Associations of Methylene Tetrahydrofolate Reductase Polymorphism and Methotrexate-Related Toxicities in Korean Treated for Malignant Lymphoma
Authors: Park Hyangmin , Yoon Dok Hyun , Song Youngcheon , Kim Heese , Huh Youngseol , Kim Shin , Jang Seongsoo , Park Chan-Jeoung , Chi Hyun-Sook , Park Chan-Sik , Huh Jooryung , Lee Sang-wook , Suh Cheolwon 
Published: October 2019

Abstract
Abstract 1607
Methotrexate is an antifolate agent commonly used for the treatment of lymphoma. The most common adverse effects include mucositis, myelosuppression, hepatic dysfunction and renal toxicities. It inhibits DNA replication by blocking the conversion of 5,10-methylene tetrahydrofolate to 5-methylene tetrahydrofolate by methylene tetrahydrofolate reductase (MTHFR). MTHFR is a key enzyme in folate metabolism and C677T is one of principal polymorphisms implicated in the metabolism of methotrexate.
We aimed to investigate the relationship of the C677T polymorphism with methotrexate concentration in serum as well as methotrexate-associated toxicities. The study cohort included 169 cases treated with regimens containing high dose methotrexate (higher than 1 g/m2) between January 2010 and May 2011. Median age of the patients was 56 years (range, 24–78 years). Concentration of methotrexate was measured daily beginning 48 hours after infusion until the concentration reaches below 0.05 μmol/L.
Forty four cases (26.0%) had a wild genotype of CC, 78 (46.2%) a heterozygous genotype of CT, and 47 (27.8%) a homozygous mutant genotype of TT. Mutant cases of TT had significantly higher MTX serum levels when compared with the other genotypes (Table 1) and required significantly longer time for elimination of methotrexate (p=0.011, Table 2). While hematologic toxicities, hepatotoxicities or number of febrile neutropenic episodes did not differ according to the genopypes, TT genotypes had significantly higher MTX levels and higher incidence of nephrotoxicity. Among them, two required therapeutic plasma exchange for prolonged exposure to high levels of methotrexate.
Table 1. Concentration of methotrexate at different time points 48 h 72 h 96 h 120 h Wild-type (CC) 0.38 ± 0.47 0.15 ± 0.20 0.08 ± 0.12 0.09 ± 0.10 Heterozygous type (CT) 0.32 ± 0.46 0.12 ± 0.20 0.08 ± 0.11 0.07 ± 0.10 Mutant type (TT) 1.93 ± 5.84 0.92 ± 2.39 0.67 ± 1.25 0.59 ± 0.83 p-value 0.020 0.011 0.002 0.006 * Data expressed as mean ± SEM
Table 2. Duration (days) to serum concentration of methotrexate < 0.05 μmol/L MTHFR C677T CC CT TT p-value Duration until methotrexate level < 0.05 μmol/L (days) 4.89 ± 2.95 4.35 ± 2.05 7.66 ± 9.00 0.011 * Data expressed as mean ± SEM
Table 3. MTHFR polymorphisms vs. grade 3/4 toxicities Grades 3/4 toxicity MTHFR C677T CC (%) CT (%) TT (%) p-value Hb 27.3 17.9 34.0 0.431 WBC 52.3 61.5 53.2 0.950 PLT 45.5 51.3 53.2 0.465 AST 2.3 10.3 8.5 0.277 ALT 11.4 11.5 10.6 0.911 Total bilirubin 6.8 1.3 4.3 0.532 Creatinine* 0 1.3 10.6 0.006 ANC 47.7 62.8 68.1 0.050 FN episodes** 31.8 37.2 42.6 0.291 Mucositis 15.9 14.1 17.0 0.650 * grade 2 toxicity ** Adverse event positive
Our data shows that cases with TT genotype for the MTHFR C677T polymorphism are associated with methotrexate-related renal toxicities. When high dose methotrexate is administered to the patients with TT genoptype, close monitoring for the nephrotoxicity seems to be required.

Disclosures:
No relevant conflicts of interest to declare.