RFC Studies

Three studies to date have evaluated RFC polymorphisms and ALL treatment response (Table 3). Laverdiere et al. reported that patients homozygous for the RFC G80A variant had a decreased EFS compared to homozygous wild-type patients. Specifically, in Cox models correcting for age, WBC count, protocol, and risk stratification, the variant genotype had an increased hazard ratio of 2.8, 95% CI, 1.0-8.1, p = 0.05 (24). Interestingly, this corresponded to statistically significant higher MTX levels in patients homozygous for the 80A allele. The authors hypothesized that reduced intracellular transport of MTX may have resulted in an increased relapse rate and higher serum MTX level.

A similar result was reported by Shimaski et al. who retrospectively evaluated toxicity in 15 Japanese children on four different protocols receiving methotrexate 3 g/m2 for 2 3 courses in leukemia or lymphoma therapy. In this study, increasing G allele copy number was significantly associated with an increased risk of emesis. However, hematologic and hepatic toxicity risks were not altered (12). Unlike these finding, the report by Kishi et al. did not find an association between neuro-toxicty and RFC G80A genotypes (7).

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