Phase 3 trial of defibrotide for the treatment of severe veno-occlusive disease and multi-organ failure

Paul G. Richardson, Marcie L. Riches, Nancy A. Kernan, Joel A. Brochstein, Shin Mineishi, Amanda M. Termuhlen, Sally Arai, Stephan A. Grupp, Eva C. Guinan, Paul L. Martin, Gideon Steinbach, Amrita Krishnan, Eneida R. Nemecek, Sergio Giralt, Tulio Rodriguez, Reggie Duerst, John Doyle, Joseph H. Antin, Angela Smith, Leslie LehmannRichard Champlin, Alfred Gillio, Rajinder Bajwa, Ralph B. D'Agostino, Joseph Massaro, Diane Warren, Maja Miloslavsky, Robin L. Hume, Massimo Iacobelli, Bijan Nejadnik, Alison L. Hannah, Robert J. Soiffer

Research output: Contribution to journalArticlepeer-review

239 Scopus citations


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 as #NCT00358501.

Original languageEnglish (US)
Pages (from-to)1656-1665
Number of pages10
Issue number13
StatePublished - Mar 31 2016

Bibliographical note

Publisher Copyright:
© 2016 by The American Society of Hematology.


Dive into the research topics of 'Phase 3 trial of defibrotide for the treatment of severe veno-occlusive disease and multi-organ failure'. Together they form a unique fingerprint.

Cite this