Effect of ABCG2, OCT1, and ABCB1 (MDR1) Gene Expression on Treatment-Free Remission in a EURO-SKI Subtrial.

Sébastien Rinaldetti, Markus Pfirrmann, Kirsi Manz, Joelle Guilhot, Christian Dietz, Panayiotidis Panagiotidis, Birgit Spiess, Wolfgang Seifarth, Alice Fabarius, Martin Müller, Maria Pagoni, Maria Dimou, Jolanta Dengler, Cornelius F Waller, Tim H Brümmendorf, Regina Herbst, Andreas Burchert, Carsten Janβen, Maria Elisabeth Goebeler, Philipp J Jost, Stefan Hanzel, Philippe Schafhausen, Gabriele Prange-Krex, Thomas Illmer, Viktor Janzen, Martine Klausmann, Robert Eckert, Gerd Büschel, Alexander Kiani, Wolf-Karsten Hofmann, François-Xavier Mahon, Susanne Saussele

Journal: Clinical lymphoma, myeloma & leukemia 2019;18(4):266-271

PMID: 29510895

Free Full Text on Elsevier Science View on PubMed

Abstract

INTRODUCTION

Tyrosine kinase inhibitors (TKIs) can safely be discontinued in chronic myeloid leukemia (CML) patients with sustained deep molecular response. ABCG2 (breast cancer resistance protein), OCT1 (organic cation transporter 1), and ABCB1 (multidrug resistance protein 1) gene products are known to play a crucial role in acquired pharmacogenetic TKI resistance. Their influence on treatment-free remission (TFR) has not yet been investigated.

MATERIALS AND METHODS

RNA was isolated on the last day of TKI intake from peripheral blood leukocytes of 132 chronic phase CML patients who discontinued TKI treatment within the European Stop Tyrosine Kinase Inhibitor Study trial. Plasmid standards were designed including subgenic inserts of OCT1, ABCG2, and ABCB1 together with GUSB as reference gene. For expression analyses, quantitative real-time polymerase chain reaction was used. Multiple Cox regression analysis was performed. In addition, gene expression cutoffs for patient risk stratification were investigated.

RESULTS

The TFR rate of 132 patients, 12 months after TKI discontinuation, was 54% (95% confidence interval [CI], 46%-62%). ABCG2 expression (‰) was retained as the only significant variable (P = .02; hazard ratio, 1.04; 95% CI, 1.01-1.07) in multiple Cox regression analysis. Only for the ABCG2 efflux transporter, a significant cutoff was found (P = .04). Patients with an ABCG2/GUSB transcript level >4.5‰ (n = 93) showed a 12-month TFR rate of 47% (95% CI, 37%-57%), whereas patients with low ABCG2 expression (≤4.5‰; n = 39) had a 12-month TFR rate of 72% (95% CI, 55%-82%).

CONCLUSION

In this study, we investigated the effect of pharmacogenetics in the context of a CML treatment discontinuation trial. The transcript levels of the efflux transporter ABCG2 predicted TFR after TKI discontinuation.

Address: Department of Hematology and Oncology, University Hospital Mannheim, Heidelberg University, Mannheim, Germany. Electronic address: [email protected].; Institut für Medizinische Informationsverarbeitung, Biometrie und Epidemiologie (IBE), Ludwig-Maximilians-Universität, München, Germany.; INSERM CIC 1402, CHU de Poitiers, Poitiers, France.; Institute for Hematology and Oncology (IHO GmbH), Mannheim, Germany.; Laikon General Hospital, National and Kapodistrian University of Athens, Athens, Greece.; Department of Hematology and Oncology, University Hospital Mannheim, Heidelberg University, Mannheim, Germany.; Evangelismos Hospital, Athens, Greece.; Onkologische Schwerpunktpraxis Heilbronn, Heilbronn, Germany.; Innere Medizin I, Universitätsklinikum Freiburg, Freiburg, Germany.; Uniklinik RWTH Aachen, Aachen, Germany.; Klinik für Innere Medizin III, Klinikum Chemnitz, Chemnitz, Germany.; Klinik für Innere Medizin, Schwerpunkt Hämatologie, Onkologie und Immunologie, Universitätsklinikum Marburg, Marburg, Germany.; Onkologie untere Ems, Leer, Germany.; Medizinische Klinik und Poliklinik, Universitätsklinikum Würzburg, Würzburg, Germany.; III. Medizinische Klinik, Klinikum rechts der Isar, Technische Universität, München, Germany.; Hämatologie, Onkologie und Palliativmedizin, Klinikverbund Kempten-Oberallgäu, Kempten, Germany.; II. Medizinische Klinik und Poliklinik, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany.; Gemeinschaftspraxis Dres Mohm und Prange-Krex, Dresden, Germany.; Fachärztliche Gemeinschaftspraxis mit Schwerpunkt Hämatologie und Onkologie, Dresden, Germany.; Medizinische Klinik und Poliklinik III, Universitätsklinikum Bonn, Bonn, Germany.; Gemeinschaftspraxis Drs Klausmann, Aschaffenburg, Germany.; Onkologische Schwerpunktpraxis Esslingen, Esslingen, Germany.; Hämatologie, Onkologie und Palliativmedizin, Vivantes Klinikum Neuköln, Berlin, Germany.; Klinik für Onkologie und Hämatologie, Klinikum Bayreuth, Bayreuth, Germany.; Bergonié Cancer Institute, INSERM Unit 916, University of Bordeaux, Bordeaux, France.

DOI: 10.1016/j.clml.2018.02.004