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

Abstract

Key Points• Defibrotide improves day 1100 survival and CR in patients with VOD and MOF compared with a historical control.• The historical control selection methodology offers a novel approach for investigation of a life-threatening orphan disease.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 with multi-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 5 102) 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 5 .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 5 .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

The use of defibrotide in blood and marrow transplantation

“…Incidence of common hemorrhagic AE and fatal AE were similar in the defibrotide-treated and historical control groups (64% and 75% and 64% and 69%, respectively). 70 Similar results were shown by a retrospective analysis of observational data for 8341 patients with hepatic VOD/SOS and MOD/ MOF by the Center for International Blood and Marrow Transplant Research. 115 In this study, survival at day 1100 (primary outcome) was 39% (95% CI, 24.8-54.3) in the defibrotide group (n 5 41) (Table 4).…”

“…70 The investigators rejected a randomized design based on ethical concerns regarding the high mortality risk of VOD/SOS with MOD/MOF coupled with prior, substantial research evidence of improved survival with defibrotide. Therefore, a historical control group was used for this study, which was selected by an independent medical review committee (MRC) whose members were blinded to outcomes.…”

Plasma biomarkers of risk for death in a multicenter phase 3 trial with uniform transplant characteristics post–allogeneic HCT

“…Similarly, CXCL9 levels on day 100 or day 180 could guide preemptive therapy for those at higher risk for chronic GVHD based on biomarker levels. Also, we are in the midst of proposing a clinical trial utilizing a VOD/SOS biomarker panel to guide preemptive defibrotide, a recently approved therapy for established VOD/SOS, 28 prior to onset of clinical features. We recognize that further refinement may be needed for specific thresholds depending on the HCT setting (GVHD prophylaxis, donor source, and/or intensity).…”

Long-awaited news for hepatic veno-occlusive disease

“…4 In the European Union, defibrotide was approved for the treatment of severe VOD/SOS following HCT in October 2013, based on several studies carried out over the last 15 years, including those of the current authors. 5,6 In the United States, there are no approved therapies for VOD/SOS; however, the phase 3 study results by Richardson et al 2 …”