Association between imatinib transporters and metabolizing enzymes genotype and response in newly diagnosed chronic myeloid leukemia patients receiving imatinib therapy
Open Access
- 8 August 2012
- journal article
- Published by Ferrata Storti Foundation (Haematologica) in Haematologica
- Vol. 98 (2), 193-200
- https://doi.org/10.3324/haematol.2012.066480
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.Keywords
This publication has 45 references indexed in Scilit:
- Chronic phase chronic myeloid leukemia patients with low OCT-1 activity randomized to high-dose imatinib achieve better responses and have lower failure rates than those randomized to standard-dose imatinibHaematologica, 2011
- Nilotinib As Front-Line Treatment for Patients With Chronic Myeloid Leukemia in Early Chronic PhaseJournal of Clinical Oncology, 2010
- Imatinib pharmacokinetics and its correlation with response and safety in chronic-phase chronic myeloid leukemia: a subanalysis of the IRIS studyBlood, 2008
- Five-Year Follow-up of Patients Receiving Imatinib for Chronic Myeloid LeukemiaThe New England Journal of Medicine, 2006
- Dasatinib induces notable hematologic and cytogenetic responses in chronic-phase chronic myeloid leukemia after failure of imatinib therapyBlood, 2006
- Imatinib mesylate discontinuation in patients with chronic myelogenous leukemia in complete molecular remission for more than 2 yearsBlood, 2006
- Phenotype–genotype variability in the human CYP3A locus as assessed by the probe drug quinine and analyses of variant CYP3A4 allelesBiochemical and Biophysical Research Communications, 2005
- Clinical Pharmacokinetics of ImatinibClinical Pharmacokinetics, 2005
- MDR1 gene C1236T and C6+139T polymorphisms in the Russian population: Associations with predisposition to lymphoproliferative diseases and drug resistanceBulletin of Experimental Biology and Medicine, 2004
- Pharmacokinetics and Pharmacodynamics of Imatinib in a Phase I Trial With Chronic Myeloid Leukemia PatientsJournal of Clinical Oncology, 2004