Comprehensive molecular characterization of treatment-free remission and molecular relapse in chronic myeloid leukemia patients: the EURO-SKI Biomarker Study

Abstract The European Stop Kinase Inhibitors (EURO-SKI) trial was launched to investigate the discontinuation of tyrosine kinase inhibitors (TKIs) in patients with chronic myeloid leukemia (CML). The molecular mechanisms underlying sustained treatment-free remission (TFR) and loss of TFR, are still poorly understood. To address this, we performed whole transcriptome gene expression analyses coupled with NanoString nCounter-based absolute gene quantification. Gene expression was assessed in peripheral blood leukocytes from 240 CML patients on the final day of TKI intake (training sample: n = 122, validation sample: n = 118) as well as from 10 healthy controls. To identify TKI-specific mechanisms, transcriptomic data from an external dataset of 96 TKI-naïve CML patients was incorporated into our analyses. TFR patients showed an activation of GATA1, KLF1 and MYBL1 regulons characteristic for erythroid progenitor cells. TFR patients maintain persistent communication between innate (natural killer and dendritic cells) and adaptive immunity (e.g., CD8+, CD4+, and γδ T lymphocytes), mirroring patterns observed in healthy controls. This intercellular communication is disrupted in patients with loss of TFR. Furthermore, we identified an FLT3 threshold that distinguished two patient groups with significantly different probabilities of TFR loss. Leveraging mechanisms that reestablish or reinforce the communication between innate and adaptive immunity could be pivotal in achieving durable TFR.

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Journal
Leukemia
Published
2026-06-18
DOI
https://doi.org/10.1038/s41375-026-03001-5
Primary Topic
Chronic Myeloid Leukemia Treatments
Type
article
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article

Comprehensive molecular characterization of treatment-free remission and molecular relapse in chronic myeloid leukemia patients: the EURO-SKI Biomarker Study

Alice Fabarius, Susanne Saußele, Petr V. Nazarov, U. Olsson-Strömberg et al.
Leukemia
Chronic Myeloid Leukemia Treatments
article

Comprehensive molecular characterization of treatment-free remission and molecular relapse in chronic myeloid leukemia patients: the EURO-SKI Biomarker Study

Alice Fabarius, Susanne Saußele, Petr V. Nazarov, U. Olsson-Strömberg, Kourosh Lotfi, P. Panayiotidis, Sébastien Rinaldetti, Tim H. Brümmendorf, C. Hoelting, Daniel Nowak, Henrik Hjorth‐Hansen, Johan Richter, Maryna Chepeleva, Markus Pfirrmann, Carsten Sticht, Andreas Burchert, Per Ljungman, V. Nowak, Mahon Fx, Hofmann Wj, W. Majeed, L. Stenke, I. Tarnopolscaia, E. Felde, M. Muciek, N. von Bubnoff, A. Hedblom, T. Gedde-Dahl
article en

Abstract

Abstract The European Stop Kinase Inhibitors (EURO-SKI) trial was launched to investigate the discontinuation of tyrosine kinase inhibitors (TKIs) in patients with chronic myeloid leukemia (CML). The molecular mechanisms underlying sustained treatment-free remission (TFR) and loss of TFR, are still poorly understood. To address this, we performed whole transcriptome gene expression analyses coupled with NanoString nCounter-based absolute gene quantification. Gene expression was assessed in peripheral blood leukocytes from 240 CML patients on the final day of TKI intake (training sample: n = 122, validation sample: n = 118) as well as from 10 healthy controls. To identify TKI-specific mechanisms, transcriptomic data from an external dataset of 96 TKI-naïve CML patients was incorporated into our analyses. TFR patients showed an activation of GATA1, KLF1 and MYBL1 regulons characteristic for erythroid progenitor cells. TFR patients maintain persistent communication between innate (natural killer and dendritic cells) and adaptive immunity (e.g., CD8+, CD4+, and γδ T lymphocytes), mirroring patterns observed in healthy controls. This intercellular communication is disrupted in patients with loss of TFR. Furthermore, we identified an FLT3 threshold that distinguished two patient groups with significantly different probabilities of TFR loss. Leveraging mechanisms that reestablish or reinforce the communication between innate and adaptive immunity could be pivotal in achieving durable TFR.

Leukemia
Oslo University Hospital (NO), Karolinska University Hospital (SE), Uppsala University Hospital (SE), Université de Bordeaux (FR), Inserm (FR), Philipps University of Marburg (DE), Centre Hospitalier de Luxembourg (LU), University of Luxembourg (LU), Lund University (SE), National and Kapodistrian University of Athens (GR), Heidelberg University (DE), Stavanger University Hospital (NO), University Hospital Heidelberg (DE), Karolinska Institutet (SE), Institut für Medizinische Informatik, Biometrie und Epidemiologie (DE), Universitäres Kinderwunschzentrum Lübeck (DE), Luxembourg Institute of Health (LU), St Olav's University Hospital (NO), University Hospital Schleswig-Holstein (DE), Laiko General Hospital of Athens (GR), Universitätsklinikum Aachen (DE), Technical University of Applied Sciences Lübeck (DE), Institut Bergonié (FR), Linköping University Hospital (SE), University Medical Centre Mannheim (DE), Ludwig-Maximilians-Universität München (DE), RWTH Aachen University (DE), University of Lübeck (DE)
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Chronic Myeloid Leukemia Treatments
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