title: Chronic myeloid leukemia patients in prolonged remission following interferon-α monotherapy have distinct cytokine and oligoclonal lymphocyte profile.
abstract: Before the era of tyrosine kinase inhibitors (TKIs), interferon-alpha (IFN-α) was the treatment of choice in chronic myeloid leukemia (CML). Curiously, some IFN-α treated patients were able to discontinue therapy without disease progression. The aim of this project was to study the immunomodulatory effects of IFN-α in CML patients in prolonged remission and isolate biological markers predicting response. Due to rarity of patients on IFN-α monotherapy, a relatively small cohort of patients still on treatment (IFN-ON, n = 10, median therapy duration 11.8 years) or had discontinued IFN-α therapy but remained in remission for >2 years (IFN-OFF, n = 9) were studied. The lymphocyte immunophenotype was analyzed with a comprehensive flow cytometry panel and plasma cytokine levels were measured with multiplex bead-based assay. In addition, the clonality status of different lymphocyte subpopulations was analyzed by TCR γ/δ rearrangement assay. Median NK-cell absolute number and proportion from lymphocytes in blood was higher in IFN-OFF patients as compared to IFN-ON patients or controls (0.42, 0.19, 0.21×10(9)/L; 26%, 12%, 11%, respectively, p<0.001). The proportion of CD8+ T-cells was significantly increased in both patient groups and a larger proportion of T-cells expressed CD45RO. Most (95%) patients had significant numbers of oligoclonal lymphocytes characterized by T-cell receptor γ/δ rearrangements. Strikingly, in the majority of patients (79%) a distinct clonal Vγ9 gene rearrangement was observed residing in γδ(+) T-cell population. Similar unique clonality pattern was not observed in TKI treated CML patients. Plasma eotaxin and MCP-1 cytokines were significantly increased in IFN-OFF patients. Despite the limited number of patients, our data indicates that IFN-α treated CML patients in remission have increased numbers of NK-cells and clonal γδ(+) T-cells and a unique plasma cytokine profile. These factors may relate to anti-leukemic effects of IFN-α in this specific group of patients and account for prolonged therapy responses even after drug discontinuation.
authors.affiliation: Hematology Research Unit, Biomedicum Helsinki, Helsinki University Central Hospital, Helsinki, Finland.
authors.forename: Anna
authors.initials: A
authors.lastname: Kreutzman
authors.forename: Peter
authors.initials: P
authors.lastname: Rohon
authors.forename: Edgar
authors.initials: E
authors.lastname: Faber
authors.forename: Karel
authors.initials: K
authors.lastname: Indrak
authors.forename: Vesa
authors.initials: V
authors.lastname: Juvonen
authors.forename: Veli
authors.initials: V
authors.lastname: Kairisto
authors.forename: Jaroslava
authors.initials: J
authors.lastname: Voglová
authors.forename: Marjatta
authors.initials: M
authors.lastname: Sinisalo
authors.forename: Emília
authors.initials: E
authors.lastname: Flochová
authors.forename: Jukka
authors.initials: J
authors.lastname: Vakkila
authors.forename: Petteri
authors.initials: P
authors.lastname: Arstila
authors.forename: Kimmo
authors.initials: K
authors.lastname: Porkka
authors.forename: Satu
authors.initials: S
authors.lastname: Mustjoki
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D001483:Base Sequence; D017252:CD3 Complex / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism*; D005260:Female; D005434:Flow Cytometry; D015329:Gene Rearrangement, T-Lymphocyte / Q000235:genetics; D006801:Humans; D007155:Immunologic Factors / Q000627:therapeutic use; D016130:Immunophenotyping; D016898:Interferon-alpha / Q000627:therapeutic use*; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D017493:Leukocyte Common Antigens / Q000378:metabolism; D008214:Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D060888:Real-Time Polymerase Chain Reaction; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000235:genetics / Q000378:metabolism*; D012074:Remission Induction; D013997:Time Factors; D055815:Young Adult
chemical_list: D017252:CD3 Complex; D016207:Cytokines; D007155:Immunologic Factors; D016898:Interferon-alpha; D016692:Receptors, Antigen, T-Cell, gamma-delta; D017493:Leukocyte Common Antigens