Dose adjustment strategy for high-dose methotrexate-induced toxicities in pediatric acute lymphoblastic leukemia: based on population PK analysis and exposure-toxicity relationship.

Abstract

Purpose: High-dose methotrexate (HD-MTX) is the cornerstone of the therapy for acute lymphoblastic leukemia (ALL). However, severe adverse events are frequently reported despite standard supportive cares. Therefore, we aim to develop a new strategy to individualize HD-MTX and improve patient safety.

Methods: A retrospective study was conducted in which toxicity were evaluated in 134 patients with 461 HD-MTX treatment courses. All of the patients experienced standard supportive cares. Exposure-toxicity analysis was conducted to obtain the target concentration and area under the curve (AUC) of MTX. Population PK model was established for dose simulations.

Results: A high rate of severe toxicities (78.1%) was observed. Patients with C_24h above 75 µmol/L were at high risk for developing serious myelosuppression (P < 0.001) or hepatic injury (P = 0.005) within each cycle. Moreover, although no effect of AUC_0-24 h was found on toxicities within the relative cycle, a prolonged effect of MTX overexposure was observed on the toxicities in the next cycle. When the AUC_0-24 h levels were above 1447 µmol/L·h, patients were more likely to develop serious myelosuppression (P = 0.004) in the subsequent cycle. Based on the C_24h and AUC_0-24 h levels and the known required effective doses, reducing the dose from 5 g/m² to 2-3 g/m² according to the risk stratification is recommended to prevent related toxicities.

Conclusion: MTX C_24h and AUC_0-24 h levels are the predictors of HD-MTX-related toxicity. For patients with overdose of HD-MTX, a new dose adjustment strategy is established to improve patient safety and optimize clinical benefit.