Influence of Methylenetetrahydrofolate Reductase C677T and A1298C Polymorphism on High-Dose Methotrexate-Related Toxicities in Pediatric Non-Hodgkin Lymphoma Patients

Abstract Purpose: This retrospective study aimed to investigate the relationships between the methylenetetrahydrofolate reductase (MTHFR) C677T/A1298C and high-dose methotrexate (HD-MTX)-related toxicities in pediatric non-Hodgkin lymphoma (NHL) patients. Patients and methods: We reviewed the medical records of 93 NHL patients aged under 18 years who received HD-MTX therapy at the dose of 5g/m2 with 24-hour infusion at Sun Yat-sen University Cancer Center between 2014 and 2019. Results: There were 61 males and 32 females, with a median age of 8.8 years (0.9-15.8 years). The tumor types included lymphoblastic lymphoma (n = 38), Burkitt's lymphoma (n = 31), anaplastic large cell lymphoma (n = 18), diffuse large B-cell lymphoma (n = 6). Overall, 355 courses of HD-MTX therapy were prescribed. All patients were rescued with calcium folinate 12 hours after the end of MTX infusion. We found that plasma MTX levels > 0.2μmol/L at 48 hours post-infusion increased the risk of developing oral mucositis (2.4 % VS. 9.5 %, P = 0.018). Also, patients carrying the C677T and T677T genotypes had tendencies to be more susceptible to oral mucositis (P = 0.034). Patients harboring mutant 677T allele were more likely to develop leucopenia (38.5% VS. 50.3%, P = 0.025) and thrombocytopenia (22.0 % VS. 32.4 %, P = 0.028). For polymorphism A1298C, the mutant genotype played a protective role in vomiting (11.1 % VS. 4.3 %, P = 0.018) but increased the risk of anemia (23.8 % VS. 41.7 %, P < 0.001) and leucopenia (38.1 % VS. 50.3 %, P = 0.021). Conclusion: Childhood NHL patients harboring C677T genotype were more vulnerable to oral mucositis, leucopenia, and thrombocytopenia, while those with A1298C genotype were at a decreased risk of vomiting and more likely to develop anemia and leucopenia.