Hepatic veno-occlusive disease (VOD), also called sinusoidal obstruction syndrome (SOS), is a potentially life-threatening complication of hematopoietic stem cell transplantation (HSCT). Untreated hepatic VOD/SOS withmulti-organ failure (MOF) is associated with >80% mortality. Defibrotide has shown promising efficacy treating hepatic VOD/SOS with MOF in phase 2 studies. This phase 3 study investigated safety and efficacy of defibrotide in patients with established hepatic VOD/SOS and advanced MOF. Patients (n = 102) given defibrotide 25 mg/kg per day were compared with 32 historical controls identified out of 6867 medical charts of HSCT patients by blinded independent reviewers. Baseline characteristics between groups were well balanced. The primary endpoint was survival at day 1100 post-HSCT; observed rates equaled 38.2% in the defibrotide group and 25% in the controls (23% estimated difference; 95.1% confidence interval [CI], 5.2-40.8; P =.0109, using a propensityadjusted analysis). Observed day 1100 complete response (CR) rates equaled 25.5% for defibrotide and 12.5% for controls (19% difference using similar methodology; 95.1% CI, 3.5-34.6; P =.0160). Defibrotide was generally well tolerated with manageable toxicity. Related adverse events (AEs) included hemorrhage or hypotension; incidence of common hemorrhagic AEs (including pulmonary alveolar [11.8% and 15.6%] and gastrointestinal bleeding [7.8%and 9.4%])was similar between the defibrotide and control groups, respectively.Defibrotide was associated with significant improvement in day 1100 survival and CR rate. The historical-control methodology offers a novel, meaningful approach for phase 3 evaluation of orphan diseases associated with high mortality. This trial was registered at www.clinicaltrials.gov as #NCT00358501.
Bibliographical noteFunding Information:
The authors gratefully acknowledge the members of the independent MRC, specifically Professors Selim Corbacioglu and Ernst Holler, for their essential role in identifying the historical controls and comprehensive chart review; all data and study monitoring members, study staff, nursing teams, and medical personnel; and in particular all participating patients and their families.Medical writing and editorial assistance for the development of this manuscript was provided by Dr Jonathan Viney (apothecom scopemedical) and The Curry Rockefeller Group, LLC, funded by Jazz Pharmaceuticals. This study was funded by Gentium SpA, now Jazz Pharmaceuticals. N.A.K.'s researchwas supported by the National Cancer Institute of the National Institutes of Health (P30 CA008748). The content is solely the responsibility of the author and does not necessarily represent the official views of the National Institutes of Health.
© 2016 by The American Society of Hematology.