The Effects of Genetic Polymorphism on Toxicity and Pharmacokinetics of Methotrexate in Egyptian Adult Patients with Leukaemia or Lymphoma.

1. Polymorphisms in genes coding folate-metabolizing enzymes might alter the pharmacokinetics and sensitivity for methotrexate "MTX". 2. The aim of the study aimed to investigate the influence of MTHFR C677T, DHFR19 Ins/del, GGH -401 C > T, and MTR A2756G polymorphisms on MTX toxicity and pharmacokinetics in Egyptian patients with Acute lymphoblastic leukaemia (ALL) or Non-Hodgkin lymphoma (NHL). 3. Fifty adult Egyptian patients with ALL and NHL, treated with high dose MTX, were prospectively enrolled in the study. Clinical and biochemical data was collected objectively from medical records after each cycle of MTX. Plasma concentrations of MTX were measured after 72 h of initiation of infusion. Genotyping was done with a PCR-ARMS and PCR-RFLP assays. 4. The MTHFR C677T T variants significantly increased the risk of leukopenia, whereas the genotype MTHFR 677C > T TT significantly associated with lymphocytopenia, thrombocytopenia, and anemia. The genotype GGH-401 TT was significantly correlated with anemia. Plasma MTX level was significantly higher in patients with MTR A2756G G variants. 5. MTHFR polymorphism played the main role in MTX toxicities. The pharmacokinetics of MTX was affected by MTR polymorphism. GGH mutation was mainly concerned with anemia. Pharmacogenetic testing are recommended to optimize MTX therapy.