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

Background The antifolate methotrexate (MTX) is an important component of maintenance therapy in acute lymphoblastic leukemia (ALL), although MTX-related toxicity is a reason for interruption of chemotherapy. Prediction of toxicity is difficult, because of inter-individual variability to antileukemic agents. The MTX action mechanism interferes with folate metabolism leading to depletion of reduced folates. DESIGN AND METHODS: The aim of this study was to investigate the influence of folate polymorphisms respect to toxicity and survival in adult ALL patients treated with MTX maintenance therapy. To this purpose, we evaluated in ALL patients possible associations between genotype and haematological and non-haematological toxicity and effects on survival at 2 years of follow-up. RESULTS: Polymorphisms in methylenetetrahydrofolate reductase (MTHFR 677C>T) and in dihydrofolate reductase (DHFR 19 bp deletion) genes significantly increased the risk of hepatotoxicity in single (OR 5.23, 95%CI 1.13-21.95 and OR 4.57, 95%CI 1.01-20.77, respectively) and in combined analysis (OR 6.82, 95%CI 1.38-33.59). MTHFR 677C>T increased also the risk of leukopenia and gastrointestinal toxicity, whilst thymidylate synthase 28 bp repeat polymorphism increased the risk of anaemia (OR 8.48, 95%CI 2.00-36.09). Finally, MTHFR 677TT patients had even a decreased rate of overall survival (HR 2.37, 95%CI 1.46-8.45). Conclusions Genotyping of folate polymorphisms might be useful in adult ALL to optimize MTX therapy reducing the associated toxicity with possible effects on survival.