[Tyrosine kinase inhibitors in the therapy of chronic myeloid leukaemia].

Chronic myeloid leukemia (CML) is a malignant clonal disorder of hematopoietic stem cells resulting in increased myeloid and erythroid cells and platelets, and marked hyperplasia in the bone marrow. The natural history of CML is progression from a benign chronic phase, often through an accelerated phase, to a rapidly fatal blast crisis within 3-5 years. The constitutively activated ABL tyrosine kinase domain of the chimeric BCR-ABL oncoprotein is responsible for the transformation of hematopoietic stem cells and the symptoms of CML. Imatinib mesylate (Glivec), a specific small-molecule inhibitor of BCR-ABL, has become the standard drug therapy in all phases of the disease. Imatinib has greatly improved the outcome for patients with CML. Unfortunately, mutations causing resistance to imatinib are leading to relapse in some patients. Considerable progress has recently been made in understanding the structural biology of ABL and the molecular basis for resistance, facilitating the discovery and development of second- generation drugs designed to combat mutant forms of BCR-ABL. The first of these compounds to enter clinical development were dasatinib (BMS-354825) and AMN107 and, from phase I results, both of these promise a breakthrough in the treatment of imatinib-resistant CML.