 Clinical Presentation
			32.2.2.2	 Biological Presentation
			32.2.2.3	 Diagnostic Criteria
		32.2.3	 Prognostic Assessment
		32.2.4	 Treatment Algorithm
		32.2.5	 Potentially Disease-Modifying Therapies
			32.2.5.1	 Allogeneic Stem Cell Transplantation
			32.2.5.2	 Intensive Chemotherapy
			32.2.5.3	 Hypomethylating Agents
			32.2.5.4	 Targeted Therapies
			32.2.5.5	 Symptomatic Treatments
			32.2.5.6	 Management of Anemia
			32.2.5.7	 Management of Thrombocytopenia
			32.2.5.8	 Management of Neutropenia
			32.2.5.9	 Management of Auto-inflammatory Manifestations
			32.2.5.10	 Management of Myeloproliferation
			32.2.5.11	 Management of Extramedullary Manifestations
	32.3	 Atypical Chronic Myeloid Leukemia
		32.3.1	 Epidemiology
		32.3.2	 Presentation and Diagnosis
		32.3.3	 Prognosis
		32.3.4	 Treatment Algorithm
			32.3.4.1	 Patients Eligible to Allogeneic Hematopoietic Stem Cell Transplantation
			32.3.4.2	 Patients Not Eligible to Allogeneic Hematopoietic Stem Cell Transplantation
	32.4	 Myelodysplastic/Myeloproliferative Neoplasm with Ring Sideroblasts and Thrombocytosis
		32.4.1	 Epidemiology
		32.4.2	 Presentation and Diagnosis
		32.4.3	 Prognosis
		32.4.4	 Treatment Algorithm
			32.4.4.1	 Management of Anemia
			32.4.4.2	 Management of Thrombocytosis
	32.5	 MDS/MPN, Unclassifiable (MDS/MPN-U)
		32.5.1	 Epidemiology
		32.5.2	 Presentation and Diagnosis
		32.5.3	 Prognosis
		32.5.4	 Treatment Algorithm
	32.6	 Conclusion
	References
33: Novel Strategies to Manage Cytopenia in Low-Risk MDS
	33.1	 Introduction
	33.2	 Quality of Life
	33.3	 Therapy of Thrombocytopenia
	33.4	 Therapy of Anemia
	33.5	 Therapy of Neutropenia
	33.6	 Therapy of Pancytopenic MDS
	References
34: Allogeneic Hematopoietic Stem Cell Transplantation for MDS and CMML: When and How?
	34.1	 Introduction
	34.2	 Disease-Related Factors in MDS
	34.3	 Disease-Related Factors in CMML
	34.4	 Patient Factors in Both MDS and CMML
		34.4.1	 Age
		34.4.2	 Comorbidity
		34.4.3	 Performance Status
	34.5	 Donor Availability
	34.6	 Conclusion
	References
35: In the Pipeline: Emerging Therapy for MDS and MDS/MPN
	35.1	 Introduction
		35.1.1	 Myelodysplastic Syndrome
		35.1.2	 Myelodysplastic Syndrome/Myeloproliferative Neoplasm
	35.2	 Pathogenesis
		35.2.1	 Pathogenesis of MDS
		35.2.2	 Pathogenesis of MDS/MPN
	35.3	 Current Treatment and Limitations
		35.3.1	 Allogenic Haematopoietic Stem Cell Transplantation
		35.3.2	 Hypomethylating Agents
	35.4	 Novel Hypomethylating Agents
	35.5	 Molecularly Targeted Agents
		35.5.1	 Bcl-2 Targeting in MDS
		35.5.2	 Targeting Vascular Endothelial Growth Factor in MDS/MPN
		35.5.3	 Thrombopoietin Mimetics in MDS/MPN
	35.6	 Targeting Epigenetic Regulators
		35.6.1	 Isocitrate Dehydrogenase 1/2 Inhibitors
		35.6.2	 P53 Modulation in MDS
	35.7	 Multi-Kinase Inhibitors
		35.7.1	 Targeting the Ras Pathway
			35.7.1.1	 Ras Inhibitors in MDS
			35.7.1.2	 Farnesyltransferase Inhibition in MDS/ MPN
			35.7.1.3	 MEK1/2 Inhibition in MDS/MPN
		35.7.2	 Targeting JAK/STAT Pathway in MDS/ MPN
	35.8	 Immunotherapy
		35.8.1	 Targeting CD47 in MDS
		35.8.2	 Targeting T-Cell Immunoglobulin and Mucin Domain-Containing Protein 3
