Safety of Defibrotide (DF) In Stem Cell Transplant (SCT) Patients (Pts).

Defibrotide (DF), a characterized mixture of polydisperse oligonucleotides, has endothelial protective properties with profibrinolytic, antithrombotic, anti-inflammatory and anti-adhesive activity. The safety of DF injectable and oral formulations has been previously established in clinical trials including more than 9000 pts in the treatment of vascular diseases (eg peripheral arterial disease, deep vein thrombosis), with related adverse events (AE) reported in 2% of these pts. The protective endothelial effects of DF combined with its low toxicity profile led to investigation of its use in the treatment and prevention of hepatic veno-occlusive disease (VOD) in SCT pts.

As pts undergoing SCT are likely to experience SCT-associated toxicities, it was difficult to assess the contribution of DF to observed toxicities in the initial single-arm trials. Chemotherapy-induced thrombocytopenia and endothelial cell injury predispose SCT pts to hemorrhagic and thrombotic complications. Bleeding is common in this population, particularly in pts with severe VOD (sVOD), characterized by multi-organ failure (MOF).

We therefore undertook a comprehensive review of safety for DF in this setting.

To date, of 1824 SCT pts (pediatric: 737; adult: 1087) who received DF for the prevention or treatment of VOD/ sVOD, 104 (6%) experienced DF-related AEs. Of these 1824, 428 were enrolled in controlled clinical trials: one randomized phase 2 trial comparing 2 doses of DF and two phase 3 trials: one comparing the toxicity profile of DF to a historical control (HC) for the treatment of sVOD, the other to ‘no prophylaxis’ for the prevention of VOD in children.

The phase 2 trial randomized 149 pts with sVOD/MOF to receive DF 25 or 40mg/kg/d (pediatric: 48; adult: 101). Both doses were well tolerated. DF-related AEs leading to treatment discontinuation (DC) occurred in 4% of pts: hemorrhage [gastrointestinal (GI), pulmonary, and diffuse alveolar], hypotension, and abdominal cramping. The percentage of pts with Grade 3–4 AEs was similar in both arms, however, pts randomized to 40 mg/kg/d were reported to have a higher incidence of all severity grade bleeding events than pts randomized to 25mg/kg/d (57% versus 46%). As efficacy parameters (CR rate; survival) were equal between the 2 dose groups, while the safety profile of the 25 mg/kg/day dose was slightly improved, the 25 mg/kg/d dose was chosen for future studies.

In the phase 3 study, 102 pts with sVOD/MOF (pediatric: 44; adult: 58) treated with 25 mg/kg/d were compared with 32 matched HC pts. DF was generally well tolerated. DF-related AEs (possibly, probably, or definitely related) of Grade 3–5 severity occurred in 27 pts (26%). The following DF-related AEs led to DC of drug in 18 pts (18%): hemorrhage (pulmonary, GI, cerebral, catheter site, and hemorrhage, site not specified; hematochezia and epistaxis), headache, lethargy, hypotension, subdural hygroma, and TTP. Overall AEs, including hemorrhagic AEs, were similarly reported between the DF and control arms. The most frequent AEs were hypotension (39 vs 50%), diarrhea (25 vs 38%), vomiting (21 vs 28%), nausea (15 vs 34%) and pyrexia (15 vs 34%). The most common hemorrhages were epistaxis (13 vs 16%), pulmonary hemorrhage (12 vs 9%), catheter site hemorrhage (12 vs 3%) and hematuria (9 vs 16%).

The phase 3 open-label study randomized pediatric pts to receive DF prophylaxis 25mg/kg/d (n=177) or control (n=176) from pre-SCT conditioning until Day+30 post SCT. Prophylactic DF was well tolerated, resulting in few related AEs (5%), including 1 GI hemorrhage which led to DF DC in 1 pt (<1%). AEs were reported at a similar incidence in the DF and control arms, including hemorrhage; the most common were hemorrhagic cystitis (11 vs 11%), GI hemorrhage (2 vs 4%), and epistaxis (2 vs 2%). Pts in both arms who reached the endpoint of VOD were treated with DF (25mg/kg/d); the incidence of DF related AEs in all pts treated for VOD was 14% (8/57).

In the SCT population, DF-related AEs occurred with an increased incidence compared to other indications. The incidence was lowest in VOD prophylaxis pts and highest in pts with sVOD. In controlled SCT studies, DF was well tolerated, with AEs (including hemorrhage) reported with similar frequency to the control. These results indicate that DF can be used without increasing the risk of complications in this population of pts at high risk.

Corbacioglu:Gentium: Consultancy, Research Funding. Carreras:Gentium: Consultancy. Niederwieser:Gentium: Honoraria. Sardella:Gentium: Employment. Hoyle:Gentium: Employment. Hume:Gentium: Employment. Massaro:Gentium: Consultancy. Hannah:Gentium: Consultancy. Iacobelli:Gentium: Employment. Richardson:Gentium: Membership on an entity's Board of Directors or advisory committees.