Book Volume 3
Page: i-i (1)
Author: Atta-ur- Rahman
Page: ii-ii (1)
Author: Atta-ur- Rahman
Page: 1-28 (28)
Author: Jose Perdomo
Immune thrombocytopenia (ITP) is an acquired autoimmune disorder characterized by a platelet count of less than 100 x 109 platelets/L. ITP results from two distinct processes: accelerated platelet destruction and reduced platelet production. A distinction of the relative contribution of these pathologies should help guide more targeted treatment decisions. Mechanistically, decreased platelet production is caused by autoantibody-mediated damage to megakaryocytes, while increased clearance of antibody opsonized platelets has traditionally been attributed to the activity of splenic and hepatic macrophages. T cell mediated toxicity has also been described as a contributor to ITP pathogenesis. Recent observations of increased platelet apoptosis and glycoprotein desialylation associated with platelet clearance by hepatocytes provide new avenues for therapeutic intervention. The aim of ITP therapy is to attain sufficient platelet levels to achieve haemostasis. Significant improvements have been obtained with first line therapies such as corticosteroids and intravenous immunoglobulins. For unresponsive patients, second line therapies (splenectomy, rituximab, TPO receptor agonists) have proved beneficial. Nevertheless, the heterogeneous nature of ITP demands further understanding of the causal biological processes to provide personalized and more effective therapies. This chapter presents an account of the current understanding of the biology of ITP and discusses the existing and potential new treatments.
Page: 29-72 (44)
Author: Massimiliano Bonifacio and Claudio Sorio
BCR-ABL1 represents a driving force in the biology of CML cell as demonstrated by the spectacular results of tyrosine kinase inhibitor (TKI) therapies. Imatinib is a highly effective therapy for chronic phase-chronic myeloid leukaemia (CP-CML) patients, as it turned CML blastic transformation into a rare event. However, responses to frontline imatinib are variable and 2nd- (nilotinib, dasatinib and bosutinib) or 3rd-generation (ponatinib) TKIs have been developed to face BCR-ABL1 mutation-induced imatinib resistance, or intolerance. Nilotinib and dasatinib have been licensed also for the frontline treatment of newly diagnosed patients and they proved to be more effective than imatinib in inducing earlier and deeper molecular responses. However, the reappearance of leukemic cells after TKI discontinuation also in patients with stable negative minimal residual disease highlighted the concept of persistence of BCR-ABL1 leukemia stem cells. Data have accumulated in the past years that the BCR-ABL1 oncogene does not operate alone to drive disease emergence, maintenance and progression: These issues will be briefly reviewed with a special focus on the emerging role of phosphatases in the pathogenesis of hematologic malignancies as new therapeutic approaches have been proposed based on findings in basic science laboratories. Critical issues and future trends will be discussed including the need to better characterize patients according to prognostic scores, paying more attention to those at high risk for disease progression, the increased importance of early monitoring and the optimization of treatment in order to provide an “operational cure” (discontinuation of treatment) in a considerable proportion of patients.
Page: 73-137 (65)
Author: Ota Fuchs
Immunomodulatory drugs (IMiDs) or cereblon (CRBN) binding drugs such as thalidomide, lenalidomide and pomalidomide have similar structures and mechanism of action. Lenalidomide (CC5013, Revlimid®) was approved by the US FDA and the EMA for the treatment of multiple myeloma (MM) patients, low or intermediate-1 risk transfusion-dependent myelodysplastic syndrome (MDS) with chromosome 5q deletion [del(5q)] and relapsed and/or refractory mantle cell lymphoma following bortezomib. Lenalidomide has also been studied in clinical trials and has shown promising activity in chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma (NHL). Lenalidomide has anti-inflammatory effects and inhibits angiogenesis. Pomalidomide (CC4047, Imnovid® [EU], Pomalyst® [USA]) has been recently approved by the US FDA and the EMA for patients with relapsed or refractory MM who have received at least two prior therapies, including lenalidomide and bortezomib. Cereblon seems to have an important role in IMiDs action in both lymphoid and myeloid hematological malignancies and has been identified as a direct molecular target for anti-neoplastic activities of IMiDs. Lenalidomide binds to cereblon (CRBN) which acts as the substrate receptor of a cullin-4 really interesting new gene (RING) E3 ubiquitin ligase CRL4CRBN. This E3 ubiquitin ligase in the absence of lenalidomide ubiquitinates CRBN itself and the other component of CRL4CRBN complex, DNA damage binding protein 1 (DDB1) but in the presence of lenalidomide it changes its specificity and ubiquitinates two transcription factors, IKZF1 (Ikaros) and IKZF3 (Aiolos), and casein kinase 1α (CK1α) and degrades them in proteasomes. Both these transcription factors IKZF1 and IKZF3 are important for the viability of MM cells. IKZF1 induces transcription from interferon regulatory factor 4 gene (IRF4) promoter and from MYC gene promoter in B cells. IKZF1/3 repress the interleukin 2 gene (IL-2) promoter in T cells. In such a way, a decline in IKZF1/3 levels explains how IMiDs stimulate the immune system and degrade B cell function. Low CRBN expression correspond with drug resistance in MM cells. CK1α is a serine/threonine kinase and the CK1α gene (CSNK1A1) is located on 5q32 in commonly deleted region (CDR) in del(5q) MDS. Inhibition of CK1α sensitizes del(5q) MDS cells to lenalidomide. CK1α mediates also the survival of malignant plasma cells in MM. Though, the inhibition of CK1α is a potential novel therapy not only in del(5q) MDS but also in MM. High level of full length CRBN mRNA in mononuclear cells of bone marrow and of peripheral blood seems to be necessary for successful lenalidomide treatment of del(5q) MDS. Bone marrow aspirates of MDS patients who responded to lenalidomide showed before treatment decreased expression of the set of genes needed for erythroid differentiation. Lenalidomide seemed to overcome differentiation block in non-del(5q) low risk MDS patients with decreased expression of these genes compared to the non-responders but this suggestion was not confirmed.
