Treatment Duration, Symptom Resolution, and Survival in Defibrotide-Treated Patients with Veno-Occlusive Disease/Sinusoidal Obstruction Syndrome after Hematopoietic Cell Transplantation: Pooled Analysis of Defifrance and EBMT PASS Registries

Veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is a potentially life-threatening complication of hematopoietic cell transplantation (HCT). Defibrotide is approved for the treatment of severe hepatic VOD/SOS post-HCT in patients aged >1 month in the European Union and for hepatic VOD/SOS with renal or pulmonary dysfunction post-HCT in the United States. Clinical guidelines endorse prompt defibrotide initiation after VOD/SOS diagnosis. Outcomes from two real-world observational studies were pooled for analysis of time to diagnosis, treatment initiation and duration, and resolution of VOD/SOS in patients given defibrotide for the treatment of severe or non-severe VOD/SOS post-HCT.

DEFIFrance was an observational, post-marketing study that collected retrospective and prospective data on patients receiving defibrotide at 53 French transplant centers from July 2014 to March 2020. VOD/SOS severity was categorized retrospectively/prospectively using adult EBMT criteria in patients aged ≥18 years, and in patients aged <18 years using pediatric EBMT criteria. EBMT PASS was a multinational, prospective, observational study that enrolled defibrotide-treated patients from April 2015 to July 2018. EBMT PASS investigators graded VOD/SOS severity based on their clinical expertise. Investigators in both registries diagnosed VOD/SOS using classical/standard criteria (including, but not limited, to hyperbilirubinemia, hepatomegaly, ascites, and weight gain >5%). Since VOD/SOS grading was performed differently in the two registries, for this pooled analysis, mild/moderate and severe/very severe cases in DEFIFrance were combined with non-severe and severe cases in EBMT PASS, respectively.

Overall, 414 defibrotide-treated patients with VOD/SOS post-HCT were included (336 from DEFIFrance and 78 from EBMT PASS). The median (range) time from HCT to VOD/SOS diagnosis was 13 (interquartile range [IQR]: 8, 21) and 14 (IQR: 8, 22) days in patients with severe and non-severe VOD/SOS, respectively. Median time to initiation of defibrotide treatment after VOD/SOS diagnosis was 0 days in both severe (IQR: 0, 1) and non-severe (IQR: 0, 1) patients. 301/414 patients (73%) had resolution of VOD/SOS. Among those with severe and non-severe VOD/SOS, respectively, 208/302 (69%) and 91/108 (84%) had VOD/SOS resolution; 2 patients had missing severity data. Median time from start of defibrotide treatment to VOD/SOS resolution was 20 days (range: 3, 110) in patients with severe VOD/SOS and 15 days (range: 1, 147) in patients with non-severe VOD/SOS. Median treatment duration among patients with severe and non-severe VOD/SOS was 16.5 days (range: 1, 258) and 16 days (range: 3, 73), respectively. Among patients with resolution of VOD/SOS, symptoms resolved after Day 21 in 36% of patients with severe VOD/SOS and 23% of patients with non-severe VOD/SOS. Kaplan-Meier (KM)-estimated survival at Day 100 post-HCT among patients with severe VOD/SOS was 84% (95% confidence interval [CI]: 78%, 88%) in those who achieved VOD/SOS resolution and 14% (95% CI: 8%, 22%) in those who did not; among patients with non-severe VOD/SOS, this was 94% (95% CI: 87%, 98%) and 35% (95% CI: 15%, 57%), respectively.

Serious treatment-emergent adverse events (TEAEs) of interest occurred in 25% of patients with VOD/SOS resolution; similar safety outcomes were observed by defibrotide duration (≤21 days [25%] or >21 days [26%]). In patients treated for ≤21 days and >21 days, respectively, the most common serious TEAEs of interest by category were infection (14% and 15%) and hemorrhage (12% and 13%). Among patients with VOD/SOS resolution, the most common causes of death were infection (severe: 11%; non-severe: 2%) and GvHD (severe: 6%, non-severe: 2%).

In conclusion, time to resolution of VOD/SOS tended to be longer in patients with severe versus non-severe disease, with a substantial proportion requiring >21 days of therapy to achieve resolution. Day 100 survival was higher in patients with VOD/SOS resolution versus without, regardless of severity, highlighting the importance of obtaining resolution of VOD/SOS symptoms. The safety profile of defibrotide in the real-world setting was consistent with reports from previous studies, supporting the utility of defibrotide treatment.