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The influence of MTHFR genetic polymorphisms on methotrexate therapy in pediatric acute lymphoblastic leukemia
Yaqing Shen1, Zhujun Wang1, Fen Zhou1
1Department of Pediatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430022, China.
Abstract:
MTHFR is a crucial enzyme in folate metabolism. This study aimed to determine the relationship between MTHFR genetic polymorphism and elimination and toxicities of methotrexate (MTX). To do that, the study enrolled 145 patients diagnosed with acute lymphoblastic leukemia, who received chemotherapy following the Chinese Children's Cancer Group Acute Lymphoblastic Leukemia (CCCG-ALL)-2015 protocol (clinical trial number: ChiCTR-IPR-14005706). We analyzed the effects of MTHFR C677T and A1298C polymorphisms on MTX elimination and toxicities. Patients with the MTHFR C677T TT genotype could tolerate a significantly higher MTX dose than those with the CC/CT genotype. However, patients with C677T TT genotypes had an increased risk of hypokalemia (1.369 to CC and 1.409 to CT types). The MTX infusion rate in patients with the MTHFR A1298C AC genotype was slightly lower than that in those with CC or AA genotypes. Patients with the A1298C AA genotype had a 1.405-fold higher risk of hepatotoxicity than those with the AC genotype (P > 0.05). There was no significant difference between the prevalence of other toxicities among MTHFR C677T or A1298C genotypes (P > 0.05). Neither MTHFR C677T nor A1298C polymorphisms were significantly associated with delayed MTX clearance. To conclude, MTHFR polymorphisms were not good predictors of MTX-related toxicities.
Insights
Methylenetetrahydrofolate reductase (MTHFR) gene variations did not predict methotrexate toxicity or clearance in acute lymphoblastic leukemia patients. Specific MTHFR genotypes showed varied tolerance and risks for hypokalemia and hepatotoxicity, but overall, they were not reliable predictors.
Area of Science:
- Pharmacogenomics
- Oncology
- Biochemistry
Background:
- Methotrexate (MTX) is a key chemotherapy agent for acute lymphoblastic leukemia (ALL).
- MTHFR enzyme activity is vital for folate metabolism, influencing drug efficacy and toxicity.
- Genetic variations in MTHFR may impact MTX treatment outcomes.
Purpose of the Study:
- To investigate the association between MTHFR C677T and A1298C polymorphisms and MTX elimination and toxicity in pediatric ALL patients.
- To determine if MTHFR genotypes can predict MTX-related adverse events.
Main Methods:
- A cohort of 145 pediatric ALL patients treated with the CCCG-ALL-2015 protocol was analyzed.
- MTHFR C677T and A1298C polymorphisms were genotyped.
- MTX doses, elimination rates, and toxicities (including hypokalemia and hepatotoxicity) were assessed in relation to MTHFR genotypes.
Main Results:
- Patients with MTHFR C677T TT genotype tolerated higher MTX doses but had increased hypokalemia risk.
- MTHFR A1298C AA genotype was linked to a higher risk of hepatotoxicity.
- No significant association was found between MTHFR polymorphisms and MTX clearance or overall toxicity prediction.
Conclusions:
- MTHFR polymorphisms showed some associations with specific toxicities like hypokalemia and hepatotoxicity, and MTX dose tolerance.
- However, MTHFR genetic variations were not found to be reliable predictors of overall MTX-related toxicities or clearance in this pediatric ALL cohort.
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