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  • Clinical Research Article
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Impact of mercaptopurine schedule on hypoglycemia in leukemic children: randomized trial and risk factor analysis

Pediatric Research (2026)Cite this article

Abstract

Background

Children with acute lymphoblastic leukemia (ALL) may develop hypoglycemia, potentially attributable to mercaptopurine (6-MP) during long-term maintenance chemotherapy. Since hypoglycemia is harmful to childhood neurodevelopment, it is necessary to examine its occurrence during chemotherapy with and without 6-MP beyond the maintenance stage for ALL, along with the risk factors.

Methods

ALL patients received CAM-1 regimen (cyclophosphamide, cytarabine, and 6-MP). 6-MP was randomized to conventional administration at night before bedtime (Group A) or in the afternoon between lunch and dinner (Group B). Children with acute myeloid leukemia received non-6MP-containing chemotherapy (Group C).

Results

Group C showed no hypoglycemia. Among patients on CAM-1, 33% developed hypoglycemia, 48% of whom were symptomatic. There was no significant difference in hypoglycemic incidence (P = 0.933) between Groups A and B. No further hypoglycemic episodes were observed after shortening overnight fasting period in most cases. Multivariate analysis identified young age, higher serum bilirubin levels, and longer overnight fasting as significant risk factors for hypoglycemia in children receiving 6-MP.

Conclusion

Hypoglycemia is also prevalent in children exposed to short-term 6-MP but not in those without such exposure. Shortening overnight fasting period, rather than changing 6-MP schedule, is more critical in preventing hypoglycemia in young children.

Impact

  • This study reveals that hypoglycemia occurs frequently in children with ‌short-term exposure to 6-MP‌, as documented for long-term exposure‌ in published literature.

  • The data demonstrate that it is 6-MP that is directly associated with hypoglycemia.

  • Prolonged durations of overnight fasting, especially in younger individuals with hepatotoxicity, constitute a risk factor for developing hypoglycemia.

  • Shortening the overnight fasting period, rather than changing the 6-MP schedule, is critical to prevent hypoglycemia and adverse neurodevelopment in children, even if they are receiving short-term 6-MP treatment.

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Fig. 1: Patients with ALL were randomized into 2 groups during therapy with CAM1.

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Data availability

The data are available on request from the authors.

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Acknowledgements

We thank the patients and their families for their willingness to participate in this trial, and all participants and research staff.

Funding

This work was supported by grants in China from the Medical Science and Technology Research Foundations of Guangdong Province, China (A2022443 and A2024559), and the Science and Technology Planning Project of Huizhou, China (2022CZ010007).

Author information

Author notes

  1. These authors contributed equally: Zhi-Yan Chen, Qiao-Ru Li, Liu‑Hua Liao.

Authors and Affiliations

  1. Department of Pediatrics, First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China

    Zhi-Yan Chen, Yu Li, Li-Na Wang, Cong Liang, Zhong Fan, Tian-Fang Yue, Cui-Yun Yang, Xue-Qun Luo, Yan‑Lai Tang, Li-Bin Huang & Xiao-Li Zhang

  2. Department of Pediatrics, Zhongshan City People’s Hospital, Zhongshan, Guangdong, China

    Qiao-Ru Li

  3. Department of Pediatrics, Huizhou Central People’s Hospital, Huizhou, Guangdong, China

    Liu‑Hua Liao

  4. Department of Pediatrics, Guangzhou Red Cross Hospital, Guangzhou, China

    Xiao-Ling Chen

  5. Department of Pediatrics, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China

    Xiao-Lan Xiao

  6. Department of Pediatrics, Clifford Hospital, Guangzhou, China

    Hui Jin

Authors
  1. Zhi-Yan Chen
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Contributions

Conception and design: Zhang X.L., Huang L.B., Tang Y.L. and Luo X.Q. Generating the random allocation sequence, assigning participants to interventions: Chen Z.Y. and Zhang X.L. Enrolling participants: Zhang X.L., Huang L.B., and Tang Y.L. Collection and assembly of data: Chen Z.Y., Li Q.R., Liao L.H., Chen X.L., Xiao X.L., Jin H., Li Y., Wang L.N., Liang C., Fan Z., Yue T.F., and Yang C.Y. Data analysis and interpretation: Zhang X.L., Huang L.B. and Tang Y.L. Statistical analysis: Zhang X.L., Huang L.B., Tang Y.L., Chen Z.Y., Li Q.R. and Liao L.H. Manuscript writing and final approval of manuscript: all authors. All authors read and approved the final version.

Corresponding authors

Correspondence to Yan‑Lai Tang, Li-Bin Huang or Xiao-Li Zhang.

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The authors declare no competing interests.

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Written informed consent was obtained from the parents of the study participants before enrollment in accordance with the Declaration of Helsinki.

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Chen, ZY., Li, QR., Liao, L. et al. Impact of mercaptopurine schedule on hypoglycemia in leukemic children: randomized trial and risk factor analysis. Pediatr Res (2026). https://doi.org/10.1038/s41390-025-04728-0

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