Defibrotide for Patients with Hepatic Veno-Occlusive Disease/Sinusoidal Obstruction Syndrome: Interim Results from a Treatment IND Study

Abstract Hepatic veno-occlusive disease, or sinusoidal obstruction syndrome (VOD/SOS), is a serious and potentially fatal complication of conditioning for hematopoietic stem cell transplantation (HSCT) or of chemotherapy regimens alone. Defibrotideis a complex mixture of single-stranded polydeoxyribonucleotides that is approved in the United States for treating hepatic VOD/SOS with renal or pulmonary dysfunction post-HSCT and in the European Union, Israel, and South Korea for treating severe hepatic VOD/SOS post-HSCT. Defibrotidewas previously available in the United States as an investigational drug through a treatment protocol ( treatment IND) study. Interim results of that large, treatment INDstudy of patients with VOD/SOS and with or without multiorgan dysfunction ( MOD; also known as multiorgan failure) are presented here. Defibrotidewas administered i.v. at 6.25 mg/kg every 6 hours (25 mg/kg/day), with a recommended treatment duration of at least 21 days. Enrolled patients (n = 681) were diagnosed with VOD/SOS based on Baltimore or modified Seattle criteria or liver biopsy analysis. Among the 573 HSCT recipients, 288 (50.3%; 95% confidence interval [CI], 46.2% to 54.4%) were alive at day +100 post-HSCT. Day +100 survival for the pediatric (≤16 years) and adult (>16 years) subgroups was 54.5% (95% CI, 49.1% to 60.0%; n = 174 of 319) and 44.9% (95% CI, 38.8% to 51.0%; n = 114 of 254), respectively. In the MODsubgroup, 159 of 351 patients (45.3%; 95% CI, 40.1% to 50.5%) of patients were alive at day +100 post-HSCT. Treatment with defibrotidewas generally well tolerated, and drug-related toxicities were consistent with previous studies. Adverse events were reported in 69.6% of safety-evaluable patients (399 of 573). Other than VOD/SOS and associated MODsymptoms, the most commonly reported treatment-emergent adverse event was hypotension (13.8%). Day +100 survival results observed in this trial were consistent with results seen in previous trials of defibrotidefor VOD/SOS in adult and pediatric patients. These data support the potential benefit of defibrotidein treating a VOD/SOS patient population that includes those with and without MOD.