Pretreatment Plasma Folate Modulates the Pharmacodynamic Effect of High-Dose Methotrexate in Children with Acute Lymphoblastic Leukemia and Non-Hodgkin Lymphoma: “Folate Overrescue” Concept Revisited

摘要

Background: To evaluate the influence of pretreatment plasma folate concentrations on methotrexate exposure in children with acute lymphoblastic leukemiaon-Hodgkin lymphoma treated with high-dose methotrexate, we assessed time profiles of plasma homocysteine, folate, and vitamin B12 concentrations in children treated with high-dose methotrexate with leucovorin rescue.Methods: We analyzed 98 treatment courses. The study endpoints were to determine how methotrexate exposure is related to homocysteine accumulation and whether it is influenced by pretreatment plasma folate.Results: Peak concentrations of homocysteine increased from the start of the intravenous infusion through cessation of methotrexate therapy up to time point t 42, when this trend was reversed by administration of folinic acid. The area under the curve (AUC) for plasma homocysteine showed decreasing course-to-course tendencies with a statistically significant decrease only between courses 1 and 2 ( P ≤0.05), indicating decreased whole-body homocysteine accumulation in response to administration of consecutive methotrexate courses. Therapeutic courses with low initial folate concentrations (≤10 nmol/L) gave significantly higher responses in homocysteine accumulation expressed both as hcysAUC0–66 h and the peak t 42 homocysteine concentrations than did courses with initial folate 10 nmol/L. Correspondingly, in the courses with low initial folate, peak plasma concentrations of methotrexate were significantly higher than in courses with high precourse concentrations of plasma folate.Conclusion: Endogenous pretreatment plasma folate modulates the magnitude of the methotrexate effect, providing support for a “folate overrescue” concept.