Hepatic veno-occlusive disease (VOD) after allogeneic hematopoietic cell transplantation (HCT) in adults conditioned with busulfan (Bu) and cyclophosphamide (Cy) at a single center: A retrospective comparison of oral vs. intravenous Bu

Abstract

6647 Background: Hepatic VOD is one of potentially fatal toxicities after allogeneic HCT and is caused by high-dose chemotherapeutic agents, one of which is Bu. High interpatient variability following oral administration of Bu (O-Bu), which is ascribed to unpredictable and erratic intestinal absorption, contributes to the occurrence of hepatic VOD. Intravenous administration of Bu (I-Bu) has shown dose assurance with predictable pharmacokinetics. We investigated the occurrence of hepatic VOD after allogeneic HCT in adults conditioned with Bu-Cy and retrospectively compared I-Bu with O-Bu. Methods: All 241 patients, who were conditioned with Bu-Cy and who underwent allogeneic HCT between December 1993 and August 2003 at the Asan Medical Center, were included in this study. The first 187 patients received O-Bu (1 mg/kg x 16 doses), and thereafter 54 patients received I-Bu (Busulfex®, 0.8 mg/dg x 16 doses). Various hemostatic parameters were determined at 5 time points (day –7, 0, 7, 14, and 21). A diagnosis of VOD was made according to clinical criteria. Results: Hepatic VOD occurred in 41.7% of O-Bu group and 18.5% of I-Bu group (P=0.002). Multivariate analysis of baseline clinico-laboratory variables revealed that O-Bu vs. I-Bu (P=0.008, OR 2.793, 95% CI 1.310–5.956) and CSA/MTX vs. CSA for GVHD prophylaxis (P=0.044, OR 2.281, 95% CI 1.022–5.087) were independent risk factors for the occurrence of hepatic VOD. Eleven patients (5.9%) of O-Bu group developed severe VOD, while none of I-Bu group developed severe VOD. On day 7 and thereafter, patients with VOD showed significantly lower levels of antithrombin III (AT3) and higher levels of tPA and PAI-1 when compared to patients without VOD. Levels of AT3 were significantly higher in I-Bu group on days 7, 14, and 21 than O-Bu group, but levels of tPA and PAI-1 were not significantly different between two groups. Conclusion: In adults conditioned with Bu-Cy, I-Bu showed significantly decreased incidence of hepatic VOD and less hypercoagulability after allogeneic HCT compared to O-Bu. No significant financial relationships to disclose.