title: Association between imatinib transporters and metabolizing enzymes genotype and response in newly diagnosed chronic myeloid leukemia patients receiving imatinib therapy.
abstract: Imatinib has so far been the first-choice treatment in chronic myeloid leukemia with excellent results. However, only a proportion of patients achieve major molecular response - hence the need to find biological predictors of outcome to select the optimal therapeutic strategy now that more potent inhibitors are available. We investigated a panel of 20 polymorphisms in seven genes, potentially associated with the pharmacogenetics of imatinib, in a subset of 189 patients with newly diagnosed chronic myeloid leukemia enrolled in the TOPS trial. The analysis included polymorphisms in the transporters hOCT1, MDR1, ABCG2, OCTN1, and OATP1A2, and in the metabolizing genes CYP3A4 and CYP3A5. In the overall population, the OCTN1 C allele (rs1050152), a simple combination of polymorphisms in the hOCT1 gene and another combination in the genes involved in imatinib uptake were significantly associated with major molecular response. The combination of polymorphisms in imatinib uptake was also significantly associated with complete molecular response. Analyses restricted to Caucasians highlighted the significant association of MDR1 CC (rs60023214) genotype with complete molecular response. We demonstrate the usefulness of a pharmacogenetic approach for stratifying patients with chronic myeloid leukemia according to their likelihood of achieving a major or complete molecular response to imatinib. This represents an attractive opportunity for therapy optimization, worth testing in clinical trials.
authors.affiliation: Department of Pharmacology, University of Bologna, Bologna, Italy. s.angelini@unibo.it
authors.forename: Sabrina
authors.initials: S
authors.lastname: Angelini
authors.forename: Simona
authors.initials: S
authors.lastname: Soverini
authors.forename: Gloria
authors.initials: G
authors.lastname: Ravegnini
authors.forename: Matt
authors.initials: M
authors.lastname: Barnett
authors.forename: Eleonora
authors.initials: E
authors.lastname: Turrini
authors.forename: Mark
authors.initials: M
authors.lastname: Thornquist
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Pane
authors.forename: Timothy P
authors.initials: TP
authors.lastname: Hughes
authors.forename: Deborah L
authors.initials: DL
authors.lastname: White
authors.forename: Jerald
authors.initials: J
authors.lastname: Radich
authors.forename: Dong Wook
authors.initials: DW
authors.lastname: Kim
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Saglio
authors.forename: Daniela
authors.initials: D
authors.lastname: Cilloni
authors.forename: Ilaria
authors.initials: I
authors.lastname: Iacobucci
authors.forename: Giovanni
authors.initials: G
authors.lastname: Perini
authors.forename: Richard
authors.initials: R
authors.lastname: Woodman
authors.forename: Giorgio
authors.initials: G
authors.lastname: Cantelli-Forti
authors.forename: Michele
authors.initials: M
authors.lastname: Baccarani
authors.forename: Patrizia
authors.initials: P
authors.lastname: Hrelia
authors.forename: Giovanni
authors.initials: G
authors.lastname: Martinelli
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism; D000293:Adolescent; D000328:Adult; D000368:Aged; D000483:Alleles; D000970:Antineoplastic Agents / Q000378:metabolism / Q000627:therapeutic use*; D001549:Benzamides / Q000378:metabolism / Q000627:therapeutic use*; D027682:Cation Transport Proteins / Q000235:genetics* / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A / Q000235:genetics / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005838:Genotype; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D027701:Organic Cation Transport Proteins / Q000235:genetics / Q000378:metabolism; D010879:Piperazines / Q000378:metabolism / Q000627:therapeutic use*; D020641:Polymorphism, Single Nucleotide; D047428:Protein Kinase Inhibitors / Q000378:metabolism / Q000627:therapeutic use*; D011743:Pyrimidines / Q000378:metabolism / Q000627:therapeutic use*; D027981:Symporters; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D001549:Benzamides; D027682:Cation Transport Proteins; D027701:Organic Cation Transport Proteins; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; C109807:SLC22A4 protein, human; D027981:Symporters; D000068877:Imatinib Mesylate; D003577:Cytochrome P-450 Enzyme System; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human