		35.8.3	 Targeting PD-1/PD-L1 and CTLA4
		35.8.4	 Interleukin 2 Inhibitors in MDS/MPN
		35.8.5	 Interleukin 3 Inhibition in MDS/MPN
	35.9	 Conclusion
	References
36: Molecular Landscape and Personalized Prognostic Prediction of MPNs
	36.1	 Introduction
	36.2	 Overview of Classical Ph-Negative MPNs
		36.2.1	 Polycythaemia Vera (PV) and Essential Thrombocythaemia (ET)
		36.2.2	 Myelofibrosis (MF)
	36.3	 Driver Mutations: JAK2, CALR and MPL
		36.3.1	 JAK2V617F
		36.3.2	 JAK2 Exon 12
		36.3.3	 CALR
		36.3.4	 MPL
		36.3.5	 Triple-Negative MPNs
	36.4	 Other Somatic Mutations
		36.4.1	 DNA Methylation
		36.4.2	 Histone Modification
		36.4.3	 mRNA Splicing
		36.4.4	 Signal Transduction
		36.4.5	 Transcription Regulation
	36.5	 Conclusion
	References
37: Treatment Algorithm for Polycythemia Vera
	37.1	 Background and Presentation
	37.2	 Work Up and Diagnosis
	37.3	 Risk Assessment and Treatment
	37.4	 Symptom Burden in PV
	37.5	 Thrombosis
	37.6	 Transformation to AML
	37.7	 Conclusions
	References
38: Treatment Algorithm of Essential Thrombocythemia
	38.1	 Background
	38.2	 Diagnosis
	38.3	 Management of ET
		38.3.1	 Therapeutic Goals
			38.3.1.1	 Vascular Sequelae
			38.3.1.2	 Symptom Burden
			38.3.1.3	 Disease Progression and Survival
	38.4	 Therapeutic Strategies
		38.4.1	 First-Line Cytoreductive Treatments
		38.4.2	 Therapies for Nonresponders/Intolerant of First-Line Treatments
		38.4.3	 Noncytoreductive Treatments
	38.5	 Role of Novel Agents in ET
	38.6	 Approach to Specific Scenarios
		38.6.1	 Young Patients
		38.6.2	 Triple-Negative Thrombocytosis
		38.6.3	 Pregnancy
		38.6.4	 Specific Thrombotic Events
	38.7	 Future Perspectives
	References
39: Prognostic Models for Primary and Secondary Myelofibrosis
	39.1	 Primary Myelofibrosis
	39.2	 Secondary Myelofibrosis
	References
40: Treatment Algorithm for Primary and Secondary Myelofibrosis
	40.1	 Introduction
	40.2	 Preventing Disease Transformation
		40.2.1	 Disease-Modifying Agents
	40.3	 Alleviating Debilitating Symptoms
		40.3.1	 Symptom Burdens
		40.3.2	 Symptom Control
		40.3.3	 Treatment for Anemia
	40.4	 Minimizing Treatment Toxicities
	40.5	 Proposed Treatment Algorithm
	References
41: Diagnosis and Management of Prefibrotic Primary Myelofibrosis (Pre-PMF)
	41.1	 Diagnosis of Pre-PMF
		41.1.1	 General Aspects
		41.1.2	 Morphology
	41.2	 Clinical and Laboratory Aspects
		41.2.1	 Clinical Data
		41.2.2	 Molecular and Cytogenetic Data
	41.3	 Management
		41.3.1	 General Aspects
		41.3.2	 Vascular Events
		41.3.3	 Progression to Myelofibrosis (Overt PMF)
		41.3.4	 Transformation to Blast Phase (BP) and Survival
	41.4	 Conclusion
	References
42: Interferons in Myeloproliferative Neoplasms
	42.1	 Interferons
	42.2	 Interferon Use in MPN
	References
43: JAK Inhibitors for the Management of Myeloproliferative Neoplasms
	43.1	 Introduction
	43.2	 Ruxolitinib for Myelofibrosis
	43.3	 Ruxolitinib for Polycythemia Vera
	43.4	 Ruxolitinib for Essential Thrombocythemia
	43.5	 Ruxolitinib for Rare, Atypical MPN
	43.6	 Fedratinib
	43.7	 Momelotinib
	43.8	 Pacritinib
	43.9	 Conclusions
	References
44: Allogeneic Hematopoietic Stem Cell Transplantation for Myelofibrosis: When and How?
