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.