IMPACT OF ABCG2, OCT1 AND ABCB1 (MDR1) ON TREATMENT FREE REMISSION IN AN EUROSKI SUBTRIAL
Author(s): ,
Sébastien Rinaldetti
Affiliations:
III. Medizinische Klinik,Universitätsmedizin Mannheim,Mannheim,Germany
,
Markus Pfirrmann
Affiliations:
Institut für Medizinische Informationsverarbeitung, Biometrie und Epidemiologie (IBE),Ludwig-Maximilians Universität,Munich,Germany
,
Kirsi Manz
Affiliations:
Institut für Medizinische Informationsverarbeitung, Biometrie und Epidemiologie (IBE),Ludwig-Maximilians Universität,Munich,Germany
,
Joelle Guilhot
Affiliations:
Institut National de la Santé et de la Recherche Médicale (INSERM),Centre Hospitalier Universitaire (CHU) de Poitiers,Poitiers,France
,
Panayiotidis Panagiotidis
Affiliations:
Molecular Hematology Laboratory, 1st Department of Propaedeutic Medicine,National and Kapodistrian University of Athens, School of Medicine, Laikon General Hospital,Athens,Greece
,
Birgit Spiess
Affiliations:
III. Medizinische Klinik,Universitätsmedizin Mannheim,Mannheim,Germany
,
Wolfgang Seifarth
Affiliations:
III. Medizinische Klinik,Universitätsmedizin Mannheim,Mannheim,Germany
,
Alice Fabarius
Affiliations:
III. Medizinische Klinik,Universitätsmedizin Mannheim,Mannheim,Germany
,
Maria Pagoni
Affiliations:
Hellenic Society of Hematology,Athens,Greece
,
Maria Dimou
Affiliations:
Hellenic Society of Hematology,Athens,Greece
,
Jolanta Dengler
Affiliations:
Onkologische Praxis Heilbronn,Heilbronn,Germany
,
Cornelius Waller
Affiliations:
Klinik für Innere Medizin I,Universitätsklinikum Freiburg,Freiburg,Germany
,
Tim H. Brümmendorf
Affiliations:
Med. Klinik IV,Uniklinik RWTH Aachen,Aachen,Germany
,
Regina Herbst
Affiliations:
Klinik für Innere Medizin III,Klinikum Chemnitz,Chemnitz,Germany
,
Andreas Burchert
Affiliations:
Klinik für Hämatologie, Onkologie und Immunologie,Universitätsklinikum Gießen und Marburg,Marburg,Germany
,
Carsten Janßen
Affiliations:
Onkologie Leer - Emden - Papenburg,Leer,Germany
,
Maria Elisabeth Goebeler
Affiliations:
Medizinische Klinik II, Schwerpunkt Hämatologie / Internistische Onkologie,Universitätsklinikum Würzburg,Würzburg,Germany
,
Philipp J. Jost
Affiliations:
III. Medizinische Klinik,Klinikum rechts der Isar, Technische Universität,München,Germany
,
Stefan Hanzel
Affiliations:
Hämatologie, Onkologie und Palliativmedizin,Klinikverbund Kempten-Oberallgäu,Kempten,Germany
,
Philippe Schafhausen
Affiliations:
II. Medizinische Klinik und Poliklinik,Universitätsklinikum Hamburg-Eppendorf,Hamburg,Germany
,
Gabriele Prange-Krex
Affiliations:
Gemeinschaftspraxis Dres. Mohm und Prange-Krex,Dresden,Germany
,
Thomas Illmer
Affiliations:
Fachärztliche Gemeinschaftspraxis mit Schwerpunkt Hämatologie und Onkologie,Dresen,Germany
,
Viktor Janzen
Affiliations:
Medizinische Klinik und Poliklinik III,Universitätsklinikum Bonn,Bonn,Germany
,
Martine Klausmann
Affiliations:
Gemeinschaftspraxis Drs. Klausmann,Aschaffenburg,Germany
,
Robert Eckert
Affiliations:
Onkologische Schwerpunktpraxis Esslingen,Esslingen,Germany
,
Gerd Büschel
Affiliations:
Hämatologie, Onkologie und Palliativmedizin,Vivantes Klinikum Neukölln,Berlin,Germany
,
Alexander Kiani
Affiliations:
Klinik für Onkologie und Hämatologie,Klinikum Bayreuth,Bayreuth,Germany
,
Wolf-Karsten Hofmann
Affiliations:
III. Medizinische Klinik,Universitätsmedizin Mannheim,Mannheim,Germany
,
François-Xavier Mahon
Affiliations:
Institut Bergonié,University Bordeaux,Bordeaux,France
Susanne Saussele
Affiliations:
III. Medizinische Klinik,Universitätsmedizin Mannheim,Mannheim,Germany
EHA Library. Rinaldetti S. Jun 23, 2017; 181542; P255
Dr. Sébastien Rinaldetti
Dr. Sébastien Rinaldetti
Contributions
Abstract

