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Defibrotide Appears Effective and Safe in a Phase II, Randomized Study of Patients with Severe Veno-Occlusive Disease and Multi-System Organ Failure Post Stem Cell Transplantation



Defibrotide Appears Effective and Safe in a Phase II, Randomized Study of Patients with Severe Veno-Occlusive Disease and Multi-System Organ Failure Post Stem Cell Transplantation



Blood 100(11): Abstract No 414, November 16



Introduction: DF, a single stranded polydeoxyribonucleotide, is an adenosine receptor agonist which has aptameric activity on endothelium with anti-thrombotic, anti-ischemic and thrombolytic properties, especially on microvasculature. DF does not produce significant systemic anti-coagulant effects. Studies have suggested that DF improves survival in pts with severe VOD and MOF with minimal toxicity. Previous dose escalation trials demonstrated responses between 20-40 mg/kg/d but no uniformly effective dose has been defined. Methods: A phase II randomized study has been carried out in pts with severe VOD to determine the effective dose. The primary endpoint was to define the complete response (CR) rate of pts treated with DF at either a dose of 25mg/kg/d (arm A) or 40 mg/kg/d (arm B), with randomization to eliminate selection bias between the 2 groups. Secondary endpoints included attributable toxicity and assessment of mortality at day (d) +100 post SCT. The clinical diagnosis of VOD was defined by Baltimore criteria and severity was determined by gtoreq 30% risk on the Bearman model and/or the presence of MOF. Abdominal US with Doppler was required prior to enrollment, with liver biopsy and wedged hepatic venous pressure gradient measurement in confounding cases. Pts with gtoreq grade II GVHD were excluded and pts had to be hemodynamically stable. Pts treated with prior tPA were ineligible. Treatment arms were stratified for age (< 18y) and cyclophosphamide (CY) - based conditioning. Treatment was planned for gtoreq 14d. Pts receiving < 3 d of therapy were inevaluable for response. CR was defined as a bilirubin < 2 mg/dl and resolution of VOD-related MOF. Results: 44 pts have been enrolled to date with a target accrual of 50; 21 pts have been randomized to arm A and 23 pts to arm B. One pt was ineligible with a negative liver biopsy and did not start therapy; 43 pts have been treated; 39 pts are currently evaluable for response, and 37 for d+100 survival. 39 pts underwent allo- and 4 auto- SCT, with 4 undergoing gtoreq 2nd SCT. Median age was 32 y (8mos-56y). Conditioning included CY in 40 pts (93%), busulfan in 15 (35%), and TBI in 27 (63%). 6 pts (14%) had previous treatment with Mylotarg as part of induction therapy pre-SCT. At DF initiation (median d +15, range 5-29), median bilirubin was 6.4 mg/dl (range 1.5- 21.1) and median weight gain was 15% (range 2 -37%). Ascites was present in 36 (84%); RUQ pain in 33 (77%); hepatomegaly in 31 (72%), and abnormal portal flow in 17 (40%). MOF was present in 40 (93%). The median duration of DF therapy was 20d (2-82). No dose limiting toxicity was observed and DF treatment was never discontinued for attributable adverse events. CR has been achieved in 20/39 pts (51%; 95% CI (35%, 68%)), including 3/6 pts (50%) who had received Mylotarg, with survival to d +100 in 17/ 37 pts (46%; 95%CI (30%, 63%)). A planned interim analysis of the first 30 pts did not show large differences in CR rate or d +100 survival between the two dose arms. Conclusion: The promising CR rate (51%), d +100 survival (46%), and favorable tolerability profile in this first prospective, randomized trial of DF in pts with severe VOD and MOF confirm the encouraging results of prior studies. Moreover, activity has been seen in pts with prior exposure to Mylotarg. No significant difference between dose arms is yet apparent and analysis of the completed trial will be required.

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Accession: 034689662

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