VOD/SOS is an unpredictable, potentially life-threatening complication of conditioning regimens for HSCT or chemotherapy without HSCT, and has been reported to have an overall incidence of 13.7% post-HSCT. VOD/SOS with multi-organ dysfunction (MOD) may be associated with >80% mortality. In the United States, defibrotide is approved for the treatment of adult and pediatric patients with hepatic VOD/SOS and renal or pulmonary dysfunction following HSCT, and it is approved in the European Union for treatment of severe hepatic VOD/SOS after HSCT. Here, a pooled analysis compared overall survival among groups based on severity of VOD/SOS, including those with MOD and those who were ventilator- or dialysis-dependent.


This analysis included data from a phase 2 trial, a phase 3 trial, and an expanded-access (T-IND) program. The phase 2 dose-finding trial (defibrotide 25 mg/kg/day [n=75] and 40 mg/kg/day [n=74]) in patients with VOD/SOS and MOD found no significant differences in efficacy or safety between doses. The phase 3 treatment trial compared the efficacy and safety of defibrotide at 25 mg/kg/day in patients with VOD/SOS with MOD (n=102) to those of patients from a historical control group (n=32) that met the study's inclusion criteria but were treated at the study's centers prior to the availability of defibrotide at that institution. The T-IND study provided access to 25 mg/kg/day defibrotide prior to regulatory approval in the United States and generated prospective data on outcomes in 1154 VOD/SOS patients with and without MOD following HSCT or chemotherapy without HSCT. Data from patients with VOD/SOS and MOD (renal or pulmonary dysfunction, Table 1) following HSCT were pooled to examine Day +100 survival in relationship to MOD severity, with dialysis and ventilator dependence at baseline indicating the most severe dysfunction.


The total pooled population from the 3 trials was 763 patients with VOD/SOS and MOD post-HSCT (phase 2 trial, n=149; phase 3 trial, n=102; T-IND study, n=512). Of these, 219 (28.7%) patients had ventilator dependence (irrespective of dialysis dependence) and 172 (22.5%) patients had dialysis dependence (irrespective of ventilator dependence; Table 2). A total of 275 patients had either dependence (ie, at least one) and 116 had both dependencies. The 32 historical control patients from the phase 3 trial were analyzed separately (Table 2). Median age in the pooled treatment population was 17 (range, 0-72) years and 18 (range, 1-57) in the historical controls.

Kaplan-Meier Day +100 estimated survival rate was 51.9% (95% confidence interval [CI], 47.3%-56.3%) in patients with neither dependence (n=488). In the 275 patients with either dependence, Kaplan-Meier Day +100 estimated survival was 36.3% (95% CI, 30.6%-42.0%); and in patients with both dependencies (n=116), Kaplan-Meier Day +100 estimated survival was 29.1% (95% CI, 21.1%-37.6%).

In the 32-patient historical control group, Kaplan-Meier Day +100 estimated survival rates were: 28.0% (95% CI, 12.4%-46.0%) in patients with neither dependence (n=25) and 14.3% (95% CI, 0.7%-46.5%) in patients with at least one dependence (n=7). One patient in this group had both ventilator and dialysis dependence and died prior to Day +100.

In the pooled group of treated patients, 627 (82.2%) had at least one adverse event, with 196 (25.7%) having a treatment-related adverse event (TRAE). The most common TRAEs (>2% of the population) were: hypotension, 4.1%; gastrointestinal hemorrhage, 3.9%; pulmonary hemorrhage, 3.9%; epistaxis, 2.8%; and pulmonary alveolar hemorrhage, 2.0%. Hemorrhagic events were reported in 40.6%; hypotension in 22.7%. All 32 historical patients had at least one adverse event.


Results from this pooled analysis of patients with VOD/SOS with MOD from 3 defibrotide studies suggest that survival outcomes are better when the treated patients have less severe forms of MOD (51.9%) vs patients with ventilator and/or dialysis dependence (36.3%) vs both ventilator plus dialysis dependence (29.1%). In the small historical control population, Day +100 survival in patients without ventilator or dialysis dependence was 28.0% and was 14.3% in patients with ventilator and/or dialysis dependence.

Support: Jazz Pharmaceuticals.


Richardson: Oncopeptides AB: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Research Funding. Kernan: Gentium: Other: Received grants from Gentium during the conduct of the study and research was supported by The National Cancer Institute of the National Institutes of Health under award number P30 CA 008748, Research Funding. Antin: Gentium SpA/Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Ryan: Celator/Jazz: Employment, Equity Ownership. Hume: Jazz Pharmaceuticals, Inc.: Employment, Other: stock options. Tappe: Jazz Pharmaceuticals, Inc.: Employment, Other: stock options. Grupp: University of Pennsylvania: Patents & Royalties; Jazz Pharmaceuticals: Consultancy; Novartis Pharmaceuticals Corporation: Consultancy, Other: grant; Adaptimmune: Consultancy.

Author notes


Asterisk with author names denotes non-ASH members.