A Pooled Analysis of Survival By Defibrotide (DF) 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 nontransplant chemotherapy. VOD/SOS with multi-organ dysfunction (MOD; eg, renal or pulmonary) 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 Canada, and severe hepatic VOD/SOS post-HSCT in patients aged >1 month in the EU. Methods Data from the international compassionate use program (CUP) and expanded-access protocol (T-IND) were pooled (due to the nature of the protocols, both studies included patients with and without MOD) to investigate whether time to DF initiation after VOD/SOS diagnosis had an impact on Day +100 survival. In the CUP (N=710) and T-IND (N=1137), VOD/SOS was diagnosed by Baltimore or modified Seattle criteria or biopsy (CUP enrollment also included hemodynamic, ultrasound, or histologic evidence of VOD/SOS). Adults (>18 years) with VOD/SOS post-HSCT who received DF 25 mg/kg/day dosage and had time to dosing data were pooled. The analyses examined (1) initiation of DF before/after Days 1, 2, 3, 4, 7, and 14 after diagnosis (Fisher's exact test) and (2) starting DF on a particular day post-diagnosis: 0, 1, 2, 3, 4, 5, 6, 7, 8–14, and ≥15 (Cochran-Armitage test for trend). Results Of 534 pooled adults (aged ≥18) receiving 25 mg/kg/day with timing data, 300 (56%) had MOD. DF was initiated by Day 1 in 273 (51%) patients. In the analysis of DF initiation before or after Days 1, 2, 3, 4, 7, and 14, earlier initiation showed numerically higher survival rates for all cut points. Cochran-Armitage test for trend in the overall group suggested that Day +100 survival was higher with earlier initiation post diagnosis (Table). AEs in the CUP were consistently reported only for certain events. In all adults post-HSCT in the T-IND, treatment-related AEs in ≥2% were epistaxis and gastrointestinal hemorrhage (3.5% each), pulmonary hemorrhage (2.3%), and hematuria and hypotension (2.1% each). Conclusions DF administered at any given time point is of therapeutic value in patients with VOD/SOS. However, the results from the pooled post hoc analysis of post-HSCT adults suggest that earlier DF initiation after VOD/SOS diagnosis may improve Day +100 survival outcomes, although no specific day post-diagnosis provides a clinically meaningful cutoff for better outcome. Causes of treatment delay were not assessed. The safety profile for these patients was consistent with other DF studies in VOD/SOS. Support Jazz Pharmaceuticals.