Tyrosine kinase inhibitors: the first decade.

Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Current Hematologic Malignancy Reports 04/2010; 5(2):70-80. DOI: 10.1007/s11899-010-0045-y
Source: PubMed

ABSTRACT The treatment of chronic myeloid leukemia (CML) drastically changed with the introduction of imatinib mesylate, a Bcr-Abl1 tyrosine kinase inhibitor (TKI), in 1998. By directly targeting this leukemogenic protein kinase, imatinib affords patients with CML sustained chromosomal remissions, which translate into prolonged survival. However, there has been concern over the emergence of resistance to imatinib, and some patients fail to respond or are intolerant of imatinib therapy because of untoward toxicity. This has spurred interest in developing novel TKIs to overcome the mechanisms of resistance that lead to treatment failure-most importantly, Bcr-Abl1 kinase domain mutations. Two of these second-generation TKIs, nilotinib and dasatinib, are approved worldwide for the treatment of CML after imatinib failure or intolerance. Although these agents are active, they fail in many patients because of the development of highly resistant mutations such as the T315I, against which several novel agents are currently being tested in clinical trials. This review provides an account of the progress made in the field of TKI therapy for CML over the past decade.

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    ABSTRACT: Tyrosine kinase inhibitors (TKIs) have dramatically improved the outcome of chronic myeloid leukemia (CML). Even though TKI therapy does not necessarily eliminate all leukemic cells, a small proportion of CML patients is able to discontinue the treatment successfully and be considered cured. Besides inhibiting the actual target BCR-ABL1 kinase in leukemic cells, TKIs inhibit several off-target kinases in normal healthy cells, such as lymphocytes. To date, little is known about the long-term in vivo effects of TKI treatment on the function of the immune system. However, constantly growing evidence suggests that some TKIs have a dual-mode of action; the direct cytotoxic effects induced by oncokinase inhibition are accompanied by the activation of immune system 2 , which is potentially relevant for the long-term control of CML. In this review, we have summarized the reported immunomodulatory effects of the three TKIs, which currently are accepted for first-line use in CML (imatinib, dasatinib and nilotinib). Understanding the mechanisms of TKI-induced functional cure and the role of immune system in this process will hopefully not only benefit CML patients, but also patients with other malignant diseases in the future.
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