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Multi-institutional emergency use of defibrotide in 75 pts post SCT with severe VOD and multi-system organ failure Response without significant toxicity in a high risk population



Multi-institutional emergency use of defibrotide in 75 pts post SCT with severe VOD and multi-system organ failure Response without significant toxicity in a high risk population



Blood 96(11 Part 1): 585a, November 16



DF, a single stranded polydeoxyribonucleotide, is an adenosine receptor agonist with aptameric activity on endothelium. It has anti-thrombotic, anti-ischemic and thrombolytic properties but does not produce significant anti-coagulant effects. Preliminary studies suggested that DF improved survival in pts with severe VOD and MOF with minimal toxicity. We report use of DF in 75 pts (52 allos:23 autos) with severe VOD post SCT. Median age was 35y (8mos-62y). Conditioning included cyclophosphamide (CY) in 56/75 (75%), busulfan (BU) in 37/75 (49%) and TBI in 28/75 (37%). VOD at diagnosis was characterized by a median bilirubin of 4.8 mg/dl (range 2-34.9), median weight gain of 7% and median onset of day(d) +11. Ascites was present in 63/75 (84%); RUQ pain in 60/75 (80%); hepatomegaly in 52/75 (69%), and abnormal portal flow in 23/75 (31%). At DF initiation (median d +18), median bilirubin was 12.7 mg/dl (range 2.-54.4). MOF was present in 69/75 (92%), with 14 pts intubated and 5 on dialysis. Intra-patient DF dose escalation ranged from 5-60 mg/kg/d. The median duration of DF was 14d. Most responses were seen between 20-40 mg/kg/d, although some occurred at 10 and 60 mg/kg/d. No significant attributable DF toxicity was reported. CR (bili ltoreq2 mg/dl) and survival to d +100 were observed in 24/75 pts (32%). In 67 (89%) pts receiving gtoreq4d of DF, the CR rate was 36%, (95% CI 22%, 44%) and d +100 survival was 34% (95% CI 23%, 47%). On univariate analysis of 19 factors, younger pts did better (p= .04), as did those with MOF in ltoreq2 systems (p=.12). Use of BU was associated with worse outcome (p=.02) and this effect was more marked in pts gtoreq18y. CR rate was higher in pts who received CY-based conditioning as opposed to those pts who did not (36% vs 21%). Given that CY metabolites have been implicated in sinusoidal endothelial damage, this observation may support the hypothesis that DF activity in VOD is related to endothelial repair. Correlation of outcome with markers of endothelial stress is ongoing. The response rate, long term survival and favorable tolerability profile in this large cohort of well-characterized, consistently treated pts confirm the encouraging results of prior studies. A Phase II, randomized dose finding trial of DF is now underway.

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Accession: 035349248

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