Evaluation of Relationship of the Methylene Tetrahydrofolate Reductase Enzyme Polymorphisms with Serum Methotrexate Concentration and Toxicity in Acute Lymphoblastic Leukemia Patients Treated with High Dose Methotrexate Infusion

ABSTRACT

Background: Methotrexate (MTX) blocks MethyleneTetrahydrofolate Reductase (MTHFR) Enzymethereby, interrupt folate metabolism, it is used in thetreatment of cancer and autoimmune disorders. Aimand Objectives: The present study aimed to evaluatethe relationship of the MTHFR polymorphisms withserum MTX concentration and its toxicity in AcuteLymphoblastic Leukemia (ALL) patients treated withhigh dose MTX infusion. Material and Methods: Levelof Serum MTX was measured, along with the detectionof MTHFR polymorphisms viz. C677T and A1298Cby Polymerase Chain Reaction (PCR) followed byDNA sequencing. The percentages of toxicitydeveloped in patients were calculated among the wildtype and carriers for both polymorphisms and werecompared between the groups. Results:The majority ofpatients 36 (72 %) were wild type for the C677Tpolymorphism and 32 (64 %) of patients were carriersfor the A1298C polymorphism [48% heterozygous(AC), and 16 % homozygous (CC)]. Among 50 ALLpatients studied, significant difference was noted in thegenotype and allele frequencies for C677Tpolymorphism, while only allele frequencies differedsignificantly for A1298C polymorphism. The serumMTX level at 48 hours after the start of High DoseMTX (HDMTX) infusion of the C677T variant (CT)was slightly high in all four cycles however, in the firstcycle, there was a significant increase in the level ofMTX. There was no significant difference in the serumMTX level found in all four cycles between patientswild type and carriers for A1298C polymorphism. ForA1298C polymorphism, the mean SGPT level incarriers was significantly high as compared to wildtype. Conclusion: The present study concludes thatpatients with C667T variant had elevated serum MTXconcentration at 48 hours after the start of HDMTXinfusion.