Defibrotide (DF) for the Treatment of Severe Veno-Occlusive Disease (sVOD) and Multi-Organ Failure (MOF) Post SCT: Final Results of a Multi-Center, Randomized, Dose-Finding Trial.

Abstract

Introduction: Severe VOD is an important regimen-related toxicity of hematopoietic SCT characterized by MOF and high mortality (>80% at d+100 post SCT). DF is a novel polydisperse oliogonucleotide with anti-thrombotic, anti-ischemic and thrombolytic properties, especially on microvasculature. DF appears to modulate endothelial cell (EC) injury in sVOD, with encouraging complete response (CR) rates, survival at d+100 post SCT and minimal toxicity reported. Methods: A multi-center, phase II trial was conducted in which patients (pts) stratified for age (<18y) and cyclophosphamide-based conditioning were randomized to 25 mg/kg/d or 40 mg/kg/d of DF. VOD diagnosis was made by Baltimore criteria, with severity determined by MOF or Bearman model (>30% risk). Study endpoints included CR, d+100 survival post SCT and toxicity. CR was defined as bilirubin <2 mg/dL and resolution of VOD-related MOF, with pts having ≥3d of DF evaluable for response. Abdominal ultrasound (US) with Doppler was required at study entry, d14 of DF, and completion of therapy, with blood collected serially to examine markers of EC stress. Results: 150 pts were treated with DF, with 75 pts on each treatment arm: 129 pts underwent allo- and 21 auto- SCT. Median age was 36y (6m–63y). At DF start, median bilirubin was 5.0 mg/dL; median weight gain 12%; ascites was present in 77%; RUQ pain in 71%; hepatomegaly in 69%; abnormal portal flow in 44%; and MOF in 99% (at study entry, 7% were dialysis-dependent (DD), 7% ventilator-dependent (VD); 28% developed DD and 23% VD during treatment). Median duration of DF therapy was 19d (1–82d). Of 150 pts treated, 141 were evaluable for response: 65 pts achieved CR (46%) and 62 survived to d+100 (41%), including pts with prior DD and VD. Results for CR and d+100 survival have been analyzed by dose level according to age, prior SCT and Mylotarg use. No significant difference in CR and d+100 survival was found between the 2 doses, although in pediatric pts receiving 25 mg/kg/d, CR and d+100 survival was 67% (p=0.06). Toxicity was limited, but more attributable G3/4 events, including bleeding and hypotension, were recorded in pts on 40 mg/kg/d, although the difference was not significant (p=0.11). Preliminary US review demonstrated improvement in portal flow abnormalities with DF therapy. EC stress markers showed reduction in median levels of PAI-1 and nitric oxide with increase in Protein C in pts achieving CR (p<0.05): median serum thrombomodulin, TFPI and soluble tissue factor increased in pts without response (p<0.05). Correlation with additional markers is ongoing. Similarly, multivariate analysis of factors predicting CR and d+100 survival is in process. Conclusion: DF treatment of sVOD/MOF results in a 46% CR rate and 41% d+100 survival post SCT: 25 mg/kg/d is the preferred dose. A phase 3 pivotal trial to confirm safety and efficacy is underway, comparing a prospective cohort of 80 DF-treated pts with sVOD/MOF to a matched historical group at 30 SCT centers across North America.

Effect of ligustrazine on mice model of hepatic veno‐occlusive disease induced by Gynura segetum

“…23 In a multicenter, phase II trial, a complete response rate of 46% was observed with 41% survival at day 100 after transplantation. 24 Nevertheless, further multi-centre randomized-controlled trials either as individual therapy or in combination with others are needed. Ligustrazine is the active ingredient of Chuanxiong, it is reported to be able to inhibit the expression of TF induced by TNF-a.…”

“…It is identified to have antithrombotic, anti‐ischemic, anti‐inflammation and thrombolytic properties without significant systemic anticoagulant effects 23 . In a multicenter, phase II trial, a complete response rate of 46% was observed with 41% survival at day 100 after transplantation 24 . Nevertheless, further multi‐centre randomized‐controlled trials either as individual therapy or in combination with others are needed.…”

Komplexe Gerinnungsstörungen

“…Vielversprechende Daten liegen für Defibrotide vor. Seit der ersten Publikation 1998 (Richardson et al 1998) sind mittlerweile etwa 300 Patienten zum Teil auch in Phase-II-Studien wegen einer VOD mit dieser Substanz behandelt worden (Chopra et al 2000;Richardson et al 2002Richardson et al , 2006Bulley et al 2006;Corbacioglu et al 2004). Hierbei wurden Dosierungen zwischen 5 und 110 mg/kgKG pro Tag als intravenöse Applikation verwandt.…”

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

“…The most recent update suggests a continued favorable CR rate, encouraging day 100 post-SCT survival, and manageable side effects, even in patients with advanced MOF (including dialysis and ventilator dependence), and marginally more attributable grade 3 events seen at higher dose (40 mg/kg/d). 138 Given that no difference in efficacy was observed between the two dose levels, the lower dose of 25 mg/kg/d has been selected as the dose for the current phase III trial. Encouraging responses to DF have also been reported in the treatment of children with severe VOD.…”