This open-label, randomised, multicentre, phase 3 trial was done in 104 centres in 14 countries. Patients who were at least 1 month old, were scheduled to receive allogeneic HSCT (adult [aged >16 years] or paediatric [aged >1 month to ≤16 years] patients) or autologous HSCT (paediatric patients only), and were at high risk or very high risk of developing
sinusoidal obstruction syndrome were eligible for inclusion. Patients were randomly assigned (1:1) by an interactive web response system to receive intravenous
defibrotide 25 mg/kg per day (four equal doses [6·25 mg/kg per dose]) and best supportive care (determined by individual institutional guidelines;
defibrotide prophylaxis group) or best supportive care only (best supportive care group). Randomisation was stratified by
sinusoidal obstruction syndrome risk, age, and country. The primary endpoint,
sinusoidal obstruction syndrome-free survival at day 30 after HSCT, was assessed by an independent Endpoint Adjudication Committee in the intention-to-treat (ITT) population. Safety was assessed in all patients who received protocol treatment. The trial is registered with ClinicalTrials.gov, NCT02851407.
FINDINGS: Between Jan 11, 2017, and Oct 20, 2020, 372 patients (172 [46%] women and 200 [54%] men; median age 14·0 years [IQR 4·0-41·0] were randomly assigned to the
defibrotide prophylaxis group (n=190) or best supportive care group (n=182; ITT population). On the basis of recommendations from the Independent Data Monitoring Committee following completion of the planned interim analysis in the first 280 recruited patients on April 29, 2020, enrolment was prematurely stopped for presumed futility. At the final analysis,
sinusoidal obstruction syndrome-free survival by day 30 after HSCT was 67% (95% CI 58-74) in the
defibrotide prophylaxis group and 73% (62-80) in the best supportive care group (HR 1·27 [95% CI 0·84-1·93]; p=0·85). Treatment-emergent adverse events were similar between groups during the randomised prophylaxis phase; most treatment-emergent adverse events were related to the
transplantation rather than to study
drug. The most common grade 3 or 4 treatment-emergent adverse events were
stomatitis (grade 3, 52 [29%] of 181 patients in the
defibrotide prophylaxis group and 56 [32%] of 174 patients in the best supportive care group; grade 4, two [1%] in the
defibrotide prophylaxis group and two [1%] in the best supportive care group) and febrile neutropaenia (grade 3, 51 [28%] in the
defibrotide prophylaxis group and 52 [30%] in the best supportive care group; grade 4, no patients in the
defibrotide prophylaxis group and three [2%] in the best supportive care group). Serious treatment-emergent adverse events occurred in 74 (41%) of 181 patients in the
defibrotide prophylaxis group and 61 (35%) of 174 patients in the best supportive care group. In the rescue phase, when patients in both treatment groups received
defibrotide as rescue treatment, fatal treatment-related adverse events occurred in one (4%) of 25 patients in the
defibrotide prophylaxis group (intracranial haemorrhage) and one (3%) of 31 patients in the best supportive care group (
sinusoidal obstruction syndrome).
INTERPRETATION: