Use of MTHFR C677T polymorphism and plasma pharmacokinetics to predict methotrexate toxicity in patients with acute...

Methotrexate (MTX) is a key component of acute lymphoblastic leukemia (ALL) therapy, but it is associated with serious toxicities in a considerable number of patients.

The aim of the current study was to determine which variables were associated with MTX toxicity in children, adolescents and young adults with ALL.

In this prospective study, 35 patients with newly diagnosed ALL, treated according to the 58951 European Organization for Research and Treatment of Cancer - Children's Leukemia Group (EORTC-CLG) protocol, were prospectively enrolled. Toxicity data was collected objectively after each high-dose methotrexate (HD-MTX) course. The risk factors of MTX toxicity were determined using multiple linear regression analysis, with age, gender, immunophenotype, risk group, plasma MTX levels, plasma homocysteine (HCY) levels, and MTHFR C677T included as independent variables.

Twenty-five (71.4%) patients experienced toxicity on at least 1 course of HD-MTX. In the univariate linear regression, the global toxicity score was associated with a significant rise in plasma HCY concentrations within 48 h after MTX administration (β = 0.4; R2 = 0.12; p = 0.02). In the multiple regression model, the global toxicity score was significantly associated with a higher MTX plasma levels at 48 h (β = 0.5; R2 = 0.38; p = 0.001) and CT 677 MTHFR genotype (β = 0.3; R2 = 0.38; p = 0.01).

Routine monitoring of plasma MTX concentrations is essential to detect patients at a high risk of MTX toxicity. MTHFR C677T genotyping may be useful for predicting MTX toxicity.