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New Thrombopoietic Agents: Introduction
Seminars in
Hematology
Vol 47, No 3 July 2010
New Thrombopoietic Agents: Introduction
T
his Seminars in Hematology issue on thrombopoietic agents and thrombocytopenia spans a wide spectrum of topics in the field. It begins with the biology of megakaryocytopoiesis and thrombocytopoiesis. This includes a discussion of the factors regulating development of megakaryocytes (Geddis) but also the exciting new developments from the work by Italiano’s group on the formation of platelets and that of Ben Kile on the emerging role of platelet apoptosis in the determination of platelet lifespan. Going more to the clinical, background chapters include the current use of platelet transfusions by McCullough, the discovery of thrombopoietin and development of thrombopoietic agents by Kuter, and a discussion combining laboratory and clinical aspects of fetal and neonatal megakaryocytopoiesis. The latter is particularly interesting because it emphasizes the differences in biologic response to thrombopoietin in this age group. The primary clinical areas in which there has been use of the thrombopoietic agents are idiopathic immune thrombocytopenic purpura (ITP), thrombocytopenia in liver disease, and the use in myelodysplastic syndromes and chemotherapy-induced thrombocytopenia. Finally, as a summary, Cuker reviews toxicities, both known and theoretical, that may occur with these agents. Overall this volume will provide the current state of the biology of thrombocytopenia and clinical use pertinent to the second generation thrombopoietic agents. Two of these agents (Nplate and Promacta) have been licensed in a number of countries and several others are in clinical trial. Some features have been expected, especially the high degree of efficacy and the low rate of toxicity. Others are more surprising, such as the relatively low rate of efficacy in chemotherapy-induced thrombocytopenia and
the high rate of efficacy in ITP, as well the sometimes cyclical nature of the ITP platelet response. Complicated questions remain to be addressed. What is the true risk of thrombosis with these agents and which factors augment this risk? Do these agents have a specific effect on platelet function separate from their effect on the platelet count? Why do certain patients not respond even to high doses of these agents? Are there groups of patients in which the risk of stimulation malignancy outweighs benefit and therefore in whom they should not be tried? Which other agents are the optimal ones to use in conjunction with the thrombopoietic agents? Finally, do these agents have curative effects in ITP patients such that they can be discontinued and the thrombocytopenia will be ameliorated if not cured rather than falling back to baseline? Partial answers to some of these questions exist and are discussed in the various chapters in this issue of Seminars. Most are the subject of active research. While this issue brings the reader up to date on the use of thrombopoietic agents in the management of thrombocytopenia, ongoing investigation provides additional information at a considerable rate such that evolution in this area is still rapid.
Seminars in Hematology, Vol 47, No 3, July 2010, p 211
211
James B. Bussel, MD Department of Pediatric Hematology Weill Cornell University Division of Pediatric Hematology New York Presbyterian Hospital New York, NY David J. Kuter, MD, DPhil Massachusetts General Hospital Boston, MA Guest Editors
Hematology
Vol 47, No 3 July 2010
New Thrombopoietic Agents: Introduction
T
his Seminars in Hematology issue on thrombopoietic agents and thrombocytopenia spans a wide spectrum of topics in the field. It begins with the biology of megakaryocytopoiesis and thrombocytopoiesis. This includes a discussion of the factors regulating development of megakaryocytes (Geddis) but also the exciting new developments from the work by Italiano’s group on the formation of platelets and that of Ben Kile on the emerging role of platelet apoptosis in the determination of platelet lifespan. Going more to the clinical, background chapters include the current use of platelet transfusions by McCullough, the discovery of thrombopoietin and development of thrombopoietic agents by Kuter, and a discussion combining laboratory and clinical aspects of fetal and neonatal megakaryocytopoiesis. The latter is particularly interesting because it emphasizes the differences in biologic response to thrombopoietin in this age group. The primary clinical areas in which there has been use of the thrombopoietic agents are idiopathic immune thrombocytopenic purpura (ITP), thrombocytopenia in liver disease, and the use in myelodysplastic syndromes and chemotherapy-induced thrombocytopenia. Finally, as a summary, Cuker reviews toxicities, both known and theoretical, that may occur with these agents. Overall this volume will provide the current state of the biology of thrombocytopenia and clinical use pertinent to the second generation thrombopoietic agents. Two of these agents (Nplate and Promacta) have been licensed in a number of countries and several others are in clinical trial. Some features have been expected, especially the high degree of efficacy and the low rate of toxicity. Others are more surprising, such as the relatively low rate of efficacy in chemotherapy-induced thrombocytopenia and
the high rate of efficacy in ITP, as well the sometimes cyclical nature of the ITP platelet response. Complicated questions remain to be addressed. What is the true risk of thrombosis with these agents and which factors augment this risk? Do these agents have a specific effect on platelet function separate from their effect on the platelet count? Why do certain patients not respond even to high doses of these agents? Are there groups of patients in which the risk of stimulation malignancy outweighs benefit and therefore in whom they should not be tried? Which other agents are the optimal ones to use in conjunction with the thrombopoietic agents? Finally, do these agents have curative effects in ITP patients such that they can be discontinued and the thrombocytopenia will be ameliorated if not cured rather than falling back to baseline? Partial answers to some of these questions exist and are discussed in the various chapters in this issue of Seminars. Most are the subject of active research. While this issue brings the reader up to date on the use of thrombopoietic agents in the management of thrombocytopenia, ongoing investigation provides additional information at a considerable rate such that evolution in this area is still rapid.
Seminars in Hematology, Vol 47, No 3, July 2010, p 211
211
James B. Bussel, MD Department of Pediatric Hematology Weill Cornell University Division of Pediatric Hematology New York Presbyterian Hospital New York, NY David J. Kuter, MD, DPhil Massachusetts General Hospital Boston, MA Guest Editors