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 A summary of the evidence pertaining to the association between methylenetetrahydrofolate reductase MTHFR C677T and overall survival in pediatric acute lymphoblastic leukemia (ALL) is not currently available. We thus reviewed the literature on the association between MTFHR C677T and overall survival in pediatric ALL. We searched PubMed/MEDLINE, Scopus, and ISI Web of Knowledge literature databases without language restrictions to identify observational studies among children diagnosed between ages 0 -19 years that assessed MTHFR 677 polymorphisms in relation to ALL survival. We identified 6 studies comprising 909 pediatric ALL patients. The magnitude of relative risk (RR) for pediatric ALL mortality varied by genotype comparison and study population, ranging from RR=0.84 (95% confidence limits [CL]: 0.24, 3.0) for a TT vs. CT/CC comparison to RR=7.0 (95% CL: 0.98, 49) for a TT vs. CC comparison. The current evidence suggests that individuals with MTHFR 677 variants (i.e. at least one T allele) may have a higher relative risk of pediatric ALL mortality, with greater statistical support for MTHFR 677TT. With more detailed supporting evidence, MTHFR 677 genotyping at diagnosis could provide an option for individualizing therapy and further reducing pediatric ALL mortality in certain populations.
    Leukemia & lymphoma 04/2013; · 2.40 Impact Factor
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    ABSTRACT: Abstract High-dose Methotrexate (MTX) is a key component of most treatment protocols for childhood and adolescent NHL. Recent studies have suggested that the toxicity of antifolate drugs, such as MTX, is affected by inherited single nucleotide polymorphisms (SNPs) in folate metabolising genes. The aim of our study was to investigate the potential influence of the C677T and A1298C genetic variants of MTHFR on the clinical toxicity and efficacy of MTX in paediatric NHL patients (n=95) treated with therapeutic protocols AIEOP NHL 97 and EURO LB-02. We demonstrated that patients with the 677T genotype had an approximately 6-fold greater risk of developing haematological toxicity compared with wild-type carriers, especially in the 1 g/sq m treatment group (p=0.01). Moreover, we identified a correlation between the risk of relapse and the T genotype; T carriers have a reduced DFS compared with wild-type patients (67% vs. 100%). Our data suggest a pharmacogenetic influence on the adverse effects of high-dose MTX in the 1 g/sq m treatment group.
    Leukemia & lymphoma 03/2013; · 2.40 Impact Factor
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