Membrane transporters are important determinants of drug bioavailability. Their expression and activity affect the intracellular drug concentration in leukemic cells impacting response to therapy. Pharmacogenomics represents genetic markers that reflect allele arrangement of genes encoding drug transporters associated with treatment response. In previous work, we identified SNP rs460089 located in the promotor of SLC22A4 gene encoding imatinib transporter OCTN1 as influential on response of patients with chronic myeloid leukemia treated with imatinib. Patients with rs460089-GC pharmacogenotype had significantly superior response to first-line imatinib treatment compared to patients with rs460089-GG. This study investigated whether pharmacogenotypes of rs460089 are associated with sustainability of treatment-free remission (TFR) in patients from the EUROpean Stop Kinase Inhibitor (EURO-SKI) trial. In the learning sample, 176 patients showed a significantly higher 6-month probability of molecular relapse free survival (MRFS) in patients with GC genotype (73%, 95% CI: 60-82%) compared to patients with GG (51%, 95% CI: 41-61%). Also over time, patients with GC genotype had significantly higher MRFS probabilities compared with patients with GG (HR: 0.474, 95% CI: 0.280-0.802, p = 0.0054). Both results were validated with data on 93 patients from the Polish STOP imatinib study. In multiple regression models, in addition to the investigated genotype, duration of TKI therapy (EURO-SKI trial) and duration of deep molecular response (Polish study) were identified as independent prognostic factors. The SNP rs460089 was found as an independent predictor of TFR.

4th Department of Internal Medicine Hematology University Hospital Hradec Kralove Hradec Kralove Czech Republic

Bergonie Institute Bordeaux Inserm U1218 University of Bordeaux Bordeaux France

Chair and Department of Hematooncology and Bone Marrow Transplantation Medical University of Lublin Lublin Poland

Department of Cancer Research and Molecular Medicine Norwegian University of Science and Technology Trondheim Norway

Department of General Pathology Pomeranian Medical University Szczecin Poland

Department of Haematology and Oncology University Hospital Mannheim Heidelberg University Mannheim Germany

Department of Hemato oncology Faculty Hospital and Faculty of Medicine and Dentistry Palacký University Olomouc Olomouc Czech Republic

Department of Hematology Jagiellonian University Hospital Kraków Poland

Department of Hematology Medical University of Lodz Copernicus Memorial Hospital Lodz Poland

Department of Hematology St Olavs Hospital Trondheim Norway

Dept of Hematology Oncology and Radiation Physics Skåne University Hospital Lund Sweden

Experimental Hematooncology Department University of Lublin Lublin Poland

Hematology and Bone Marrow Transplantation Department Medical Silesian University Katowice Poland

Hematology and Transplantology Department Medical University of Gdańsk Gdańsk Poland

Hematology Clinic National and kapodistrian University Athens Greece

Hematology Department Medical University of Białystok Białystok Poland

Hematology Oncology and Internal Medicine Department Medical University of Warsaw Warsaw Poland

Hematology Research Unit Helsinki University of Helsinki and Helsinki University Hospital Comprehensive Cancer Center Helsinki Finland

Institut für Medizinische Informationsverarbeitung Biometrie und Epidemiologie Medizinische Fakultät Ludwig Maximilians Universität Munich Germany

Institute of Clinical and Experimental Hematology 1st Medicine Faculty Charles University Prague Czech Republic

Institute of Hematology and Blood Transfusion Prague Czech Republic

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

Onkologische Praxis Heilbronn Heilbronn Germany

Translational Immunology Research Program and Department of Clinical Chemistry University of Helsinki Helsinki Finland

UNIVERSITÄTSKLINIKUM FREIBURG Klinik für Innere Medizin 1 Schwerpunkt Hämatologie Onkologie und Stammzelltransplantation Freiburg Germany

Universitätsklinikum RWTH Aachen and Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf Aachen Germany

Universitätsklinikum Würzburg Medizinische Klinik und Poliklinik 2 Würzburg Germany

University Hospital Marburg Marburg Germany

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Burger H, van Tol H, Brok M, Wiemer EA, de Bruijn EA, Guetens G, et al. Chronic imatinib mesylate exposure leads to reduced intracellular drug accumulation by induction of the ABCG2 (BCRP) and ABCB1 (MDR1) drug transport pumps. Cancer Biol Ther. 2005;4:747–52. doi: 10.4161/cbt.4.7.1826. PubMed DOI

Hamada A, Miyano H, Watanabe H, Saito H. Interaction of imatinib mesilate with human P-glycoprotein. J Pharm Exp Ther. 2003;307:824–8. doi: 10.1124/jpet.103.055574. PubMed DOI

Burger H, Nooter K. Pharmacokinetic resistance to imatinib mesylate: role of the ABC drug pumps ABCG2 (BCRP) and ABCB1 (MDR1) in the oral bioavailability of imatinib. Cell Cycle. 2004;3:1502–5. doi: 10.4161/cc.3.12.1331. PubMed DOI

