Defibrotide (DF) for the Treatment of Severe Veno-Occlusive Disease (sVOD) and Multi-Organ Failure (MOF) Post SCT: Final Results of a Multi-Center, Randomized, Dose-Finding Trial.

Abstract

Introduction: Severe VOD is an important regimen-related toxicity of hematopoietic SCT characterized by MOF and high mortality (>80% at d+100 post SCT). DF is a novel polydisperse oliogonucleotide with anti-thrombotic, anti-ischemic and thrombolytic properties, especially on microvasculature. DF appears to modulate endothelial cell (EC) injury in sVOD, with encouraging complete response (CR) rates, survival at d+100 post SCT and minimal toxicity reported.Methods: A multi-center, phase II trial was conducted in which patients (pts) stratified for age (<18y) and cyclophosphamide-based conditioning were randomized to 25 mg/kg/d or 40 mg/kg/d of DF. VOD diagnosis was made by Baltimore criteria, with severity determined by MOF or Bearman model (>30% risk). Study endpoints included CR, d+100 survival post SCT and toxicity. CR was defined as bilirubin <2 mg/dL and resolution of VOD-related MOF, with pts having ≥3d of DF evaluable for response. Abdominal ultrasound (US) with Doppler was required at study entry, d14 of DF, and completion of therapy, with blood collected serially to examine markers of EC stress.Results: 150 pts were treated with DF, with 75 pts on each treatment arm: 129 pts underwent allo- and 21 auto- SCT. Median age was 36y (6m–63y). At DF start, median bilirubin was 5.0 mg/dL; median weight gain 12%; ascites was present in 77%; RUQ pain in 71%; hepatomegaly in 69%; abnormal portal flow in 44%; and MOF in 99% (at study entry, 7% were dialysis-dependent (DD), 7% ventilator-dependent (VD); 28% developed DD and 23% VD during treatment). Median duration of DF therapy was 19d (1–82d). Of 150 pts treated, 141 were evaluable for response: 65 pts achieved CR (46%) and 62 survived to d+100 (41%), including pts with prior DD and VD. Results for CR and d+100 survival have been analyzed by dose level according to age, prior SCT and Mylotarg use. No significant difference in CR and d+100 survival was found between the 2 doses, although in pediatric pts receiving 25 mg/kg/d, CR and d+100 survival was 67% (p=0.06). Toxicity was limited, but more attributable G3/4 events, including bleeding and hypotension, were recorded in pts on 40 mg/kg/d, although the difference was not significant (p=0.11). Preliminary US review demonstrated improvement in portal flow abnormalities with DF therapy. EC stress markers showed reduction in median levels of PAI-1 and nitric oxide with increase in Protein C in pts achieving CR (p<0.05): median serum thrombomodulin, TFPI and soluble tissue factor increased in pts without response (p<0.05). Correlation with additional markers is ongoing. Similarly, multivariate analysis of factors predicting CR and d+100 survival is in process.Conclusion: DF treatment of sVOD/MOF results in a 46% CR rate and 41% d+100 survival post SCT: 25 mg/kg/d is the preferred dose. A phase 3 pivotal trial to confirm safety and efficacy is underway, comparing a prospective cohort of 80 DF-treated pts with sVOD/MOF to a matched historical group at 30 SCT centers across North America.