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Defibrotide for the Treatment of Hepatic Veno-Occlusive Disease: Final Results From the International
Selim Corbacioglu1, Enric Carreras2, Mohamad Mohty3
1Department of Pediatric Hematology, Oncology and Stem Cell Transplantation, University of Hospital Regensburg, Regensburg, Germany.
Insights
Defibrotide treatment for hepatic veno-occlusive disease (VOD/SOS) showed a 54% day +100 survival rate in a compassionate-use program. The 25 mg/kg/day dose demonstrated promising efficacy and safety in this high-mortality patient population.
Area of Science:
- Hematology
- Transplantation Medicine
- Pharmacology
Background:
- Hepatic veno-occlusive disease (VOD/SOS) is a severe complication of hematopoietic cell transplantation (HCT) and chemotherapy.
- Mortality for severe VOD/SOS with multiorgan failure (MOF) exceeds 80%.
Purpose of the Study:
- To evaluate the efficacy and safety of defibrotide in patients with hepatic VOD/SOS through a compassionate-use program.
- To identify an optimal dose for defibrotide treatment in this patient population.
Main Methods:
- An international multicenter compassionate-use program collected data for 710 patients treated with defibrotide.
- Patients received defibrotide at doses ranging from 10 to 80 mg/kg/day.
- Kaplan-Meier analysis was used to estimate overall survival and assess adverse events.
Main Results:
- The overall day +100 survival rate was 54%, with 58% survival in the 25 mg/kg/day dose group.
- Adverse events were reported in 53% of patients, consistent with the expected complications in this population.
- No significant trends in adverse events were observed based on gender, age, or dose.
Conclusions:
- Defibrotide demonstrates potential efficacy and a manageable safety profile for treating hepatic VOD/SOS.
- Subgroup analyses support the 25 mg/kg/day dose as a potentially optimal regimen.
- These findings support further investigation into defibrotide for hepatic VOD/SOS.
Abstract:
Hepatic veno-occlusive disease, also called sinusoidal obstruction syndrome (VOD/SOS), is an unpredictable and potentially fatal complication of hematopoietic cell transplantation (HCT) or nontransplantation-associated chemotherapy/radiotherapy. In cases of severe hepatic VOD/SOS, typically defined by associated multiorgan failure (MOF, also known as multiorgan dysfunction), mortality exceeds 80%. Preclinical and early clinical data have provided a rationale for defibrotide treatment in hepatic VOD/SOS. Based on this evidence and in recognition of the dismal prognosis for these patients, defibrotide was made available through an international multicenter compassionate-use program conducted from December 1998 to March 2009. Physicians participating in the program voluntarily provided demographic and outcome data for patients given defibrotide. Efficacy and safety analyses were performed using the data received for 710 treated patients. Defibrotide was given at 10, 25, 40, 60, or 80 mg/kg/day for a median of 15 days (range, 1 to 119 days). By Kaplan-Meier analysis, the estimated overall day +100 survival was 54% (58% in the 25 mg/kg/day dose group). Adverse events (AEs) were reported in 53% of patients. The most common AEs were MOF, progression of hepatic VOD/SOS, sepsis, and graft-versus-host disease, which were consistent with the AEs expected for this patient population. No clinically meaningful trends in AEs were identified by gender, age, or dose group. Safety and efficacy resultswere consistent with prior studies of defibrotide in hepatic VOD/SOS, and subgroup analyses lend support to the use of the 25 mg/kg/day dose.
