The American Journal of Human Genetics, 102 (2017) 175-187. doi:10.1016/j.ajhg.2017.11.013

In the history of world religions, as a Sikh it is my belief that there is no other book on world religions that clarifies the areas of revelations and also their limitations in their manifestation on the variety of life and how they justify to establish a real history according to the new concepts of the writer. The fear of death, jealousy, and prejudice are very natural to such religions that lack the blessings of a prophet. With comparison to a complete revelation upon this globe as the Sikh Gurus and their continuous manifestations in life with unselfish kindness and sublimity of martyrdom in variety of horrible trials through our Gurus and Khalsa, which is illumined by the word in book and word in flesh of Gurus, no other religion can compete with it. The greater holy wars of Sikh Gurus and Khalsa are unsurpassable in holy wrath and immeasurable mercy in the history of world religions with comparison to especially the greater holy wars of Islam. Dr. Gurtarn Singh Sidhu

This book covers a comprehensive update on acute and chronic leukemia. In 54 chapters, authors introduce research progress and clinical trials of acute myeloid leukaemia (AML), acute promyelocytic leukaemia (APL), acute lymphoblastic leukaemia (ALL), myelodysplastic syndrome (MDS), myeloproliferative neoplasm (MPN) and chronic myeloid leukemia (CML). The last decade has seen the integration of genetic and clinical information to determine the prognosis and treatment strategies. This book provides practitioners, researchers and graduate students of Hematology and Hematopathology a comprehensive update on the pathobiology, genomics, classification, diagnosis, monitoring, prognostication and therapy of both acute and chronic leukemias.

The year is 1971 Tension is brewing between India and Pakistan One secret could change the course of history . . . It's now up to her When a young college-going Kashmiri girl, Sehmat, gets to know her dying father's last wish, she can do little but surrender to his passion and patriotism and follow the path he has so painstakingly laid out. It is the beginning of her transformation from an ordinary girl into a deadly spy. She's then married off to the son of a well-connected Pakistani general, and her mission is to regularly pass information to the Indian intelligence. Something she does with extreme courage and bravado, till she stumbles on information that could destroy the naval might of her beloved country. Inspired from real events, Calling Sehmat . . . is an espionage thriller that brings to life the story of this unsung heroine of war.

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 3.4.3.3 Genome Sequencing for Cytogenomic Investigations 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 3.9.1 Brief Review of GEP Platforms 3.9.2 Clinical Applications of GEP in Leukaemias 3.10 Newer Techniques 3.10.1 Long-Read Sequencing 3.10.2 Single-Cell Sequencing 3.10.3 Optical Genome Mapping 3.10.4 Circulating Tumour DNA Testing in Leukaemia 3.11 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/Int

Hsuan-Tsang (602 – 664) was a Chinese Buddhist monk, scholar, traveller, and translator who travelled to India in the seventh century and described the interaction between Chinese Buddhism and Indian Buddhism during the early Tang dynasty. This boos is a detailed descriptive account of the trails and travails of this famous Chinese traveller who came to India, visited the famous seats of learning and carried valuable Buddhist doctrines with him back to China.

The year is 1971 Tension is brewing between India and Pakistan One secret could change the course of history . . . It's now up to her When a young college-going Kashmiri girl, Sehmat, gets to know her dying father's last wish, she can do little but surrender to his passion and patriotism and follow the path he has so painstakingly laid out. It is the beginning of her transformation from an ordinary girl into a deadly spy. She's then married off to the son of a well-connected Pakistani general, and her mission is to regularly pass information to the Indian intelligence. Something she does with extreme courage and bravado, till she stumbles on information that could destroy the naval might of her beloved country. Inspired from real events, Calling Sehmat . . . is an espionage thriller that brings to life the story of this unsung heroine of war.

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 Treatment

Faith & Followers is a 32-page full-color richly illustrated booklet intended for a broader audience. The booklet traces the roots and history of the faith explaining the conditions under which Sikh arose, Sikh articles of faith, the Sikh world view, Guru, and the formation of the Khalsa. The booklet also covers Sikhs in the Panjab and the Diaspora, the institution of the gurduara, and the impact Sikhs have had on global society and culture through their unique lifestyle and belief system.

