MTHFR variants 677TT and 677CT/1298AC are associated with decreased tolerance to methotrexate in pediatric acute lymphoblastic leukemia

Background: Methotrexate (MTX) remains a critical component in the treatment of pediatric acute lymphoblastic leukemia (ALL), exerting its antileukemic effect through interference of the folate metabolic pathway. MTHFR is an enzyme that serves as the rate limiting step within this pathway and there has been speculation that certain MTHFR single nucleotide polymorphisms (SNPs) alter physiologic responses to MTX and affects drug toxicity. Methods: We performed a retrospective analysis of pediatric patients treated at our institution to assess correlation between different MTHFR genotypes and MTX induced toxicities. Specifically, we examined maximum tolerated Capizzi and oral MTX doses, MTX clearance times during high dose MTX (HDMTX), and frequency of MTX-associated toxicities. Results: Within our study population, 46 out of 242 patients were tested for MTHFR SNPs with 33 resulting positive for a known MTHFR polymorphism. Patients with MTHFR genotypes including those who were homozygous 677TT and compound heterozygous 677CT/1298AC demonstrated significantly decreased tolerance to oral MTX as demonstrated by decreased maximum tolerated MTX dosing relative to control and the 677TT genotype also demonstrated reduced tolerance to IV MTX (Capizzi MTX). Clinically significant MTHFR genotypes were likely to be detected in the presence of myelosuppression, but no other known MTX adverse effects demonstrated predictive ability. Lastly, no genotype was associated with increased risk of developing MTX leukoencephalopathy or thrombosis with any SNP. Conclusions: MTHFR genotypes including homozygous 677TT and compound heterozygous 677CT/1298AC are associated with decreased tolerance to both Capizzi and oral MTX, manifested by increased myelosuppression.