مرزهای تحقیقات دارویی بالینی - هماتولوژی: جلد سوم

Frontiers in Clinical Drug Research - Hematology is a book series that brings updated reviews to readers interested in learning about advances in the development of pharmaceutical agents for the treatment of hematological disorders. The scope of the book series covers a range of topics including the medicinal chemistry, pharmacology, molecular biology and biochemistry of natural and synthetic drugs employed in the treatment of anemias, coagulopathies, vascular diseases and hematological malignancies. Reviews in this series also include research on specific antibody targets, therapeutic methods, genetic hemoglobinopathies and pre-clinical / clinical findings on novel pharmaceutical agents. Frontiers in Clinical Drug Research - Hematology is a valuable resource for pharmaceutical scientists and postgraduate students seeking updated and critically important information for developing clinical trials and devising research plans in the field of hematology, oncology and vascular pharmacology.The third volume of this series features 6 reviews: -Advances in the understanding and treatment of immune thrombocytopenia-Recent developments in chronic myeloid leukemia biology and treatment-Role of immunomodulatory drugs in the treatment of lymphoid and myeloid malignancies-Pediatric hematological malignancies - clinical manifestation, treatment and follow-up-Novel therapies and immunotherapeutic approaches to treat childhood leukemia-Erythrocyte turnover and erythropoietic patterns in two different experimental mouse models of anemia CONTENTS 6 PREFACE 10 List of Contributors 11 Advances in the Understanding and Treatment of Immune Thrombocytopenia 12 José Perdomo* 12 INTRODUCTION 12 Platelet Biogenesis 13 Platelet Function 16 Epidemiology, Aetiology and Disease Progression 17 Platelet Destruction in ITP 18 Recent Developments 19 Impairment of Platelet Production in ITP 21 Disease Characteristics and Therapies 23 Need for Novel Therapies 26 CONCLUDING REMARKS 28 CONSENT FOR PUBLICATION 28 CONFLICT OF INTEREST 28 ACKNOWLEDGEMENTS 28 REFERENCES 28 Recent Developments in Chronic Myeloid Leukemia Biology and Treatment 40 Massimiliano Bonifacio1,* and Claudio Sorio2,* 40 INTRODUCTION 41 PART I: BIOLOGY 42 Signaling Mechanisms Altered in CML 42 Oncosuppressors Genes in CML: A Role for Cytosolic and Receptor-like PTPs 43 Oncogenic PTPs 45 Non-coding RNAs in CML 45 Other Tumor Promoting Pathways 45 Identifying Cancer Stem Cell in CML 47 Targeting LSCs 48 PART II: CLINICS 49 OPTIONS OF FRONT-LINE MANAGEMENT OF CML 49 Imatinib 49 Nilotinib 51 Dasatinib 52 Bosutinib and Ponatinib 53 THE SEQUENTIAL USE OF TKI IN SECOND OR FURTHER LINES OF TREATMENT 54 BCR-ABL Mutations 54 After Imatinib Failure 55 After Failure of Nilotinib or Dasatinib 55 Indications for HSCT 56 THE PROGNOSTIC SIGNIFICANCE OF EARLY MOLECULAR RESPONSE 56 Imatinib 58 Nilotinib 59 Dasatinib 59 Bosutinib 59 Absolute vs Relative Reduction of BCR-ABL1 Levels 60 Therapeutic Strategies Based on EMR 60 DEEP MOLECULAR RESPONSE AND DISCONTINUATION OF TREATMENT 61 Discontinuation Studies 61 Predictive Factors of DMR 62 The Impact of DMR on Survival 63 PREDICTING RESPONSE TO TKI 63 Risk Score Systems 63 Age 64 Comorbidities 64 Gender 65 Cytogenetic at Diagnosis 65 Transcript Type 65 Mutations 66 Predicting Response to 2G TKI After Imatinib Failure 67 New and Alternative Biomarkers of Response to Treatment 67 CONCLUDING REMARKS 68 ABBREVIATIONS 68 CONSENT FOR PUBLICATION 69 CONFLICT OF INTEREST 69 ACKNOWLEDGEMENTS 69 REFERENCES 69 Role of Immunomodulatory Drugs in the Treatment of Lymphoid and Myeloid Malignancies 84 Ota Fuchs* 84 INTRODUCTION 85 CRL4CRBN as a Part of Ubiquitin-Proteasome System 87 Regulation of CRBN-Associated Proteins in Multiple Myeloma by Lenalidomide 89 Biomarker of Response or Resistance to Lenalidomide and Pomalidomide 91 Therapy for Multiple Myeloma Patients with Low CRBN Expression 92 Importance of CRBN for Immunomodulatory