Principles and Current Topics Concerning Management of Tyrosine Kinase Inhibitor Therapy for Chronic Myelogenous Leukemia

Abstract

Chronic myeloid leukemia (CML) is a chronic myeloproliferative disorder with leukemic cells featuring the Philadelphia (Ph1) chromosome comprising the reciprocal chromosomal translocation t(9;22)(q34;q22) and the resultant constitutive active Bcr-Abl tyrosine kinase (TK). The introduction of disease-specific molecular targeted agents, that is, TK inhibitors (TKIs) for Bcr-Abl TK, such as the first-in-class TKI imatinib mesylate (IM) or the secondgeneration TKIs (SGIs) nilotinib and dasatinib, has dramatically improved the long-term treatment outcome for CML in this century. In addition, several new SGIs, such as bosutinib or bafetinib, are under development, while ponatinib, which is active against CML refractory for all preceding TKIs, for example, CML with T315I Abl kinase domain mutation, is currently being evaluated in clinical trials. Because those TKIs have different sensitivity for BcrAbl mutation and profiles for adverse effects, a thorough understanding of the pharmacologic characteristics of TKIs is mandatory for their safe and effective clinical use. Recent studies have clearly shown the faster and deeper responses to SGIs, both nilotinib and dasatinib, compared with those to IM, indicating the need for a paradigm shift in approaches to TKI therapy for treatment-naïve CML. In addition, evidence accumulated during the past decade has indicated optimal methodologies for monitoring the treatment effect of TKIs, selecting the appropriate therapeutic strategies, and predicting the outcome for treatment with TKIs for individual patients with CML. In this article, we review the principles and current knowledge and topics of the various uses of TKIs for CML. We also touch upon the reason why the faster and the deeper responses to TKIs is the prerequisite for their safer use and longer-lasting positive treatment outcome for CML.