Chronic Myeloid Leukemia Patients in Prolonged Remission following Interferon-α Monotherapy Have Distinct Cytokine and Oligoclonal Lymphocyte Profile

Before the era of tyrosine kinase inhibitors (TKIs), interferon-alpha (IFN-alpha) was the treatment of choice in chronic myeloid leukemia (CML). Curiously, some IFN-alpha treated patients were able to discontinue therapy without disease progression. The aim of this project was to study the immunomodulatory effects of IFN-alpha in CML patients in prolonged remission and isolate biological markers predicting response. Due to rarity of patients on IFN-alpha monotherapy, a relatively small cohort of patients still on treatment (IFN-ON, n = 10, median therapy duration 11.8 years) or had discontinued IFN-alpha 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 gamma/delta 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, 0.21x10(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 gamma/delta rearrangements. Strikingly, in the majority of patients (79%) a distinct clonal V gamma 9 gene rearrangement was observed residing in gamma delta(+) 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-alpha treated CML patients in remission have increased numbers of NK-cells and clonal gamma delta(+) T-cells and a unique plasma cytokine profile. These factors may relate to anti-leukemic effects of IFN-alpha in this specific group of patients and account for prolonged therapy responses even after drug discontinuation.