This book covers a comprehensive update on acute and chronic leukemia. In 54 chapters, authors introduce research progress and clinical trials of acute myeloid leukaemia (AML), acute promyelocytic leukaemia (APL), acute lymphoblastic leukaemia (ALL), myelodysplastic syndrome (MDS), myeloproliferative neoplasm (MPN) and chronic myeloid leukemia (CML). The last decade has seen the integration of genetic and clinical information to determine the prognosis and treatment strategies. This book provides practitioners, researchers and graduate students of Hematology and Hematopathology a comprehensive update on the pathobiology, genomics, classification, diagnosis, monitoring, prognostication and therapy of both acute and chronic leukemias.

The year is 1971 Tension is brewing between India and Pakistan One secret could change the course of history . . . It's now up to her When a young college-going Kashmiri girl, Sehmat, gets to know her dying father's last wish, she can do little but surrender to his passion and patriotism and follow the path he has so painstakingly laid out. It is the beginning of her transformation from an ordinary girl into a deadly spy. She's then married off to the son of a well-connected Pakistani general, and her mission is to regularly pass information to the Indian intelligence. Something she does with extreme courage and bravado, till she stumbles on information that could destroy the naval might of her beloved country. Inspired from real events, Calling Sehmat . . . is an espionage thriller that brings to life the story of this unsung heroine of war.

circa 174 Seiten. : Auf dem Umschlag: "More than 70 labs. Topics include Virtual Networks, Network Security Groups, Availability Set, Azure Compute, Azure Storage, Azure Active Directory, Backup, SQL Database, Securtiy Center, Operations Management Suite, Web Apps and Load Balancers."

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Beyond Crisis: Achieving Renewal in a Turbulent World 7 Contents 9 Preface 15 Acknowledgements 19 Introduction 21 Part I: What Happened? 33 Chapter 1: A Short History of the Crisis 35 The roots of the financial crisis 35 The role of the financial sector 38 Personal, corporate and government debt 43 Executive Summary 48 Chapter 2: The New Operating Environment 49 Demographics 49 Economic development and social interactions 52 Communications, science and technology 59 Resource and other systemic challenges 60 Executive Summary 62 Chapter 3: What Lies Ahead? 63 The short term 63 The medium term 65 Longer-term scenarios 71 Executive Summary 77 Part II: What Organisations Can Do 79 Chapter 4: Organisational Design 81 Aligned to the previous environment 81 Dealing with the next decades 87 Successful organisations in very challenging environments 89 Executive Summary 94 Chapter 5: Renewal 97 Measuring renewal 97 Firms’ self-perceived weaknesses 100 Hurdles to innovation 102 Foxes and Hedgehogs: their roles in renewal 106 The double-cone: a framework for Foxes and Hedgehogs 110 Executive Summary 113 Chapter 6: The Importance of Purpose 115 Clarity of purpose 115 Senior management and the Board 116 Leadership 118 Competence 121 Setting a purpose 123 Executive Summary 126 Chapter 7: Five Qualities for Renewal 127 The journey and destination 127 Values 128 Narrative 131 Insight 135 Generating Options 137 Machinery 139 Executive Summary 141 Chapter 8: The Structure of Renewal 143 Organisational change 143 The Three Ring Circus 144 Linking the Three Ring Circus 148 Executive Summary 152 Chapter 9: Managing Renewal 153 Getting going 153 Evolution of a PS-RO 157 Managing a PS-RO system 159 What about the workers? 161 The diagnostic tool 164 Executive Summary 165 Part III: A Toolkit for Purposeful Renewal 167 Chapter 10: Values 169 Core Values 170 The origins of Values 175 Aligning your Values with a PS-RO 177 Unlocking extraordinary competence 182 Measuring behaviours 186 Legacy 193 Executive Summary 193 Chapter 11: Insight 195 Scenarios as a source of Insight 196 Relationship of Insight to the other PS-RO qualities 197 Methods for developing Insight 198 Horizon scanning 199 Forecasting as part of Insight 202 The scenario process 206 Describing the organisation 210 Audit of exposure to risks 213 Practical aspects of gathering Insight 222 Quantifying scenarios 228 Insight and the Three Ring Circus 229 Executive Summary 232 Chapter 12: Generating Options 233 The Options journey 235 Innovation 238 Changing the portfolio 248 Executive Summary 255 Chapter 13: Narrative 257 What is a Narrative? 259 The individual Narrative 265 The organisational Narrative 269 Developing organisational Narrative 275 Executive Summary 281 Chapter 14: Machinery 283 Renewal 284 The formal planning system: the role of the Three Ring Circus 285 Five interlocking parts in the Machinery 293 The ‘95’ organisation 307 The ‘99’ organisation 309 Groups 312 Executive Summary 318 Conclusion: A Purposeful Self-Renewing Organisation 319 Endnotes 325 Index 337

