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      Tyrosine Kinase Inhibitors and Interferon

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          Abstract

          The use of interferon-a (INF) in chronic myeloid leukemia, when it started in the 80s, was considered as a breakthrough in the therapy of this disease; INF administered alone or in combination with aracytin was the standard choice for treatment for Chronic Myeloid Leukemia (CML) patients unfit for bone marrow transplantation. With the appearance of the first Tyrosine Kinase Inhibitor (TKI) (imatinib) and based on the results of the pivotal IRIS trial, imatinib monotherapy was the new treatment of choice for CML, according to the ELN recommendations. The possibility of combining INF with imatinib, for obtaining better therapeutic responses in CML patients has been already tested and reported. The current challenge is the combined use of second generation TKIs with pegylated –IFN, in order to minimize failures to therapy and increase the number of CML patients with deep molecular responses, who may be able to discontinue lifelong treatment.

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          IFNalpha activates dormant haematopoietic stem cells in vivo.

          Marieke Essers, Sandra Offner, William E. Blanco-Bose … (2009)
          Maintenance of the blood system is dependent on dormant haematopoietic stem cells (HSCs) with long-term self-renewal capacity. After injury these cells are induced to proliferate to quickly re-establish homeostasis. The signalling molecules promoting the exit of HSCs out of the dormant stage remain largely unknown. Here we show that in response to treatment of mice with interferon-alpha (IFNalpha), HSCs efficiently exit G(0) and enter an active cell cycle. HSCs respond to IFNalpha treatment by the increased phosphorylation of STAT1 and PKB/Akt (also known as AKT1), the expression of IFNalpha target genes, and the upregulation of stem cell antigen-1 (Sca-1, also known as LY6A). HSCs lacking the IFNalpha/beta receptor (IFNAR), STAT1 (ref. 3) or Sca-1 (ref. 4) are insensitive to IFNalpha stimulation, demonstrating that STAT1 and Sca-1 mediate IFNalpha-induced HSC proliferation. Although dormant HSCs are resistant to the anti-proliferative chemotherapeutic agent 5-fluoro-uracil, HSCs pre-treated (primed) with IFNalpha and thus induced to proliferate are efficiently eliminated by 5-fluoro-uracil exposure in vivo. Conversely, HSCs chronically activated by IFNalpha are functionally compromised and are rapidly out-competed by non-activatable Ifnar(-/-) cells in competitive repopulation assays. Whereas chronic activation of the IFNalpha pathway in HSCs impairs their function, acute IFNalpha treatment promotes the proliferation of dormant HSCs in vivo. These data may help to clarify the so far unexplained clinical effects of IFNalpha on leukaemic cells, and raise the possibility for new applications of type I interferons to target cancer stem cells.
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            Dasatinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia.

            Hagop Kantarjian, Neil P. Shah, Andreas Hochhaus … (2010)
            Treatment with dasatinib, a highly potent BCR-ABL kinase inhibitor, has resulted in high rates of complete cytogenetic response and progression-free survival among patients with chronic myeloid leukemia (CML) in the chronic phase, after failure of imatinib treatment. We assessed the efficacy and safety of dasatinib, as compared with imatinib, for the first-line treatment of chronic-phase CML. In a multinational study, 519 patients with newly diagnosed chronic-phase CML were randomly assigned to receive dasatinib at a dose of 100 mg once daily (259 patients) or imatinib at a dose of 400 mg once daily (260 patients). The primary end point was complete cytogenetic response by 12 months, confirmed on two consecutive assessments at least 28 days apart. Secondary end points, including major molecular response, were tested at a significance level of 0.0001 to adjust for multiple comparisons. After a minimum follow-up of 12 months, the rate of confirmed complete cytogenetic response was higher with dasatinib than with imatinib (77% vs. 66%, P=0.007), as was the rate of complete cytogenetic response observed on at least one assessment (83% vs. 72%, P=0.001). The rate of major molecular response was higher with dasatinib than with imatinib (46% vs. 28%, P<0.0001), and responses were achieved in a shorter time with dasatinib (P<0.0001). Progression to the accelerated or blastic phase of CML occurred in 5 patients who were receiving dasatinib (1.9%) and in 9 patients who were receiving imatinib (3.5%). The safety profiles of the two treatments were similar. Dasatinib, administered once daily, as compared with imatinib, administered once daily, induced significantly higher and faster rates of complete cytogenetic response and major molecular response. Since achieving complete cytogenetic response within 12 months has been associated with better long-term, progression-free survival, dasatinib may improve the long-term outcomes among patients with newly diagnosed chronic-phase CML. (ClinicalTrials.gov number, NCT00481247.) 2010 Massachusetts Medical Society
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              Nilotinib versus imatinib for newly diagnosed chronic myeloid leukemia.

