title: Expression of the CTLA-4 ligand CD86 on plasmacytoid dendritic cells (pDC) predicts risk of disease recurrence after treatment discontinuation in CML.
abstract: It is unknown, why only a minority of chronic myeloid leukemia (CML) patients sustains treatment free remission (TFR) after discontinuation of tyrosine kinase inhibitor (TKI) therapy in deep molecular remission (MR). Here we studied, whether expression of the T-cell inhibitory receptor (CTLA-4)-ligand CD86 (B7.2) on plasmacytoid dendritic cells (pDC) affects relapse risk after TKI cessation. CML patients in MR displayed significantly higher CD86+pDC frequencies than normal donors (P<0.0024), whereas TFR patients had consistently low CD86+pDC (n=12). This suggested that low CD86+pDC might be predictive of TFR. Indeed, in a prospective analysis of 122 patients discontinuing their TKI within the EURO-SKI trial, the one-year relapse-free survival (RFS) was 30.1% (95% CI 15.6-47.9) for patients with >95 CD86+pDC per 105lymphocytes, but 70.0% (95% CI 59.3-78.3) for patients with <95 CD86+pDC (hazard ratio (HR) 3.4, 95%-CI: 1.9-6.0; P<0.0001). Moreover, only patients with <95 CD86+pDC derived a significant benefit from longer (>8 years) TKI exposure before discontinuation (HR 0.3, 95% CI 0.1-0.8; P=0.0263). High CD86+pDC counts significantly correlated with leukemia-specific CD8+T-cell exhaustion (Spearman correlation: 0.74, 95%-CI: 0.21-0.92; P=0.0098). Our data demonstrate that CML patients with high CD86+pDC counts have a higher risk of relapse after TKI discontinuation.
authors.affiliation: Department of Hematology, Oncology and Immunology, University Hospital Marburg, Marburg, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Schütz
authors.affiliation: Department of Hematology, Oncology and Immunology, University Hospital Marburg, Marburg, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Inselmann
authors.affiliation: III. Medizinische Klinik, Medizinische Fakultät Mannheim, University Heidelberg, Mannheim, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Saussele
authors.affiliation: III. Medizinische Klinik, Medizinische Fakultät Mannheim, University Heidelberg, Mannheim, Germany.
authors.forename: C T
authors.initials: CT
authors.lastname: Dietz
authors.affiliation: III. Medizinische Klinik, Medizinische Fakultät Mannheim, University Heidelberg, Mannheim, Germany.
authors.forename: M C
authors.initials: MC
authors.lastname: Mu Ller
authors.affiliation: Department of Hematology and Oncology, University Hospital Jena, Jena, Germany.
authors.forename: E
authors.initials: E
authors.lastname: Eigendorff
authors.affiliation: Department of Hematology, Oncology and Immunology, University Hospital Marburg, Marburg, Germany.
authors.forename: C A
authors.initials: CA
authors.lastname: Brendel
authors.affiliation: Department of Hematology, Oncology and Immunology, University Hospital Marburg, Marburg, Germany.
authors.forename: S K
authors.initials: SK
authors.lastname: Metzelder
authors.affiliation: Department of Hematology, Oncology, Hemostaseology, and Stem Cell Transplantation, RWTH Aachen University Hospital, Aachen, Germany.
authors.forename: T H
authors.initials: TH
authors.lastname: Bru Mmendorf
authors.affiliation: Department of Hematology and Oncology, University Hospital Freiburg.
authors.forename: C
authors.initials: C
authors.lastname: Waller
authors.affiliation: Onkologische Praxis Heilbronn, Heilbronn, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Dengler
authors.affiliation: Department of Hematology and Oncology, University Hospital Würzburg, Würzburg, Germany.
authors.forename: M E
authors.initials: ME
authors.lastname: Goebeler
authors.affiliation: Department of Hematology/Oncology, Klinikum Chemnitz, Chemnitz, Germany.
authors.forename: R
authors.initials: R
authors.lastname: Herbst
authors.affiliation: MVZ Klinikum Straubing GmbH, Straubing, Germany.
authors.forename: G
authors.initials: G
authors.lastname: Freunek
authors.affiliation: Klinikum Kempten-Oberallgäu GmbH, Kempten, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Hanzel
authors.affiliation: BAG Freiberg-Richter, Jacobasch, Wolf, Illmer, Dresden, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Illmer
authors.affiliation: Department of Hematology, Oncology and Immunology, University Hospital Marburg, Marburg, Germany.
authors.forename: Y
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Asklepios Klinikum Weißenfels, Weißenfels, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Lange
authors.affiliation: Center for Tumor and Immunbiology, University Marburg, Marburg, Germany.
authors.forename: F
authors.initials: F
authors.lastname: Finkernagel
authors.affiliation: III. Medizinische Klinik, Medizinische Fakultät Mannheim, University Heidelberg, Mannheim, Germany.
authors.forename: R
authors.initials: R
authors.lastname: Hehlmann
authors.affiliation: Institute for Medical Microbiology and Hospital Hygiene, University of Marburg, Biomedical Research Center (BMFZ), Marburg, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Huber
authors.affiliation: Department of Hematology, Oncology and Immunology, University Hospital Marburg, Marburg, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Neubauer
authors.affiliation: Department of Hematology and Oncology, University Hospital Jena, Jena, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Hochhaus
authors.affiliation: Clinical Investigation Center, Poitiers, France.
authors.forename: J
authors.initials: J
authors.lastname: Guilhot
authors.affiliation: Hematology Laboratory, CHU Bordeaux, Bordeaux, France.
authors.forename: F
authors.initials: F
authors.lastname: Xavier Mahon
authors.affiliation: Institut für Medizinische Informationsverarbeitung, Biometrie und Epidemiologie, Ludwig-Maximilians-Universität München, Munich, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Pfirrmann
authors.affiliation: Department of Hematology, Oncology and Immunology, University Hospital Marburg, Marburg, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Burchert
mesh_terms: D000328:Adult; D000368:Aged; D051940:B7-2 Antigen / Q000235:genetics / Q000378:metabolism*; D015415:Biomarkers; D060908:CTLA-4 Antigen / Q000378:metabolism*; D002452:Cell Count; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism*; D005260:Female; D015870:Gene Expression; D006801:Humans; D016130:Immunophenotyping; D053208:Kaplan-Meier Estimate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000175:diagnosis / Q000188:drug therapy / Q000378:metabolism* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D012008:Recurrence; D012074:Remission Induction; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D051940:B7-2 Antigen; D015415:Biomarkers; D060908:CTLA-4 Antigen; D047428:Protein Kinase Inhibitors