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Dose-individualization Efficiently Maintains Sufficient Exposure to Methotrexate without Additional Toxicity in High-dose Methotrexate Regimens for Pediatric Acute Lymphoblastic Leukemia

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Abstract

Objective

Methotrexate (MTX) can be safely administered to most patients but may cause severe toxicity in others. This study aimed to summarize the characteristics of high-dose methotrexate (HD-MTX) chemotherapy and to evaluate whether the modified dose-adjustment program was able to improve the maintenance of sufficient MTX exposure levels while minimizing toxicities.

Methods

We evaluated 1172 cycles of high-dose MTX chemotherapy from 294 patients who were treated according to the CCCG-ALL-2015 protocol (clinical trial number: ChiCTR-IPR-14005706) and analyzed the data of actual MTX dosage, MTX concentration, toxicity, and prognosis. We compared data between the dose-adjustment Program 1 (fixed 20% reduction in dose) and the dose-adjustment Program 2 (dose-individualization based on reassessment of the creatine clearance rate and the MTX concentration-monitoring point at 16 h), which were applied if the MTX clearance was delayed in the previous cycle.

Results

The patients who used Program 2 had higher actual MTX infusion doses and infusion rates and were able to better maintain the MTX concentration at 44 h at the established target value than those on Program 1 (P<0.001). No significant differences in toxicities were found between these two programs except that abnormal serum potassium levels and prolonged myelosuppression in intermediate-risk/high-risk patients were more frequently observed in patients using Program 2 (P<0.001). No significant correlations were observed between the MTX dose, dose-adjustment programs, or MTX concentrations and relapse-free survival.

Conclusion

Adjusting the MTX dose using Program 2 is more efficient for maintaining sufficient MTX exposure without significantly increasing the toxicity.

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Author notes

  1. The authors contributed equally to this study.

Authors and Affiliations

  1. Department of Pediatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China

    Ya-qing Shen, Zhu-jun Wang, Xiao-yan Wu, Kun Li, Zhong-jian Wang, Wen-fu Xu, Fen Zhou & Run-ming Jin

Authors
  1. Ya-qing Shen
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  2. Zhu-jun Wang
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  3. Xiao-yan Wu
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  4. Kun Li
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  5. Zhong-jian Wang
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  6. Wen-fu Xu
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  7. Fen Zhou
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  8. Run-ming Jin
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Corresponding authors

Correspondence to Fen Zhou or Run-ming Jin.

Ethics declarations

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Author Run-ming JIN is a member of the Editorial Board for Current Medical Science. Author Fen ZHOU is a member of Youth Editorial Committee for Current Medical Science. The paper was handled by other editors and has undergone rigorous peer review process. Authors Run-ming JIN and Fen ZHOU were not involved in the journal’s review of, or decisions related to, this manuscript.

Additional information

The present study was supported by the National Natural Science Foundation of China (No. 81700147 and No. 82070172).

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Shen, Yq., Wang, Zj., Wu, Xy. et al. Dose-individualization Efficiently Maintains Sufficient Exposure to Methotrexate without Additional Toxicity in High-dose Methotrexate Regimens for Pediatric Acute Lymphoblastic Leukemia. CURR MED SCI 42, 769–777 (2022). https://doi.org/10.1007/s11596-022-2589-1

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  • DOI: https://doi.org/10.1007/s11596-022-2589-1

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