              Giuseppe Saglio, Dong-Wook Kim, Philipp le Coutre … (2010)
              Nilotinib has been shown to be a more potent inhibitor of BCR-ABL than imatinib. We evaluated the efficacy and safety of nilotinib, as compared with imatinib, in patients with newly diagnosed Philadelphia chromosome-positive chronic myeloid leukemia (CML) in the chronic phase. In this phase 3, randomized, open-label, multicenter study, we assigned 846 patients with chronic-phase Philadelphia chromosome-positive CML in a 1:1:1 ratio to receive nilotinib (at a dose of either 300 mg or 400 mg twice daily) or imatinib (at a dose of 400 mg once daily). The primary end point was the rate of major molecular response at 12 months. At 12 months, the rates of major molecular response for nilotinib (44% for the 300-mg dose and 43% for the 400-mg dose) were nearly twice that for imatinib (22%) (P<0.001 for both comparisons). The rates of complete cytogenetic response by 12 months were significantly higher for nilotinib (80% for the 300-mg dose and 78% for the 400-mg dose) than for imatinib (65%) (P<0.001 for both comparisons). Patients receiving either the 300-mg dose or the 400-mg dose of nilotinib twice daily had a significant improvement in the time to progression to the accelerated phase or blast crisis, as compared with those receiving imatinib (P=0.01 and P=0.004, respectively). No patient with progression to the accelerated phase or blast crisis had a major molecular response. Gastrointestinal and fluid-retention events were more frequent among patients receiving imatinib, whereas dermatologic events and headache were more frequent in those receiving nilotinib. Discontinuations due to aminotransferase and bilirubin elevations were low in all three study groups. Nilotinib at a dose of either 300 mg or 400 mg twice daily was superior to imatinib in patients with newly diagnosed chronic-phase Philadelphia chromosome-positive CML. (ClinicalTrials.gov number, NCT00471497.) 2010 Massachusetts Medical Society
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                Author and article information

                Journal
                Journal ID (nlm-ta): Mediterr J Hematol Infect Dis
                Journal ID (iso-abbrev): Mediterr J Hematol Infect Dis
                Journal ID (publisher-id): Mediterranean Journal of Hematology and Infectious Diseases
                Title: Mediterranean Journal of Hematology and Infectious Diseases
                Publisher: Università Cattolica del Sacro Cuore
                ISSN (Electronic): 2035-3006
                Publication date Collection: 2014
                Publication date (Electronic): 02 January 2014
                Volume: 6
                Issue: 1
                Electronic Location Identifier: e2014006
                Affiliations
                1 st Department of Propaedeutic Medicine, Division of Hematology, University of Athens, Greece.
                Author notes
                Correspondence to: Panagiotis Panayiotidis, Assoc. Professor in Hematology, 1 st Department of Propaedeutic Medicine, Division of Hematology, 3 rd floor, Laikon General Hospital of Athens, Agiou Thoma 17, Athens - 11526, Greece. Tel: +3 (0)210-7456181,+30(0)210-7462183. E-mail: ppanayi@ 123456med.uoa.gr
                Article
                Publisher ID: mjhid-6-1-e2014006
                DOI: 10.4084/MJHID.2014.006
                PMC ID: 3894836
                SO-VID: da93ddf9-5945-4485-be56-ac6dbff947a1
                Copyright statement: Copyright @ 2014
                License:

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                Date received : 20 November 2013
                Date accepted : 24 November 2013
                Categories
                Subject: Review Articles

                ScienceOpen disciplines: Infectious disease & Microbiology
                Data availability:
                ScienceOpen disciplines: Infectious disease & Microbiology

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