Biology and Treatment of Leukemia and Bone Marrow Neoplasms

This book provides a concise update on current understanding of the biology of acute and chronic leukemias and other bone marrow neoplasms, including myelodysplastic and myeloproliferative disorders, and explores new and emerging treatments. There is a particular focus on the molecular abnormalities that are drivers of leukemia and on their detection by modern molecular techniques. Knowledge of the ways in which genomic and metabolic abnormalities in the hematologic neoplasms affect prognosis and treatment decision making is reviewed. Detailed attention is devoted to targeted therapies, including novel drugs, and to potential targets for future drug development. In addition, readers find in-depth discussion of cellular and antibody-based immunotherapies as well as the role of hematopoietic stem cell transplantation in the treatment of leukemias and bone marrow malignancies. The book is of special interest for hematologists, oncologists, and cancer researchers; it is also of value for hematology trainees and medical students. Introduction 6 Contents 8 1 Advances in Diagnosis and Risk Stratification of Acute Myeloid Leukemia and Myelodysplastic Syndromes 10 1.1 Next Generation Sequencing (NGS)- Based Testing in Hematologic Malignancies 10 1.2 CASE 1: 69 Year Old with Pancytopenia 12 1.3 Discussion 13 1.4 Genomic Alterations in MDS 14 1.5 Clonal Hematopoiesis of Indeterminate Potential and Pathogenesis of MDS 14 1.6 Interpretation of Results of Genomic Testing 15 1.7 Role of Genomic Testing in Diagnosis and Prognosis of MDS 16 1.8 Case 2: 52-Year-Old Male with Pancytopenia 17 1.9 Discussion 18 1.9.1 Genetic Alterations in AML 18 1.9.2 ELN Classification Integrating Cytogenetics and Mutation Analysis 18 1.9.3 Interpretation of NGS Mutation Panel Results 19 1.9.4 Evaluation of Minimal/Measurable Residual Disease (MRD) in Management of AML 22 1.9.5 Future Perspectives 23 References 24 2 Genetics and Diagnostic Approach to Lymphoblastic Leukemia/Lymphoma 26 2.1 Introduction 27 2.2 B-lymphoblastic Leukemia/Lymphoma 28 2.2.1 Epidemiology and Risk Factors 28 2.2.2 Genomic Classification of B-Lymphoblastic Leukemia 28 2.3 B-ALL with Recurrent Genetic Abnormalities 29 2.3.1 B-ALL with BCR/ABL1 29 2.3.2 B-ALL with KMT2A (MLL) Rearrangement 29 2.3.3 ETV6/RUNX1 t(12;21) 30 2.3.4 TCF3/PBX1 t(1;19) 30 2.3.5 Hyperdiploidy 30 2.3.6 Hypodiploidy 31 2.3.7 IL3/IGH, t(5;14) 31 2.3.8 Intrachromosomal Amplification of Chromosome 21 (iAMP21) 31 2.3.9 Ph-Like ALL 31 2.4 B-ALL Not-Otherwise Specified 32 2.4.1 TCF3 (E2A)/HLF, t(17;19) 33 2.4.2 IKZF1 Alterations 33 2.5 T-lymphoblastic Leukemia/lymphoma 33 2.6 Diagnostic Work up of ALL 35 2.7 Our Approach to Genomic Testing of ALL 36 2.8 Case 1: BCR-ABL1 (Ph) Positive B-ALL 39 2.8.1 Clinical Presentation and Pathology 39 2.8.2 Genomic Evaluation 39 2.9 Case 2: Ph-Like B-ALL 39 2.9.1 Clinical Presentation and Pathology 39 2.9.2 Genomic Evaluation 40 2.9.3 Interpretation of NGS Results 40 2.10 Case 3. T-ALL 41 2.10.1 Clinical Presentation and Pathology 41 2.10.2 Molecular Genomic Evaluation 42 2.10.3 Interpretation of NGS Mutation Panel Results 42 2.10.4 Follow up and Treatment 43 References 43 3 Acute Promyelocytic Leukemia: Update on Risk Stratification and Treatment Practices 53 3.1 Background and Epidemiology 53 3.2 Pathogenesis 53 3.3 Coagulopathy 54 3.4 Drug Development in APL 54 3.5 Diagnosis and Initial Management 55 3.6 Case 1 55 3.7 Risk stratification 56 3.8 Management of Low-Risk Disease 56 3.9 Case 2 57 3.10 High-Risk Disease 57 3.11 Practical Aspects of ATRA and ATO Dosing 58 3.12 Differentiation Syndrome 58 3.13 Pseudotumor Cerebri (PTC) 59 3.14 Response Assessment and Surveillance 59 3.15 Role of Maintenance Therapy 60 3.16 Case 3 60 3.17 Management of Relapsed APL 60 References 61 4 Current and Emerging Therapies for Acute Myeloid Leukemia 64 4.1 Introduction 65 4.1.1 Case 1 65 4.2 Induction Therapy 66 4.2.1 Induction Therapy for Unfit Patients 67 4.3 Post-Remission Consolidation 68 4.3.1 Case 1 (Continued) 69 4.4 Relapsed/Refractory Disease 69 4.4.1 Case 1 (Continued) 70 4.5 FLT3-Mutated AML 70 4.5.1 Case 2 70 4.5.2 Case 2 (Continued) 71 4.6 Other Novel Targeted Therapies 72 4.7 Antibody-Based Therapies and Immunotherapies 73 4.7.1 Antibody-Based Therapy 73 4.8 Chimeric Antigen Receptor (CAR) Modified Cellular Therapy 75 References 76 5 Current Management and New Developments in the Treatment of ALL 81 5.1 Case 1 82 5.1.1 Newly Diagnosed T-Cell Acute Lymphoblastic Leukemia (T-ALL) 82 5.1.2 Discussion 82 5.1.3 Recent Clinical Observations in Pediatrics 83 5.2 Case 2 84 5.2.1 Philadelphia Chromosome-Negative (Ph-Negative) B-Cell Acute Lymphoblastic Leukemia (B-ALL) 84 5.2.2 Which Treatment Regimen Should Be Used? 84 5.2.3 Should Asparaginase Be Included? 