Phase II trial of heparin prophylaxis for veno-occlusive disease of the liver in children undergoing bone marrow transplantation.

Veno-occlusive disease (VOD) of the liver is an early complication of bone marrow transplantation (BMT). The initial event has been hypothesized to be an injury to the endothelial cells eventually resulting in post-sinusoidal obstruction and hepatic failure. The role of anticoagulants for the prevention of VOD is controversial. Continuous infusion of heparin has been reported to be effective in preventing VOD in adults undergoing myeloablative therapy and BMT. An unblinded, historical controlled study was carried out to assess the safety and efficacy of continuous infusion of low-dose heparin in prevention of VOD in children undergoing BMT following myeloablative therapy. Fifty consecutively BMT-treated children (10 months to 18 years 7 months) were enrolled into the study group and received continuous heparin infusion (100 units/kg/day) from the first day of the preparative regimen to day +30 or until discharge, whichever occurred earlier. These were compared with a control group of 70 patients who received BMT for a variety of disorders. Patient groups were similar with respect to primary diagnosis, age, sex, and baseline organ functions. Heparin was well-tolerated, with only minor grade I-II hemorrhagic episodes occurring in 28 patients (56%), compared to 50 patients in the control group (71%) (P = 0.184). Bleeding was significantly less following autologous BMT compared to allogeneic BMT (P < 0.05). VOD was diagnosed in five patients (10%) compared to 18 of 70 in the control group (25.7%) (P < 0.05). Analysis of risk factors demonstrated a significantly higher incidence of VOD in patients undergoing allogeneic BMT (matched related, mismatched related and matched unrelated), patients older than 15 years of age, and patients with advanced disease (> or = 2 CR). In summary, this phase II trial has demonstrated that continuous heparin infusion can be safely used prophylactically in children undergoing myeloablative therapy and BMT. The incidence of moderate and serious VOD was significantly less compared to historical controls. A future randomized, double-blinded, placebo-controlled phase III trial is, however, required to determine the efficacy of heparin in preventing VOD in children undergoing myeloablative therapy and BMT.