Defibrotide for the Treatment of Hepatic Veno-Occlusive Disease/Sinusoidal Obstruction Syndrome Following Hematopoietic Stem Cell Transplantation or Chemotherapy--Results from the Italian Therapeutic Use Protocol (2015)

Introduction Hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is an unpredictable, potentially life-threatening complication of chemotherapy (CT) given as conditioning for hematopoietic stem cell transplantation (HSCT), or as primary treatment. Severe hepatic VOD/SOS, traditionally defined by occurrence of multi-organ dysfunction/failure (MOD/MOF), may be associated with mortality rates >80%. In the European Union, defibrotide is approved for treatment of severe VOD/SOS post-HSCT. It is not approved in the United States, but is available through an expanded-access program. Here, we report the results of an Italian therapeutic use program, defibrotide treatment protocol (TUT), in which defibrotide was provided upon physician request for treatment of patients with VOD/SOS. Methods This was a multicenter, single-arm, open-label program of defibrotide treatment in patients with hepatic VOD/SOS, with or without MOD/MOF, from 2010-2014. Patients were eligible if they were diagnosed with VOD/SOS having met ≥2 of the following criteria: bilirubin (>2 mg/dL), ascites, unexplained weight gain >5% above baseline (weight on day 1 of HSCT conditioning or CT), or hepatomegaly. Patients with biopsy-proven VOD/SOS were also eligible. Exclusion criteria were use of anticoagulants (beyond those for IV line maintenance), significant uncontrolled acute bleeding (transfusions after dialysis were allowed), pregnancy, and hemodynamic instability requiring >2 vasopressor drugs. MOD/MOF was defined as renal (creatinine >3x baseline, creatinine clearance or glomerular filtration rate <40% of baseline, or dialysis dependence) or pulmonary (oxygen saturation <90% on room air, requiring oxygen supplementation, or ventilator dependence) dysfunction. Patients were treated with defibrotide 25 mg/kg/d in 4 divided doses given intravenously over 2 hours each. Outcomes included survival at day +100 post-HSCT or post-CT and adverse events (AEs). VOD/SOS and MOD/MOF were not reported as AEs unless the event was considered serious. Demographics and AEs were analyzed using descriptive statistics; efficacy was estimated by the SAS/STAT LifeTest Procedure. Results A total of 98 patients had hepatic VOD/SOS (92% had VOD/SOS post-HSCT [81% allogeneic, 10% autologous, 1% unknown], 8% post-CT); of these, 21% had MOD/MOF and 79% did not. Median age was 13.4 years (range 0-68; 57 [58%] aged <18 years and 41 [42%] ≥18 years), 55% were male, and 65% were white. The most common primary diseases were acute myelogenous leukemia (25%) and acute lymphoblastic leukemia (19%). The most common prophylaxis regimens for graft-vs-host disease (GvHD) were reported as cyclosporine + methotrexate (38%), cyclosporine (12%), and cyclosporine + methotrexate + other (12%); tacrolimus- and sirolimus-containing regimens, which have been associated with development of VOD/SOS, were received by 5% and 4% of patients, respectively. The median defibrotide dose was 25 mg/kg/d (range, 6.15-40.0) and median duration of treatment was 14 days (range: 1-84). The estimated day +100 survival for all patients was 68.4% (95% CI, 58.0%-76.7%). Day +100 survival in post-HSCT patients was 67.0% (95% CI, 56.2%-75.8%) and for post-CT patients was 85.7% (95% CI, 33.4%-97.9%). Across the entire study, 38 deaths were reported; primary causes were progression of VOD/SOS and MOD/MOF (44.7%), infection (21.1%), GvHD (15.8%), and disease progression (13.2%). Treatment-emergent AEs were reported in 21% of patients in this therapeutic use program; the most common (reported in ≥2 patients) were MOD/MOF (9%), VOD/SOS (6%), and cytomegalovirus infection and acute respiratory distress syndrome (2% each). Treatment-related AEs were reported by 5% of patients, and included hemorrhagic cystitis, urinary tract hemorrhage, hemorrhages (unspecified), hemorrhagic diathesis, and pulmonary hemorrhage (1 patient each). Serious AEs were reported in 15% of patients, most commonly MOD/MOF (7%), VOD/SOS (4%), and acute respiratory distress syndrome (2%). Conclusion In the Italian therapeutic use program, defibrotide treatment protocol (TUT), approximately one-fifth of the patients with hepatic VOD/SOS had MOD/MOF. The estimated survival rate of 68.4% at day +100, and the AE profile, was consistent with efficacy and safety data reported in previous studies in similar VOD/SOS patient populations. Support: Jazz Pharmaceuticals. Disclosures Off Label Use: Defibrotide is an investigational treatment for hepatic veno-occlusive disease/sinusoidal obstruction syndrome in the United States.. Amber:Jazz Pharmaceuticals: Employment, Equity Ownership. Banerjee:Jazz Pharmaceuticals: Employment, Equity Ownership. Finetto:Gentium S.p.A.: Employment; Jazz Pharmaceuticals: Equity Ownership.