Gene polymorphisms in folate metabolizing enzymes in adult acute lymphoblastic leukemia: effects on methotrexate-related toxicity and survival

Abstract

BackgroundThe antifolate agent methotrexate is an important component of maintenance therapy in acute lymphoblastic leukemia, although methotrexate-related toxicity is often a reason for interruption of chemotherapy. Prediction of toxicity is difficult because of inter-individual variability susceptibility to antileukemic agents. Methotrexate interferes with folate metabolism leading to depletion of reduced folates. Design and MethodsThe aim of this study was to investigate the influence of polymorphisms for folate metabolizing enzymes with respect to toxicity and survival in adult patients with acute lymphoblastic leukemia treated with methotrexate maintenance therapy. To this purpose, we evaluated possible associations between genotype and hematologic and non-hematologic toxicity and effects on survival at 2 years of follow-up in patients with acute lymphoblastic leukemia. ResultsPolymorphisms in the genes encoding for methylenetetrahydrofolate reductase (MTHFR 677C>T) and in dihydrofolate reductase (DHFR 19 bp deletion) significantly increased the risk of hepatotoxicity in single (odds ratio 5.23, 95% confidence interval 1.13-21.95 and odds ratio 4.57, 95%confidence interval 1.01-20.77, respectively) and in combined analysis (odds ratio 6.82, 95% confidence interval 1.38-33.59). MTHFR 677C>T also increased the risk of leukopenia and gastrointestinal toxicity, whilst thymidylate synthase 28 bp repeat polymorphism increased the risk of anemia (odds ratio 8.48, 95% confidence interval 2.00-36.09). Finally, patients with MTHFR 677TT had a decreased overall survival rate (hazard ratio 2.37, 95% confidence interval 1.46-8.45). ConclusionsGenotyping of folate polymorphisms might be useful in adult acute lymphoblastic leukemia to optimize methotrexate therapy, reducing the associated toxicity with possible effects on survival. Haematologica 2009;94:1391-1398. doi:10.3324/haematol.2009 This is an open-access paper.Gene polymorphisms in folate metabolizing enzymes in adult acute lymphoblastic leukemia: effects on methotrexate-related toxicity and survival

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

“…The second polymorphism is G to C substitution at the 12th nucleotide in the 3R allele repeats (3RG-3RC) [55]. This was confirmed by Ongaro et al [53] who reported that TS 3R3R had a higher risk of developing anemia grade ≥1 [OR=8. 48 [9] found that TS 2R-3R polymorphism was a predictor of stomatitis (B=−0.48; 95 %CI=−0.84, −0.12; R 2 =0.018; P=0.009) in a multiple regression model when considering sex, age, minimal residual disease (MRD) class, white blood cell (WBC), MTX AUC 0-48 h, and also the genotypes as independent variables.…”

“…Erčulj et al [57] found that MTHFD1 A1958G and MTHFR C677T polymorphisms had an antagonistic effect interaction on hepatotoxicity [SF=0.02, 95 %CI=0.00-0.58, P=0.022]. Other authors were also analyzed by the gene-gene interactions between MTHFR and other polymorphisms which have referred in the former sections [53,57,58].…”

“…The mechanism of MTX is to inhibit DHFR which causing the impairment of regenerating THF from DHF [52]. A study conducted by Ongaro et al [53] found that DHFR 19-bp deletion was associated with hepatotoxicity. The patients with the homozygous (DD) genotype were associated with increasing hepatic toxicity grade ≥1 [OR=4.57, 95 %CI=1.01-20.77, P = 0.05], compared with the wild-type genotype (WW).…”

Distribution of TYMS, MTHFR, p53 and MDR1 gene polymorphisms in patients with breast cancer treated with neoadjuvant chemotherapy

“…MTHFR C677T has been shown to alter enzyme activity as well as 5-FU and MTX sensitivity [9,29]. This polymorphism increased the risk of leucopoenia, gastrointestinal toxicity and hepatotoxicity in adult and childhood acute lymphoblastic leukemia patients treated with MTX [28,30]. Common genetic variation in MTHFR but not TYMS may be useful for predicting toxicity in patients with advanced colorectal cancer treated with capacitabine [31] and in metastatic colorectal cancer patients treated with FOLFOX [32].…”

Influence of Reduced Folate Carrier and Dihydrofolate Reductase Genes on Methotrexate-Induced Cytotoxicity

“…Polymorphisms of the MTX transporter (i.e., RFC 80G＞A), MTX targets (i.e., DHFR 19-bp deletion and TS enhancer 28-bp tandem repeat) and the folate-metabolizing enzyme (i.e., MTHFR 677C＞T and 1298A＞C) can affect the anti-tumor activity and toxicities of MTX. The influence of folate polymorphisms in relation with MTXrelated toxicity has recently been studied mainly in childhood acute lymphoblastic leukemia, while only a few studies have investigated this relationship in adult hematological patients (10,11).…”