Association Between Imatinib (IM) Transporters and Metabolizing Enzymes Genotype and Response in Newly Diagnosed Chronic Myeloid Leukemia (CML) Patients (Pts) Is Influenced by Ethnicity.

Abstract 3283

Poster Board III-1

IM is the first-choice treatment in CML and allows to obtain excellent response rates. Some pts, however, experience suboptimal response or resistance, which highlights the need to find biological predictors of outcome in order to guide therapy optimization. Since blood and tissue concentrations of drugs may be influenced by variations between individuals (single nucleotide polymorphisms, SNPs) in genes encoding drug metabolizing enzymes and drug transporters, we have investigated if SNPs influencing the delivery if IM to target cells may account for differences in response. To test that hypothesis, we have genotyped a panel of SNPs known to affect the activity of the cytochrome p450 family isoforms and of the transporters that have been implicated in IM metabolism and transport in a subset of pts enrolled in the TOPS trial -; a randomized phase III study of IM 400 mg/d vs IM 800 mg/d in newly diagnosed CML (Cortes et al, ASH 2008). Included in this analysis were 18 SNPs in 7 genes: hOCT1 (ins/del, rs12208357, rs683369, rs4646277, rs4646278, rs2282143); ABCB1 (rs60023214, rs1128503, rs10245483, rs3213619, rs1128501), ABCG2 (rs2231137, rs2231142); OCTN1 (rs1050152); OATP1A2 (rs11568563); CYP3A5 (rs28365083, rs776746); CYP3A4 (rs28371759). Genotype distributions were tested for Hardy-Weinberg equilibrium (HWE). Additive models were used to assess association between individual SNPs and three response outcomes: major molecular response (MMR) at 12 months, optimal CgR and optimal response as defined by European LeukemiaNet (ELN) recommendations (Baccarani, Blood 2006). Summary measures based on SNPs from the same gene and those related functionally (uptake and efflux) were defined as the number of alleles, across the genes of interest, hypothesized to be associated with favorable response. Association of individual SNPs and summary variables with response was assessed with logistic regression models and likelihood ratio and exact tests. A total of 166 pts were genotyped, out of which 133 whites from Italy (N=21), the U.S.A. (N=66) and Australia (N=46); 22 Asian from Korea (N=17), Italy (N=1), and Australia (N=4); and 11 non-white and non-Asian from the U.S.A (N=6) and Australia (N=5). Selection of pts was based exclusively on availability of a written informed consent for correlative substudies and of a sufficient amount of archived DNA material. The response rates by 12 months among the subset of pts analyzed were 51% for MMR, 87% for optimal cytogenetic response according to ELN, and 85% for optimal response according to ELN. Our analyses have identified four monomorphic, non-informative SNP ( hOCT1: rs4646278, rs2282143; MDR1: rs1128501; and CYP3A4: rs28371759). The results have shown, when analyzing the patient population as a whole, that no association could be found between individual SNPs and any of the response variables considered. However, among whites, but not other pts, we have observed a trend of association between achievement of MMR and two SNPs in the hOCT1 and CYP3A5 genes. Namely, the wild type allele for hOCT1 rs683369 was associated with a higher response rate compared to heterozygote and homozygote mutants (60% vs 36%, p=0.057). Also, the mutant allele for CYP3A5 rs28365083 was associated with a higher response rate (p=0.058). In the subset of pts from the U.S.A, there was a evidence of association between achievement of MMR and three SNPs in the hOCT1 and MDR1 genes. Those with the wild type allele for hOCT1 ins/del had a lower MMR rate compared to those carrying at least one minor allele (48% vs 81%, p=0.08). The wild type for hOCT1 rs683369 was associated with a higher response rate compared to heterozygote and homozygote mutants (65% vs 36%, p=0.05). MDR1 rs60023214 (p=0.08) and the MDR1 gene summary measure of total number of favorable alleles among all MDR1 SNPs (p=0.08) were correlated with MMR, with improved response in the wild type group. Our study suggests for the first time a role of ethnicity in determining correlations between SNP-based molecular signature and response to treatment. If confirmed by larger studies, this suggests that ethnicity should be taken in consideration to better interpret pharmacogenetic analyses in CML and could explain the differences in results of the studies published so far. Supported by Novartis Oncology, Clinical Development, TOPS Correlative Studies Network