Methotrexate toxicity and efficacy during the consolidation phase in paediatric acute lymphoblastic leukaemia and MTHFR polymorphisms as pharmacogenetic determinants.

Pediatric Department, Second University of Naples, Naples, Italy.
Cancer Chemotherapy and Pharmacology (Impact Factor: 2.8). 05/2011; 68(5):1339-46. DOI: 10.1007/s00280-011-1665-1
Source: PubMed

ABSTRACT Folate-metabolizing single-nucleotide polymorphisms (SNPs) are emerging as important pharmacogenetic prognostic determinants of the response to chemotherapy. With high doses of methotrexate (MTX) in the consolidation phase, methylenetetrahydrofolate reductase (MTHFR) polymorphisms could be potential modulators of the therapeutic response to antifolate chemotherapeutics in identifying a possible correlation with the outcome. This study aims to analyse the potential role of the MTHFR C677T and A1298C genetic variants in modulating the clinical toxicity and efficacy of high doses of MTX in a cohort of paediatric ALL patients (n = 151) treated with AIEOP protocols.
This work includes DNA extraction by slides and RFLP-PCR.
The first observation relative to early toxicities (haematological and non-haematological), after the first doses of MTX in all protocols, was an association between the 677T and 1298C carriers and global toxicity. We found that in the 2 g/m(2) MTX group, patients harbouring 677TT homozygously exhibited a substantial 12-fold risk of developing toxicity. In this study, we demonstrate that the MTHFR 677TT variant is associated with an increased risk of relapse when compared to other genotypes. The Kaplan-Meier analysis showed that the 677TT variant had a lower 7-year DFS(disease-free survival) probability compared to the 677C carrier genotype (log-rank test P = 0.003) and OS (overall survival) and also confirms the lower probability of survival for patients with the 677TT variant (log-rank test, P = 0.006).
Our study provides further evidence of the critical role played by folate pathway enzymes in the outcome of ALL, possibly through the interference of MTX.

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    ABSTRACT: ABSTRACT The aim of this study is to investigate the influence of daily 6-MP and low-dose weekly MTX combination treatment and methylenetetrahydrofolate reductase (MTHFR) haplotypes on toxicity during maintenance therapy in Japanese childhood acute lymphoblastic leukemia (ALL). We retrospectively analyzed the MTHFR C677T and A1298C polymorphisms and influence of haplotypes on toxicity in 73 patients. Patients with the MTHFR 677TT and 677CT+1298AC were associated with severe liver toxicity (p = 0.014, OR = 3.82, 95% CI = 1.27-11.46) more rapid in onset of liver toxicity (p = 0.010). Patients with the MTHFR 677TT and 677CT+1298AC were associated with less frequency of 6-MP and MTX dose reduction due to leucopenia (p < 0.05). No difference was observed in the average drug doses in the MTHFR genotypes. In conclusion, the MTHFR C677T and A1298C haplotypes might be useful for monitoring adverse effects in childhood ALL maintenance therapy in Japanese patients.
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    ABSTRACT: Methotrexate (MTX) is an important component of therapy used to treat childhood acute lymphoblastic leukemia (ALL). Two single-nucleotide polymorphisms (SNPs) in the methylenetetrahydrofolate reductase (MTHFR) gene, C677T and A1298C, affect MTHFR activity. A large body of studies has investigated the potential role of MTHFR SNPs in MTX toxicity in pediatric ALL. However, the results are controversial. In this review and meta-analysis, we critically evaluate the relationship between the C677T and A1298C polymorphisms of MTHFR and MTX toxicity in pediatric ALL. The majority of published reports do not find associations between MTHFR polymorphisms and toxicity in pediatric ALL. When associations are reported, often the results are contradictory to each other. The meta-analysis confirms a lack of association. In conclusion, MTHFR, C677T and A1298C polymorphisms do not seem to be good markers of MTX-related toxicity in pediatric ALL.The Pharmacogenomics Journal advance online publication, 23 October 2012; doi:10.1038/tpj.2012.44.
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    ABSTRACT: Abstract The aim of this study was to evaluate the influence of the most common genetic variants in methylenetetrahydrofolate reductase (MTHFR), thiopurine methyltransferase (TPMT), and glutathione-S-transferases (GSTs) on the outcome of acute lymphoblastic leukemia (ALL) treatment in Argentinean children. Two hundred and eighty-six patients with ALL treated with two BFM-based protocols were analyzed. Ten genetic variants were studied. Toxicity was evaluated during the consolidation phase. Children who received 2 g/m²/day of methotrexate and carried at least one 677T allele in MTHFR showed an increased risk of developing severe leukopenia (p=0.004) and neutropenia (p=0.003). Intermediate-risk (IR) patients with a heterozygous TPMT genotype had a higher pEFS than those with a wild-type genotype. Genotyping of MTHFR polymorphisms might be useful to optimize consolidation therapy reducing the associated severe hematologic toxicity. Further studies are necessary to establish the usefulness of MTHFR and TPMT variants as additional markers to predict outcome in the IR group.
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