	44.1	 When?
		44.1.1	 Disease-Specific Risk Score Models
		44.1.2	 Comparison Between Hematopoietic Stem Cell Transplant and Conventional Therapy According to Disease-Risk Models
		44.1.3	 Transplant-Specific Risk Factors and Transplant-Specific Risk Score
	44.2	 How?
		44.2.1	 Donor Selection and Stem Cell Source
		44.2.2	 Intensity of Conditioning Regimen
		44.2.3	 Splenectomy and Spleen Irradiation
		44.2.4	 JAK Inhibitor Prior to Transplantation
		44.2.5	 Minimal Residual Disease and Relapse Prevention
	References
45: Thrombosis and Myeloproliferative Neoplasms
	45.1	 MPNs and Thrombotic Risk
		45.1.1	 Clinical Risk Factors for Thrombosis
		45.1.2	 Impact of Mutational Status
	45.2	 Factors Involved in the Pathophysiology of Thrombosis Associated with MPNs
		45.2.1	 Platelets
		45.2.2	 Leukocytes
		45.2.3	 Red Blood Cells
		45.2.4	 Endothelial Cells
		45.2.5	 Plasma Factors
	45.3	 Conclusion
	References
46: Eosinophilic Disorders and Systemic Mastocytosis
	46.1	 Introduction
	46.2	 Eosinophilia and Hypereosinophilic Syndrome (HES)
	46.3	 Primary Eosinophilic Disorders
		46.3.1	 Myeloid/Lymphoid Neoplasms with Eosinophilia and Rearrangement of PDGFRA, PDGFRB, FGFR1, or PCM1-JAK2 Fusion Gene (MLN-Eo)
			46.3.1.1	 MPN with Eosinophilia Associated with FIP1L1-PDGFRA
			46.3.1.2	 Myeloid/Lymphoid Neoplasms Associated with ETV6-PDGFRB Fusion Gene or Other Rearrangement of PDGFRB
			46.3.1.3	 MPN or Acute Leukaemia Associated with FGFR1 Rearrangement
			46.3.1.4	 Myeloid/Lymphoid Neoplasms with PCM1-JAK2
		46.3.2	 Chronic Eosinophilic Leukaemia, No Otherwise Specified (CEL, NOS)
		46.3.3	 Idiopathic HES
	46.4	 Secondary Eosinophilia
	46.5	 Systemic Mastocytosis
	46.6	 Summary
	References
47: In the Pipeline: Emerging Therapy for Classical Ph-Negative MPNs
	47.1	 Introduction
	47.2	 Emerging JAK Inhibitors
		47.2.1	 Fedratinib
		47.2.2	 Pacritinib
		47.2.3	 Momelotinib
		47.2.4	 Other JAK Inhibitors
	47.3	 Targeting Haematopoietic Stem Cells (HSCs) in MPNs
		47.3.1	 Novel Interferon Preparations
		47.3.2	 Telomerase Inhibition
		47.3.3	 Targeting Epigenetic Regulators
			47.3.3.1	 Lysine-Specific Demethylase-1 (LSD1) Inhibition
			47.3.3.2	 Bromodomain and Extraterminal (BET) Protein Inhibition
			47.3.3.3	 Histone Deacetylase (HDAC) Inhibition
			47.3.3.4	 Protein Arginine Methyltransferase 5 (PRMT5) Inhibition
		47.3.4	 Induction of Pro-apoptotic Pathway
			47.3.4.1	 B-Cell Lymphoma-Extra Large (BCL-xL) Inhibition
			47.3.4.2	 Second Mitochondria-Derived Activator of Caspase (SMAC) Mimetics
			47.3.4.3	 Murine Double Minute 2 (MDM2) Inhibition
			47.3.4.4	 Exportin 1 (XPO1) Inhibition
			47.3.4.5	 Proviral Integration Site for Moloney Murine Leukaemia Virus (PIM) Kinase Inhibition
			47.3.4.6	 CD123 Inhibition
			47.3.4.7	 Heat-Shock Protein (HSP) Chaperone Inhibition
