A Phase 3, Randomized, Adaptive Study of Defibrotide (DF) Vs Best Supportive Care (BSC) for the Prevention of Hepatic Veno-Occlusive Disease/Sinusoidal Obstruction Syndrome (VOD/SOS) in Patients (pts) Undergoing Hematopoietic Cell Transplantation (HCT): Preliminary Results

Introduction: Hepatic VOD/SOS is a potentially life-threatening complication of HCT. VOD/SOS with multiorgan dysfunction/multiorgan failure (MOD/MOF) is associated with a mortality rate >80% if untreated. DF is approved for VOD/SOS with renal or pulmonary dysfunction post-HCT in the US and for severe VOD/SOS post-HCT in pts aged >1 month in the EU. A recent meta-analysis of >1000 pts, including a phase 3 trial in high-risk pediatric pts, reported a significantly lower risk of VOD/SOS with prophylactic DF vs controls. This phase 3 study compared the efficacy and safety of DF vs BSC for prevention of VOD/SOS in pts undergoing HCT and at high risk of developing VOD/SOS.

Methods: This study (NCT02851407) enrolled pts aged >1 month, who were scheduled to undergo allogeneic (adult/pediatric pts) or autologous HCT (pediatric pts) and at high risk of developing VOD/SOS. High-risk pts underwent myeloablative conditioning (MAC) and had ≥1 hepatic-related EBMT risk factor or advanced-stage neuroblastoma. Very high-risk pts had osteopetrosis or hemophagocytic lymphohistiocytosis (or related disorder) and were undergoing MAC, or had received prior treatment with an ozogamicin-containing monoclonal antibody, or had class III high-risk thalassemia. Pts receiving rapamycin for GvHD prophylaxis were not included as a pre-specified high-risk group. Eligible pts were randomized 1:1 to DF prophylaxis (IV DF 25 mg/kg/day for up to 21 days + BSC) or BSC per institutional guidelines. VOD/SOS was diagnosed using modified Seattle criteria by investigators and evaluated by an Endpoint Adjudication Committee (EPAC) using a prespecified, blinded algorithm. Pts who developed VOD/SOS were treated with DF until resolution of VOD/SOS and related MOD/MOF.

The primary endpoint was VOD/SOS-free survival by Day 30 post-HCT, as assessed by EPAC. Secondary endpoints included VOD/SOS-free survival by Day 100 post-HCT and incidence of VOD/SOS by Day 30. Investigator-assessed VOD/SOS-free survival by Day 30 post-HCT is also reported.

Results: Overall, 372 pts were enrolled: 190 in the DF group (median age [range]: 13.0 [0, 72] years) and 182 in the BSC group (median age [range]: 15.0 [0, 69]). Common primary diseases included acute lymphoblastic leukemia (26% vs 28%, respectively), acute myeloid leukemia (27% vs 24%) and neuroblastoma (14% vs 17%). Per EPAC, Kaplan-Meier (KM)-estimated VOD/SOS-free survival by Day 30 was similar in the DF and BSC groups (primary endpoint: 67% [95% Cl: 58, 74%] vs 73% [95% Cl: 62, 80%], respectively; P = 0.85) and at Day 100 (50% [95% Cl: 26, 70%] vs 57% [95% Cl: 37, 73%]; nominal P = 0.81). The KM-estimated investigator-assessed VOD/SOS-free survival by Day 30 was 85% (95% Cl: 79, 90%) in the DF group and 80% (95% Cl: 73, 86%) in the BSC group (hazard ratio = 0.760 [95% CI: 0.450, 1.29]; nominal P = 0.14). EPAC and investigators were discordant in 28% of VOD/SOS assessments. By Day 30 post-HCT, EPAC had diagnosed VOD/SOS more frequently in both groups vs investigators. There were 50 pts diagnosed with VOD/SOS by EPAC but not by investigators; 4 pts were diagnosed with VOD/SOS by investigators but not EPAC.

In the DF and BSC groups, a comparable percentage of pts (99% and 100%, respectively) had adverse events (AEs); the most common (>50% of pts) were pyrexia (61% and 64%), nausea (60% and 56%), diarrhea (58% and 61%), stomatitis (58% and 67%) and vomiting (57% and 52%). Serious AEs (SAEs) occurred in 45% and 43% of pts in the DF and BSC groups, respectively; AEs/SAEs reflected HCT. Incidence of AEs of special interest (AESI) were similar between the DF and BSC groups (hypersensitivity reactions [50% and 45%, respectively], pulmonary hemorrhage [24% and 26%] and GI bleeding [9% and 8%]). AEs leading to death occurred in 6% of pts in each group.

Conclusions: No significant difference was observed between the DF-treated and BSC groups in the primary endpoint, as assessed by EPAC; secondary endpoints were consistent with this result. A comparable percentage of pts had AEs, SAEs, and AESIs, supporting the safety of DF in this setting. No new safety signals were identified. Substantial differences between EPAC and investigators' assessment of VOD/SOS highlight the challenges in VOD/SOS diagnosis and confound interpretation of these results. Potential differences between the trial population and current clinical practice, including limited representation of some at-risk groups, may further limit interpretation of these data.