86 5.2.4 Should Rituximab Be Used? 87 5.2.5 When Should Allogeneic Stem Cell Transplant Be Considered? 88 5.3 Case 3 91 5.3.1 Philadelphia Chromosome-Positive (Ph-Positive) B-Cell Acute Lymphoblastic Leukemia (B-ALL) 91 5.3.2 Which Induction Regimen Should Be Used? 91 5.3.3 Which TKI Should Be Used? 92 5.3.4 Post-Remission Treatment 92 5.4 Case 4 93 5.4.1 Relapsed ALL 93 5.4.2 Discussion 94 References 97 6 CML Chapter 103 6.1 Case 1 103 6.2 Discussion 104 6.3 Case 2 108 6.4 Discussion 108 6.5 Case 3 109 6.6 Discussion 110 6.7 Risks of TKIs 111 6.8 Future Directions and Unmet Needs 113 References 115 7 Current Management and New Developments in the Treatment of Myelodysplastic Syndrome 121 7.1 Myelodysplastic Syndrome: Overview 121 7.2 CASE 1—High-Risk MDS 123 7.3 Discussion 123 7.3.1 Azacytidine 124 7.3.2 Decitabine 124 7.3.3 Combination Therapy with HMA 125 7.4 Allogeneic HCT 126 7.4.1 Who Should Be Considered for Allogeneic HCT? 127 7.5 CASE 2—Low-Risk MDS with Cytopenia 129 7.6 Discussion 129 7.6.1 Luspatercept 131 7.7 CASE 3—Del(5q) Syndrome 132 7.8 Discussion 132 7.9 Clonal Cytopenia Versus MDS 133 7.10 Novel Agents for MDS 133 References 133 8 Chronic Lymphocytic Leukemia (CLL): Biology and Therapy 139 8.1 Introduction and Epidemiology 140 8.2 Workup and Diagnosis 140 8.2.1 Immunophenotyping 141 8.2.2 Additional Testing 141 8.3 Prognostic Factors 141 8.3.1 Cytogenetics/FISH 141 8.3.2 IGHV Mutation Status 142 8.3.3 Lymphocyte Doubling Time 142 8.3.4 Other Prognostic Markers 143 8.3.5 Disease Stage 143 8.4 Case 1: Good Risk CLL, Previously Untreated 144 8.5 Case 2: Poor Risk CLL, Previously Untreated 145 8.6 Indications for Treatment of CLL/SLL 145 8.7 Frontline Treatment Options for CLL/SLL 146 8.7.1 BTK inhibitors 147 8.7.2 BCL2 inhibitor 149 8.8 Case 3: Relapsed/refractory CLL 150 8.9 Treatment of Relapsed/Refractory Disease 150 8.10 Complications 152 8.10.1 Autoimmune Complications [31] 152 8.10.2 Infections 152 8.10.3 Richter’s Transformation 153 References 153 9 Biology and Current Treatment of Myeloproliferative Neoplasms 156 9.1 Introduction 156 9.2 Diagnosis 157 9.3 Biology and Genetics of MPN 157 9.3.1 Driver Mutations 157 9.4 CASE 1: Primary Myelofibrosis 161 9.5 Discussion 161 9.6 CASE 2. Polycythemia Vera 163 9.7 CASE 3: Essential Thrombocythemia 165 References 168 10 Systemic Mastocytosis: Advances in Diagnosis and Current Management 171 10.1 Introduction 171 10.2 Biology and Genetics of SM 172 10.3 Diagnosis and Classification of SM 173 10.3.1 Case 1. SM-AHN 176 10.3.2 Case 2. ISM 177 10.4 Clinical Features of SM 179 10.5 Treatment of SM 180 References 181 11 Chimeric Antigen Receptor (CAR) T Cell Therapy for B-Acute Lymphoblastic Leukemia (B-ALL) 183 11.1 CASE 1: CAR-T Cell Therapy for Refractory/Relapsed B-ALL with Extramedullary Disease 183 11.2 Discussion 185 11.3 CASE 2: Identification and Management of CAR-T Cell Toxicities 187 11.4 Discussion 188 11.5 CASE 3: Sequencing CAR-T Cell Therapy with Other Treatments for Refractory/Relapsed B- ALL 193 11.6 Discussion 193 11.7 Summary and Future Directions 195 References 196 This book presents a timely and multidisciplinary update on the modalities currently available for treating the most feared symptom of patients diagnosed with cancer. The various cancer pain syndromes are explored in detail, covering those related directly to malignancy and those due to the after-effects of cancer therapy. Treatment modalities, including pharmacologic approaches, interventional procedures, and palliative surgical options, are discussed clearly and concisely, with provision of recommendations for the practitioner. Further topics include new and emerging treatments for cancer pain, survivorship considerations, pain management in special populations, and implementation of systems-based pain programs. The book has been written by a multidisciplinary group of experts, reflecting the evolution in pain and symptom management that has occurred in parallel with progress toward more targeted oncologic treatments. Oncologists, palliative care physicians, allied health professionals, and other practitioners involved in caring for cancer patients will find Fundamentals of Cancer Pain Management to be a rich source of evidence-based insights into effective pain management