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

Autor: George B. McDonald, L. J. Wei, David Avigan, Aparna Krishnan, Allen R. Chen, Joseph H. Antin, Eva C. Guinan, Paul G. Richardson, Diane Warren, Paul L. Martin, Zhezhen Jin, Massimo Iacobelli, Thomas R. Spitzer, Georgia B. Vogelsang, Carolyn Revta, Robert J. Soiffer, K. F. Murray, Joanne Kurtzberg, Nancy A. Kernan, Gideon Steinbach
Rok vydání: 2006
Předmět:
Zdroj: Memorial Sloan Kettering Cancer Center
ISSN: 1528-0020
0006-4971
DOI: 10.1182/blood.v108.11.43.43
Popis: 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 (30% risk). Study endpoints included CR, d+100 survival post SCT and toxicity. CR was defined as bilirubin 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 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.
Databáze: OpenAIRE
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