Defibrotide for the Treatment of Veno-Occlusive Disease Post SCT: Preliminary Results of EU Compassionate Use Program in 332 Patients Confirm Promising Activity and Manageable Toxicity.

Introduction: Hepatic veno-occlusive disease (VOD) is one of the most significant regimen-related toxicities of stem cell transplantation (SCT), which when complicated by multi-organ failure (MOF) has a case fatality rate >90%. Defibrotide (DF) is a polydisperse oligonucleotide, with anti-thrombotic, anti-ischemic and thrombolytic properties, especially on microvasculature. Results in earlier studies of DF therapy for VOD/MOF have consistently shown manageable toxicity with promising complete response (CR) rates and D+100 survival post SCT. We report the results of the largest compassionate use program (CUP) performed to date.

Methods: Physicians in Europe requesting DF for the treatment of pts with VOD obtained the drug on a named patient basis and were requested to collect data by a standardized CRF. Patients (pts) were reviewed to identify the nature and frequency of Suspected Adverse Drug Reactions (SADR). CR and D+100 survival post-SCT were assessed with CR defined as bilirubin <2 mg/dl and resolution of VOD-related end-organ dysfunction. From February 1999 to July 2007, 332 pts (215 men (65%), 117 women (35%), with a median age of 28 years) from 96 European centers received DF (Gentium SpA, Como, Italy). Pts were both adults (208 pts 63%, range: 18–66 yrs) and pediatric (124 pts, 37%, range: 2 months-17 years). 253 pts underwent allo-SCT (77%), and 76 auto-SCT (23%). At entry, all pts had VOD defined by either Baltimore criteria (205, 62%), modified Baltimore criteria [within 35 days of SCT] (n=42, 13%), Seattle criteria (84, 25%) or were biopsy proven (n=1). MOF was present in 113 pts (34%): 90/332 (27%) pts had renal, 53/332 (16%) had respiratory and 15/332 (5%) had CNS dysfunction. Median dose of DF was 37 mg/kg/d (range: 10–120 mg/kg/d). Median duration of DF therapy was 14d. Overall, D+100 survival was 46% (154 pts). CR was achieved in 173 pts (52%), with 142 alive in CR at D+100 (82%). NR was seen in 159 (48%), with only 12 alive at D+100 (8%). In a subset of 73 pts with severe VOD (defined by Baltimore criteria and MOF), survival at D+100 was 34% (25 pts). The overall incidence of attributable SADRs was 8% (n=28) and consisted predominantly of haemorrhages (n=27, 8%), most of which proved reversible.

Conclusions: In this largest study of pts treated with DF to date, no unexpected toxicities were reported and side effects were generally manageable. CR was obtained in 52% with D+100 survival in 46%, including 34% in those pts with severe disease. This is consistent with prior studies and suggests that DF offers a relatively safe and effective treatment for hepatic VOD post SCT.