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Purpose <p>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.</p> Methods <p>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.</p> Results <p>A high rate of severe toxicities (78.1%) was observed. Patients with C<sub>24h</sub> above 75 µmol/L were at high risk for developing serious myelosuppression (<i>P&#xa0;</i>&lt;&#xa0;0.001) or hepatic injury (<i>P</i> = 0.005) within each cycle. Moreover, although no effect of AUC<sub>0−24&#xa0;h</sub> 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<sub>0−24&#xa0;h</sub> levels were above 1447 µmol/L·h, patients were more likely to develop serious myelosuppression (<i>P</i> = 0.004) in the subsequent cycle. Based on the C<sub>24h</sub> and AUC<sub>0−24&#xa0;h</sub> levels and the known required effective doses, reducing the dose from 5&#xa0;g/m<sup>2</sup> to 2–3&#xa0;g/m<sup>2</sup> according to the risk stratification is recommended to prevent related toxicities.</p> Conclusion <p>MTX C<sub>24h</sub> and AUC<sub>0−24&#xa0;h</sub> 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.</p>

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

  • 期刊论文

  • 发表日期：

    2025年2月15日

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  • Ailing Cao,
  • Yanping Guan,
  • Jian Wang,
  • Xinyu Li,
  • Shu Liu,
  • Qiaolan Xuan,
  • Kunyin Qiu,
  • Yating Zhang,
  • Lvhong Xu,
  • Jianpei Fang,
  • Zhong Zuo,
  • Min Huang,
  • Xueding Wang,
  • Dunhua Zhou

摘要

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 C24h 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 AUC0−24 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 AUC0−24 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 C24h and AUC0−24 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 C24h and AUC0−24 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.