The Association of the MTHFR Gene Polymorphisms C677T and A1298C with Methotrexate-Related Toxicity in Patients with Primary CNS Lymphoma (S34.006)

OBJECTIVE: To evaluate the association of the MTHFR SNPs C667T and A1298C with MTX-related toxicity in PCNSL.BACKGROUND: Treatment with HD-MTX for PCNSL can cause significant toxicity and there are no biomarkers to estimate the toxicity risk. The MTHFR gene SNPs C677T and A1298C have been associated with an increased risk for MTX-related toxicity in hematopoietic malignancies but little is known about the impact of these SNPs on MTX-associated toxicity in PCNSL.METHODS: We performed a retrospective chart review on patients with PCNSL treated with HD-MTX (u003e 3.5 gm/m2) who were tested for MTHFR C677T and A1298. Toxicities were graded according to the Common Terminology Criteria for Adverse Event (CTCAE 4.0). Statistical analysis was performed using JMP Pro (v. 11).RESULTS:42/322 patients (female n=18, male n=24) were tested for MTHFR C677T and A1298C in cases where there was higher than expected toxicity. At least one MTHFR SNP was present in 39/42 patients (93[percnt]). C677T was present in 34/39 (87[percnt]) patients (homozygous n=10, heterozygous n=24), A1298C was present in 13/39 (33[percnt]) patients (heterozygous n=13), and both SNPs were present in 8/39 (21[percnt]) patients (compound heterozygous n=8). These rates were higher than reported in the general population (21-31.7[percnt]).Toxicities were analyzed for 20 patients (C677T n= 13, A1298C n=6, no MTHFR polymorphism n=3). 46.3[percnt] of HD-MTX infusions were associated with at least grade 3 hepatotoxicity compared to 19-42[percnt] reported in the literature. MTHFR A1298C was associated with an especially high rate of hepatotoxicity (75[percnt] of all infusions).There was no association of either SNP with high-grade myelotoxicity (10-14[percnt] of treatments) or mucositis (0[percnt]).CONCLUSION:Patients with higher than expected toxicity during HD-MTX treatment have high rates of SNPs in the MTHFR gene (C677T or A1298C); MTHFR A1298C may be a biomarker of particularly high risk. Updated results will be presented. Disclosure: Dr. Eisele has nothing to disclose. Dr. Gill has nothing to disclose. Dr. Pisapia has nothing to disclose. Dr. Jones has nothing to disclose. Dr. Batchelor has received personal compensation for activities with Merck, Roche, Foundation Medicine, Proximagen/Upsher, Oxigene, Oakstone Publishing, Champtions Biotechnology as a presenter, consultant and lecturer. Dr. Batchelor has received personal Dr. Plotkin has nothing to disclose.