Activated Recombinant Factor VII (rFVIIa/NovoSeven®) in the Treatment of Bleeding Complications Following Hematopoietic Stem Cell Transplantation (HSCT).

HSCT is a common treatment of hematological or oncological disorders. Many HSCT-associated complications, including prolonged aplasia, infection and graft-versus-host disease (GVHD) predispose to bleeding, resulting in increased morbidity and mortality. Platelet concentrates, fresh frozen plasma, antifibrinolytic agents or prothrombin complex concentrates are often ineffective. Although licensed for use in hemophilia pts with inhibitors, rFVIIa has been reported to be effective for the treatment of bleeding related to thrombocytopenia, thrombasthenia and other coagulation disorders. We conducted a multicenter, randomized, double-blind, placebo-controlled trial to evaluate the efficacy and safety of rFVIIa in treatment of bleeding from days 2 to 180 after HSCT (F7BMT-1360 trial). Patients received rFVIIa (40, 80, 160 μg/kg) or placebo every 6h for 36h and were followed up for 96h after the initial dose. Exclusion criteria were recent thromboembolic events, atherosclerotic disease, DIC, thrombotic microangiopathy, venoocclusive disease and active AML (M3, M4, M5). The primary efficacy endpoint was the change in bleeding from 0h to 38h after initial dose. Secondary endpoints were transfusion requirements, change of coagulation parameters, and adverse events (AEs). One hundred patients (64 m; 36 f; 97 allogeneic; 3 autologous; 67 PBSC; 30 bone marrow; 2 cord blood; 1 unknown) with moderate or severe bleeding were included (38 lower GI; 26 hemorrhagic cystitis; 14 upper GI; 7 pulmonary; 1 intracerebral; 14 other). 80 μg/kg rFVIIa was effective, however no significant reduction in bleeding was seen at 160 μg/kg. There were no differences in transfusion requirements and changes in coagulation parameters across dose groups. Thirteen serious adverse events (SAEs) were reported within the trial period; there was no apparent drug or dose-related trend in the type or number of SAEs. One thromboembolic SAE (catheter thrombosis, 160 μg/kg) was observed within the trial period (2 days after last dosing) and two thromboembolic SAEs (cerebral infarction, 80 μg/kg; myocardial infarction, 40 μg/kg) were reported 4 and 14 days after last dosing. In this first controlled study on the use of rFVIIa after HSCT we found a significant effect of 80 μg/kg rFVII versus the standard hemostatic treatment. The diversity of the hemostatic disturbances and the heterogeneity of the patient population may have contributed to the lack of an increasing effect with increased dose. No safety issues were identified. Further trials with higher numbers of patients should focus upon optimizing the dose regimen of rFVIIa and on severe bleeding complications

Bleeding status 38h after initial dose