Hepatic veno-occlusive disease is a leading cause of morbidity and mortality after haemopoietic stem-cell transplantation (HSCT). Only a few prospective studies have suggested a benefit for the prophylactic use of drugs such as heparin, PGE1, pentoxifylline, or ursodeoxycholic acid. Though the evidence base is sparse, heparin (100 U/kg per day) and ursodeoxycholic acid are widely used in transplantation centres worldwide.

In the therapeutic setting, however, objective response rates have been reported with the use of defibrotide, a mixture of porcine oligodeoxyribonucleotides with procoagulant and fibrinolytic properties. One randomised dose-finding trial has been published in this indication, which suggested that an IV daily dose of 25 mg/kg, could be applied safely to paediatric and adult patients after HSCT, but that higher or lower doses were probably not more effective. Preliminary results from another trial, in which patients receiving defibrotide were compared with historical controls treated at the same centres for an equivalent time before the initiation of routine defibrotide therapy, also suggest a reduction in the incidence of veno-occlusive disease-associated mortality.

An RCT from 28 centres within the European Group for Blood and Marrow Transplantation has now been published which compared defibrotide prophylaxis with standard of care in 356 paediatric patients at high risk for development of veno-occlusive disease after HSCT. They were randomised to IV defibrotide prophylaxis (treatment group, n= 180) or not (control group, n= 176). The primary endpoint was incidence of veno-occlusive disease by 30 days after HSCT. Patients in either group who developed veno-occlusive disease received defibrotide for treatment. Adverse events to 180 days after HSCT were assessed in all patients who received allocated prophylaxis.

In the intention-to-treat population:

• 22 (12%) patients randomised to the defibrotide group had veno-occlusive disease by 30 days after HSCT vs. 35 (20%) of controls (risk difference −7.7%, p=0.0507).

• 154 (87%) of 177 patients in the defibrotide group had adverse events by day 180 compared with 155 (88%) of 176 controls.

The researchers conclude that “defibrotide prophylaxis seems to reduce incidence of veno-occlusive disease and is well tolerated. Thus, such prophylaxis could present a useful clinical option for this serious complication of HSCT.”

A comment article notes that restriction by the legislative authorities means that there are few randomised trials in children, and this pivotal European study is one that will hopefully change practice in paediatric patients and might also provide an impetus to investigate treatment options for adult patients.

A Marketing Authorisation Application for defibrotide for the treatment and prevention of hepatic veno-occlusive disease in HSCT therapy, in adults and children was submitted to the European Medicines Agency in May 2011.