Impact of methylenetetrahydrofolate reductase (MTHFR) polymorphisms on methotrexate-induced toxicities in acute lymphoblastic leukemia: a meta-analysis

Abstract

The associations between methylenetetrahydrofolate reductase (MTHFR) polymorphism and methotrexate (MTX)-induced toxicities in patients with acute lymphoblastic leukemia (ALL) have been evaluated in various populations, with the results remained conflicting. Therefore, we conducted a meta-analysis by combining available data to derive a more precise estimation of the association. PubMed, Embase, and China National Knowledge Infrastructure were searched until 21 September 2011 to identify eligible studies. A total of 14 studies were included, with all studies investigating MTHFR C677T polymorphism while nine of them investigating MTHFR A1298C polymorphism only. Results suggested that MTHFR C677T polymorphism was associated with significantly increased risk of MTX-induced toxicity, specifically liver toxicity (TT/CT vs. CC: odds ratio (OR) = 1.70, 95 % confidence interval (CI) = 1.05-2.75), myelosuppression (TT vs. CT/CC: OR = 2.82, 95 %CI = 1.25-6.34), oral mucositis (TT/CT vs. CC: OR = 3.68, 95 %CI = 1.73-7.85), gastrointestinal toxicity (TT/CT vs. CC: OR = 2.36, 95 %CI = 1.36-4.11), and skin toxicity (T vs. C: OR = 2.26, 95 %CI = 1.07-4.74). MTHFR A1298C polymorphism was found to be associated with decreased risk of skin toxicity (CC/AC vs. AA: OR = 0.11, 95 %CI = 0.01-0.85). Genotyping of MTHFR polymorphism, C677T particularly, prior to treatment for ALL is likely to be useful with the aim of tailoring MTX therapy and thus reducing the MTX-related toxicities. However, further studies with larger data set and well-designed models are required to validate our findings.

3405 The role of pharmacogenetics in osteosarcoma

“…One study showed a positive association between the 677C>T variant and hepatotoxicity 25 , but similar to our results this was not confirmed in the second study by Lopez-Lopez and colleagues…”

“…metabolism of the used medication. However, replication studies often show inconsistent results making it difficult to interpret the clinical value of these studies [23][24][25][26][27][28] , e.g. these problems may be addressed by combining results from different studies in a meta-analysis.…”

“…Treatment characteristics examined included chemotherapy, histological response, type of surgery and surgical margins. Factors found to influence prognosis by univariate analysis were analyzed by stepwise multivariate analysis using Cox's proportional hazard regression model 25 . All analyses were performed using SPSS statistical analysis software (version 16.0, SPSS Inc, Chicago, IL).…”

Pharmacogenetics of methotrexate in pediatric hematological neoplasm treatment: does it need a personalized regimen based on MTHFR polymorphisms?

“…Yang et al analyzed a total of 104 studies in the literature, selecting 14 eligible studies to assess the possible associations between MTHFR polymorphisms and MTX-induced toxicities in patients with ALL. In summary, this meta-analysis provided evidence for the association between MTHFR C677T polymorphism and increased risk of MTX-induced toxicities [2]. Hagleitner et al studied in a Dutch cohort of 98 pediatric patients treated with high doses of MTX, the influence of MTHFR 677C> T on hepatotoxicity using a generalized estimating equation (GEE) analysis that showed an increased risk of developing hepatotoxicity for T allele versus C allele in patients with osteosarcoma (odds ratio: 1.8; 95% CI: 1.0-3.2; p = 0.04).…”

“…Many studies have reported that the two common functional polymorphisms of MTHFR, C677T and A1298C, are associated with MTX-related toxicity and survival both in adults and in children with ALL, while others showed controversial results [1][2][3].…”