A tragic discovery was made at Bishop's Hotel last evening when a maid, on entering the suite of Signora da Costa, a rich Argentine guest at the hotel, found her dead body on the bed wrapped in an eiderdown. Paul Ashby is excited to be heading off on holiday to the South of France. But on the day before departure he is entrusted with a strange mission – to find a missing young man. When he arrives in St. Antoine, he falls quickly in with the local artistic set, including alluring Adelaide Moon and Argentian playboy Hernandez de Najera. Also present is eccentric painter Benvenuto Brown who suspects de Najera of murder most foul, and a Scotland Yard detective looking for the 'slosher', a noted jewel thief. Are thief and killer one and the same, and what is the connection to the missing boy? Benvenuto and Paul will travel from exotic watering spots to the dangerous backstreets of Marseilles in their search for the solution to this clever and elegant whodunit. The Crime Coast (also known as Strange Holiday) was originally published in 1931. This new edition features an introduction by crime fiction historian Curtis Evans. "A first-rate story all the way through ... there is not a trick in this particular type of craftsmanship that she does not employ completely and to good advantage—suspense, plausibility, characterization and a fast tempo that carries the reader to an ingenious conclusion." New York Times Book Review

The year is 1971 Tension is brewing between India and Pakistan One secret could change the course of history . . . It's now up to her When a young college-going Kashmiri girl, Sehmat, gets to know her dying father's last wish, she can do little but surrender to his passion and patriotism and follow the path he has so painstakingly laid out. It is the beginning of her transformation from an ordinary girl into a deadly spy. She's then married off to the son of a well-connected Pakistani general, and her mission is to regularly pass information to the Indian intelligence. Something she does with extreme courage and bravado, till she stumbles on information that could destroy the naval might of her beloved country. Inspired from real events, Calling Sehmat . . . is an espionage thriller that brings to life the story of this unsung heroine of war.

Cover 1 Playing at Home: The House in Contemporary Art 5 Imprint Page 6 Contents 7 Introduction 9 1. Family Traces 35 2. Scaled Down 61 3. Broken Homes 91 4. Beach Houses 119 5. Haunted Houses 145 6. Green Houses 173 7. Mobile Homes 197 Conclusion: Our House? 221 References 227 Select Bibliography 249 Acknowledgements 255 Photo Acknowledgements 257 Index 259

The rapid pace of technological innovation and the effects of the Information and Communications Technology (ICT) revolution have resulted in dramatic changes on a global scale, from the empowerment of the individual to the spawning of global markets. From the business perspective, the widespread deployment of Information Technology (IT) has resulted in many organisational changes and the development and use of new management and business processes. An important challenge for today's manufacturing organisations is to be able to anticipate the impact of investments in new (frequently IT-based) manufacturing technologies and programmes. Ideally, management needs to be able to identify and articulate the many ways in which investment decisions influence their organisation - in terms of performance across a range of measures. Furthermore, in today's manufacturing environment, it is increasingly necessary that a close relationship exists between manufacturing decision making and corporate business strategy, so that manufacturing decisions complement and are fully aligned with the organisation's strategic objectives. Strategic Decision Making in Modern Manufacturing introduces and explains the AMBIT (Advanced Manufacturing Business ImplemenTation) approach, which has been developed to bridge the gap between strategic management considerations and the operational effects of technology investment decisions on the manufacturing organisation, so that the likely impact of new manufacturing technology and/or programme implementations can be evaluated, anticipated and accurately predicted. The AMBIT approach focuses specifically on the non-financial aspects of such investment decisions and offers an approach that allows a manager, or more frequently a management team, to understand the impacts of a new technology or a new programme on the manufacturing organisation in terms of manufacturing performance. The prediction of future trends and patterns is a very imprecise and ambiguous activity at the best of times. Yet despite such ambiguity, managers need to be forward looking. They need appropriate tools and approaches to help them anticipate the future. Thus, whilst the pages of organisational history may be filled with anecdotes about organisations that failed to "predict" the future, it is the challenge of today's organisations to evade such a fate. The AMBIT approach delineated in this book has been specifically developed to anticipate the future by analysing the impact of managerial decisions.

