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.

Figures

Figure 1

Disposition of patients. Flowchart illustrating the progression of patients with severe hepatic VOD after HSCT by treatment group (arm A, 25 mg/kg/day i.v. defibrotide; arm B, 40 mg/kg/day i.v. defibrotide).

Figure 2

Survival of patients with severe hepatic VOD by treatment arm post-HSCT (A) and after randomization (B) (treated population). Kaplan-Meier curves show survival distributions for patients in treatment arms A and B.

Figure 3

Survival of patients with severe hepatic VOD by treatment arm for adult patients post-HSCT (A) and after randomization (B) and for pediatric patients post-HSCT (C) and after randomization (D) (treated population). Kaplan-Meier curves show survival distributions for patients aged ≥18 years and aged

Figure 4

Mean (standard deviation) PAI-1 (A) and total bilirubin (B) by treatment arm and outcome in patients with severe hepatic VOD treated with i.v. defibrotide. Bar charts illustrate PAI-1 levels (A) and total bilirubin levels (B) by CR/nonresponse, day +100 post-HSCT survival/nonsurvival, and treatment arm. D, day; NR, nonresponder.