BUSULFAN DISPOSITION AND HEPATIC VENOOCCLUSIVE DISEASE IN CHILDREN UNDERGOING BONE-MARROW TRANSPLANTATION

Hepatic veno-occlusive disease (HVOD) is a frequent life-threatening t oxicity in patients undergoing bone marrow transplantation (BMT) after the administration of a high-dose busulfan-containing regimen. Recent studies have shown that the morbidity and mortality of HVOD may be re duced in adults by pharmacologically guided dose adjustment of busulfa n. We analyzed the pharmacodynamic relationship between busulfan dispo sition and HVOD in 61 children (median age, 5.9 years) with malignant disease. Busulfan, given at a dose ranging from 16 mg/kg to 600 mg/m(2 ), was combined with one or two other alkylating agents (cyclophospham ide, melphalan, thiotepa). Only 3 patients received the standard busul fan/cyclophosphamide (BUCY) regimen. A total of 24 patients (40%) deve loped HVOD, which resolved in all cases. A pharmacokinetics study conf irmed the previously reported wide interpatient variability in busulfa n disposition but did not reveal any significant alteration in childre n with HVOD. The mean area under the concentration-time curve (AUG) af ter the first dose of busulfan was higher in patients with HVOD (6,811 +/- 2,943 ng h ml(-1)) than in patients without HVOD (5,760 +/- 1,891 ng h ml(-1); P = 0.10). This difference reflects the higher dose of b usulfan given to patients with HVOD. No toxic level could be defined a nd, moreover, none of the toxic levels identified in adults were relev ant. The high incidence of HVOD in children given 600 mg/m(2) busulfan may be linked to the use of more intensive than usual high-dose chemo therapy regimens and/or drug interactions. Before the prospective eval uation of busulfan dose adjustment in children, further studies are re quired to demonstrate firmly the existence of a pharmacodynamic relati onship in terms of toxicity and allogeneic engraftment, especially whe n busulfan is combined with cyclophosphamide. The maximal tolerated an d minimal effective AUCs in children undergoing BMT are likely to depe nd mainly upon the disease, the nature of the combined high-dose regim en, and the type of bone marrow transplant.