Earlier defibrotide initiation post-diagnosis of veno-occlusive disease/sinusoidal obstruction syndrome improves Day +100 survival following haematopoietic stem cell transplantation

Abstract

Hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is a progressive, potentially fatal complication of conditioning for haematopoietic stem cell transplant (HSCT). The VOD/SOS pathophysiological cascade involves endothelial-cell activation and damage, and a prothrombotic-hypofibrinolytic state. Severe VOD/SOS (typically characterized by multi-organ dysfunction) may be associated with >80% mortality. Defibrotide is approved for treating severe hepatic VOD/SOS post-HSCT in the European Union, and for hepatic VOD/SOS with renal or pulmonary dysfunction post-HSCT in the United States. Previously, defibrotide (25 mg/kg/day in 4 divided doses for a recommended ≥21 days) was available through an expanded-access treatment protocol for patients with VOD/SOS. Data from this study were examined post-hoc to determine if the timing of defibrotide initiation post-VOD/SOS diagnosis affected Day +100 survival post-HSCT. Among 573 patients, defibrotide was started on the day of VOD/SOS diagnosis in approximately 30%, and within 7 days in >90%. The relationship between Day +100 survival and treatment initiation before/after specific days post-diagnosis showed superior survival when treatment was initiated closer to VOD/SOS diagnosis with a statistically significant trend over time for better outcomes with earlier treatment initiation (P < 0·001). These results suggest that initiation of defibrotide should not be delayed after diagnosis of VOD/SOS.

Keywords: defibrotide; sinusoidal obstruction syndrome; survival; treatment initiation; veno-occlusive disease.

Fig 1. Day +100 survival by day of dosing (P<0.001 by Cochran-Armitage test for trend)^a

^aBars around point estimates denote 95% confidence intervals. Note: Among all HSCT VOD/SOS patients, 13 with a recorded negative dosing delay were adjusted to have 0 days dosing delay; 1 patient with −293 days dosing delay was excluded from this analysis. In the subgroup with MOD, 12 patients with a recorded negative dosing delay were adjusted to have 0 days dosing delay. HSCT, haematopoietic stem cell transplantation; MOD, multi-organ dysfunction; VOD/SOS, veno-occlusive disease/sinusoidal obstruction syndrome.