Hepatic veno-occlusive disease (VOD) is a potentially devastating complication of both allogeneic and autologous stem cell transplantation. Severe VOD usually occurs very early in the course of transplantation, and the mortality rate of these cases is at least 90%. The pathogenesis of VOD involves injury to the sinusoidal endothelial cells, leading to occlusion of small vessels with fibrin deposition and disruption of hepatic function. Previous attempts at therapy using either heparin or tissue plasminogen activator have been unsuccessful.

Defibrotide is a single-stranded polydeoxyribonucleotide that has effects on the vascular endothelial cells, particularly those of small vessels. After binding to endothelial cells defibrotide enhances factors that contribute to fibrinolysis and suppresses those that promote coagulation. These effects are predominately local within the vascular bed, and there is no significant effect on systemic coagulation. Previous pilot trials of defibrotide for VOD have suggested both efficacy and lack of significant toxicity (Richardson et al, Blood. 1998; 92:737-744).

In this issue Richardson and colleagues (page 4337) report on a multicenter phase 2 trial of defibrotide for treatment of patients with severe VOD. Thirty-six percent of patients responded, and 35% survived to day +100. Of patients alive at this time point, the majority became the long-term survivors and there were no late deaths due to recurrence of VOD. Defribrotide caused only modest toxicity, even in these critically ill patients, and there was no evidence of coagulopathy or increased risk of bleeding.

These results are encouraging and suggest that, for the first time, a therapy is available that can impact on the very poor outcome of patients with hepatic VOD. A prospective randomized phase 2 trial is near completion to confirm these observations and to better define the optimal dose.