Resolution of Veno-Occlusive Disease/Sinusoidal Obstruction Syndrome (VOD/SOS) with Defibrotide Following HCT in Adult and Pediatric Patients: Pooled Analysis of Defifrance and EBMT PASS Registries

Abstract

Introduction 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 VOD/SOS post-HCT in patients aged >1 month in the European Union and for VOD/SOS with renal or pulmonary dysfunction post-HCT in the United States. Outcomes from two real-world observational studies were pooled for analysis of treatment duration and time to resolution of VOD/SOS in patients given defibrotide for the treatment of severe or nonsevere VOD/SOS post-HCT. Methods DEFIFrance was an observational 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 European Group for Blood and Marrow Transplantation (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. VOD/SOS severity was graded based on investigators' clinical expertise. For this pooled analysis, mild/moderate and severe/very severe cases in DEFIFrance were combined with nonsevere and severe cases in EBMT PASS, respectively. Investigators in both registries diagnosed VOD/SOS using classical/standard criteria. Results Overall, 414 defibrotide-treated patients with VOD/SOS post-HCT were included (336 from DEFIFrance and 78 from EBMT PASS). The median (interquartile range [IQR]) time from HCT to VOD/SOS diagnosis was 13 (IQR: 8, 21) and 14 (IQR: 8, 22) days in patients with severe and nonsevere VOD/SOS, respectively. Overall, 299/410 patients (73%) had resolution of VOD/SOS. Disease severity data was missing from 4 patients. Among 275 adult patients, VOD/SOS resolution was achieved in 44/60 (73.3%) with nonsevere and 128/215 (59.5%) with severe VOD/SOS. Median treatment duration was 15.5 days (IQR: 13, 22) for nonsevere and 18.5 days (IQR: 13.5, 22) for severe VOD/SOS. Of 135 pediatric patients, VOD/SOS resolution occurred in 47/48 (98%) with nonsevere and 80/87 (92%) with severe VOD/SOS. Median treatment duration was 16 days (IQR: 13, 21) in nonsevere and 21 days (IQR: 12.5, 29) in severe VOD/SOS. Among adult patients with resolution of VOD/SOS, symptoms resolved after day 21 in 32% of patients with nonsevere and 31% of patients with severe VOD/SOS. A higher proportion of pediatric patients with severe (44%) compared with nonsevere VOD/SOS (15%) required >21 days of treatment for resolution of symptoms; correspondingly, 85% of pediatric patients with nonsevere and 56% with severe VOD/SOS had resolution with ≤21 days of defibrotide treatment. 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 nonsevere 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. 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%; nonsevere: 2%) and graft-versus-host disease (severe: 6%; nonsevere: 2%). Conclusion Time to resolution of VOD/SOS tended to be longer in patients with severe versus nonsevere VOD/SOS, with many patients requiring >21 days of therapy to achieve resolution. A higher proportion of adult vs pediatric patients attained a CR >21 days after initiation of defibrotide treatment. Day 100 survival was higher in patients with VOD/SOS resolution versus without, regardless of severity, highlighting the importance of VOD/SOS resolution. The safety profile of defibrotide in the real-world setting was consistent with reports from previous studies, supporting the utility of defibrotide treatment per the prescribing information.