Defibrotide (DF) for the Treatment of Severe Veno-Occlusive Disease (VOD) and Multi-System Organ Failure (MOF) Post SCT: Final Results of a Phase II, Multicenter, Randomized Study and Preliminary Analyses of Surrogate Markers and Ultrasound Findings.

Abstract

Introduction: DF, a polydisperse oligonucleotide, has anti-thrombotic, anti-ischemic and thrombolytic properties, especially on microvasculature. Studies have suggested that DF modulates endothelial injury in VOD. Methods: A phase II randomized study of two doses, 25 mg/kg/d [arm A] or 40 mg/kg/d [arm B], was carried out in pts with severe VOD. Correlation with markers of vascular injury was undertaken. Endpoints included CR rate, toxicity and mortality at d+100 post SCT. VOD diagnosis was by Baltimore criteria and severity by ≥30% risk on the Bearman model or MOF. Abdominal ultrasound (US) was required prior to enrollment, repeated during therapy and at completion of treatment.Pts with ≥ grade II GVHD were excluded. Treatment arms were stratified for age (<18y) and cyclophosphamide-based conditioning. Treatment was planned for ≥14d. Pts receiving ≤3d of therapy were inevaluable for response. CR was defined as a bilirubin <2 mg/dl and resolution of VOD-related MOF. Results: 102 pts have been treated; 51 pts on arm A and 51 pts on arm B: 87 pts underwent allo- and 15 auto-SCT. Median age was 33y (6 mos - 63y). At DF initiation, median bilirubin was 7.1 mg/dl; median wt gain 12%; ascites in 78%; RUQ pain in 65%; hepatomegaly in 71%; abnormal portal flow in 42%, and MOF in 97%. Median duration of therapy was 20d. There were no unexpected side effects and no treatment related deaths. In a subset of pts (n=14), central review of US was performed. Portal flow improved by wk 3 in pts with CR (n=8). Improvement was not seen in nonresponders (NR) (n=6), suggesting changes in portal flow may help predict outcome. Median values of markers of endothelial stress with DF treatment are summarized below. In pts with CR, median PAI-1 levels decreased and Protein C increased. Median NO declined regardless of response. Median thrombomodulin, tissue factor and TFPI increased in NR. CR was achieved in 50/93 pts (54%; 95% CI (43%,64%)), with survival to d+100 in 43/91 pts (47%; 95% CI (37%,58%)). No difference in outcome between the 2 dose arms was seen. An analysis using 38 controls matched for VOD severity confirmed a survival advantage (p=0.0004). Conclusion: US findings and trends in endothelial stress markers may help predict successful DF treatment. The CR rate (54%) and d+100 survival (47%) in this first prospective, randomized trial of DF in pts with severe VOD and MOF confirm the encouraging results of prior studies, and a case control analysis shows a highly significant survival benefit with DF treatment. *p<0.05 Arm A Arm B **p<0.001 CR NR CR NR Pre/Post Pre/Post Pre/Post Pre/Post PAI-1 (nl<40) 109/53** 84/92 87/64* 99/102 Protein C (nl>70) 35/50** 33/31 29/43* 26/31 NO (nl<58) 98/68* 119/91 84/67 108/57 Thrombomodulin (nl<40) 144/135 149/178* 149/140 139/283** TFPI (nl<111) 116/124 154/213* 132/138 150/196* Tissue Factor (nl<162) 195/164 176/278* 197/202 179/298**

Defibrotide for the Treatment of Hepatic Veno-Occlusive Disease: Final Results From the International Compassionate-Use Program

“…When the CUP was initiated, the recommended starting dose of defibrotide was 10 mg/kg/day, administered intravenously in 4 divided doses over 2 hours each, with titration up to a recommended maximum of 60 mg/ kg/day based on tolerability and response. However, based on the 2004 presentation of results from a phase 2 study from the United States [27], the recommended dose of defibrotide was amended to a fixed 25 mg/kg/ day, in 4 divided doses, each administered over 2 hours. Recommended treatment duration was a minimum of 14 days (with the final decision on duration at discretion of treating physician), and therapy could be continued until the patient had a complete response or was discharged from the hospital.…”

Hepatic Veno-Occlusive Disease after Hematopoietic Stem Cell Transplantation: Review and Update on the Use of Defibrotide

“…A total of 102 patients had been treated at the time of preliminary analysis in December 2004, with each patient randomly assigned to 25 or 40 mg/kg/d, and both groups stratified for age and cyclophosphamide use in the conditioning regimen to maintain balance between the treatment arms. 137 Ninety-three patients were evaluable for response and ninety-one patients were evaluable for day 100 post-SCT survival. The overall CR rate was 54% and the day 100 post-SCT survival rate was 47%, with no significant difference in efficacy seen between the two arms.…”