Gromicho M, Magalhaes M, Torres F, Dinis J, Fernandes AR, Rendeiro P, et al. Instability of mRNA expression signatures of drug transporters in chronic myeloid leukemia patients resistant to imatinib. Oncol Rep. 2013;29:741–50. doi: 10.3892/or.2012.2153. PubMed DOI

White DL, Saunders VA, Dang P, Engler J, Venables A, Zrim S, et al. Most CML patients who have a suboptimal response to imatinib have low OCT-1 activity: higher doses of imatinib may overcome the negative impact of low OCT-1 activity. Blood. 2007;110:4064–72. doi: 10.1182/blood-2007-06-093617. PubMed DOI

Hu S, Franke RM, Filipski KK, Hu C, Orwick SJ, de Bruijn EA, et al. Interaction of imatinib with human organic ion carriers. Clin Cancer Res. 2008;14:3141–8. doi: 10.1158/1078-0432.CCR-07-4913. PubMed DOI

Racil Z, Razga F, Polakova KM, Buresova L, Polivkova V, Dvorakova D, et al. Assessment of adenosine triphosphate-binding cassette subfamily B member 1 (ABCB1) mRNA expression in patients with de novo chronic myelogenous leukemia: the role of different cell types. Leuk Lymphoma. 2011;52:331–4. doi: 10.3109/10428194.2010.533220. PubMed DOI

Razga F, Racil Z, Machova Polakova K, Buresova L, Klamova H, Zackova D, et al. The predictive value of human organic cation transporter 1 and ABCB1 expression levels in different cell populations of patients with de novo chronic myelogenous leukemia. Int J Hematol. 2011;94:303–6. doi: 10.1007/s12185-011-0924-6. PubMed DOI

Giannoudis A, Wang L, Jorgensen AL, Xinarianos G, Davies A, Pushpakom S, et al. The hOCT1 SNPs M420del and M408V alter imatinib uptake and M420del modifies clinical outcome in imatinib-treated chronic myeloid leukemia. Blood. 2013;121:628–37. doi: 10.1182/blood-2012-01-405035. PubMed DOI

Kim DH, Sriharsha L, Xu W, Kamel-Reid S, Liu X, Siminovitch K, 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. doi: 10.1158/1078-0432.CCR-09-0145. PubMed DOI

Dulucq S, Bouchet S, Turcq B, Lippert E, Etienne G, Reiffers J, et al. Multidrug resistance gene (MDR1) polymorphisms are associated with major molecular responses to standard-dose imatinib in chronic myeloid leukemia. Blood. 2008;112:2024–7. doi: 10.1182/blood-2008-03-147744. PubMed DOI

Maffioli M, Camos M, Gaya A, Hernandez-Boluda JC, Alvarez-Larran A, Domingo A, et al. Correlation between genetic polymorphisms of the hOCT1 and MDR1 genes and the response to imatinib in patients newly diagnosed with chronic-phase chronic myeloid leukemia. Leuk Res. 2011;35:1014–9. doi: 10.1016/j.leukres.2010.12.004. PubMed DOI

Ni LN, Li JY, Miao KR, Qiao C, Zhang SJ, Qiu HR, et al. Multidrug resistance gene (MDR1) polymorphisms correlate with imatinib response in chronic myeloid leukemia. Med Oncol. 2011;28:265–9. doi: 10.1007/s12032-010-9456-9. PubMed DOI

Jaruskova M, Curik N, Hercog R, Polivkova V, Motlova E, Benes V, et al. Genotypes of SLC[A4 and SLC22A5 regulatory loci are predictive of the response of chronic myeloid leukemia patients to imatinib treatment. J Exp Clin Cancer Res. 2017;36:55. doi: 10.1186/s13046-017-0523-3. PubMed DOI PMC

Angelini S, Soverini S, Ravegnini G, Barnett M, Turrini E, Thornquist M, 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. doi: 10.3324/haematol.2012.066480. PubMed DOI PMC

Saussele S, Richter J, Guilhot J, Gruber FX, Hjorth-Hansen H, Almeida A, et al. Discontinuation of tyrosine kinase inhibitor therapy in chronic myeloid leukaemia (EURO-SKI): a prespecified interim analysis of a prospective, multicentre, non-randomised, trial. Lancet Oncol. 2018;19:747–57. doi: 10.1016/S1470-2045(18)30192-X. PubMed DOI

Cross NC, White HE, Colomer D, Ehrencrona H, Foroni L, Gottardi E, et al. Laboratory recommendations for scoring deep molecular responses following treatment for chronic myeloid leukemia. Leukemia. 2015;29:999–1003. doi: 10.1038/leu.2015.29. PubMed DOI PMC

