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.

Disclosures: Defibrotide is an investigational agent in the U.S.A, but approved in Italy for the treatment of vascular disorders.; M Iacobelli is Medical Director of Gentium, SpA.; RJ Soiffer, MD, EC Guinan, MD, P Richardson, MD.; M Iacobelli has stock options.; Research support from Orphan Drug Grant (FD-R-002548-01), FDA: P Richardson, D Warren, C Revta, GB McDonald, EC Guinan, A Krishnan, PL Martin, N Kernan, G Vogelsang.; M Iacobelli is the Medical Director for Gentium SpA, Como Italy who manufactures Defibrotide.

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