Efficacy and safety of defibrotide (DF) to treat hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) after primary chemotherapy (CT): A post hoc analysis of final data.

Abstract

10513 Background: VOD/SOS, which may be unpredictable and potentially life-threatening, is typically considered a complication of hematopoietic stem cell transplantation (HSCT); VOD/SOS with multi-organ dysfunction (MOD) may be associated with >80% mortality. DF is approved to treat hepatic VOD/SOS with renal or pulmonary dysfunction post-HSCT in the US and to treat severe hepatic VOD/SOS post-HSCT in the EU. However, VOD/SOS can occur after CT without HSCT. Methods: In an expanded-access protocol for patients (pts) with VOD/SOS post-HSCT or CT, with/without MOD (renal/pulmonary), DF 25 mg/kg/d (6.25 mg/kg q6h) was given a recommended ≥21 days. Post-CT subgroup survival was analyzed post hoc from the day DF was started (days 0–30 after start of CT) for 70 days (ie, up to 100 days, as follow-up was collected for 100 days post-CT). Results: Of 1154 VOD/SOS pts receiving DF, 137 (12%) developed VOD/SOS post-CT without HSCT. Among 82 pts (38 with MOD) treated by day 30 after start of CT, median age was 7.5 yrs (range, 0–68 years) and 66 (81%) were ≤16 yrs. Most common primary diseases were acute leukemias (65%). Kaplan-Meier estimated survival at day +70 was 74% overall (95% CI, 63–82%); 66% (49–79%) and 81% (66–90%) in pts with/without MOD, respectively. In the pediatric pts, estimated survival at day +70 was 80% (68–88%); in adult pts, 50% (25–71%). Adverse events (AEs) were reported in 54/82 pts (66%); 22 (27%) had AEs assessed as possibly related to DF, most commonly (≥2%) pulmonary or mouth hemorrhage (4% each) and hematochezia, nausea, encephalopathy, epistaxis, or hypotension (2% each). Hemorrhagic AEs of any relatedness (≥2%) were pulmonary (6%), epistaxis or mouth (4%), and hematochezia (2%). Related AEs led to discontinuation in 6 pts and were associated with 1 death (pulmonary hemorrhage, hypotension). Conclusions: The 74% survival rate at day +70 in pts with VOD/SOS receiving DF within 30 days of starting CT (80% in pts ≤16 yrs) is clinically encouraging. Of note is the 66% survival rate in pts with MOD. The safety profile was consistent with that previously reported in the overall population of this protocol. Support: Jazz Pharmaceuticals Clinical trial information: NCT00628498.