Abstract: P255

Type: Poster Presentation

Presentation during EHA22: On Friday, June 23, 2017 from 17:15 - 18:45

Location: Poster area (Hall 7)

Background
Several studies showed that tyrosine kinase inhibitors (TKIs) can safely be discontinued in patients with sustained deep molecular response. So far, deep molecular response (DMR) and treatment duration were predictive for successful treatment-free remission (TFR) whereas age, risk scores, gender and molecular response level before stopping were without influence (Mahon FX. et al. and Pfirrmann M. et al., ASH 2016). In addition, biomarkers like NK-cells and CD86+ cells (Ilander M. et al. and Schütz C. et al., Leukemia 2017) seem to be of impact. ABCG2, OCT1 and ABCB1 are known to play a crucial role in acquired pharmacokinetic drug resistance and DMR in the context of nilotinib, imatinib and dasatinib. The influence of these mechanisms have not yet been analyzed for their correlation with TFR.

Aims
In a substudy of the EUROSKI trial, expression levels of the influx transporter OCT1 and the efflux transporters ABCG2 and ABCB1 (MDR1) have been quantified in order to investigate their impact on TFR. As all patients are in DMR, we investigate whether these transporters confer a constitutional disposition for TFR.

Methods
The expression levels of OCT1, ABCG2 and ABCB1 have been determined by an absolute transcript quantification method in the peripheral blood of patients, enrolled in the EUROSKI trial and screened in our center. Minimal inclusion criteria were three years TKI treatment and one year MR4 duration (BCR-ABLIS < 0.01%). Plasmid standards have been designed including the genes OCT1, ABCG2, ABCB1 together with GUS as reference gene. Expression measurements were performed by qRT-PCR on baseline (day of stopping TKI treatment) samples. Cutoff levels were determined by the minimal p-value approach and adjusted for multiple testing by the Bonferroni method. The predictive significance of the efflux and influx channel transcript levels was quantified by a multivariate Cox’s regression model. Relapse has been defined as loss of major molecular response at one time point.

Results

In our cohort, 132 chronic phase CML patients discontinued TKI treatment (87% imatinib 1st line treatment), showing a relapse rate of 46%. Median MR4 and TKI treatment duration was 4.3 and 7.6 years respectively. The majority of patients were positive for the e14a2 transcript (e14a2+: 63%, e13a2+: 28%, e13a2+/e14a2+: 9%). The mean expression of OCT1 and ABCB1 between ‘relapse’ and ‘no-relapse’ patients showed no significant difference (p=0.99 and p=0.66), whereas ABCG2 showed a weak differential expression (1.1% vs. 0.8%, p=0.065). Cutoff analyses showed a significant risk stratification only for the ABCG2 efflux transporter at a distinct cutoff value of 4.5‰ (p=0.04). Patients with an ABCG2/GUS transcript level above 4.5‰ (n=93) had a 30-months TFR of 47%, whereas patients with low ABCG2 expression (<4.5‰, n=39) showed a 12-months TFR of 67%. The hazard ratio and predictive significance of the ABCG2 transcript levels were investigated by a multivariate Cox’s regression model. Only ABCG2 expression was retained as independent covariate in this model (p=0.033). Thus, patients with an ABCG2/GUS transcript level above 4.5‰ showed an up to two-time higher risk of relapse after treatment discontinuation (HR=2.1, 95% CI: 1.06-4.05).

Conclusion
Here we investigated for the first time the impact of pharmacokinetics in the context of a CML discontinuation trial. ABCG2 but not OCT1 and ABCB1 (MDR1) predicted treatment-free remission after TKI discontinuation. High expression of the ABCG2 efflux transporter correlated with a two-time higher risk of relapse in multivariate analysis. Further prospective validation is warranted.

Session topic: 8. Chronic myeloid leukemia - Clinical

Keyword(s): Tyrosine kinase inhibitor, Therapy, Chronic myeloid leukemia, ABCG2

By clicking “Accept Terms & all Cookies” or by continuing to browse, you agree to the storing of third-party cookies on your device to enhance your user experience and agree to the user terms and conditions of this learning management system (LMS).

Cookie Settings
Accept Terms & all Cookies