Chronic myelogenous leukemia is characterized by the Philadelphia-chromosome, a 
shortened chromosome 22 which is the result of a reciprocal translocation 
between chromosome 9 and 22. The fusion gene is called BCR-ABL. After 
transcription and translation the constitutively activated p210 BCR-ABL 
oncoprotein is formed. This leads to uncontrolled activation of the ABL tyrosin 
kinase. Deregulated cellular proliferation and diminished apoptosis of BCR-ABL 
transformed cells is the result. Expression of the BCR-ABL oncoprotein is 
sufficient and necessary for the development of a CML phenotype. Imatinib 
mesylate (Glivec) is a small molecule that binds to the ATP pocket of ABL and 
blocks downstream signalling events. Imatinib is very effective in the treatment 
of CML in all stages of the disease. Patients with newly diagnosed chronic phase 
CML were randomized to imatinib or to interferon plus cytarabine in the IRIS 
trial. Imatinib showed significantly superior tolerability, hematologic and 
cytogenetic resposes and increased time to progression. In patients with 
advanced phase CML, imatinib is less effective and response duration is short. 
Median overall survival of blast crisis patients is 6.9 months only. Additional 
BCR-ABL independent chromosomal abnormalities are common in advanced phase CML 
and result in resistance to imatinib. BCR-ABL kinase-domaine mutations are 
frequently found in imatinib resistant patients and confer diminished 
sensitivity to imatinib. Second generation, more powerful ABL kinase inhibitors, 
which are effective against most of the known mutations are currently tested in 
clinical trials.