Correlation of major cytogenetic response with a pharmacogenetic marker in chronic myeloid leukemia patients treated with imatinib (STI571)

Purpose: Imatinib, an inhibitor of the Bcr-Abl tyrosine kinase, is indicated for the treatment of patients with Philadelphia chromosome-positive chronic myeloid leukemia. We examined genotypes from patients enrolled in the International Randomized Study of IFN-alpha versus ST1571 in an attempt to identify factors that associate with cytogenetic response. Experimental Design: Sixty-eight polymorphic loci in 26 genes were examined in a subset of 187 patients (imatinibtreated patients, n = 113; IFN + 1-beta-D-arabinofuranosyl-cytosine-treated patients, n = 74). Correlations between genotype and major cytogenetic response (MCyR) were examined by Fisher's exact tests. Multivariate and survival analyses were also performed. Results: A significant association between MCyR and the rs2290573 polymorphism mapped to 15q22.33 was observed in imatinib-treated patients (P = 0.00037, Bonferroni corrected P = 0.025). Individuals with a CC genotype at this locus had a MCyR rate of 52% compared with individuals with a CT or TT genotype that had a MCyR rate of 89% (odds ratio, 6.72; 95% confidence interval, 1.51-29.91). In a multivariate analysis, the rs2290573 polymorphism was significant, whereas Sokal score was not. Time to progression analysis illustrated a significant difference based on genotype for the rs2290573 polymorphism. Conclusions: A significant association was identified between the genetic polymorphism rs2290513 and MCyR in imatinib-treated patients. This polymorphism is located in the intronic sequence of a putative gene with a tyrosine kinase domain. Multivariate analysis suggests that an individual's genotype for rs2290573 has more predictive value for MCyR than prognostic variables such as Sokal score. The clinical relevance of these results requires validation in future clinical trials.