Tolerance to oral MTX based on MTHFR genotype
During maintenance therapy for ALL, patients continue a regimen of oral chemotherapy, including 6-MP and MTX, which can be frequently adjusted based upon hematologic parameters. Here, we had 190 patients who met criteria for evaluation. The MTX dosing for patients with the homozygous 677TT genotype was significantly decreased when compared to patients with either wildtype or not tested (11.9 ± 9.5 vs. 19.9 ± 7.5 mg/m2, p < 0.05) (Fig. 2A). In addition, patients classified as compound heterozygous 677CT/1298AC, being heterozygous for both SNPs of interest, were also significantly decreased compared to patients identified as wildtype or not tested (11.4 ± 6.1 vs. 19.9 ± 7.5 mg/m2, p < 0.01). In comparison, patients with either heterozygous SNP, although with an overall decreased average MTX dose, did not reach statistical significance (heterozygous 677CT = 14.4 ± 7.8 mg/m2, p = 0.11 and heterozygous 1298AC = 17.5 ± 6.9 mg/m2, p = 0.50). Considering that lower dosing could overall reflect greater patient sensitivity to medication in general, we also examined the effect of specific MTHFR genotypes on 6-MP dosing. When compared to patients with control, no group required significantly lower doses of 6-MP (Fig. 2B). Additionally, we assessed 6-MP metabolites, 6-TG and 6-MMP, while on 100% recommended stating dose for both oral MTX and oral 6-MP for each patient where data was available. Overall, there was no significant correlation between either 6-TG or 6-MMP levels and maximum tolerated oral MTX (R2 < 0.1) or 6-MP (R2 < 0.1) (Fig. 2C and 2D). However, there was an overall negative trend between 6-MP metabolite level and oral 6-MP dosing, which would be expected whereas there is no negative trend seen when correlated with oral MTX. These findings support the notion that patients carrying either the homozygous 677TT genotype or the compound heterozygous 677CT/1298AC genotype have decreased tolerance to oral MTX.