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

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.