INTRODUCTION: Imatinib mesylate is the drug of choice for patients with chronic myeloid leukemia (CML). Imatinib pharmacokinetics is affected by a number of transport proteins and enzymes. MATERIAL AND METHODS: In the present study we evaluated the association of eight polymorphisms in the seven genes CYP3A5*3 (rs776746), CYP3A4*1 (rs2740574), CYP2C9*3 (rs1057910), SLC22A1 (rs683369), ABCB1 (rs1045642, rs1128503), ABCG2 (rs2231142) and ABCC2 (rs717620) with imatinib plasma level and achieving an optimal clinical response in 112 CML patients (53 men and 59 women). RESULTS: No association was found between the examined polymorphisms in rs776746, rs2740574, rs1057910, rs683369, rs1045642, rs1128503, rs2231142, rs717620 and the achieved imatinib plasma level. The influence of rs776746 (CYP3A5*3) on the achievement of a complete cytogenetic response (CCyR) at 6 months was borderline non-significant (p = 0.06). Furthermore, no association was demonstrated between rs776746 polymorphisms and the achievement of a major molecular response (MMR) at 12 or 18 months. Polymorphisms rs776746, rs2740574, rs1057910, rs683369, rs1045642, rs1128503, rs2231142, rs717620 showed no impact on the optimal therapeutic response. CONCLUSIONS: Despite the results of some other studies, no other polymorphism we analyzed was associated with imatinib plasma level or clinical response. The treatment outcomes cannot be predicted using the candidate gene approach and treatment decisions cannot be made according to the polymorphisms investigated in this study.

Department of Clinical Biochemistry Charles University Faculty Hospital and Faculty of Medicine Hradec Kralove Czech Republic

Department of Internal Medicine and Hematology Charles University Faculty Hospital and Faculty of Medicine Hradec Kralove Czech Republic

Department of Internal Medicine Hematology and Oncology Masaryk University and University Hospital Brno Brno Czech Republic

Department of Internal Medicine Hematology Charles University Hospital Hradec Kralove Czech Republic

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de Lavallade H, Apperley J, Khorashad J, et al. Imatinib for newly diagnosed patients with chronic myeloid leukemia: incidence of sustained responses in an intention-to-treat analysis. J Clin Oncol. 2008;26:3358–63. PubMed

Hughes T, Hochhaus A, Branford S, et al. IRIS investigators Long-term prognostic significance of early molecular response to imatinib in newly diagnosed chronic myeloid leukemia: an analysis from the International Randomized Study of Interferon and STI571 (IRIS) Blood. 2010;116:3758–65. PubMed PMC

Marin D, Bazeos A, Mahon F, et al. Adherence is the critical factor for achieving molecular responses in patients with chronic myeloid leukemia who achieve complete cytogenetic responses on imatinib. J Clin Oncol. 2010;28:2381–8. PubMed PMC

Apperley J. Part I: mechanisms of resistance to imatinib in chronic myeloid leukaemia. Lancet Oncol. 2007;8:1018–29. PubMed

Apperley J. Part II: management of resistance to imatinib in chronic myeloid leukaemia. Lancet Oncol. 2007;8:1116–28. PubMed

Baccarani M, Cortes J, Pane F, et al. European Leukemia Net. Chronic myeloid leukemia: an update of concepts and management recommendations of European LeukemiaNet. J Clin Oncol. 2009;27:6041–51. PubMed PMC

Baccarani M, Deininger M, Rosti G, et al. European LeukemiaNet recommendations for the management of chronic myeloid leukemia: 2013. Blood. 2013;122:872–84. PubMed PMC

Peng B, Lloyd P, Schran H. Clinical pharmacokinetics of imatinib. Clin Pharmacokinet. 2005;44:879–94. PubMed

Cortes JE, Egorin MJ, Guilhot F, et al. Pharmacokinetic/pharmacodynamic correlation and blood-level testing in imatinib therapy for chronic myeloid leukemia. Leukemia. 2009;23:1537–44. PubMed

Bruhn O, Cascorbi I. Polymorphisms of the drug transporters ABCB1, ABCG2, ABCC2 and ABCC3 and their impact on drug bioavailability and clinical relevance. Expert Opinion. 2014;10:1337–54. PubMed

Zhai X, Wang H, Zhu X, et al. Gene polymorphisms of ABC transporters are associated with clinical outcomes in children with acute lymphoblastic leukemia. Arch Med Sci. 2012;8:659–671. PubMed PMC

Hosseini M, Houshmand M, Ebrahimi A. MTHFR polymorphisms and breast cancer risk. Arch Med Sci. 2011;7:134–7. PubMed PMC

Mrozikiewicz-Rakowska B, Malinowski M, Nehring P, et al. The MDR1/ABCB1 gene rs1045642 polymorphism in colorectal cancer. Arch Med Sci. doi: 10.5114/aoms.2017.70329. PubMed DOI PMC

Takahashi N, Miura M, Scott SA, et al. Influence of CYP3A5 and drug transporter polymorphisms on imatinib trough concentration and clinical response among patients with chronic phase chronic myeloid leukemia. J Hum Gene. 2010;55:731–7. PubMed

Seong S, Lim M, Sohn S, et al. Influence of enzyme and transporter polymorphisms on trough imatinib concentration and clinical response in chronic myeloid leukemia patients. Ann Oncol. 2013;24:756–60. PubMed

Kim D, Sriharsha L, Xu W, et al. Clinical relevance of a pharmacogenetic approach using multiple candidate genes to predict response and resistance to imatinib therapy in chronic myeloid leukemia. Clin Cancer Res. 2009;15:4750–8. PubMed

Au A, Aziz Baba A, Goh A, et al. Association of genotypes and haplotypes of multi-drug transporter genes ABCB1 and ABCG2 with clinical response to imatinib mesylate in chronic myeloid leukemia patients. Biomed Pharmacother. 2014;68:343–9. PubMed

Salimizand H, Amini S, Abdi M, et al. Concurrent effects of ABCB1 C3435T, ABCG2 C421A, and XRCC1 Arg194Trp genetic polymorphisms with risk of cancer, clinical output, and response to treatment with imatinib mesylate in patients with chronic myeloid leukemia. Tumour Biol. 2016;1:791–8. PubMed

Wang J, Liu H, Li F, et al. Multidrug resistance gene (MDR1) polymorphisms may not be directly associated with response to imatinib in chronic myeloid leukemia. Genet Mol Res. 2015;14:14967–78. PubMed

Bedewy A, El-Maghraby S. Do SLCO1B3 (T334G) and CYP3A5*3 polymorphisms affect response in Egyptian chronic myeloid leukemia patients receiving imatinib therapy? Hematology. 2013;18:211–6. PubMed

Angelini S, Soverini S, Ravegnini G, et al. Association between imatinib transporters and metabolizing enzymes genotype and response in newly diagnosed chronic myeloid leukemia patients receiving imatinib therapy. Haematologica. 2013;98:193–200. PubMed PMC