title: Assessment of bone marrow lymphocytic status during tyrosine kinase inhibitor therapy and its relation to therapy response in chronic myeloid leukaemia.
abstract: OBJECTIVE
  Tyrosine kinase inhibitors (TKIs) used in the treatment of chronic myeloid leukaemia have been reported to induce immunomodulatory effects. We aimed to assess peripheral blood (PB) and bone marrow (BM) lymphocyte status at the diagnosis and during different TKI therapies and correlate it with treatment responses.
  
  
  METHODS
  BM and PB samples were acquired from 105 first-line TKI-treated patients. Relative number of BM lymphocytes was evaluated from MGG-stained BM aspirates, and immunophenotypic analyses were performed with multicolour flow cytometry.
  
  
  RESULTS
  Early 3-month expansion of BM lymphocytes was found during all different TKIs (imatinib n = 71, 20 %; dasatinib n = 25, 21 %; nilotinib n = 9, 22 %; healthy controls n = 14, 12 %, p < 0.0001). Increased PB lymphocyte count was only observed during dasatinib therapy. The BM lymphocyte expansion was associated with early molecular response; patients with 3-month BCR-ABL1 <10 % showed higher lymphocyte counts than patients with BCR-ABL1 >10 % (23 vs. 17 %, p < 0.05). Detailed phenotypic analysis showed that BM lymphocyte expansion consisted of various lymphocyte subclasses, but especially the proportion of CD19+ B cells and CD3negCD16/56+ NK cells increased from diagnostic values. During dasatinib treatment, the lymphocyte balance in both BM and PB was shifted more to cytotoxic direction (increased CD8+CD57+ and CD8+HLA-DR+ cells, and low T regulatory cells), whereas no major immunophenotypic differences were observed between imatinib and nilotinib patients.
  
  
  CONCLUSIONS
  Early BM lymphocytosis occurs with all current first-line TKIs and is associated with better treatment responses. PB and BM immunoprofile during dasatinib treatment markedly differs from both imatinib- and nilotinib-treated patients.
authors.affiliation: Hematology Research Unit Helsinki, Department of Hematology, University of Helsinki and Helsinki University Central Hospital Comprehensive Cancer Center, Haartmaninkatu 8, P.O. Box 700, 00290, Helsinki, Finland.
authors.forename: Mohamed
authors.initials: M
authors.lastname: El Missiry
authors.affiliation: Hematology Research Unit Helsinki, Department of Hematology, University of Helsinki and Helsinki University Central Hospital Comprehensive Cancer Center, Haartmaninkatu 8, P.O. Box 700, 00290, Helsinki, Finland.
authors.forename: Shady
authors.initials: S
authors.lastname: Adnan Awad
authors.affiliation: Hematology Research Unit Helsinki, Department of Hematology, University of Helsinki and Helsinki University Central Hospital Comprehensive Cancer Center, Haartmaninkatu 8, P.O. Box 700, 00290, Helsinki, Finland.
authors.forename: Hanna L
authors.initials: HL
authors.lastname: Rajala
authors.affiliation: Institute of Clinical Medicine, University of Helsinki, Helsinki, Finland.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Al-Samadi
authors.affiliation: Skåne University Hospital, Lund, Sweden.
authors.forename: Marja
authors.initials: M
authors.lastname: Ekblom
authors.affiliation: Department of Hematology, Umeå University Hospital, Umeå, Sweden.
authors.forename: Berit
authors.initials: B
authors.lastname: Markevän
authors.affiliation: Skåne University Hospital, Lund, Sweden.
authors.forename: Ingbritt
authors.initials: I
authors.lastname: Åstrand-Grundström
authors.affiliation: Department of Hematology, St Olavs Hospital, Norwegian University of Science and Technology (NTNU), Trondheim, Norway.
authors.forename: Maren
authors.initials: M
authors.lastname: Wold
authors.affiliation: Department of Hematology, St Olavs Hospital, Norwegian University of Science and Technology (NTNU), Trondheim, Norway.
authors.forename: Ellen Rabben
authors.initials: ER
authors.lastname: Svedahl
authors.affiliation: Department of Pathology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Birgitte Ravn
authors.initials: BR
authors.lastname: Juhl
authors.affiliation: Department of Hematology, Rigshospitalet, University Hospital of Copenhagen, Copenhagen, Denmark.
authors.forename: Ole Weis
authors.initials: OW
authors.lastname: Bjerrum
authors.affiliation: Department of Pathology, Uppsala University Hospital, Uppsala, Sweden.
authors.forename: Inger
authors.initials: I
authors.lastname: Haulin
authors.affiliation: Hematology Research Unit Helsinki, Department of Hematology, University of Helsinki and Helsinki University Central Hospital Comprehensive Cancer Center, Haartmaninkatu 8, P.O. Box 700, 00290, Helsinki, Finland.
authors.forename: Kimmo
authors.initials: K
authors.lastname: Porkka
authors.affiliation: Department of Hematology, Uppsala University Hospital, Uppsala, Sweden.|Department of Clinical Chemistry, University of Helsinki, Helsinki, Finland.
authors.forename: Ulla
authors.initials: U
authors.lastname: Olsson-Strömberg
authors.affiliation: Department of Hematology, St Olavs Hospital, Norwegian University of Science and Technology (NTNU), Trondheim, Norway.
authors.forename: Henrik
authors.initials: H
authors.lastname: Hjorth-Hansen
authors.affiliation: Hematology Research Unit Helsinki, Department of Hematology, University of Helsinki and Helsinki University Central Hospital Comprehensive Cancer Center, Haartmaninkatu 8, P.O. Box 700, 00290, Helsinki, Finland. satu.mustjoki@helsinki.fi.|Department of Clinical Chemistry, University of Helsinki, Helsinki, Finland. satu.mustjoki@helsinki.fi.
authors.forename: Satu
authors.initials: S
authors.lastname: Mustjoki
mesh_terms: D001853:Bone Marrow / Q000187:drug effects / Q000276:immunology / Q000473:pathology*; D020732:Cytogenetic Analysis; D003602:Cytotoxicity, Immunologic; D000069439:Dasatinib / Q000627:therapeutic use; D005434:Flow Cytometry; D006801:Humans; D007107:Immune System / Q000187:drug effects / Q000276:immunology / Q000473:pathology*; D016130:Immunophenotyping; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000276:immunology / Q000473:pathology*; D008214:Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000473:pathology*; D010641:Phenotype; D011379:Prognosis; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*
chemical_list: D047428:Protein Kinase Inhibitors; D011505:Protein-Tyrosine Kinases; D000069439:Dasatinib
keywords: Bone marrow; CML; Lymphocyte; Therapy response; Tyrosine kinase inhibitor