Standard management of patients with chronic myeloid leukemia

The successful introduction of the tyrosine kinase inhibitors (TKIs) has revolutionized the treatment of patients with chronic myeloid leukemia (CML). Imatinib therapy induces high rates of complete cytogenetic and major molecular responses, and improves survival in CML. Following imatinib treatment, more than 90% of patients obtain complete hematologic response, and over 80% achieve a complete cytogenetic response. With 7 years of follow-up, the results are still very favorable, resulting in a major change in the natural history of the disease. Resistance to imatinib represents a clinical challenge. Although some clinical and biologic features have been found to be associated with a lower probability of response to imatinib, at present no precise markers allowing for the prediction of outcome for individual patients exist. The most common mechanisms of resistance to imatinib include BCR-ABL kinase domain mutations, amplification, and overexpression of the BCR-ABL oncogene, and clonal evolution with activation of additional transformation pathways. These mechanisms are eventually caused by the genomic instability, which characterizes the Philadelphia chromosome-positive clone. Several approaches to overcome resistance have been proposed. The understanding of at least some of the mechanisms of resistance to imatinib has led to a rapid development of new therapeutic agents that might overcome this resistance. Novel targeted agents designed to overcome imatinib resistance include second-generation TKIs such as dasatinib, nilotinib, bosutinib, bafetinib, and others. Other approaches are exploring combination therapy, with agents affecting different oncogenic pathways, and immune modulation. Herein, we review some of these targeted therapies, particularly those for which clinical data are already available.