Effects of Methylenetetrahydrofolate Reductase and Reduced Folate Carrier 1 Polymorphisms on High-Dose Methotrexate-Induced Toxicities in Children With Acute Lymphoblastic Leukemia or Lymphoma

Abstract

The authors investigated whether high-dose methotrexate-induced toxicity differed according to the presence of methylenetetrahydrofolate reductase (MTHFR) or reduced folate carrier 1 (RFC1) genetic polymorphism. The authors studied 15 children with acute lymphoblastic leukemia or lymphoblastic lymphoma who were treated using protocols that included high-dose methotrexate (3.0 g/m), for an overall total of 43 courses. Methotrexate-induced toxicities and the plasma methotrexate concentrations were evaluated retrospectively. Hematologic toxicity was the most frequently observed toxicity, appearing in 87% of the patients. In a subset of patients (47%), elevation of liver transaminase levels showed a repeated tendency to develop. High plasma methotrexate concentrations at 48 hours after the methotrexate infusion were not significantly related to methotrexate-induced toxicities except for mucositis. A generalized estimating equation analysis revealed that vomiting during the high-dose methotrexate treatment was more pronounced in patients who had a larger number of G alleles at the RFC1 80G>A polymorphism. No significant differences in the development of other toxicities or in the plasma methotrexate concentrations were observed for the different MTHFR 677C>T or RFC1 80G>A polymorphisms. This study suggests but does not prove that the RFC1 80G>A polymorphism may contribute to interindividual variability in responses to high-dose methotrexate.

Gene polymorphisms in the folate metabolism and their association with MTX-related adverse events in the treatment of ALL

“…Some other authors confirmed the above analysis in recent studies [45,75]. In contrast with above results, some other authors did not find any association between MTHFR and MTX-related toxicity or other side effects [22,26,27,31,35,73,76]. MTHFR polymorphisms may associate with MTX dosage.…”

“…In a study by Shimasaki et al [31], although they did not find any association between G80A polymorphism and MTX plasma concentration, vomiting episodes of grade 2 or worse were more frequently in G allele.…”

Pharmacogenetics/genomics of membrane transporters in cancer chemotherapy

“…The 80G>A SNP was also associated with methothexate bioavailability in the treatment of rheumatoid arthritis [119]. In other studies, however, no significant differences in methothexate uptake rates or toxicities were found between leukemia blast cells from ALL patients with the 80G and those with the 80A allele [120,121]. Pharmacogenetic studies investigating several targets of folate-related drugs have been recently reviewed and no clear evidence for the involvement of several known SLC19A1 polymorphisms [122].…”

Effects of High Dose Methotrexate and Delayed Elimination on Myelotoxicity Progression in Children with Acute Lymphoblastic Leukemia

“…. Unfortunately, MTX therapy may lead to myelosuppression, acute liver toxicity, nephrotoxicity, mucositis, and neurotoxicity [4,[6][7][8][9][10][11].MTX-associated toxicity is associated with several factors including dose, the duration of administration, patient risk factors, and genetic factors [12,13]. There are no sufficient data involving the use of HDMTX pharmacokinetic and toxicity information to anticipate hematologic toxicity in children with ALL.…”