Defibrotide for the treatment of severe hepatic veno-occlusive disease and multiorgan failure after stem cell transplantation: a multicenter, randomized, dose-finding trial.

Abstract

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.

• Authors: Paul G Richardson, Robert J Soiffer, Joseph H Antin, Hajime Uno, Zhezhen Jin, Joanne Kurtzberg, Paul L Martin, Gideon Steinbach, Karen F Murray, Georgia B Vogelsang, Allen R Chen, Amrita Krishnan, Nancy A Kernan, David E Avigan, Thomas R Spitzer, Howard M Shulman, Donald N Di Salvo, Carolyn Revta, Diane Warren, Parisa Momtaz, Gary Bradwin, L J Wei, Massimo Iacobelli, George B McDonald, Eva C Guinan
• Journal: Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation (Biol Blood Marrow Transplant) Vol. 16 Issue 7 Pg. 1005-17 (Jul 2010) ISSN: 1523-6536 [Electronic] United States
• PMID: 20167278 (Publication Type: Clinical Trial, Phase II, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• Fibrinolytic Agents
• Polydeoxyribonucleotides
• defibrotide

Topics

• Adolescent
• Adult
• Child
• Child, Preschool
• Dose-Response Relationship, Drug
• Female
• Fibrinolytic Agents (adverse effects, pharmacokinetics, therapeutic use)
• Hematopoietic Stem Cell Transplantation (adverse effects)
• Hepatic Veno-Occlusive Disease (drug therapy, etiology, metabolism, pathology)
• Humans
• Infant
• Infant, Newborn
• Male
• Middle Aged
• Multiple Organ Failure (drug therapy, etiology, metabolism)
• Polydeoxyribonucleotides (adverse effects, pharmacokinetics, therapeutic use)
• Survival Rate
• Treatment Outcome
• Young Adult