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. Defibrotide is 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. Defibrotide was previously available in the United States as an investigational drug through a treatment protocol (treatment IND) study. Interim results of that large, treatment IND study of patients with VOD/SOS and with or without multiorgan dysfunction (MOD; also known as multiorgan failure) are presented here. Defibrotide was 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 MOD subgroup, 159 of 351 patients (45.3%; 95% CI, 40.1% to 50.5%) of patients were alive at day +100 post-HSCT. Treatment with defibrotide was 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 MOD symptoms, 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 defibrotide for VOD/SOS in adult and pediatric patients. These data support the potential benefit of defibrotide in treating a VOD/SOS patient population that includes those with and without MOD.

Defibrotide for children and adults with hepatic veno-occlusive disease post hematopoietic cell transplantation

“…Clinical studies of defibrotide support its use in the regulatoryapproved indication of treatment for hepatic VOD/SOS in children and adults following HSCT, with concomitant renal or pulmonary dysfunction in the USA and in patients with severe VOD/SOS in the European Union [38,39,59,[61][62][63].…”

“…As part of an expanded access treatment (T-IND) protocol, patients with VOD/SOS (with or without MOD) received IV defibrotide 6.25 mg/kg every 6 h (25 mg/kg/day) with a recommended treatment duration of ≥21 days [63]. In an interim analysis of 681 patients enrolled in the study, 642 met VOD/SOS criteria and received defibrotide; 573 (89.3%) had undergone HSCT, and the other 69 (10.7%) had developed VOD/SOS following chemotherapy alone.…”

“…Kaplan-Meier estimated survival at Day +100 was 53.8% for the overall HSCT population, 54.5% for the pediatric subgroup, and 44.9% for the adult subgroup. A subgroup of 76 patients with late-onset VOD/ SOS (VOD/SOS diagnosed >30 days post-HSCT (median age, 42 years) had a 34.2% Day +100 survival rate [63]. A post hoc analysis of the smaller post-chemotherapy group (82 patients treated by day 30 after start of chemotherapy) showed a Day +70 survival rate of 74.1% [64].…”

“…Related AEs in the defibrotide arm included hemorrhagic events and hypotension. In the interim report of the expanded-access T-IND study, which included patients with and without MOD as well as patients who had received chemotherapy without HSCT, AEs that occurred in >10% of patients were hypotension (13.8%) and new or worsening MOD (12.7%), and AEs that were attributed by investigators to treatment occurred in 21.6% of patients [63]. In the pediatric prevention trial, the incidence of AEs was much the same between groups: 154/ 177 (87%) in the defibrotide prophylaxis group and 155/176 (88%) in the controls [26].…”

Consolidation Therapy for Newly Diagnosed Pediatric Patients with High-Risk Neuroblastoma Using Busulfan/Melphalan, Autologous Hematopoietic Cell Transplantation, Anti-GD2 Antibody, Granulocyte-Macrophage Colony–Stimulating Factor, Interleukin-2, and Haploidentical Natural Killer Cells

“…It is important to interpret VOD in the context of the criteria, prophylactic regimen and grading systems used, as these factors are not uniform across institutions. The criteria and grading system we used were based on that used in the Defibrotide Treatment IND protocol (NCT 00628498) that was available at that time 39 , and our VOD prophylaxis was heparin/enoxaparin with or without ursodiol. In our study, 8 patients (n =30, 26.7%) developed VOD, 7 of which then received treatment with defibrotide.…”