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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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.
Hepatic Veno-Occlusive Disease
Multiple Organ Failure
Hematopoietic Stem Cell Transplantation
Dose-Response Relationship, Drug
Published Version (Please cite this version)10.1016/j.bbmt.2010.02.009
Publication InfoRichardson, Paul G; Soiffer, Robert J; Antin, Joseph H; Uno, Hajime; Jin, Zhezhen; Kurtzberg, Joanne; ... Guinan, Eva C (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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Jerome S. Harris Distinguished Professor of Pediatrics
Dr. Kurtzberg is an internationally renowned expert in pediatric hematology/oncology, pediatric blood and marrow transplantation, umbilical cord blood banking and transplantation, and novel applications of cord blood and birthing tissues in the emerging fields of cellular therapies and regenerative medicine. Dr. Kurtzberg serves as the Director of the Marcus Center for Cellular Cures (MC3), Director of the Pediatric Transplant and Cellular Therapy Program, Director of the Carolina
Paul Langlie Martin
Professor of Pediatrics
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 clinic
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