Drugs Activity in Lymphoid Malignancies 92 CLINICAL STUDIES IN LYMPHOID MALIGNANCIES 94 Relapsed/ Refractory CLL 94 B-Cell NHL 94 Multiple Myeloma 96 CLINICAL STUDIES IN MYELOID MALIGNANCIES 98 Myelodysplastic Syndrome 98 Randomized Phase III Placebo-Controlled Study of Lenalidomide in del(5q) Patients 104 Further Clinical Studies of Lower Risk MDS Patients with del(5q) Treated with Lenalidomide 105 Treatment of del(5q) Patients with Relapse during Lenalidomide Exposure 106 Therapy with Lenalidomide in Combination with Another Drug in MDS 106 Mechanisms of Action of Lenalidomide 109 Role of Cereblon in the Efficacy of Lenalidomide in del(5q) MDS and non-del(5q) MDS 112 Further Prognostic Factors for the Efficacy of Lenalidomide in del(5q) MDS and non-del(5q) MDS 115 High-Risk MDS and AML 117 CONCLUSION AND PERSPECTIVES 119 CONSENT FOR PUBLICATION 120 CONFLICT OF INTEREST 120 ACKNOWLEDGEMENTS 120 REFERENCES 120 Pediatric Hematological Malignancies – Clinical Manifestation, Treatment and Follow-Up 149 Naga Ramya Lanka1 and Krishna Kanth Pulicherla2,* 149 INTRODUCTION 149 Pediatric Hematological Malignancies 151 Non-Hodgkin’s Lymphoma 153 Etiology of Hematological Malignancies in Children 154 Signs and Symptoms 156 Occular Symptoms 158 Genitourinary Symptoms 158 Staging of Leukemia and Lymphomas 162 Staging of Leukemia 162 Staging of Lymphoma 163 Treatment Strategies 164 Side Effects of Treatment 169 Advanced Therapies to Treat Hematological Malignancies 174 Immunotherapy 174 Immunotherapy Using Gene Transfer: CAR and TCR 175 Targeted Therapy 175 After Treatment - Follow-up 177 Paediatric Cancer Emergencies 179 CONCLUSION 181 ABBREVATIONS 181 CONSENT FOR PUBLICATION 183 CONFLICT OF INTEREST 183 ACKNOWLEDGEMENTS 183 REFERENCES 183 Novel Therapies and Immunotherapeutic Approaches to Treat Childhood Leukemia 195 Natasha Ali* 195 INTRODUCTION 196 Biology 197 Literature Search 200 ACUTE LYMPHOBLASTIC LEUKAEMIA 201 Nucleoside Analogues 202 Monoclonal Antibodies 202 Bispecific Antibodies and Diabody 203 Advantages/Disadvantages of Monoclonal Antibodies 203 Proteasome Inhibitor 204 Tyrosine Kinase Inhibitors 204 CAR T Cells 205 Toxicities of CAR T Cells 206 ACUTE MYELOID LEUKAEMIA 208 Nucleoside Antimetabolites 208 Tyrosine Kinase Inhibitors 208 CAR T Cells 209 Epigenetic Agents 210 Gemtuzumab Ozogamicin [GO] 211 GO as Single Agent 212 GO Combined With Chemotherapy 212 GO as Part of Conditioning OR Post Allogeneic HSCT 212 Proteasome Inhibitors 212 STEM CELL TRANSPLANT IN CHILDHOOD ACUTE LEUKAEMIAS 213 CONCLUSION 215 ABBREVIATIONS 215 CONSENT FOR PUBLICATION 216 CONFLICT OF INTEREST 216 ACKNOWLEDGEMENTS 216 REFERENCES 216 Erythrocyte Turnover and Erythropoietic Patterns in Two Different Experimental Mouse Models of Anemia 231 Sreoshi Chatterjee1,2 and Rajiv K. Saxena2,* 231 INTRODUCTION 232 Erythroid Differentiation in Bone Marrow (BM) and Spleen 232 Erythrocyte Turnover in Circulation: Double In Vivo Biotinylation (DIB) 234 INDUCTION OF ANEMIA 236 Cadmium Induced Anemia 236 Mouse Model of Cadmium Induced Anemia 236 Autoimmune Hemolytic Anemia (AIHA) 237 Induction of Autoimmune Hemolytic Anemia in Mice 238 TURNOVER OF CIRCULATING ERYTHROCYTES IN ANEMIC MICE 239 Double in vivo Biotinylation (DIB) of Erythrocytes in Anemic Mice 239 Turnover Kinetics of Circulating Erythrocytes 239 Young vs. Aged Erythrocytes 239 Reactive Oxygen Species (ROS) Generation in Circulating Erythrocytes 242 Phosphatidylserine (PS) Externalization in Circulating Erythrocytes 245 CD47 Expression in Circulating Erythrocytes 247 ERYTHROPOIETIC ACTIVITY IN CADMIUM EXPOSED MICE 247 Plasma Epo Concentration 247 Erythroid Precursors 248 Membrane bound Autoantibodies on Erythroid Cells in AIHA Mice 250 ROS Generation in Erythroid Cells in Anemic Mice 250 Apoptotic Activity in Erythroid Cells in Anemic Mice 251 CONCLUDING REMARKS 252 CONCLUSION 254 CONSENT FOR PUBLICATION 256 CONFLICT OF INTEREST 256 DISCLOSURE 256 ACKNOWLEDGEMENTS 256 REFERENCES 256 SUBJECT INDEX 263