Methotrexate pharmacogenetics in Uruguayan adults with hematological malignant diseases

Abstract

Background: Individual variability is among the causes of toxicity and interruption of treatment in acute lymphoblastic leukemia (ALL) and severe non-Hodgkin lymphoma (NHL) patients under protocols including Methotrexate (MTX): 2,4-diamino-N10-methyl propyl-glutamic acid. Methods: 41 Uruguayan patients were recruited. Gene polymorphisms involved in MTX pathway were analyzed and their association with treatment toxicities and outcome was evaluated. Results: Genotype distribution and allele frequency were determined for SLC19A1 G80A, MTHFR C677T and A1298C, TYMS 28 bp copy number variation, SLCO1B1 T521C, DHFR C−1610G/T, DHFR C-680A, DHFR A-317G and DHFR 19 bp indel. Multivariate analysis showed that DHFR-1610G/T (OR =0.107, p=0.018) and MTHFR677T alleles (OR= 0.12, p=0.026) had a strong protective effect against hematologic toxicity, while DHFR-1610CC genotype increased this toxicity (OR =9, p=0.045). No more associations were found. Conclusions: The associations found between gene polymorphisms and toxicities in this small cohort are encouraging for a more extensive research to gain a better dose individualization in adult ALL and NHL patients. Besides, genotype distribution showed to be different from other populations, reinforcing the idea that genotype data from other populations should not be extrapolated to ours.