Early Initiation of Defibrotide in Patients with Hepatic Veno-Occlusive Disease/Sinusoidal Obstruction Syndrome Following Hematopoietic Stem Cell Transplantation Improves Day +100 Survival
Authors: Richardson Paul G. , Smith Angela R. , Triplett Brandon M. , Kernan Nancy A. , Grupp Stephan A. , Antin Joseph H. , Lehmann Leslie E. , Miloslavsky Maja , Hume Robin L. , Hannah Alison L. , Nejadnik Bijan , Soiffer Robert J. 
Published: October 2019

Abstract
Introduction
Hepatic veno-occlusive disease, also called sinusoidal obstruction syndrome (VOD/SOS), is an unpredictable, potentially life-threatening complication of conditioning for hematopoietic stem cell transplant (HSCT). Severe VOD/SOS (ie, with multi-organ dysfunction [MOD]) may be associated with >80% mortality. Defibrotide is approved for treatment of severe VOD/SOS in the EU. In the US, defibrotide is available through an ongoing, expanded-access study. The optimal time to initiate VOD/SOS treatment with defibrotide is of interest.
Methods
In the expanded-access study, patients were eligible in the original protocol if they had VOD/SOS and renal/pulmonary MOD by Baltimore criteria post-HSCT or by biopsy. The protocol was amended to include (1) post-chemotherapy patients, (2) patients without MOD, and (3) VOD/SOS per modified Seattle criteria. Defibrotide 25 mg/kg/day was given in 4 divided doses for a recommended ≥21 days. Here, Day +100 survival in patients with HSCT was examined post hoc based on time from VOD/SOS diagnosis (with or without MOD as relevant to study entry criterion) to initiation of defibrotide. Two analyses were conducted: (1) survival rate analyzed by treatment initiation for the entire population before or after each of the following days: 1, 2, 3, 4, 7, and 14, using Fisher's exact test; (2) survival rate for only those patients with treatment initiated on a particular day: 0, 1, 2, 3, 4, 5, 6, 7, 8-14, and ≥15, with a Cochran-Armitage test for trend across days.
Results
Among HSCT patients enrolled through 2013 who received ≥1 dose of defibrotide, treatment date was available for 573 patients. Of these, 351 also had MOD. Defibrotide was started on the day of diagnosis in >30% of patients; >90% of patients started defibrotide before day 7 post-diagnosis.
In the population-wide analysis of treatment initiation before or after days 1, 2, 3, 4, 7, and 14, earlier initiation of defibrotide was associated with higher survival rates (Table), and was statistically significant for all cut-points considered except 14 days, with only 2.8% of patients beginning treatment post-day 14. Survival differences between earlier vs. later initiation ranged from 8.8% to 22.1% overall (MOD: 12.8% to 25.6%; Table) for the cut-points considered. In the analysis of relationship between Day +100 survival and treatment initiation day, survival rates were generally higher if treatment was initiated earlier. This was demonstrated by a statistically significant trend over time for better outcomes with earlier initiation (Figure). Similar results for both analyses were obtained for all patients with VOD/SOS and for the subgroup of patients with MOD.
Conclusions
Data indicate decreased Day +100 survival associated with longer treatment delays, confirmed by the Cochran Armitage trend test (P<0.001). Thus, defibrotide treatment should be initiated as soon as possible after VOD/SOS diagnosis.
Table. Day +100 Survival by Defibrotide Initiation Day n (%) HSCT VOD/SOS (N=573) HSCT VOD/SOS with MOD (n=351) Initiation Period Alive Dead Unknown Alive Dead Unknown ≤1 Day 183 (53.5) 142 (41.5) 17 (5.0) 103 (50.2) 93 (45.4) 9 (4.4) >1 Day 105 (45.5) 116 (50.2) 10 (4.3) 56 (38.4) 85 (58.2) 5 (3.4) Difference (95% CI)a 8.8% (0.2%, 17.3%) 12.8% (2.0%, 23.4%) P valueb 0.045 0.021 ≤2 Days 235 (55.7) 166 (39.3) 21 (5.0) 132 (52.2) 111 (43.9) 10 (4.0) >2 Days 53 (35.1) 92 (60.9) 6 (4.0) 27 (27.6) 67 (68.4) 4 (4.1) Difference (95% CI)a 22.1% (12.6%, 31.2%) 25.6% (13.8%, 36.9%) P valueb <.001 <.001 ≤3 Days 251 (53.5) 193 (41.2) 25 (5.3) 138 (49.5) 129 (46.2) 12 (4.3) >3 Days 37 (35.6) 65 (62.5) 2 (1.9) 21 (29.2) 49 (68.1) 2 (2.8) Difference (95% CI)a 20.3% (9.6%, 30.8%) 21.7% (8.6%, 34.5%) P valueb <.001 0.001 ≤4 Day 263 (52.6) 212 (42.4) 25 (5.0) 146 (48.7) 142 (47.3) 12 (4.0) >4 Day 25 (34.2) 46 (63.0) 2 (2.7) 13 (25.5) 36 (70.6) 2 (3.9) Difference (95% CI)a 20.2% (7.7%, 32.4%) 24.2% (9.1%, 38.9%) P valueb 0.002 0.002 ≤7 Days 275 (51.6) 232 (43.5) 26 (4.9) 152 (47.4) 156 (48.6) 13 (4.0) >7 Days 13 (32.5) 26 (65.0) 1 (2.5) 7 (23.3) 22 (73.3) 1 (3.3) Difference (95% CI)a 20.9% (4.5%, 37.1%) 25.2% (6.1%, 43.8%) P valueb 0.013 0.011 ≤14 Days 282 (50.6) 249 (44.7) 26 (4.7) 156 (45.9) 171 (50.3) 13 (3.8) >14 Days 6 (37.5) 9 (56.3) 1 (6.3) 3 (27.3) 7 (63.6) 1 (9.1) Difference (95% CI)a 13.1% (-12.9%, 39.5%) 17.7% (-14.6%, 51.5%) P valueb 0.433 0.344 aAlive and Dead. 95% CI calculated using exact method. bFisher's exact test, Alive and Dead. Support: Jazz Pharmaceuticals.

Disclosures
Richardson: Gentium S.p.A.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Off Label Use: Defibrotide is an investigational treatment for hepatic veno-occlusive disease/sinusoidal obstruction syndrome in the United States.. Kernan:Gentium S.p.A.: Research Funding. Grupp:Novartis: Consultancy, Research Funding. Antin:Gentium S.p.A.: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Miloslavsky:Jazz Pharmaceuticals: Employment, Equity Ownership. Hume:Jazz Pharmaceuticals: Employment, Equity Ownership. Hannah:Jazz Pharmaceuticals: Consultancy. Nejadnik:Jazz Pharmaceuticals: Employment, Equity Ownership. Soiffer:Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Gentium S.p.A.: Membership on an entity's Board of Directors or advisory committees.