Abstract
Titolo

Association Between Transporters Genotype and Response to the treatment in a Subset of Previously Untreated Chronic Myeloid Leukemia Patients Enrolled into the TOPS Trial

 
Autori

Sabrina ANGELINI1, Simona Soverini2 Eleonora Turrini1, Giovanni Perini3, Fabrizio Pane4, Fabrizio Quarantelli5, Timothy Hughes6, Deborah White6, Dong Wook Kim7, Harriet Goh7, Jerald Radich8, Lan Beppu9, Giuseppe Saglio 10, Daniela Cilloni11, Carolina Terragna2, Ilaria Iacobucci2, Patrizia Hrelia1, Giorgio Cantelli-Forti1, Thea Kalebic12, Mark Thornquist9, Michele Baccarani2, and Giovanni Martinelli2 (1)Department of Pharmacology, University of Bologna, via Irnerio 48, Bologna, (2)Department of Hematology and Oncological Sciences “L. e A. Seràgnoli", University of Bologna, via Massarenti 9, Bologna, Italy, (3)Depatment of Biology, University of Bologna, va Selmi 2, Bologna, (4)CEINGE- Biotecnologie Avanzate, Haematology AF -University of Naples Federico II, via Comunale Margherita 482, Naples, Italy, (5)Ceinge, University of Naples Federico II, Naples, Italy, (6)Haematology, Institute of Medical and Veterinary Science, Adelaide, Australia, (7)The Catholic University of Korea, St Mary's Hospital, Seoul, South Korea, (8)Fred Hutchinson Cancer Research Center, Seattle, WA, (9)Fred Hutchinson Cancer Research Center, 1100 Fairview Ave., N, #D4-100, Seattle, WA, (10)Department of Clinical and Biological Sciences, University of Turin, Regione Gonzole 10, Orbassano,Turin, 10043, Italy, (11)Department of Clinical and Biological Sciences, University of Turin, Regione Gonzole 10, Turin, 10043, Italy, (12)Novartis Oncology Clinical Development NJ.

 
Abstract

Imatinib mesylate (IM) is the gold standard for chronic myeloid leukemia (CML) treatment with excellent long lasting response rates. Some patients (pts), however, experience suboptimal response or resistance which highlights the possibility for a further treatment optimization, potentially guided by molecular predictors of response. Since blood and tissue concentrations of drugs may be influenced by interindividual variations (single nucleotide polymorphisms, SNPs) in genes encoding drug metabolizing enzymes and drug transporters, we reasoned that SNPs influencing the extent to which IM is delivered to target cells may account for differences in response. To test our hypothesis, we have genotyped a panel of SNPs known to affect the activity of MDR1, BCRP and hOCT1 transporters (see Table) in a subgroup of 82 pts (minimum follow-up, 12 months; all ethnicities represented) enrolled into TOPS (Cortes, EHA, 2008), a “randomized phase III trial of 400mg vs 800mg IM in previously untreated CML pts".

SLC22A1 (hOCT1)    
Arg61Cys rs12208357 C/T
Phe160Leu rs683369 C/G
Pro283Leu rs4646277 C/T
Arg287Gly rs4646278 C/G
Pro341Leu rs2282143 C/T
420 ins/del / GAT ins/del
ABCB1 (MDR1)    
Ile1145Ile rs1045642 C/T
Gly412Gly rs1128503 C/T
Ala893Ser rs2032582 G/T
promoter rs10245483 G/T
promoter rs3213619 C/T
Gly185Val rs1128501 G/T
ABCG2 (BCRP)    
Gln141Lys rs2231142 A/C
Each SNP listed in the Table was first assessed individually for associations with cytogenetic response (CgR) and molecular response (MR). CgR was classified in three categories, following European LeukemiaNet recommendations: a) failure if the pt either had no CgR at 6 months or had less than a partial CgR at 12 months; b) suboptimal response if the pt had not failed but either had less than a partial CgR at 6 months or had less than a complete CgR at 12 months; c) ‘optimal’ response if the pt was not classified as a failure or suboptimal response and did have at least one cytogenetic response measured. MR, as assessed by real-time quantitative PCR and expressed on the international scale, was classified as either major MR (MMR) or no MMR. We found that MDR1 SNP rs1045642 was statistically significantly associated with CgR achieved within 12 months: 72% of the homozygous wild type (CC), 85% of the heterozygous (CT) and 100% of the homozygous mutant (TT) pts had ‘optimal’ CgR (p=0.044). In contrast, neither ABCG2 nor hOCT1 SNPs were found to correlate with response at any level. As far as MDR1 and hOCT-1 SNPs were concerned, we also tested associations with CgR or MR at the haplotype level. To this purpose, we classified pts on the basis of a) the highest level of mutant SNP (if a pt were homozygous mutant for at least one SNP s/he was classified as homozygous mutant, otherwise if s/he were heterozygous for at least one SNP s/he was classified as heterozygous, otherwise s/he was classified as homozygous wild type); b) the total number of mutant SNPs (i.e., the count of mutant SNPs alleles - two for homozygous mutant, one for heterozygous - summed over all SNPs) c) the number of distinct mutant SNPs (i.e., the number of different SNPs the pt had that had at least one mutant allele). For both MDR1 and hOCT1, correlations of pt status classified as above and CgR achieved within 12 months had p-values between 0.064 and 0.18. Potentially, if the same level of association were seen in a larger sample size the results could reach statistical significance. In all cases, the greater the level of mutant SNPs present, the higher the fraction with ‘optimal’ CgR. In conclusion, in this preliminary exploratory study we found that genotypic variations in IM transporters and metabolizing enzymes may be associated with response to IM. Our plan is to conduct the analysis on a larger series of pts to further expand these observations, including the meaning of ABCB1 and hOCT1 haplotypes, and to better investigate potential correlations with treatment outcome, treatment regimen and drug levels. - This investigation was conducted by CML Correlative Studies Network (CCSN), TOPS, which is sponsored by Novartis Oncology