Impact Of CYP2D6 Polymorphisms On Anthracycline-Induced Cardiotoxicity In Pediatric Acute Myeloid Leukemia Patients: A Systematic Review And Meta-Analysis

Abstract

Background/Purposes: Anthracyclines have a central role in the treatment of pediatric acute myeloid leukemia (AML)/cardiotoxicity Anthracyclines are limited by dose-dependent cardiotoxicity. Genetic diversity of the major drug metabolizing enzyme CYP2D6 can be a factor in individual susceptibility. The aim of this systematic review and meta-analysis was to assess the effect of CYP2D6 polymorphisms on cardiotoxicity by anthracycline in children with AML.

Materials/Patients and Methods: The search performed on PubMed, Scopus, Web of Science, and Google Scholar through to December 2025. The eligible studies were pediatric AML patients who had the CYP2D6 genotypes recorded on anthracyclines and reported the outcomes of cardiotoxicity. Information on the demographics of patients, genotypes, treatment regimens, and the incidence of cardiotoxicity were obtained. The calculation of pooled risk ratios (RRs) with 95% confidence interval (CIs) was done using a random-effects model as a way of meta-analysis. I²was used to measure heterogeneity and the funnel plots were used to determine publication bias.

Findings: Twenty-eight articles with 1,246 children with AML were included. The distribution of CYP2D6 metabolizers was as follows; poor metabolizers (PM) 1826, intermediate metabolizers (IM) 15 and extensive metabolizers (EM) 10. The total incidence of cardiotoxicity caused by anthracycline was 15 percent. Genotype stratified cardiotoxicity was also the highest in PMs (21%), then IMs (15%), and EMs (10%). Cardiotoxicity of severe type was observed in 4% of patients, and they were mostly PMs (65%). Dose of >350 mg/m²anthracycline showed a risk of cardiotoxicity of 28%. The heterogeneity was moderate (I² = 52 percent) and very little publication bias was found.

Conclusion: CYP2D6 polymorphisms are important in regulating the risk of anthracycline induced cardiotoxicity in pediatric AML patients. Phenotype discovery of PM and IM may inform genotype-based dosing, enhance the clinical power of the therapeutic approach, and mitigate CVD adverse outcomes. Pharmacogenomic testing should be incorporated in the practice of pediatric oncology to promote the field of precision cardio-oncology.