The relationship between HİGH-DOSE methotrexate terapy i̇nduced hepatotoxicity and methylenetetrahydrofolate reductase gene mutation in onkology patients

Objective: Methotrexate, which is one of the chemotherapeutic medicines frequently used in childhood cancers, is an important component in the treatment. In the use of MTX, it is stated in the literature that variations in the genetic structure of the individual may have an effect on the efficacy and toxicity of the medicine, as well as environmental reasons. There are many studies in the literature suggesting that methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphisms are associated with MTX metabolism. We conducted this study to examine the effects of MTHFR polymorphisms on methotrexate toxicity and liver function test elevation due to the inconsistencies in the studies. Patients and Methods: In Cukurova University Child Health and Diseases Pediatric Hematology-Oncology Unit, cancer patients who were given high-dose methotrexate were evaluated. Demographic characteristics, methotrexate dose and duration of administration given to the patients, laboratory findings after treatment and clinical findings related to toxicity were examined retrospectively from the files of the patients, and methylene tetrahydrofolate reductase (MTHFR) enzyme gene polymorphism was evaluated prospectively. Findings: 130 patients who were given high-dose methotrexate therapy were included in the study. 59.2% (n=77) of the patients were male and 40.8% were female (n=53). The mean age at diagnosis was 89.2±60.5 months (6 months-213 months). Of the patients, 22 (16.9%) were diagnosed with Non-Hodgkin Lymphoma, 19 with osteosarcoma (14.6%), and 89 (68.5%) with Acute Lymphoblastic Leukemia. It was determined that 38 (29.2%) of the patients were given methotrexate at a dose of 5 gr/m2, 46 (35.3%) of them were given at a dose of 1 gr/m2 and less, 17 (13.1%) were given at a dose of 2gr/m2, 10 7.7% of them were given at a dose of 3gr/m2 and 19 (14.6%) of them were given at a dose of 12 gr/m2. According to clinical and laboratory findings, toxicity developed in 90 (69.2%) patients, it was observed that there was an elevation in liver function tests of 71 (54.6%) patients (p=0.028). According to MTHFR gene polymorphism analysis, no significant correlation was found between the incidence of toxicity in patients with and without any mutation. When compared in terms of toxicity rates, toxicity findings were found in 69.2% of the patients without any mutation, while toxicity findings were found in 68.9% of the patients with any mutation. No significant correlation was found between elevation in liver function test and MTHFR polymorphisms. Result: In our study, it was concluded that methotrexate dose is one of the most important factors determining toxicity. No significant correlation was found between MTHFR polymorphisms and methotrexate toxicity and elevation in liver function tests.