title: Increased proportion of mature NK cells is associated with successful imatinib discontinuation in chronic myeloid leukemia.
abstract: Recent studies suggest that a proportion of chronic myeloid leukemia (CML) patients in deep molecular remission can discontinue the tyrosine kinase inhibitor (TKI) treatment without disease relapse. In this multi-center, prospective clinical trial (EURO-SKI, NCT01596114) we analyzed the function and phenotype of T and NK cells and their relation to successful TKI cessation. Lymphocyte subclasses were measured from 100 imatinib-treated patients at baseline and 1 month after the discontinuation, and functional characterization of NK and T cells was done from 45 patients. The proportion of NK cells was associated with the molecular relapse-free survival as patients with higher than median NK-cell percentage at the time of drug discontinuation had better probability to stay in remission. Similar association was not found with T or B cells or their subsets. In non-relapsing patients the NK-cell phenotype was mature, whereas patients with more naïve CD56brightNK cells had decreased relapse-free survival. In addition, the TNF-α/IFN-γ cytokine secretion by NK cells correlated with the successful drug discontinuation. Our results highlight the role of NK cells in sustaining remission and strengthen the status of CML as an immunogenic tumor warranting novel clinical trials with immunomodulating agents.
authors.affiliation: Hematology Research Unit Helsinki, University of Helsinki and Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland.
authors.forename: M
authors.initials: M
authors.lastname: Ilander
authors.affiliation: Division of Hematology, Uppsala University Hospital, Uppsala, Sweden.|Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
authors.forename: U
authors.initials: U
authors.lastname: Olsson-Strömberg
authors.affiliation: Centre for Infectious Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.
authors.forename: H
authors.initials: H
authors.lastname: Schlums
authors.affiliation: Institut National de la Sante' et de la Recherche Medicale (INSERM), CHU de Poitiers, Poitiers, France.
authors.forename: J
authors.initials: J
authors.lastname: Guilhot
authors.affiliation: Hematology Research Unit Helsinki, University of Helsinki and Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland.
authors.forename: O
authors.initials: O
authors.lastname: Brück
authors.affiliation: Hematology Research Unit Helsinki, University of Helsinki and Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland.
authors.forename: H
authors.initials: H
authors.lastname: Lähteenmäki
authors.affiliation: Hematology Research Unit Helsinki, University of Helsinki and Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland.
authors.forename: T
authors.initials: T
authors.lastname: Kasanen
authors.affiliation: Hematology Research Unit Helsinki, University of Helsinki and Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland.
authors.forename: P
authors.initials: P
authors.lastname: Koskenvesa
authors.affiliation: Division of Hematology, Uppsala University Hospital, Uppsala, Sweden.
authors.forename: S
authors.initials: S
authors.lastname: Söderlund
authors.affiliation: Division of Hematology, Uppsala University Hospital, Uppsala, Sweden.
authors.forename: M
authors.initials: M
authors.lastname: Höglund
authors.affiliation: Department of Hematology, Umeå University Hospital, Umeå, Sweden.
authors.forename: B
authors.initials: B
authors.lastname: Markevärn
authors.affiliation: Department of Public Health and Clinical Medicine, Umeå University, Umeå, Sweden.
authors.forename: A
authors.initials: A
authors.lastname: Själander
authors.affiliation: Department of Hematology, Linköping University Hospital, Linköping, Sweden.
authors.forename: K
authors.initials: K
authors.lastname: Lotfi
authors.affiliation: Department of Hematology, Linköping University Hospital, Linköping, Sweden.
authors.forename: A
authors.initials: A
authors.lastname: Dreimane
authors.affiliation: Department of Hematology and Vascular Disorders, Skåne University Hospital, Lund, Sweden.
authors.forename: A
authors.initials: A
authors.lastname: Lübking
authors.affiliation: Department of Hematology and Vascular Disorders, Skåne University Hospital, Lund, Sweden.
authors.forename: E
authors.initials: E
authors.lastname: Holm
authors.affiliation: Department of Hematology, University Hospital, Örebro, Sweden.
authors.forename: M
authors.initials: M
authors.lastname: Björeman
authors.affiliation: Division of Hematology, Uppsala University Hospital, Uppsala, Sweden.|Department of Medical Sciences, Uppsala University, Uppsala, Sweden.|Department of Medicine, Division of Hematology, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: S
authors.initials: S
authors.lastname: Lehmann
authors.affiliation: Department of Medicine, Division of Hematology, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: L
authors.initials: L
authors.lastname: Stenke
authors.affiliation: Department of Medicine, Division of Hematology, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: L
authors.initials: L
authors.lastname: Ohm
authors.affiliation: Department of Hematology, Oslo University Hospital, Rikshospitalet, Oslo, Norway.
authors.forename: T
authors.initials: T
authors.lastname: Gedde-Dahl
authors.affiliation: Department of Hemato-oncology, Stavanger University hospital, Stavanger, Norway.
authors.forename: W
authors.initials: W
authors.lastname: Majeed
authors.affiliation: Department of Clinical Genetics, Skåne University Hospital, Lund, Sweden.
authors.forename: H
authors.identifier: 0000-0002-5589-3622
authors.initials: H
authors.lastname: Ehrencrona
authors.affiliation: Finnish Red Cross Blood Service, Research and Development, Helsinki, Finland.
authors.forename: S
authors.initials: S
authors.lastname: Koskela
authors.affiliation: III. Medizinische Klinik, Universitätsmedizin Mannheim, Universität Heidelberg, Mannheim, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Saussele
authors.affiliation: Inserm U1035, Université Bordeaux Segalen, Bordeaux, France.
authors.forename: F-X
authors.initials: FX
authors.lastname: Mahon
authors.affiliation: Hematology Research Unit Helsinki, University of Helsinki and Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland.
authors.forename: K
authors.initials: K
authors.lastname: Porkka
authors.affiliation: Department of Hematology, St Olavs University Hospital, Trondheim, Norway.
authors.forename: H
authors.initials: H
authors.lastname: Hjorth-Hansen
authors.affiliation: Centre for Infectious Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.
authors.forename: Y T
authors.initials: YT
authors.lastname: Bryceson
authors.affiliation: Department of Hematology and Vascular Disorders, Skåne University Hospital, Lund, Sweden.
authors.forename: J
authors.initials: J
authors.lastname: Richter
authors.affiliation: Hematology Research Unit Helsinki, University of Helsinki and Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland.|Department of Clinical Chemistry, University of Helsinki, Helsinki, Finland.
authors.forename: S
authors.initials: S
authors.lastname: Mustjoki
mesh_terms: D016022:Case-Control Studies; D016207:Cytokines / Q000378:metabolism; D000069439:Dasatinib / Q000627:therapeutic use; D018572:Disease-Free Survival; D006801:Humans; D000068877:Imatinib Mesylate / Q000627:therapeutic use*; D007694:Killer Cells, Natural / Q000166:cytology*; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000473:pathology; D018655:Lymphocyte Count; D016131:Lymphocyte Subsets / Q000166:cytology; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D011743:Pyrimidines / Q000627:therapeutic use; D028761:Withholding Treatment
chemical_list: D016207:Cytokines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D000068877:Imatinib Mesylate; C498826:nilotinib; D000069439:Dasatinib