		47.3.5	 Targeting Cell Signalling Pathways
			47.3.5.1	 PI3K/AKT/mTOR Pathway Inhibition
	47.4	 Targeting of Bone Marrow Microenvironment
		47.4.1	 Depleting Cytokine Production: Transforming Growth Factor-Beta (TGF-β) Inhibition
		47.4.2	 Inducing Megakaryocyte Differentiation: Aurora a Kinase (AURKA) Inhibition
		47.4.3	 Eliminating Neoplastic Fibroblasts: Serum Amyloid P (SAP)
		47.4.4	 Promoting Neuroprotection: β-3 Sympathomimetic Agonist
	47.5	 Immunotherapy
		47.5.1	 Immune Checkpoint Inhibitor
		47.5.2	 Tumour-Specific Vaccination
	47.6	 Conclusion
	References
48: Current Guidelines and Treatment Algorithm of Chronic Myeloid Leukemia
	48.1	 Introduction
	48.2	 Clinical Presentation
	48.3	 Diagnostic Work-Up
	48.4	 Prognostic Scores
	48.5	 Monitoring Treatment Response
	48.6	 Treatment Algorithm
		48.6.1	 Initial Treatment for CML
		48.6.2	 First-Line Treatment in CP
			48.6.2.1	 Imatinib
			48.6.2.2	 2G-TKIs
			48.6.2.3	 Nilotinib
			48.6.2.4	 Dasatinib
			48.6.2.5	 Bosutinib
			48.6.2.6	 Radotinib
		48.6.3	 Choice of First-Line TKI
		48.6.4	 Resistance to and/or Intolerance of First-Line Treatment
		48.6.5	 Second-Line Treatment
		48.6.6	 First-Line Treatment in Advance Phases
	48.7	 Role of Allogeneic Hematopoietic Stem Cell Transplantation (Allo-HSCT) in CML
	References
49: Treatment-Free Remission in Chronic Myeloid Leukemia
	49.1	 Introduction
	49.2	 Deep Molecular Response (DMR)
	49.3	 Summary of the TFR Clinical Trials
		49.3.1	 Ceasing Imatinib Vs. Second-Generation TKIs
		49.3.2	 TKI De-escalation Prior to TFR Attempt
	49.4	 Molecular Monitoring in Treatment-Free Remission Attempts
	49.5	 Potential Risks of TKI Discontinuation
		49.5.1	 TKI Withdrawal Syndrome
		49.5.2	 Disease Responsiveness to Retreatment
		49.5.3	 Risk of Blast Crisis
	49.6	 Special Circumstances
		49.6.1	 Pregnancy
		49.6.2	 Paediatric CML and TFR
		49.6.3	 TKI Discontinuation after TKI Resistance or Prior Advanced Phase
		49.6.4	 Second TFR Attempts
	49.7	 Predictors of Successful TFR
		49.7.1	 Exploring the Optimal Duration of TKI Exposure and DMR Prior to TFR
		49.7.2	 Other Clinical Predictors
	49.8	 TFR in Current Guidelines
	49.9	 Summary
	References
50: Treatment Options in CML Resistant or Intolerant to Second-Generation Tyrosine Kinase Inhibitors
	50.1	 Introduction
	50.2	 CML Intolerant of Second-Generation Tyrosine Kinase Inhibitors
		50.2.1	 Haematological Toxicities
		50.2.2	 Non-haematological Toxicities
	50.3	 CML Resistant to Second-Generation Tyrosine Kinase Inhibitors
		50.3.1	 Ponatinib
		50.3.2	 Asciminib
	50.4	 Options Other than TKIs for Patients Ineligible for HSCT
		50.4.1	 Omacetaxine Mepesuccinate
		50.4.2	 TKI Plus Interferon-α Combination
	References
51: Allogeneic Hematopoietic Cell Transplantation in CML: When and How?
