A Pooled Analysis of Survival By Defibrotide Timing of Initiation in Adults with Veno-Occlusive Disease/Sinusoidal Obstruction Syndrome (VOD/SOS) Following Hematopoietic Stem Cell Transplant (HSCT)

Abstract Introduction Hepatic VOD/SOS is a potentially life-threatening complication of HSCT or of nontransplant-associated high-dose chemotherapy. VOD/SOS associated with multi-organ dysfunction (MOD; eg, renal or pulmonary dysfunction) may be associated with >80% mortality. Defibrotide is approved to treat hepatic VOD/SOS with renal and/or pulmonary dysfunction post-HSCT in the United States and Canada, and to treat severe hepatic VOD/SOS post-HSCT in patients aged >1 month in the European Union. Prior to US approval, defibrotide was available through an international compassionate-use program (CUP; 1998-2009) and an expanded-access protocol (T-IND; 2007-2016). Data for adults with VOD/SOS post-HSCT from the CUP and the T-IND were pooled to investigate whether the time to initiate defibrotide therapy after VOD/SOS diagnosis had an impact on Day +100 survival. Methods In both the CUP (N=710) and the T-IND (N=1137), defibrotide was used to treat hepatic VOD/SOS following HSCT or nontransplant-associated chemotherapy in pediatric and adult patients with or without MOD. Diagnosis of VOD/SOS was made using the Baltimore or modified Seattle criteria or was proven by biopsy (the CUP also allowed patients with hemodynamic, ultrasound, or histologic evidence of VOD/SOS to enroll). In the CUP cohort, the defibrotide median daily dose was 25 mg/kg/day administered for a median of 15 days; only patients who received 25 mg/kg/day were included in the analysis. In the T-IND, the defibrotide dose was 25 mg/kg/day for a recommended administration ≥21 days. In this analysis, adult patients (aged >18 years) from the CUP and the T-IND with VOD/SOS post-HSCT were pooled to examine Day +100 survival rates by time to start of defibrotide post-diagnosis. The first analysis examined patients who initiated defibrotide before/after Days 1, 2, 3, 4, 7, and 14 after VOD/SOS diagnosis, using Fisher's exact test, and the second examined starting defibrotide on a particular day: 0, 1, 2, 3, 4, 5, 6, 7, 8-14, and ≥15 (Cochran-Armitage test for trend across days). Results Of 534 pooled adult patients with VOD/SOS following HSCT who were treated with defibrotide 25 mg/kg/day and had reported time to dosing, 300 (56%) patients had MOD. Defibrotide treatment was initiated by Day 1 in 273 (51%) patients. In the analysis of treatment initiation before or after Days 1, 2, 3, 4, 7, and 14, earlier initiation of defibrotide showed numerically higher survival rates for all cut points (Day +100 survival before and after all cut points is provided in Table 1). Cochran-Armitage test for trend in the overall group suggested that Day +100 survival was higher with earlier initiation following diagnosis (nominal P=0.011; for patients with MOD, P=0.048; Table 2). Safety information for the CUP and T-IND were not pooled, as adverse events in the CUP were reported only if those events caused death in a consistent fashion. In all adult patients with post-HSCT VOD/SOS in the T-IND, treatment-related adverse events that occurred in ≥2% of adults were epistaxis and gastrointestinal hemorrhage (3.5% each), pulmonary hemorrhage (2.3%), and hematuria and hypotension (2.1% each). Conclusion: These results from the pooled post hoc analysis of adult patients with VOD/SOS post-HSCT from the CUP and T-IND studies suggest that earlier defibrotide initiation post-VOD/SOS diagnosis may improve Day +100 survival outcomes, although no specific day post-diagnosis provides a clinically meaningful cutoff for better outcome, suggesting that later intervention still retains value if therapy is not initiated sooner. Causes of treatment delay were not assessed. The safety profile for these patients was consistent with other defibrotide studies in VOD/SOS. Support: Jazz Pharmaceuticals. Disclosures Richardson: Janssen: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Carreras:Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Pagliuca:Gentium: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Ryan:Jazz Pharmaceuticals: Employment, Other: Stock and stock options. Tappe:Jazz Pharmaceuticals: Employment, Other: Stock and stock options. Mohty:Molmed: Consultancy; Servier: Consultancy; Jazz Pharmaceuticals: Honoraria, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Honoraria, Research Funding, Speakers Bureau; MaaT Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol Myers: Consultancy, Research Funding; Celgene: Consultancy, Honoraria; Takeda: Honoraria, Speakers Bureau.

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