ORIGINAL ARTICLESC677T and A1298C polymorphisms of the methylenetetrahydrofolate reductase gene: effect on methotrexate-related toxicity in adult acute lymphoblastic leukaemiaEissa, Deena Samira; Ahmed, Tamer MohamedbAuthor Information aClinical Pathology Department bInternal Medicine Department, Haematology Unit, Faculty of Medicine, Ain Shams University, Cairo, Egypt Correspondence to Dr Deena Samir Eissa, Clinical Pathology Department, Ain Shams University Hospitals, Ramses St., Postal code 11566, Abbasia, Cairo, Egypt Tel: +20 1005785658; e-mail: firstname.lastname@example.org Received 26 July, 2012 Accepted 6 October, 2012 Blood Coagulation & Fibrinolysis: March 2013 - Volume 24 - Issue 2 - p 181-188 doi: 10.1097/MBC.0b013e32835b249d Buy Metrics Abstract Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme involved in folate metabolism. Two polymorphisms, C677T and A1298C, were described leading to reduced enzyme activity. Methotrexate (MTX) is an antifolate agent of consolidation and maintenance therapy of acute lymphoblastic leukaemia (ALL). Despite its clinical success, MTX can be associated with serious toxicities resulting in treatment interruption or discontinuation, impacting disease outcome. There is evidence that MTX toxicity can be affected by polymorphisms in genes encoding for drug-metabolizing enzymes such as MTHFR. Therefore, we aimed to investigate the influence of MTHFR C677T and A1298C polymorphisms on the frequency of MTX-related toxicity, disease outcome and patients’ survival. MTHFR polymorphisms were assessed in 50 adult patients with de novo ALL using real-time PCR. Patients were followed-up for the development of haematologic and/or nonhaematologic toxicity and assessment of clinical outcome. Frequency of C677T polymorphisms was 42% for TT, 24% for CT and 34% for CC; A1298C polymorphisms were 28, 6 and 66% for CC, AC and AA, respectively. MTX therapy was significantly associated with neutropaenia, hepatic and gastrointestinal toxicities, unfavourable response at day 14 of induction therapy, increased relapse and mortality rates and shorter survival in patients with 677 TT genotype than in those with CC and CT, whereas 1298 CC genotype patients had lower frequency of neutropaenia, hepatic toxicity and relapse than in those with AA and AC. Our study suggests MTHFR polymorphism as an attractive predictor of MTX-related toxicity in adult ALL, considering it a potential prognostic factor influencing disease outcome. © 2013 Lippincott Williams & Wilkins, Inc.