Harinder Baweja, an Editor with Hindustan Times has earned a reputation as a fearless, committed reporter through her prolonged coverage of conflict zones. Her experience of covering the Kashmir crisis gave her access to a wide range of sources, particularly among the army units that were sent to Kargil. She covered the sharp, short war for India Today magazine, using her enviable range of sources to compile a definite account of the Kargil war. She has also edited and authored chapters for 26/11 Mumbai Attacked.|Kargil, 1999. Two entire brigades of Pakistani army regulars infiltrated Indian territory and fortified themselves before the Indian army even realized they were there. The top army brass ignored warnings, downplayed the threat and the number of infiltrators till it was almost too late. They were also poorly prepared, operationally and in every other respect. Infantry soldiers were pushed up with inadequate maps, clothing and weapons and no information of either the enemy's numbers or their weapon strength. With foreword by GL Batra, father of Capt. Vikram Batra, the Kargil war hero and recipient of the highest gallantry award, Param Vir Chakra, this is the true story of Kargil as seen through the eyes of one of the front-line commanders. Written in the form of a diary, it offers the first really detailed and exclusive account of the events that led to the invasion and the subsequent battle to retake the peaks occupied by the intruders. Even after almost two decades, the book is still the most accurate account of the many Indian soldiers who laid down their lives in the line of duty.

A tragic discovery was made at Bishop's Hotel last evening when a maid, on entering the suite of Signora da Costa, a rich Argentine guest at the hotel, found her dead body on the bed wrapped in an eiderdown. Paul Ashby is excited to be heading off on holiday to the South of France. But on the day before departure he is entrusted with a strange mission – to find a missing young man. When he arrives in St. Antoine, he falls quickly in with the local artistic set, including alluring Adelaide Moon and Argentian playboy Hernandez de Najera. Also present is eccentric painter Benvenuto Brown who suspects de Najera of murder most foul, and a Scotland Yard detective looking for the 'slosher', a noted jewel thief. Are thief and killer one and the same, and what is the connection to the missing boy? Benvenuto and Paul will travel from exotic watering spots to the dangerous backstreets of Marseilles in their search for the solution to this clever and elegant whodunit. The Crime Coast (also known as Strange Holiday) was originally published in 1931. This new edition features an introduction by crime fiction historian Curtis Evans. "A first-rate story all the way through ... there is not a trick in this particular type of craftsmanship that she does not employ completely and to good advantage—suspense, plausibility, characterization and a fast tempo that carries the reader to an ingenious conclusion." New York Times Book Review

Gill Gartenstadt, Designerin und alleinerziehende Mutter zweier Kinder, lebt nach 13 Jahren Berlin wieder auf dem Land. ber die Partnerbrsen Stelldichein (teuer und elitr) und Schnappie (kostenlos und fr Schnppchenjger) sucht sie einen Mann, was einfach nicht gelingen will. Einer will sie im Chat auf QuickCloud nackt sehen. Sie erhlt eindeutige SMS und beginnt an Short Message Sex sogar Gefallen zu finden. Seitenweise tauscht sie Lebenslufe aus, aber die meisten Mnner, wenn berhaupt, rufen erst spt abends an. Steigt dann der mnnliche Testosteronspiegel? Gill wartet und wartet. Sie ist eine MILF BING.* AUTOMATENHELDEN ist eine sarkastische bitterbse Studie ber das heutige Paarungsverhalten in den unendlichen Weiten des Internets. * Das wird im Buch erklrt.

A pair of star-crossed lovers search for a way back to one another against all odds A girl fights for her life against a malignant, generations-old evil A peri seeks to reclaim her lost powers A warrior rebels against her foretold destiny From chudails and peris to jinn and goddesses, this lush collection of South Asian folklore, legends, and epics reimagines stories of old for a modern audience. This fantasy and science fiction teen anthology edited by Samira Ahmed and Sona Charaipotra contains a wide range of stories from fourteen bestselling, award-winning, and emerging writers from the South Asian diaspora that will surprise, delight, and move you. So read on, for after all, magic has no borders. With stories by: Sabaa Tahir, #1 New York Times bestselling author of the Ember in the Ashes series, and winner of the National Book Award and Printz Award for All My Rage Sayantani DasGupta, New York Times bestselling author of the Kiranmala and the Kingdom Beyond series Preeti Chhibber, author of Spider-Mans Social Dilemma Sona Charaipotra, author of Symptoms of a Heartbreak and How Maya Got Fierce, and coauthor of The Rumor Game and Tiny Pretty Things, now a Netflix original series. Tanaz Bhathena, award-winning author of Hunted by the Sky and Of Light and Shadow Sangu Mandanna, bestselling author of The Very Secret Society of Irregular Witches and the Celestial Trilogy Olivia Chadha, author of Rise of the Red Hand Nafiza Azad, author of William C. Morris Award nominee, The Candle and the Flame Tracey Baptiste, New York Times bestselling author of The Jumbies series and Minecraft: The Crash Naz Kutub, author of The Loophole Nikita Gill, bestselling author of Wild Embers and Fierce Fairytales Swati Teerdhala, author of the Tiger at Midnight trilogy Shreya Ila Anasuya, New Voices selection Tahir Abrar, New Voices selection

