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Arch Hellen Med, 21(4), July-August 2004, 325-335


Tyrosine kinase inhibitor –
a new targeted therapy for chronic myeloid leukemia

2nd Propedeutic Clinic of Internal Medicine, Aristotle University of Thessaloniki,
“Ippokration” General Hospital, Thessaloniki, Greece

The treatment of patients with Ph(+) or BCR-ABL(+) chronic myeloid leukemia (CML) did not improve very greatly in the 1990s. It is now widely accepted that patients treated by allogeneic stem cell transplantation may be cured, but only a minority of CML patients are eligible for this procedure and the risks for morbidity and mortality directly attributable to the procedure remain appreciable. The majority of patients have hitherto been treated with hydroxyurea, interferon-α or interferon-α + cytarabine; with these approaches the median survival is about 6 years and none can be regarded as curative. The recent introduction of imatinib (imatinib mesylate, Glivec, formerly STI571) appears to constitute a major advance in the treatment of CML. The new molecule was found to inhibit the BCR-ABL tyrosine kinase activity, which represents the main pathogenetic mechanism in CML. The BCR-ABL gene is the chimeric gene produced by the t(9;22) translocation in CML and it encodes a protein with deregulated tyrosine kinase activity that is known to induce leukemia, deregulating signal transduction pathways and causing abnormal cell cycling, inhibition of apoptosis and increased proliferation of cells. Imatinib occupies the kinase pocket of the BCR-ABL protein and blocks access to ATP, thereby preventing phosphorylation of any substrate. The new agent has proved very effective in the treatment of CML patients, producing remarkable clinical benefits and very high grades of complete or major cytogenetic response. Although it is early to be sure, it is believed that this can be translated into better results in survival and disease progression. Imatinib now seems to be the initial treatment of choice for patients with CML, at least for those who are not candidates for transplantation. The incorporation of this drug in the treatment of young patients with a suitable bone marrow donor is a great challenge. As relapses using single agent imatinib have occurred, though infrequently, particularly in advanced phase patients with CML, the issue of whether its combination with other antileukemic agents may yield improved results is addressed.

Key words: Chronic myeloid leukemia, Imatinib, Tyrosine kinase.

© Archives of Hellenic Medicine