Updated Results from the Ongoing US Treatment IND Study Using Defibrotide for Patients with Hepatic Veno-Occlusive Disease

Introduction: Severe hepatic veno-occlusive disease (VOD, also called sinusoidal obstruction syndrome) with multi-organ failure (MOF) is a life-threatening complication of hematopoietic stem cell transplant (HSCT), with a mortality rate of >80%. Defibrotide has a protective effect on injured endothelium and restores thrombo-fibrinolytic balance. In severe VOD, defibrotide improves complete response (CR) rates and survival at Day+100 post-HSCT, with a favorable safety profile. In the EU, defibrotide is approved for treatment of severe hepatic VOD in HSCT therapy in adults and children. In the US, there are no approved therapies for VOD; however, defibrotide is available through an expanded access, protocol-directed treatment IND (T-IND). The T-IND gathers data on safety/efficacy of defibrotide in patients (pts) with severe and non-severe VOD post-HSCT, as well as post-chemotherapy (CT) alone.

Methods: The original T-IND protocol required VOD diagnosed by Baltimore criteria (total bilirubin ≥2.0 mg/dL with ≥2 of hepatomegaly, ascites, or 5% weight gain) with MOF (renal and/or pulmonary failure) following HSCT; the study was amended to include non-severe VOD (defined as no MOF) post-HSCT or post-CT. Exclusion criteria include clinically significant bleeding or need for >1 vasopressor. Defibrotide was given as a 2-hour infusion at 6.25 mg/kg IV q6h (25 mg/kg/d) for a recommended ≥21 days.

Results: This interim safety analysis update is based on 612 pts enrolled from December 2007 to December 2013 (including 99 in 2013) who received ≥1 defibrotide dose. Median patient age was 12 years (range <0.1–69).

Overall, ≥1 treatment emergent adverse event (AE) was reported in 454 pts (74.2%). Of these, 138 pts (22.5%) had AEs possibly, probably, or definitely related to defibrotide. Related AEs in >2.0% included pulmonary hemorrhage (4.7%), gastrointestinal hemorrhage (3.6%), epistaxis (3.1%), and hypotension (2.8%). Serious AEs (SAEs) were reported by 368 pts (60.1%) and most were assessed as not related to defibrotide; 82 pts (13.4%) had an SAE at least possibly related to study treatment, most commonly pulmonary hemorrhage (3.9%) and gastrointestinal hemorrhage (2.9%). AEs leading to death occurred in 254 pts (41.5%); these AEs were deemed possibly related to study medication in only 17 pts (2.8%).

Previously reported efficacy data at Day+100 in 425 evaluable pts showed survival of 55% (by Kaplan-Meier estimate) following HSCT, and 62% (by Kaplan-Meier estimate) in 45 pts following CT.

Conclusions: Defibrotide in pts with VOD was generally well tolerated in this population, with manageable toxicity and promising response rates and survival. Safety results from prior studies are consistent with the favorable tolerability profile seen in this largest experience to date. Enrollment to the T-IND study continues, with updated results to be presented at the meeting.

Support: Jazz Pharmaceuticals