In CML, Future Directions Include TKI Sequencing Strategies and Mutational Profiles

The management of chronic myeloid leukemia (CML) marks a major milestone with the 25th anniversary of the approval of imatinib, the first targeted therapy in oncology, according to Daniel DeAngelo, MD, PhD, of Dana-Farber Cancer Institute. Before targeted tyrosine kinase inhibitors (TKIs), allogeneic stem cell transplantation was the sole curative option, curing roughly 70% of patients but carrying substantial treatment-related morbidity and mortality. Today, newly diagnosed patients with CML enjoy a life expectancy equivalent to that of the general population, representing a functional cure achieved primarily through oral targeted agents.

A key development in modern CML care is the growing achievement of treatment-free remission (TFR). Approximately 25% to 30% of patients who achieve deep, sustained molecular responses can safely discontinue TKI therapy without disease relapse, which DeAngelo says was an outcome unimagined when targeted agents were first introduced.

With 6 currently approved TKIs to treat CML in the US, clinical focus has shifted toward personalized drug selection and optimal sequencing. DeAngelo says that TKI selection is tailored to individual patient profiles, mitigating distinct cardiovascular, gastrointestinal, or pulmonary toxicities. Genomic profiling identifies specific secondary mutations such as BCR::ABL1 fusions, which can guide the transition other TKIs or STAMP inhibitors meant to target the resistance. Newer agents continue to demonstrate enhanced potency and superior safety profiles, further refining long-term disease control.

Although frontline and chronic-phase management have been largely solved, DeAngelo says that clinical challenges remain. Treatment options for rare, aggressive presentations like CML blast crisis require further optimization, as do strategies for highly refractory mutational profiles. Nevertheless, the evolution of targeted therapy over the last quarter-century has transformed CML from a fatal malignancy into a highly manageable condition, offering clinicians a broad array of effective options to ensure durable, long-term survival for the vast majority of patients.