Chronic myeloid leukemia (CML) is characterized by the presence of the 
Philadelphia (Ph) chromosome, which results from a reciprocal translocation 
between the long arms of the chromosomes 9 and 22 t(9;22)(q34;q11). This 
translocation creates two new genes, BCR-ABL on the 22q- (Ph chromosome) and the 
reciprocal ABL-BCR on 9q-. The BCR-ABL gene encodes for a 210-kD protein with 
deregulated tyrosine kinase (TK) activity, which is crucial for malignant 
transformation in CML. The recognition of the BCR-ABL gene and corresponding 
protein led to the synthesis of small-molecule drugs, designed to interfere with 
BCR-ABL tyrosine kinase activation by competitive binding at the ATP-binding 
site. The first tyrosine kinase inhibitor (TKI), introduced into clinical 
practice in 1998, was imatinib mesylate. Imatinib became the first choice drug 
in chronic phase CML, because of its high efficacy, low toxicity and ability to 
maintain durable hematological and cytogenetic responses. However, approximately 
20-25% of patients initially treated with imatinib will need alternative 
therapy, due to drug resistance, which is often caused by the appearance of 
clones expressing mutant forms of BCR-ABL. Second-generation TKIs have provided 
new therapeutic option for the patients resistant to imatinib. Dasatinib is the 
first, second-generation TKI, approved in the US and European Union for the 
treatment of CML patients with imatinib resistance or intolerance. This drug is 
a dual SRC-ABL kinase inhibitor, active in most clinically relevant BCR-ABL 
mutations, except highly resistant T315I. Other second-generation TKIs include 
nilotinib, bosutinib and INNO 406. Apart from TKIs, the promising group of 
molecules is inhibitors of Aurora family of serine-threonine kinases. One of 
these molecules, MK0457, has entered clinical trials, and initial reports 
indicate that this compound could be active in disease associated with T315I 
mutation. Thus, wide spectrum of new agents, with different mode of action, is 
currently in clinical development for CML. It is likely that combination therapy 
will be the best therapeutic strategy in the future.