title: Methotrexate toxicity and efficacy during the consolidation phase in paediatric acute lymphoblastic leukaemia and MTHFR polymorphisms as pharmacogenetic determinants.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  This work includes DNA extraction by slides and RFLP-PCR.
  
  
  RESULTS
  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).
  
  
  CONCLUSIONS
  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.
authors: Pediatric Department, Second University of Naples, Naples, Italy. velia.dangelo@unina2.it
authors: Velia
authors: V
authors: D'Angelo
authors: Maria
authors: M
authors: Ramaglia
authors: Adriana
authors: A
authors: Iannotta
authors: Stefania
authors: S
authors: Crisci
authors: Paolo
authors: P
authors: Indolfi
authors: Matteo
authors: M
authors: Francese
authors: Maria Carmen
authors: MC
authors: Affinita
authors: Giulia
authors: G
authors: Pecoraro
authors: Addolorata
authors: A
authors: Napolitano
authors: Claudia
authors: C
authors: Fusco
authors: Matilde
authors: M
authors: Oreste
authors: Cristiana
authors: C
authors: Indolfi
authors: Fiorina
authors: F
authors: Casale