Summary:Autologous recovery is a major problem with busulfan as a marrow ablative agent in conditioning children for allogeneic BMT. Data suggest the average concentration of busulfan at steady state (Bu Css) is critical for successful engraftment. We prospectively evaluated busulfan pharmacokinetics in 31 children (age 0.6-18 years) with AML (n = 9), and non-malignant diseases (n = 22) receiving HLA-closely matched (sibling, parent, unrelated) donor grafts. Blood samples were obtained following dose 1 and 13 of a standard 16 dose, 4-day regimen. The busulfan dose varied from 14 to 20 mg/kg. Patients received cyclophosphamide 200-240 mg/kg; 22/31 received 80-90 mg/kg of ATG. Eight patients failed to engraft (26%). ATG did not appear to influence engraftment (P = 0.38). Bu Css levels Ͻ600 ng/ml correlated with autologous recovery/mixed chimerism (P = 0.018). There were no graft failures in patients with a Bu Css Ͼ600 ng/ml. A correlation between Bu Css levels and regimen-related toxicity (RRT) was not identified for grade 2 or higher toxicities, only 1/31 had a Bu Css Ͼ900 ng/ml. Our data support the use of pharmacokinetic monitoring of busulfan. Bone Marrow Transplantation (2000) 25, 925-930. Keywords: busulfan; children; bone marrow transplantation; cyclophosphamide; toxicity Busulfan is a potent myelotoxin that complements the lymphocyte toxicity of cyclophosphamide in preparative regimens for hematopoietic stem cell transplantation. 1-3 The standard dose is 1 mg/kg administered orally every 6 h over 4 days. However, this regimen results in highly variable concentrations in plasma, particularly when young children are compared to older children or adults. 4-7 At a given dose, normalized to either body weight or surface area, young children exhibit average busulfan steady-state concentrations (Css) or an area under the curve (AUC) substantially less than do older children or adults. 7-9 The Css corresponds to the AUC over a dosing interval divided by the 6 h between doses. The AUC over a dosing interval is equal to the AUC from the time the first dose is ingested to infinity if no subsequent doses are taken. A Css of 900 ng/ml is equal to an AUC of 1350 m × min.Few studies of the relationship between busulfan Css (Bu Css) or AUC and outcome of the busulfan/ cyclophosphamide preparative regimen have focused on children. Adults with CML have been shown to be at increased risk of relapse if Bu Css is low and exhibit less busulfan-related toxicity compared to patients with other diseases receiving similar treatment. 10,11 Excessively low levels of busulfan have been related to graft rejection, while high levels have been related to severe toxicities. 12,13 Of particular interest in children is the issue of graft rejection. Since cyclophosphamide is directly toxic to mature lymphocytes and busulfan is not, graft rejection has been thought to be due to inadequate dosing of cyclophosphamide. 1,14 Thus, the relatively high incidence of graft rejection in children receiving a busulfan/cyclophosphamide preparative regime...

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