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Chronic myeloid leukemia patients in prolonged remission following interferon-? monotherapy have distinct cytokine and oligoclonal lymphocyte profile.

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

SUBMITTER: Kreutzman A

PROVIDER: S-EPMC3153480 | biostudies-literature | 2011

REPOSITORIES: biostudies-literature

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Chronic myeloid leukemia patients in prolonged remission following interferon-α monotherapy have distinct cytokine and oligoclonal lymphocyte profile.

Kreutzman Anna A Rohon Peter P Faber Edgar E Indrak Karel K Juvonen Vesa V Kairisto Veli V Voglová Jaroslava J Sinisalo Marjatta M Flochová Emília E Vakkila Jukka J Arstila Petteri P Porkka Kimmo K Mustjoki Satu S

PloS one 20110809 8

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 ...[more]

PMID: 21857985

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Project description:Chronic myeloid leukemia (CML) is a hematological cancer, characterized by a reciprocal chromosomal translocation between chromosomes 9 and 22 [t(9;22)], producing the Bcr-Abl oncogene. Tyrosine kinase inhibitors (TKIs) represent the standard of care for CML patients and exert a dual mode of action: direct oncokinase inhibition and restoration of effector-mediated immune surveillance, which is rendered dysfunctional in CML patients at diagnosis, prior to TKI therapy. TKIs such as imatinib, and more potent second-generation nilotinib and dasatinib induce a high rate of deep molecular response (DMR, BCR-ABL1 ≤ 0.01%) in CML patients. As a result, the more recent goal of therapy in CML treatment is to induce a durable DMR as a prelude to successful treatment-free remission (TFR), which occurs in approximately half of all CML patients who cease TKI therapy. The lack of overt relapse in such patients has been attributed to immunological control of CML. In this review, we discuss an immunological timeline to successful TFR, focusing on the immunology of CML during TKI treatment; an initial period of immune suppression, limiting antitumor immune effector responses in newly diagnosed CML patients, linked to an expansion of immature myeloid-derived suppressor cells and regulatory T cells and aberrant expression of immune checkpoint signaling pathways, including programmed death-1/programmed death ligand-1. Commencement of TKI treatment is associated with immune system re-activation and restoration of effector-mediated [natural killer (NK) cell and T cell] immune surveillance in CML patients, albeit with differing frequencies in concert with differing levels of molecular response achieved on TKI. DMR is associated with maximal restoration of immune recovery in CML patients on TKI. Current data suggest a net balance between both the effector and suppressor arms of the immune system, at a minimum involving mature, cytotoxic CD56dim NK cells may be important in mediating TFR success. However, a major goal remains in CML to identify the most effective pathways to target to maximize an advantageous immune response and promote TFR success.

Dataset Information

Chronic myeloid leukemia patients in prolonged remission following interferon-? monotherapy have distinct cytokine and oligoclonal lymphocyte profile.

Publications

Chronic myeloid leukemia patients in prolonged remission following interferon-α monotherapy have distinct cytokine and oligoclonal lymphocyte profile.

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