Impact On Outcomes Of Baseline Bilirubin In Patients With Hepatic Veno-Occlusive Disease/Sinusoidal Obstruction Syndrome Receiving Defibrotide Treatment: A Post-Hoc Analysis

Introduction Hepatic veno-occlusive disease, also called sinusoidal obstruction syndrome (VOD/SOS), is a difficult to predict, and potentially life-threatening complication of conditioning for hematopoietic stem cell transplant (HSCT). VOD/SOS develops via a pathophysiologic cascade, and VOD/SOS with multi-organ dysfunction (MOD)/multi-organ failure (MOF) may be associated with u003e80% mortality. Defibrotide was recently approved in the United States for treating hepatic VOD/SOS with renal or pulmonary dysfunction post-HSCT and is approved in the European Union to treat severe hepatic VOD/SOS post-HSCT. In the United States, defibrotide had been available through an expanded-access program. Methods Patients in the expanded-access program were diagnosed with VOD/SOS by investigators using Baltimore criteria (bilirubin ≥2 mg/dL and ≥2 of the following: hepatomegaly, ascites, ≥5% weight gain), modified Seattle criteria (≥2 of the following: total bilirubin u003e2 mg/dL, hepatomegaly, or ascites and/or ≥5% weight gain [in this study]), or biopsy; elevated bilirubin was not required for patients with biopsy or who met modified Seattle criteria by presence of hepatomegaly with ascites/weight gain. This program included patients with or without MOD/MOF (defined by renal and/or pulmonary dysfunction). Defibrotide 25 mg/kg/day was given in 4 divided doses for a recommended ≥21 days. Here, Day +100 survival post-HSCT is explored post hoc based on 4 bilirubin-level categories at time of study entry; together these categories have been defined as 1 of the criteria in the proposed VOD/SOS grading scale for adults from the European Society for Blood and Marrow Transplantation (EBMT; ≥2 mg/dL to Bone Marrow Transplant. 2016;51:906-912]). It is important to note that bilirubin Results Among 756 post-HSCT patients enrolled through April 18, 2015, who received ≥1 dose of defibrotide, 427 also had MOD/MOF. Median age was lowest in patients with bilirubin Day +100 survival in the overall HSCT population of the expanded-access program was 55.4% by Kaplan-Meier estimate. The survival rate was 81.4% in patients with bilirubin Table ). Day +100 survival patterns by bilirubin level were generally similar in the subgroups of patients with and without MOD/MOF ( Table ). Overall, 515 post-HSCT patients (67%) reported ≥1 adverse event (AE). Serious AEs were reported by 386 patients (50%), and AEs leading to death occurred in 250 patients (33%). Among all AEs, 158 patients (21%) had AEs that investigators assessed as related (possibly, probably, or definitely) to study medication. Conclusions Overall, higher bilirubin levels were associated with worse Day +100 outcomes (with the exception of the ≥5 to Support: Jazz Pharmaceuticals. Disclosures Richardson: Jazz Pharmaceuticals: Consultancy, Membership on an entity9s Board of Directors or advisory committees. Kernan: Gentium: Research Funding; The National Cancer Institute of the National Institutes of Health: Research Funding. Grupp: Novartis: Consultancy, Research Funding; Pfizer: Consultancy; Jazz Pharmaceuticals: Consultancy. Antin: Gentium SpA/Jazz Pharmaceuticals: Membership on an entity9s Board of Directors or advisory committees. Liang: Jazz Pharmaceuticals, Inc.: Employment, Other: stock options exercisable for, and other stock awards of, ordinary shares of Jazz Pharmaceuticals plc. Hume: Jazz Pharmaceuticals, Inc.: Employment, Other: stock options exercisable for, and other stock awards of, ordinary shares of Jazz Pharmaceuticals plc. Tappe: Jazz Pharmaceuticals, Inc.: Employment, Other: stock options exercisable for, and other stock awards of, ordinary shares of Jazz Pharmaceuticals plc. Soiffer: GentiumSpA/Jazz Pharmaceuticals: Membership on an entity9s Board of Directors or advisory committees.