Hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is a potentially life-threatening complication that occurs after hematopoietic cell transplantation (HCT). The mortality associated with untreated VOD/SOS with multiorgan dysfunction (MOD) has been reported to be >80%. The recommended dose of defibrotide is 6.25 mg/kg every 6 hours, administered as a 2-hour i.v. infusion, for a minimum of 21 days or until resolution of VOD/SOS signs and symptoms. The objective of this analysis was to evaluate the time to complete response (CR) in patients with post-HCT VOD/SOS treated with defibrotide. The time to defibrotide discontinuation due to a CR served as a surrogate for time to CR in an expanded access study (T-IND; ClinicalTrials.gov NCT00628498; n = 1000), and was analyzed separately from the time to CR data pooled from a phase 2 randomized dose-finding study (NCT00003966; n = 74 patients who received 25 mg/kg/day) and a phase 3 historically controlled study (NCT00358501; n = 102). For all studies, a CR was defined as total serum bilirubin <2 mg/dL with resolution of VOD/SOS-related MOD (renal and/or pulmonary dysfunction); the phase 2 study also required resolution of central nervous system dysfunction. In the T-IND, 390 patients discontinued treatment due to a CR and had sufficient data for analysis. The median time to discontinuation was 22 days (range, 2 to 64 days). Discontinuation due to CR occurred beyond 21 days in 235 patients (60%) and beyond 28 days in 57 patients (15%). The pooled phase 2 and 3 studies included 60 patients who achieved a CR, with a median time to CR of 24.5 days (range, 7 to 123 days). A CR was achieved beyond 21 days in 32 patients (53%) and beyond 28 days in 24 patients (40%). The Kaplan-Meier estimate of day +100 survival rate was substantially higher in patients who discontinued due to a CR compared with those who did not (92.5% versus 37.3%). Treatment-emergent adverse events occurred in 185 of 390 patients (47%) who discontinued due to a CR in the T-IND and in 55 of 60 patients (92%) who achieved a CR in the pooled phase 2 and 3 studies, and rates did not differ according to duration of treatment (≤21 days versus >21 days). Taken together, these results highlight the importance of continued defibrotide therapy until resolution of VOD/SOS signs and symptoms, as currently indicated in the approved product labels, which may occur beyond the recommended minimum of 21 days.
Bibliographical noteFunding Information:
The authors acknowledge William Tappe, MD, for thoughtful commentary on the data. Medical writing and editorial assistance were provided by Erica Chevalier-Larsen, PhD, of SciFluent Communications, financially supported by Jazz Pharmaceuticals.
Financial disclosure: This study was funded by Jazz Pharmaceuticals.
Conflict of interest statement: P.G.R. has served on advisory committees for and received research funding from Jazz Pharmaceuticals. A.R.S. has served on advisory boards for Orchard Therapeutics and Amgen and has received research funding from Amgen and Jazz Pharmaceuticals. N.A.K. has received research grants from Jazz Pharmaceuticals and grants from Gentium during the conduct of the study, and her research was supported by the National Cancer Institute of the National Institutes of Health (Award 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. L.L. has no conflicts of interest to disclose. R.J.R. is an employee of and holds stock ownership and/or stock options in Jazz Pharmaceuticals. S.A.G. has received research funding from and has served on a steering committee and as a consultant for Jazz Pharmaceuticals.
- Complete response
- Hematopoietic cell transplantation
- Veno-occlusive disease/sinusoidal obstruction syndrome