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Multi-institutional phase II, randomized dose finding study of defibrotide in patients with severe veno-occlusive disease and multi-system organ failure post stem cell transplantation Promising response rate without significant toxicity in a high risk population



Multi-institutional phase II, randomized dose finding study of defibrotide in patients with severe veno-occlusive disease and multi-system organ failure post stem cell transplantation Promising response rate without significant toxicity in a high risk population



Blood 98(11 Part 1): 853a, 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, but does not produce significant systemic anti-coagulant effects. Studies have suggested that DF improved survival in pts with severe VOD and MOF with minimal toxicity. Most responses have been recorded between 20-40mg kg/d in intra-pt dose escalation trials but a uniformly effective dose has not been defined. Methods: A phase II randomized study is being carried out in pts with severe VOD and MOF to determine the effective dose. The primary endpoint is to define the complete response (CR) rate of pts with severe VOD treated with DF at either a dose of 25mg/kg/d (arm A) or 40 mg/kg/d (arm B). Secondary endpoints include any attributable toxicity; correlation of response with outcome and PAI-1 levels in pts treated with DF, and whether either dose shows a trend toward decreased mortality at day (d) +100 post SCT. The clinical diagnosis of VOD is defined by Baltimore criteria and severity determined by gtoreq30% risk on the Bearman model and/or the presence of MOF. Abdominal US with doppler is required prior to enrollment with liver biopsy and wedged hepatic venous pressure gradient measurement, necessary in confounding cases. Pts with gtoreq grade II GVHD are excluded and pts must be hemodynamically stable. Pts treated with prior tPA are ineligible. Pts are centrally registered and randomized with subsequent third party chart review. Treatment arms are stratified for age (<18y) and cyclophosphamide (Cy)- based conditioning. Treatment should continue gtoreq14d. Pts receiving <3d of therapy are inevaluable for response. CR is defined as a bilirubin <2 mg/dl with resolution of VOD-related MOF. Samples for special lab studies including PAI-1 are drawn prior to therapy and every 3d until completion of treatment. Results: 24 of the required 30 evaluable pts have been enrolled to date. 1 pt was found ineligible on liver biopsy and did not start therapy. 14 pts have been randomized to arm A and 9 pts to arm B with 23 pts treated and 20 pts currently evaluable for response. 20 pts underwent allo- and 3 auto- SCT, with 4 undergoing gtoreq2nd SCT. Median age was 22y (8mos-56y). Conditioning included CY in 20 pts (87%), busulfan in 6 (26%) and TBI in 14 (61%). At DF initiation (median d+14, range 6-30), median bilirubin was 8.4 mg/dl (range 2-21.1) and median weight gain of 15.9% (range 2.7-36.6%). Ascites was present in 21/23 (91%); RUQ pain in 16/23 (73%); hepatomegaly in 17/23 (74%), and abnormal portal flow in 13/23 (57%). MOF was present in 22/23 (96%), with 2 pts intubated. The median duration of DF therapy was 18d (2-41). No significant attributable DF toxicity has been reported. CR was observed in 9/20 pts (45%; 95% CI (23.1%, 68.5%)) with survival to d+100 in 8/20 (40%; 95% CI (19.1%, 64%)). Analysis of PAI-1 and a comparison between the two doses will be completed upon enrollment of the entire study cohort. Conclusion: The promising response rate, long term survival 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 single arm, emergency use studies. Moreover, the use of rigorous selection criteria and central review has minimized the confounding effects of investigator variability in the diagnosis and assessment of acuity in this multi-institutional study of DF in severe VOD.

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Accession: 035349254

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