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Abstract 670 The availability of multiple options for chronic myeloid leukemia (CML) treatment is not paralleled by the availability of biological predictors of outcome allowing to identify patients (pts) who are more likely to benefit from dasatinib or nilotinib rather than imatinib (IM). Pharmacogenetics has proven a potential source of biomarkers given the known influence of polymorphisms in key genes encoding drug transporters and metabolizing enzymes on drug delivery – hence effectiveness. In CML, only two studies had so far explored this field, but both were conducted in heterogeneous populations including pts at different stages of disease, not all receiving IM first-line. We thus aimed to investigate a panel of 20 single nucleotide polymorphisms (SNPs) in ABCB1, ABCG2, SLC22A1, OATP1A2, OCTN1, CYP3A4 and CYP3A5 genes that can be hypothesized to influence IM transport and metabolism in 189 newly diagnosed CML pts enrolled in the TOPS phase III trial (Cortes et al, J Clin Oncol 2010). Pts selection was exclusively based on availability of written informed consent and sufficient amount of archived material. Median age was 46 years; male to female ratio was 103 to 86; 156 (83%) pts were Caucasian and 23 (12%) were Asian; low, intermediate and high Sokal risk pts were 84 (44.4%), 65 (34.4%) and 40 (21.2%), respectively. Baseline demographic/clinical features did not differ significantly from those of the overall population. Treatment outcomes (complete cytogenetic response [CCyR]; major molecular response [MMR] and complete molecular response [CMR]) were compared according to i) each candidate genotype ii) summary measures based on combinations of SNPs in the same gene and iii) summary measures based on combinations of SNPs in functionally related genes (uptake; efflux). CC genotype in OCTN1 had a favorable impact on the achievement of MMR at 12 months (MMR@12m; P = 0.03). With respect to the summary measures, combination of SNPs in the SLC22A1 gene was significantly correlated with MMR@12m (P = 0.03). When considering summary measures of uptake and efflux, the former was found to be associated with both MMR@12m and CMR@12m (P = 0.003 and P = 0.01, respectively). A separate analysis limited to Caucasian pts (n=156) yielded similar results (Table 1). In addition, the analysis in the Caucasian subgroup evidenced a significant association between the CC genotype in ABCB1 rs60023214 and MMR@12m (P = 0.005) (Table 1). Cumulative incidence plots based on the Kaplan-Meier method were also analyzed in the overall population and in Caucasians, with comparable results. Representative plots are shown in Figure 1. There was evidence for difference among MMR cumulative incidence curves for 2 single SNPs and 2 score measures. Presence of the major allele in OCTN1 (CC) and of the minor allele in CYP3A4 rs2740574 (GG) were associated with increased MMR rate (P = 0.028 and P = 0.042, respectively, in the overall population and P = 0.027 and P = 0.038, respectively, in Caucasians). Similarly, an increase in the number of favorable alleles in the SLC22A1 gene was associated with increased MMR rate (P = 0.030 and P = 0.043 in the overall population and in Caucasians, respectively). In addition, the combination of favorable alleles in the genes involved in IM uptake was associated with increased rates of both MMR and CMR (P = 0.004 and P = 0.015, respectively, in the overall population and P = 0.005 and P = 0.009, respectively, in Caucasians). Our results suggest that SNP genotyping might be helpful in selecting pts who are more likely to benefit from first-line use of more potent inhibitors. Further assessment of the SNPs here identified in larger series of pts is warranted. Table 1 . Summary of significant associations Overall population (n=189) Caucasians (n=156) Gene, rs Outcome P Hazard ratio[95% CI] P Hazard ratio[95% CI] OCTN1 - rs1050152 MMR@12m 0.03 0.78 (0.63, 0.98) 0.03 0.77 (0.60, 0.97) ABCB1 (MDR1) - rs60023214 CMR@12m 0.06 0.71 (0.49, 1.02) 0.005 0.56 (0.37, 0.84) SLC22A1 (hOCT1) - SNP combination MMR@12m 0.03 1.24 (1.02, 1.50) 0.04 1.24 (1.00, 1.54) Uptake - SNP combination MMR@12m 0.003 1.21 (1.06, 1.37) 0.005 1.24 (1.06, 1.44) Uptake - SNP combination CMR@12m 0.01 1.30 (1.05, 1.61) 0.01 1.37 (1.08, 1.74) Download : Download high-res image (197KB) Download : Download full-size image Figure 1: . Cumulative incidence of pts achieving MMR and CMR according to the # of major alleles in uptake-related gene (SLC22A1, OATP1A2, OCTN1) SNPs Supported by Novartis Oncology, Clinical Development, TOPS Correlative Studies Network Disclosures: Hughes: Novartis: Honoraria, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Honoraria, Research Funding; Ariad: Honoraria. White: Novartis: Honoraria, Research Funding; Bristol-Myers Squibb: Research Funding. Saglio: Novartis: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria. Rosti: Novartis: Consultancy, Honoraria; BMS: Consultancy, Honoraria. Hatfield: Novartis: Employment. Martinelli: Novartis: Consultancy, Honoraria; BMS: Honoraria; Pfizer: Consultancy.

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 Disclosures: White: Novartis and Britol-Myers Squibb: Research Funding. Baccarani:Novartis: Research Funding, Speakers Bureau; Bristol-Myers Squibb: Research Funding, Speakers Bureau.