The introduction of the tyrosine kinase inhibitors (TKIs) imatinib, dasatinib, and nilotinib has dramatically improved the treatment of chronic myeloid leukemia (CML). However, a minority of CML patients in chronic phase (CP) and a substantial proportion of patients in advanced phase are either initially refractory to TKIs or eventually develop resistance. Rates of resistance and relapse directly correlate with disease progression. The most frequently identified mechanism of acquired TKI resistance is BCR-ABL1 kinase domain (KD) mutations that impair TKI binding by disrupting the drug contact sites or causing conformational changes that make the contact sites inaccessible. The underlying mechanisms of disease progression are heterogeneous and only poorly understood. So far the most frequent and best characterized include genomic instability, loss of tumor-suppressor functions, and differentiation arrest. Clinical data indicate that both development of a BCR-ABL1 KD mutation during TKI treatment and/or disease progression are associated with a poorer outcome. Thus, therapeutic strategies are needed for the treatment or prevention of resistance and disease progression. They include, for example, TKI dose escalation, treatment interruption to stop selection of resistant cells, and allogeneic stem cell transplantation in eligible patients, as well as the use of novel TKIs with activity against resistant mutations and/or inhibition of alternative pathways.
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