	51.1	 Introduction
	51.2	 Principles of Transplant and Their Application in CML
	51.3	 Current Indications for Allogenic SCT in CML
		51.3.1	 Transplant Indications and Outcomes in Chronic Phase
		51.3.2	 Transplant Outcomes in Accelerated Phase
		51.3.3	 Transplant Outcomes in Blast Phase
	51.4	 Transplant Optimisation
		51.4.1	 Pre-transplant Therapy
		51.4.2	 Optimal Conditioning Regimen
		51.4.3	 The Effect of Graft vs Leukaemia
		51.4.4	 Source of Stem Cells
	51.5	 Conclusion
	References
52: In the Pipeline: Emerging Therapy for CML
	52.1	 Introduction
	52.2	 Current Therapy for CML
		52.2.1	 TKIs
		52.2.2	 Interferon-α
	52.3	 Limitations of Current Therapeutic Options: TKI Resistance and LSCs Persistence
	52.4	 Novel Therapies
		52.4.1	 Novel Therapies that Target the Signaling Pathways in CML LSCs (Fig. 52.1)
			52.4.1.1	 Novel TKIs
			52.4.1.2	 miRNA as Direct Inhibitors of BCR-ABL
			52.4.1.3	 Inhibition of Grb2 Phosphorylation
			52.4.1.4	 Inhibition of mTOR
			52.4.1.5	 Inhibition of MNK1/2
			52.4.1.6	 Inhibition of B-Cell Lymphoma 2 (Bcl-2)
			52.4.1.7	 Inhibition of JAK2
			52.4.1.8	 PPAR-γ Agonists
			52.4.1.9	 Prostaglandin E (PGE) 1 Analogue
			52.4.1.10	 Activation of Promyelocytic Leukemia: Nuclear Bodies (PML-NB)
		52.4.2	 Targeting the Bone Marrow Microenvironment
			52.4.2.1	 Inhibition of Dipeptidyl-Peptidase (DPP-4)
			52.4.2.2	 E-Selectin Antagonist
			52.4.2.3	 Inhibition of SDF1-CXCR4
			52.4.2.4	 Inhibition of Hypoxia-Inducible Factor (HIF)
			52.4.2.5	 Inhibition of Hedgehog (Hh) Pathway
			52.4.2.6	 Inhibition of Wnt/β-Catenin Signaling
			52.4.2.7	 Re-establishment of PP2A Activity
		52.4.3	 Modulation of P53, a Key Regulatory Network
			52.4.3.1	 Inhibition of Sirtuin 1 (SIRT1)
			52.4.3.2	 Inhibition of Human Double Minute 2 Protein (HDM2)
		52.4.4	 Epigenetic Regulators
			52.4.4.1	 Inhibition of Histone Deacetylase (HDAC)
			52.4.4.2	 Inhibition of Enhancer of Zeste Homolog 2 (EZH2)
			52.4.4.3	 Inhibition of PRMT5
			52.4.4.4	 Inhibition of Bromodomain and Extra-terminal Motif (BET)
		52.4.5	 Targeting Autophagy
			52.4.5.1	 Tigecycline
			52.4.5.2	 Chloroquine and Hydroxychloroquine
		52.4.6	 Immunotherapy
			52.4.6.1	 Vaccinations
			52.4.6.2	 Immune Checkpoint Inhibitors (Fig. 52.2)
	52.5	 Conclusion
	References