Machiela MJ, Chanock SJ. LDlink: a web-based application for exploring population-specific haplotype structure and linking correlated alleles of possible functional variants. Bioinformatics. 2015;31:3555–7. doi: 10.1093/bioinformatics/btv402. PubMed DOI PMC

Wilson EB. Probable inference, the law of succession, and statistical inference. J Am Stat Assoc. 1927;22:209–12. doi: 10.1080/01621459.1927.10502953. DOI

Sy JP, Taylor JM. Estimation in a Cox proportional hazards cure model. Biometrics. 2000;56:227–36. doi: 10.1111/j.0006-341X.2000.00227.x. PubMed DOI

Corbiere F, Joly P. A SAS macro for parametric and semiparametric mixture cure models. Comput Methods Prog Biomed. 2007;85:173–80. doi: 10.1016/j.cmpb.2006.10.008. PubMed DOI

Machova Polakova K, Albeer A, Polivkova V, Vlcanova K, Fabarius A, Klamova H, et al. Genotypes of the gene encoding the membrane transporter SLC22A4 are associated with molecular relapse-free survival after discontinuation of imatinib therapy in patients with chronic myeloid leukemia. Blood. 2019;134:1647. doi: 10.1182/blood-2019-129710. DOI

Hochhaus A, Baccarani M, Silver RT, Schiffer C, Apperley JF, Cervantes F, et al. European LeukemiaNet 2020 recommendations for treating chronic myeloid leukemia. Leukemia. 2020;34:966–84. doi: 10.1038/s41375-020-0776-2. PubMed DOI PMC

Clark RE, Polydoros F, Apperley JF, Milojkovic D, Rothwell K, Pocock C, et al. De-escalation of tyrosine kinase inhibitor therapy before complete treatment discontinuation in patients with chronic myeloid leukaemia (DESTINY): a non-randomised, phase 2 trial. Lancet Haematol. 2019;6:e375–83. doi: 10.1016/S2352-3026(19)30094-8. PubMed DOI

Mahon FX, Réa D, Guilhot J, Guilhot F, Huguet F, Nicolini F. Discontinuation of imatinib in patients with chronic myeloid leukaemia who have maintained complete molecular remission for at least 2 years: the prospective, multicentre Stop Imatinib (STIM) trial. Lancet Oncol. 2010;11:1029–35. doi: 10.1016/S1470-2045(10)70233-3. PubMed DOI

Nicolini FE, Dulucq S, Boureau L, Cony-Makhoul P, Charbonnier A, Escoffre-Barbe M, et al. The evaluation of residual disease by digital PCR, and TKI duration are critical predictive factors for molecular recurrence after for stopping imatinib first-line in chronic phase CML patients: results of the STIM2 study. Blood. 2018;132:462. doi: 10.1182/blood-2018-99-113029. PubMed DOI

Ross DM, Branford S, Seymour JF, Schwarer AP, Arthur C, Yeung DT, et al. Safety and efficacy of imatinib cessation for CML patients with stable undetectable minimal residual disease: results from the TWISTER study. Blood. 2013;122:515–22. doi: 10.1182/blood-2013-02-483750. PubMed DOI

Ilander M, Olsson-Strömberg U, Schlums H, Guilhot J, Brück O, Lähteenmäki H, et al. Increased proportion of mature NK cells is associated with successful imatinib discontinuation in chronic myeloid leukemia. Leukemia. 2017;31:1108–116. doi: 10.1038/leu.2016.360. PubMed DOI PMC

Irani YD, Hughes A, Clarson J, Kok CH, Shanmuganathan N, White DL, et al. Successful treatment-free remission in chronic myeloid leukaemia and its association with reduced immune suppressors and increased natural killer cells. Br J Haematol. 2020;191:433–41. doi: 10.1111/bjh.16718. PubMed DOI

Schütz C, Inselmann S, Saussele S, Dietz CT, Müller MC, Eigendorff E, et al. Expression of the CTLA-4 ligand CD86 on plasmacytoid dendritic cells (pDC) predicts risk of disease recurrence after treatment discontinuation in CML. Leukemia. 2017;32:1–8. PubMed

Machova Polakova K, Zizkova H, Zuna J, Motlova E, Hovorkova L, Gottschalk A, et al. Analysis of chronic myeloid leukaemia during deep molecular response by genomic PCR: a traffic light stratification model with impact on treatment-free remission. Leukemia. 2020;34:2113–124. doi: 10.1038/s41375-020-0882-1. PubMed DOI

Pagani IS, Dang P, Saunders VA, Grose R, Shanmuganathan N, Kok CH, et al. Lineage of measurable residual disease in patients with chronic myeloid leukemia in treatment-free remission. Leukemia. 2020;34:1052–61. doi: 10.1038/s41375-019-0647-x. PubMed DOI

Apperley JF. Part I: mechanisms of resistance to imatinib in chronic myeloid leukaemia. Lancet Oncol. 2007;8:1018–29. doi: 10.1016/S1470-2045(07)70342-X. PubMed DOI