Defibrotide for the Treatment of Hepatic Veno-Occlusive Disease: An Update from the International Compassionate Use Program in 710 Patients

Introduction: Hepatic veno-occlusive disease (VOD, or sinusoidal obstruction syndrome) is a potentially fatal complication of stem cell transplantation (SCT). Severe VOD (sVOD) is usually characterized by multi-organ failure (MOF) and >80% mortality. Defibrotide (DF) is approved in the EU for the treatment of sVOD in SCT. We report the final results of a large, international compassionate use program (CUP; 1998-2009) in Europe, the US, Asia, and the Middle East.

Methods: DF was provided on a compassionate basis or via single patient (pt) emergency-use requests post-SCT or chemo-/radiotherapy. Eligibility, DF use, safety, and outcomes were collected with case record forms. In the US, pts met Baltimore criteria for VOD and had MOF. At other sites, pts met Seattle or Baltimore, ultrasound, and/or histological criteria. Initial dosing recommendation was 10 mg/kg/d (4 divided doses/d IV) titrated up to 60 mg/kg/d based on tolerability/response. Following results of a US Phase 2 study, the recommended dose was 25 mg/kg/d. Treatment duration was up to investigators. Data included adverse events (AEs) and survival at Day+100 post-SCT or start of chemo-/radiotherapy.

Results: Safety/outcome data were submitted voluntarily for 710 pts receiving ≥1 DF dose. VOD developed post-SCT in 89% (71% allogeneic; 16% autologous; 2% missing), and post-chemo-/radiotherapy in 11%. Median age was 25 (range, 0.2-70) years; 43% were <18 years.

Median days to VOD onset was 13. Symptoms were bilirubin >2 mg/dL (88% of patients), weight gain >5% (82%), hepatomegaly (77%), ascites (67%), right upper quadrant pain (64%), and MOF (41%). Per Bearman criteria or MOF, 60% had sVOD.

The median dose was 25 mg/kg/d given for a median of 15d.

AEs were reported in 378 pts (53%; < 20% related); most were serious (364) and fatal (350). Causes of death were generally reported as AEs; hence the most common new or worsening AEs were MOF (144, all fatal), VOD (79, 78 fatal), and sepsis (49, 48 fatal). Serious AEs/fatalities were generally similar across doses. Hemorrhage was reported by 85 pts (55 serious, including 37 fatal), most commonly gastrointestinal (33) or respiratory (24). Central nervous system (CNS) hemorrhage was reported in 10 pts. Respiratory tract hemorrhage was highest in the 60/80 mg/kg/d dose group (9%) vs lower doses (<5%), but gastrointestinal and CNS hemorrhages were similar across doses (≤6%). Withdrawals due to an AE (63) were mostly due to hemorrhage (50), primarily gastrointestinal (22).

The Kaplan-Meier (KM) estimate of Day+100 survival was 54%. The figure shows KM survival curve by dose group; in the 25 mg/kg/d group (the approved EU dose) estimated survival was 58% at Day+100 (Figure).

Conclusions: DF was generally well tolerated in this large CUP; AEs were typical for VOD pts. Consistent with prior studies, survival was 54% at Day+100. Subgroup analyses support 25 mg/kg/d as the optimal dose.

Support: Jazz Pharmaceuticals