Defibrotide for the treatment of severe hepatic veno-occlusive disease and multiorgan failure after stem cell transplantation: a multicenter, randomized, dose-finding trial.
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2010-07
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Therapeutic options for severe hepatic veno-occlusive disease (VOD) are limited and outcomes are dismal, but early phase I/II studies have suggested promising activity and acceptable toxicity using the novel polydisperse oligonucleotide defibrotide. This randomized phase II dose-finding trial determined the efficacy of defibrotide in patients with severe VOD following hematopoietic stem cell transplantation (HSCT) and identified an appropriate dose for future trials. Adult and pediatric patients received either lower-dose (arm A: 25 mg/kg/day; n = 75) or higher-dose (arm B: 40 mg/kg/day; n = 74) i.v. defibrotide administered in divided doses every 6 hours for > or =14 days or until complete response, VOD progression, or any unacceptable toxicity occurred. Overall complete response and day +100 post-HSCT survival rates were 46% and 42%, respectively, with no significant difference between treatment arms. The incidence of treatment-related adverse events was low (8% overall; 7% in arm A, 10% in arm B); there was no significant difference in the overall rate of adverse events between treatment arms. Early stabilization or decreased bilirubin was associated with better response and day +100 survival, and decreased plasminogen activator inhibitor type 1 (PAI-1) during treatment was associated with better outcome; changes were similar in both treatment arms. Defibrotide 25 or 40 mg/kg/day also appears effective in treating severe VOD following HSCT. In the absence of any differences in activity, toxicity or changes in PAI-1 level, defibrotide 25 mg/kg/day was selected for ongoing phase III trials in VOD.
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Richardson, Paul G, Robert J Soiffer, Joseph H Antin, Hajime Uno, Zhezhen Jin, Joanne Kurtzberg, Paul L Martin, Gideon Steinbach, et al. (2010). Defibrotide for the treatment of severe hepatic veno-occlusive disease and multiorgan failure after stem cell transplantation: a multicenter, randomized, dose-finding trial. Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation, 16(7). pp. 1005–1017. 10.1016/j.bbmt.2010.02.009 Retrieved from https://hdl.handle.net/10161/24611.
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Paul Langlie Martin
For most of my career in Pediatric Hematology/Oncology I have focused on the use of stem cell transplant for the treatment of pediatric leukemias (ALL, AML, CML and JMML) and other non-malignant blood disorders, such as sickle cell disease, hemaphagocytic disorders, Wiskott-Aldrich, aplastic anemia, Diamond-Blackfan Anemia, as well as inherited metabolic diseases. In addition to focusing on determining the best use of stem cell transplants for these disorders, I have also been involved in clinical research investigating the prevention and treatment of transplant related morbidity, particularly veno-occlusive disease of the liver, infections and diffuse alveolar hemorrhage. As study chair for the Children's Oncology Group protocol 9904, I was involved in the development, implementation and analysis of a large, international frontline study of childhood acute lymphoblastic leukemia. Results from this study show that a significant number of children with certain favorable cytogenetic abnormalities in their leukemic cells and who have a rapid response to their initial chemotherapy can expect to have a >95% chance of cure when treated with relatively low intensity chemotherapy.
I have concentrated on providing high quality care for high risk leukemia patients who require high intensity therapies, such as stem cell transplant and immunotherapy. As a member of the Pediatric Transplant and Cellular Therapy Division I provide clinical care for these patients. As a member of various cooperative groups and local PI for several drug trials, I have worked to provide better care and more specific therapies for the toxicities associated with stem cell transplant.
I have also collaborated with the Pediatric Immunology Division to provide a life-saving therapy for a small group of patients with thymic dysfunction, which causes severe immunodeficiency. Our clinical team now provides support during these patients hospital admissions for donor thymus tissue implantation. We once again achieved a new record for the number of implanted patients during the 2022-2023 academic year.
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