Chronic myeloid leukemia (CML) results from the clonal expansion of pluripotent hematopoietic stem cells containing the active BCR/ABL fusion gene produced by a reciprocal translocation of the ABL1 gene to the BCR gene. The BCR/ABL protein displays a constitutive tyrosine kinase activity and confers on leukemic cells growth and proliferation advantage and resistance to apoptosis. Introduction of imatinib (IM) and other tyrosine kinase inhibitors (TKIs) has radically improved the outcome of patients with CML and some other diseases with BCR/ABL expression. However, a fraction of CML patients presents with resistance to this drug. Regardless of clinical profits of IM, there are several drawbacks associated with its use, including lack of eradication of the malignant clone and increasing relapse rate resulting from long-term therapy, resistance, and intolerance. Second and third generations of TKIs have been developed to break IM resistance. Clinical studies revealed that the introduction of second-generation TKIs has improved the overall survival of CML patients; however, some with specific mutations such as T315I remain resistant. Second-generation TKIs may completely replace imatinib in perspective CML therapy, and addition of third-generation inhibitors may overcome resistance induced by every form of point mutations. 1. Introduction Chronic myeloid leukemia (CML) was a fatal disorder until the introduction of imatinib (IM, also known as STI571, Gleevec, Glivec), which revolutionized its therapy, changing CML into a chronic disease. This was the advent of the “imatinib era.” IM is a model drug of targeted cancer therapy, in which only cancer phenotype, associated with BCR/ABL enhanced tyrosine kinase activity, was affected and normal features were unchanged. This gave new hope for avoidance of unwanted side effects, which are usually associated with the use of chemotherapeutic drugs. However, some patients do not tolerate IM and some display resistance to it, resulting in increasing doses of the drug associated with its increased toxicity. To fight IM resistance several other tyrosine kinase inhibitors have been worked out, but soon it became clear that they have several advantages over IM and may completely replace it in CML therapy. 2. Chronic Myeloid Leukemia: pathogenesis and Treatment CML is characterized by the expansion of bone marrow CML stem cell progeny. In 1960 Rudkin et al. detected a consistent chromosomal abnormality characteristic of CML, which later was named as the Philadelphia (Ph) chromosome [1, 2]. The Ph chromosome results from a
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