Although
imatinib remains the gold standard for first-line treatment of
chronic myeloid leukemia (CML), increasing recognition of
imatinib resistance and intolerance has led to the development of additional
tyrosine kinase inhibitors (TKIs), which have demonstrated effectiveness as
salvage therapies or alternative first-line treatments. Although additional options represent progress, the availability of 3 second-generation TKIs (
dasatinib,
nilotinib, and
bosutinib) and 1 third-generation TKI (
ponatinib) has added complexity to the treatment paradigm for CML, particularly CML in the chronic phase. Two second-generation agents (
dasatinib and
nilotinib) are approved for use as first-line and subsequent
therapy. Thus, the appropriate sequencing of TKIs is a frequent quandary, and is incompletely addressed in clinical guidelines. Here, we review studies that might guide selection of a second- or third-generation TKI after failure of TKI
therapy in patients with chronic-phase CML. These studies evaluate prognostic factors such as first-line cytogenetic response and BCR-ABL1 mutation status, which might help physicians identify patients who are likely to respond to second-generation TKIs, and those for whom
ponatinib or an investigational agent might be more appropriate. We summarize evidence to date that suggests that use of a second-generation TKI as third-line
therapy confers limited value in most CML patients, and we also explore the utility of current event-free survival versus traditional outcomes to predict long-term benefits of sequential TKI use. Finally, we present 3 case studies to illustrate how prognostic factors and other considerations (eg, tolerability) can be used to individualize subsequent
therapy in cases of TKI resistance or intolerance.