Association between imatinib transporters and metabolizing enzymes genotype and response in newly diagnosed chronic myeloid leukemia patients receiving imatinib therapy
Sabrina Angelini,
Simona Soverini,
Gloria Ravegnini,
Matt Barnett,
Eleonora Turrini,
Mark Thornquist,
Fabrizio Pane,
Timothy P. Hughes,
Deborah L. White,
Jerald Radich,
Dong Wook Kim,
Giuseppe Saglio,
Daniela Cilloni,
Ilaria Iacobucci,
Giovanni Perini,
Richard Woodman,
Giorgio Cantelli-Forti,
Michele Baccarani,
Patrizia Hrelia,
Giovanni Martinelli
Affiliations
Sabrina Angelini
Department of Pharmacology, University of Bologna, Bologna, Italy
Simona Soverini
Department of Haematology/Oncology “L. e A. Seràgnoli”, University of Bologna, Bologna, Italy
Gloria Ravegnini
Department of Pharmacology, University of Bologna, Bologna, Italy
Matt Barnett
Fred Hutchinson Cancer Research Center, Seattle, WA, USA
Eleonora Turrini
Department of Pharmacology, University of Bologna, Bologna, Italy
Mark Thornquist
Fred Hutchinson Cancer Research Center, Seattle, WA, USA
Fabrizio Pane
Haematology Unit and Department of Biochemistry and Medical Biotechnology, CEINGE-Advanced Biotechnology, University of Naples “Federico II”, Naples, Italy
Timothy P. Hughes
Department of Haematology, SA Pathology, Royal Adelaide Hospital, Adelaide, Australia
Deborah L. White
Department of Haematology, SA Pathology, Royal Adelaide Hospital, Adelaide, Australia
Jerald Radich
Fred Hutchinson Cancer Research Center, Seattle, WA, USA
Dong Wook Kim
The Catholic University of Korea, Seoul St Mary's Hospital, Seoul, South Korea
Giuseppe Saglio
Department of Clinical and Biological Sciences, University of Turin, Orbassano, Italy
Daniela Cilloni
Department of Clinical and Biological Sciences, University of Turin, Orbassano, Italy
Ilaria Iacobucci
Department of Haematology/Oncology “L. e A. Seràgnoli”, University of Bologna, Bologna, Italy
Giovanni Perini
Department of Biology, University of Bologna, Bologna, Italy
Richard Woodman
Novartis Oncology, Florham Park, NJ, USA
Giorgio Cantelli-Forti
Department of Pharmacology, University of Bologna, Bologna, Italy
Michele Baccarani
Department of Haematology/Oncology “L. e A. Seràgnoli”, University of Bologna, Bologna, Italy
Patrizia Hrelia
Department of Pharmacology, University of Bologna, Bologna, Italy
Giovanni Martinelli
Department of Haematology/Oncology “L. e A. Seràgnoli”, University of Bologna, Bologna, Italy
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.