The SNP rs460089 in the gene promoter of the drug transporter OCTN1 has prognostic value for treatment-free remission in chronic myeloid leukemia patients treated with imatinib

Author:

Polakova Katerina Machova1ORCID,Albeer Ali2ORCID,Polivkova Vaclava1,Krutska Monika1,Vlcanova Katerina1,Curik Nikola1,FABARIUS Alice3,Klamova Hana1,Spieß B4,Waller Cornelius5ORCID,Bruemmendorf Tim6ORCID,Dengler Jolanta7,Kunzmann Volker8,Burchert Andreas9ORCID,Belohlavkova Petra10,Mustjoki Satu11ORCID,Faber Edgar12,Mayer Jiri13,Zackova Daniela14,Panayiotidis Panayiotis15,Richter Johan16ORCID,Hjorth-Hansen Henrik17,Kamińska Magdalena18,Płonka Magdalena18,Szczepanek Elżbieta18,Szarejko Monika,Bober Grażyna19,Hus Iwona20,Grzybowska-Izydorczyk Olga21,Wasilewska Ewa22,Paczkowska Edyta23,Niesiobędzka-Krężel Joanna24,Giannopoulos Krzysztof25,Mahon Francois-Xavier,Sacha Tomasz26ORCID,Saussele Susanne27ORCID,Pfirrmann Markus28ORCID

Affiliation:

1. Institute of Hematology and Blood Transfusion

2. Institut für Medizinische Informationsverarbeitung, Biometrie und Epidemiologie, Ludwig-Maximilians-Universität, Munich, Germany

3. III. Medizinische Klinik, Mannheim

4. Universitätsmedizin Mannheim

5. University of Freiburg

6. University Hospital RWTH Aachen

7. Onkologische Praxis Heilbronn

8. University Hospital Würzburg

9. Department of Internal Medicine, Hematology, Oncology and Immunology, Philipps University Marburg and University Hospital Giessen and Marburg, Campus Marburg

10. 4th Department of Internal Medicine Hematology, Charles University Faculty Hospital and Faculty of Medicine

11. Hematology Research Unit Helsinki, University of Helsinki and Helsinki University Hospital Comprehensive Cancer Center

12. University Hospital Olomouc

13. University Hospital Brno and Masaryk University Brno

14. Internal Hematology and Oncology Clinic, Faculty Hospital Brno and Faculty of Medicine, Masaryk University, Brno

15. Laikon Hospital

16. Skåne University Hospital

17. St Olavs Hospital

18. Dept. of Hematology, Jagiellonian University Hospital,

19. Hematology and Bone Marrow Transplantation Department, Medical Silesian University

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

21. Medical University of Lodz

22. Hematology Department, Medical University of Białystok

23. Department of General Pathology, Pomeranian Medical University,

24. Hematology, Oncology and Internal Medicine Department, Medical University of Warsaw

25. Medical University of Lublin

26. Jagiellonian University Hospital

27. University Hospital Mannheim, Heidelberg University

28. Ludwig-Maximilians-Universität München

Abstract

Abstract 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. The SNP rs460089 was found as an independent predictor of TFR.

Publisher

Research Square Platform LLC

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