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