Standard treatment of Ph+ CML in 2010: how, when and where not to use what BCR/ABL1 kinase inhibitor?

Abstract

Chronic myeloid leukaemia (CML) is a haematopoietic neoplasm characterised by the BCR/ABL1 oncoprotein. In chronic phase CML, the neoplastic clone exhibits multilineage differentiation and maturation capacity. The BCR/ABL1 kinase blocker imatinib shows major antileukaemic effects in most patients and is considered standard frontline therapy. However, not all patients have a long-lasting response to imatinib. Notably, resistance to imatinib has been recognised as an emerging problem and challenge in CML. Whereas CML stem cells are considered to exhibit intrinsic resistance, acquired resistance may, in addition, develop in subclones over time, resulting in an overt relapse. A key trigger of resistance in subclones are BCR/ABL1 mutations. For such patients, novel multikinase inhibitors such as nilotinib, dasatinib, bosutinib or bafetinib, which block the kinase activity of various BCR/ABL1 mutants, have been developed and reportedly exert antileukaemic effects in drug-resistant cells. For highly resistant patients, haematopoietic stem cell transplantation is an alternative option. Treatment decisions and the selection of drugs are based on the presence and type of BCR/ABL1 mutation(s), phase of disease, other disease-related variables and patient-related factors including age, compliance and co-morbidity. The current review provides an overview on standards in the diagnosis and therapy in CML, with special reference to novel BCR/ABL1 inhibitors.