Before she could touch him she saw it—the handle of a weapon sticking out between his shoulder-blades. Playwright Martin Pitt's acclaimed new play, The Lily Flower, is having its London premiere. When the curtain rises, in attendance are the lovely Julia Dallas; Lord Charles Kulligrew; absent-minded professor Edward Milk and his opinionated spinster sister, Agatha; and Julia's friend Benvenuto Brown, the accomplished artist and amateur sleuth. Before the evening is through, rave notices for the play will have to sit beside the reports of a grisly murder which takes place during the performance itself. Benvenuto Brown's investigation will take him far beyond theatreland, to France and the suspected lair of an assassin ... What Dread Hand? was originally published in 1932. This new edition features an introduction by crime fiction historian Curtis Evans. "Miss Gill is a consummate artist ... [Her work] may be unhesitatingly recommended to detective fiction fans and others who want to be converted." Brooklyn Eagle

viii, 172 pages ; 21 cm Includes bibliographical references (pages 163-171)

A Fast Paced Mystery, Suspense Story All Wrapped Up In The Exciting World Of Whisky. A Unique Combination Of Whisky Facts And Fiction Written By A Whisky Expert And Novelist. Intrigue, International Travel, Sex And Whisky The Isle Of Bute Distillery Was Fast Becoming One Of The Most Popular In The World, Thanks In Part To The New Pun On All The Social Media Networks - What A Beaut. Raymond Armstrong, Is Enjoying His Retirement When He Hears Of The News. Gordon Reid, The Owner Of Bute Distillery Is A Lifelong Friend. Raymond Immediately Visits The Island To Join His Best Friend In The Success Of The Distillery. On His Return To Yorkshire, He Receives Devastating News! Little Did He Know That This News Would Draw Him Into A Conspiracy, An Attempt To Take Over The Distillery By A Casino Company In Las Vegas Who Will Stop At Nothing To Take Control, Including Murder! The Mysterious Events That Occur, Reawakens His Instincts And Training As A Former Member Of A Special M16 Unit, And Propels Him Back Into The World Of Espionage And Intrigue. Raymond Must Use All Of His Skills To Stop The People Behind This Hostile Take-over Attempt, And Protect The Reid Family At All Costs!!

本书旨在提供对客戶关系管理系统概念的理解及电子客戶关系管理的规划和实施所涉及的问题, 共分为三个部分:客戶关系管理的先决条件, 理解客戶关系管理, 计划和实施客戶关系管理

The year is 1950; the Liaquat-Nehru Pact has been signed between India and Pakistan; she doesn't know it will change her life forever; it will also make her stronger Bibi Amrit Kaur's life is literally torn apart in the 1947 riots. She's now in a different country with a different identity. She accepts this new life gracefully and begins a new chapter. She gets married and has two children. Life, however, has something else in store for her. It breaks her apart. Again. This time the pain is unbearable. But the hope that she will reunite with her children and be whole again keeps her alive. And she doesn't let the bitterness cloud her days, becoming a beacon of hope and courage for all. From the bestselling author of Calling Sehmat comes another hitherto untold story of strength, sacrifice and resilience. A must read.

<p>Strategic Decision Making in Modern Manufacturing introduces and explains the AMBIT (Advanced Manufacturing Business ImplemenTation) approach, which has been developed to bridge the gap between strategic management considerations and the operational effects of technology investment decisions on the manufacturing organisation, so that the likely impact of new manufacturing technology and/or programme implementations can be evaluated, anticipated and accurately predicted. The AMBIT approach focuses specifically on the non-financial aspects of such investment decisions and offers an approach that allows a manager, or more frequently a management team, to understand the impacts of a new technology or a new programme on the manufacturing organisation in terms of manufacturing performance.</p>