Plasma creatinine as predictor of delayed elimination of high-dose methotrexate in childhood acute lymphoblastic leukemia: A Danish population-based study.

Background Severely delayed elimination of methotrexate (MTX) is difficult to predict in patients treated with high-dose MTX (HD-MTX), but it may cause life-threatening toxicity. It has not been defined how an increase in plasma creatinine can be best used as a predictor for severely delayed MTX elimination, thus providing a guide for therapeutic interventions to minimize renal toxicity. Methods Pharmacokinetic data were retrospectively collected on 218 Danish children with acute lymphoblastic leukemia treated with HD-MTX 5 or 8 g/m(2) on the NOPHO2000 protocol. Moderately delayed MTX elimination was defined as 42-hour plasma MTX >= 4.0-9.9 mu M, and severely delayed elimination was defined as 42-hour plasma MTX >= 10 mu M. Results Median 42-hour plasma MTX was 0.61 mu M (interquartile range, 0.4-1.06 mu M). Of 1295 MTX infusions with 5 g/m(2) (n = 140 patients) or 8 g/m(2) (n = 78 patients), 5.1% were severely (1.5%) or moderately (3.6%) delayed. The risk of having delayed elimination was highest in the first of eight infusions with MTX 5 g/m(2) (7.4% vs 0.0 to 4.1% for subsequent MTX infusions) (P < 0.02). A 25 mu M increase or a 1.5-fold increase in plasma creatinine within 36 hours from start of the MTX infusion had a sensitivity of 92% (95% CI, 82%-97%) and a specificity of 85% (95% CI, 83%-87%) for predicting 42-hour MTX >= 4.0 mu M. Conclusions A 25 mu M increase or a 1.5-fold in plasma creatinine within 36 hours after start of an HD-MTX infusion can predict delayed MTX elimination, thus allowing intensification of hydration and alkalization to avoid further renal toxicity and promote the elimination of MTX.