[Tyrosine kinase inhibitors for the treatment of CML]

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.