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.

Conflict of interest statement

Conflict of interest statement

Paul G. Richardson has served on an advisory committee and as a consultant to Jazz Pharmaceuticals and Gentium, and has received research funding from Gentium; Angela R. Smith has no relevant financial relationships to disclose; Brandon M. Triplett has no relevant financial relationships to disclose; Nancy A. Kernan has received research funding from Gentium; Nancy A. Kernan’s research was supported by National Cancer Institute of the National Institutes of Health under award number P30 CA008748; the content is solely the responsibility of the author and does not necessarily represent the official views of the National Institutes of Health; Stephan A. Grupp has served as a consultant to Jazz Pharmaceuticals; Joseph H. Antin has served on an advisory board for Jazz Pharmaceuticals and for Gentium; Leslie Lehmann has no relevant financial relationships to disclose; Maja Miloslavsky and Robin Hume are employees of Jazz Pharmaceuticals, who in the course of their employment have received stock options exercisable for, and other stock awards of, ordinary shares of Jazz Pharmaceuticals plc; Alison L. Hannah served as a consultant to Jazz Pharmaceuticals; Bijan Nejadnik is a former employee of Jazz Pharmaceuticals, who in the course of his employment had received stock options exercisable for, and other stock awards of, ordinary shares of Jazz Pharmaceuticals plc; Robert J. Soiffer has served on an advisory board for Gentium and Jazz Pharmaceuticals.

© 2017 The Authors. British Journal of Haematology published by John Wiley & Sons Ltd.

Figures

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.