Page: 138-183 (46)
Author: Naga Ramya Lanka and Krishna Kanth Pulicherla
Hematological malignancies are the forms of cancer that begin in the cells of the blood- forming tissue, such as the bone marrow. Childhood blood cancers are relatively rare but are still found to be the major cause of death in children aged 1-14. Early detection increases the chances of successful treatment which paves the way to reduce the rate of mortality. Leukemias and lymphomas account for more than one half of new cancer cases in children. Despite major advances – from an overall survival rate of 10 percent to nearly 90 percent today, for many rare cancers, the survival rate is much lower. Enhancement of anti-leukemic efficacy and reduction of treatment related morbidity or mortality can be achieved by targeted therapy, but requires detailed understanding of pathways and genetic defects involved in leukemogenesis.
Page: 184-219 (36)
Author: Natasha Ali
One third of all paediatric cancer is acute leukaemia which includes acute lymphoblastic and acute myeloid leukaemia. Acute lymphoblastic leukaemia accounts for 75% of cases. Multiple genetic factors contribute in predisposing a child to the development of leukaemia. The major scope of research has been to design therapies that improve overall survival in paediatric patients with high risk or relapsed acute leukemias. This is the largest population of children who are refractory to current treatment modalities. The main aim of novel and immunotherapeutic treatment is target-specific therapies with much decreased toxicities compared to those associated with high dose chemotherapeutic agents. Insights into various “driver” mutations and signaling pathways have led to the discovery of novel agents. Immunotherapeutic agents exploit the mechanism of cytotoxic immunity directed against leukaemic cells. Apart from targeted therapies, haematopoietic stem cell transplant has revolutionized the treatment of acute leukaemias. Particularly in high-risk patients, this treatment modality is the only potential curative option available. This review highlights the upcoming agents that are being used in acute paediatric leukaemias. Topics include nucleoside analogues, monoclonal antibodies, CAR T cells, tyrosine kinase inhibitors, epigenetic agents and proteasome inhibitors. The benefit of allogeneic stem cell transplant in high risk or relapsed/refractory patients with acute leukaemia has also been summarized.
Erythrocyte Turnover and Erythropoietic Patterns in Two Different Experimental Mouse Models of Anemia
Page: 220-251 (32)
Author: Sreoshi Chatterjee and Rajiv K. Saxena
Murine models of cadmium induced anemia (50 ppm and 1000 ppm CdCl2 in drinking water) and autoimmune hemolytic anemia (AIHA) were compared to gain a holistic understanding of the modulation of erythroid homeostasis in anemia. Our results indicated completely contrasting changes in the modulation of erythroid homeostasis in the two forms of anemia. The novel DIB (double in vivo biotinylation) technique developed in our laboratory revealed that older erythrocytes with significantly high level of intracellular reactive oxygen species (ROS) were preferentially more prone to elimination in CdCl2 fed mice, indicated by a significant decline in the relative proportions of older erythrocytes along with a concomitant increase in the proportion of young erythrocytes in circulation. On the contrary, in mice with induced AIHA, selective susceptibility of younger erythrocytes was observed, with more autoantibody binding and highest accumulation of intracellular ROS. Cadmium exposure resulted in a significant yet transient reticulocytosis, whereas an acute reticulocytopenia was observed in autoimmune anemia. Erythropoietic activity in the bone marrows (BM) and the spleen of anemic mice were examined by monitoring the relative proportion of erythroid cells at various stages of differentiation in these organs. Results indicate a suppressed BM erythropoietic activity in both the models of anemia. In cadmium-induced anemia the early erythroid precursors (proerythroblasts) suffered the maximum, while in AIHA-induced mice the later stages of erythroid differentiation (erythroblasts C) were affected the most (50% decline). These populations also showed high intracellular ROS level along with enhanced apoptotic response. A stress erythropoietic response in spleen was seen in mice with induced AIHA, which was however absent in cadmium induced anemia (though increased erythropoietic activity in the early stages of differentiation was evident in spleen).
Page: 252-260 (9)
Author: Atta-ur- Rahman
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.