Pharmacokinetics of High-Dose Methotrexate in Infants Treated for Acute Lymphoblastic Leukemia

Background. Interfant-99 was an international collaborative treatment protocol for infants with acute lymphoblastic leukemia (ALL). Procedure. We collected data on 103 infants at the time of their first treatment with high-close methotrexate (HD MTX), 5 g/m(2). Children <6 months of age received two-third of the calculated close based on body surface area (BSA), children 6-12 months three-fourth of the calculated dose, and children >12 months full dose. Results. The median steady-state MTX concentration at the end of the 24-hr infusion was 57.8 mu M (range 9.5-313). The median systemic clearance was 6.22 L/hr/m(2) BSA, and tended to increase with age (P = 0.099). Boys had higher clearance than girls, 6.77 and 5.28 L/hr/m(2) (P = 0.030), and tended to have lower median MTX concentration at 24 hr. Eight infants had MTX levels below 20 mu M, a level judged to be sufficient in B-lineage ALL in children >1 year of age. All infants tolerated the close well enough to receive a second dose of HD MTX without dose reduction. We found no significant effect on disease-free survival for MTX steady-state concentration, MTX clearance, or time to MTX below 0.2 mu M. Conclusions. Our data provide no Support for a change in the dosing rules for MTX used in Interfant-99. However, in view of the poor treatment results for infants, one might consider increase in the dose for patients who reach plasma levels below median after the first MTX dose. Pediatr Blood Cancer 2009;52:596-601. (C) 2009 Wiley-Liss, Inc.