Blood, 15 December 2002, Vol. 100, No. 13, pp. 4255-4255
Defibrotide as treatment for hepatic veno-occlusive disease
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.
Charles Linker
University of California, San
Francisco
