Management of Chronic Myeloid Leukemia with BCR/ABL Inhibitors: Current Status and Future Perspectives

Chronic myeloid leukemia (CML) is a hematopoietic neoplasm characterized by the Philadelphia chromosome (Ph) and the BCR/ABL oncoprotein. In chronic phase (CP) CML, leukemic cells display multilineage differentiation and maturation capacity. The BCR/ABL inhibitor imatinib exerts profound antileukemic effects in these patients and is considered standard frontline therapy. However, not all patients show a long-lasting response to this drug. Rather, resistance to imatinib has been recognized as an emerging clinical problem in CML. While CML stem cells exhibit intrinsic resistance against imatinib and thus survive therapy, one or more stem cell-derived subclones may acquire additional hits over time, so that an overt relapse occurs. A major triggering hit in such subclones are BCR/ABL mutations. For these patients, novel multikinase inhibitors targeting BCR/ABL such as nilotinib, dasatinib, bosutinib, bafetinib, as well as Aurora kinase inhibitors have been developed and shown to exert antileukemic effects in imatinib-resistant CML. In addition, hematopoietic stem cell transplantation (HSCT) remains an important treatment option for drug-resistant patients. The decision concerning second- or third line therapy, selection of drugs, and HSCT, is usually based on the presence and type of BCR/ABL mutation(s), phase of disease, other disease-related factors, and patient-related variables including age and co-morbidity. The current article provides an overview on current diagnostic and therapeutic strategies for patients with drug-naive and drug-resistant CML.