Defibrotide (DF) for the Treatment of Veno-Occlusive Disease (VOD) and Multi-System Organ Failure (MOF) Post SCT: Analysis of Response and Survival According to Degree and Type of MOF.

Introduction: Veno-Occlusive Disease (VOD) is a significant regimen-related toxicity of hematopoietic stem cell transplant (SCT), which when complicated by multi-system organ failure (MOF) has a case fatality rate >90%. We have treated 139 patients (pts) with VOD/MOF in a randomized, multicenter Phase II dose-finding study of Defibrotide (DF), a polydisperse oligonucleotide, with anti-thrombotic, anti-ischemic and thrombolytic properties, especially on microvasculature. Earlier studies of DF therapy for VOD/MOF have consistently shown manageable toxicity with promising complete response (CR) rates and d+100 survival post SCT.

Methods: We reviewed pts to define status of renal, pulmonary, and CNS dysfunction at entry and on DF therapy. We also determined dialysis dependence (DD) and/or ventilator dependence (VD) at study entry or when newly acquired while on study. These subgroups were examined for response to treatment (CR vs no CR) and d+100 survival.

Results: Of 139 pts treated, 97 had creatinine (creat) ≥ 2x admission value at study entry, of whom 42 pts had creat ≥ 3x admission value, and 12 were DD. 35 pts developed new DD on DF therapy. At entry, 69 pts had room air O₂ saturation ≤ 90%, 10 were VD and 34 developed new VD on DF therapy. 33 pts were encephalopathic at study entry and 23 became encephalopathic during treatment. CR was achieved in 59/124 (48%) evaluable pts. By Kaplan Meier and on intent to treat, d+100 survival was 51/133 (38%). Pts were analyzed according to MOF (Table 1). In those with both renal and pulmonary dysfunction at study entry, 44% achieved CR and 39% d+100 survival. Pts with renal or pulmonary dysfunction at study entry, combined with encephalopathy, had a CR rate of 55% and d+100 survival of 45%. Those with MOF in all 3 systems achieved a CR rate of 50%, although d+100 survival was lower at 33%. The presence of DD at study entry or newly acquired on DF therapy reduced CR rates to 33 and 20% respectively, with a similar reduction in CR rates for VD at 20 and 25%. D+100 survival in both categories was also reduced.

Conclusion: DF therapy achieved encouraging CR rates and d+100 survival in pts with MOF in up to three systems complicating VOD post SCT, and clinical benefit was seen even if pts were DD and/or VD. However, CR rates and d+100 survival were lower with DD and/or VD both at study entry and when newly acquired on DF therapy, which suggests that earlier intervention with DF may further improve outcome.