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Clinical use of tyrosine kinase inhibitors for chronic myeloid leukemia

Robert S Negrin, MD
Charles A Schiffer, MD
Section Editor
Richard A Larson, MD
Deputy Editor
Alan G Rosmarin, MD


Chronic myeloid leukemia (CML) is a myeloproliferative disorder associated with the Philadelphia chromosome t(9;22)(q34;q11) resulting in the BCR-ABL1 fusion gene. This genetic abnormality results in the formation of a unique gene product (Bcr-Abl1), a constitutively active tyrosine kinase that produces a continued proliferative signal resulting in the clinical manifestations of CML.

Once this mechanism was understood, efforts were aimed at developing compounds that could selectively inhibit the aberrant tyrosine kinase resulting from this molecular rearrangement. Imatinib mesylate (previously CFP-57148 or STI-571) was the first of these to be used in the treatment of CML. Since then, several other tyrosine kinase inhibitors (TKIs) have been developed and tested in patients with CML, most notably dasatinib (BMS-354825, Sprycel) and nilotinib (AMN 107,Tasigna). TKIs have become the initial treatment of choice for most patients with CML.

This topic will review the clinical use of TKIs for the treatment of CML. The mechanisms of action and resistance will be discussed along with practical information about dosing, drug interactions, and management of side effects. The treatment options for chronic myeloid leukemia at various phases of disease and monitoring of disease are discussed separately. (See "Overview of the treatment of chronic myeloid leukemia" and "Initial treatment of chronic myeloid leukemia in chronic phase" and "Treatment of chronic myeloid leukemia in accelerated phase" and "Treatment of chronic myeloid leukemia in blast crisis".)

Imatinib also inhibits c-kit and platelet-derived growth factor receptor (PDGFR), and has been successfully employed in other malignancies in which these kinases are mutated. This is discussed separately. (See "Tyrosine kinase inhibitor therapy for advanced gastrointestinal stromal tumors" and "Hypereosinophilic syndromes: Treatment" and "Dermatofibrosarcoma protuberans: Treatment", section on 'Treatment of locally advanced, recurrent, and metastatic disease'.)


Tyrosine kinase inhibitors (TKIs) block the initiation of the Bcr-Abl1 pathway [1-6]. As described below, many of the TKIs also affect other signaling pathways. These differences in targeted pathways may be responsible for their varied clinical effects in tumors with different mechanisms of resistance to imatinib.


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