Individualized methotrexate dosing in children with relapsed acute lymphoblastic leukemia

Although high-dose methotrexate has been extensively studied in children wi th newly diagnosed acute lymphoblastic leukemia (ALL), there are fewer data in children with relapsed ALL, many of whom have been heavily pretreated a nd have subclinical kidney dysfunction. We characterized the pharmacokineti cs of adaptively controlled methotrexate given as a 24-h infusion during co nsolidation therapy in 24 children with relapsed ALL. To achieve the target steady-state concentration of 65 mu M, dosage adjustments were required in 14 patients, with doses ranging from 2854 to 6700 mg/m2 per course. The me an steady-state plasma concentration (Cp-ss) of 68.0 mu M was different (P = 0.025) than the predicted Cp-ss (mean = 87.4 mu M; range 35.7-184 mu M) h ad no adjustment in dose been made. The coefficient of variation in Cp-ss w as reduced from 41% to 18% by individualizing doses. Predisposing factors t hat correlated with decreased methotrexate clearance were female sex (P = 0 .03), age greater than 6 years (P = 0.01), and prior history of heavy ampho tericin B treatment (>30 mg/kg) (P = 0.03), but no factor predicted low cle arance as well as the measured initial methotrexate clearance during the in fusion (P < 0.0001). There was no life-threatening toxicity with the regime n. We conclude that dosage individualization decreases interpatient variabi lity and avoids potentially toxic methotrexate exposures in heavily pretrea ted ALL patients.