How I individualize treatment for chronic-phase CML.

Chronic myeloid leukemia (CML) has served as a paradigm for the development of effective initial and next-generation targeted therapies. The availability of five effective and generally well-tolerated BCR::ABL1 tyrosine kinase inhibitors for the treatment of newly diagnosed chronic phase CML offers patients and their treating physicians a welcome luxury of choice. The long-term outlook for newly diagnosed chronic phase CML patients is excellent, with expected survival similar to age-matched controls.

Resistance to Allosteric Inhibitors.

Allosteric inhibitors have emerged as powerful therapeutic agents capable of overcoming resistance mutations that impair the efficacy of orthosteric inhibitors. However, resistance to allosteric inhibitors can also arise, posing a challenge to their long-term effectiveness. Mechanisms of resistance include altered inhibitor affinity and kinetics, disruption of the allosteric mechanism, changes in receptor recycling and activity, and off-target adaptations such as upregulation of drug efflux pumps or activation of compensatory signaling pathways.

BCR::ABL1 kinase N-lobe mutants confer moderate to high degrees of resistance to asciminib.

Secondary kinase domain mutations in BCR::ABL1 represent the most common cause of resistance to tyrosine kinase inhibitor (TKI) therapy in patients with chronic myeloid leukemia. The first 5 approved BCR::ABL1 TKIs target the adenosine triphosphate (ATP)-binding pocket. Mutations confer resistance to these ATP-competitive TKIs and those approved for other malignancies by decreasing TKI affinity and/or increasing ATP affinity.

ATP-Competitive Inhibitors Midostaurin and Avapritinib Have Distinct Resistance Profiles in Exon 17-Mutant KIT.

KIT is a type-3 receptor tyrosine kinase that is frequently mutated at exon 11 or 17 in a variety of cancers. First-generation KIT tyrosine kinase inhibitors (TKI) are ineffective against KIT exon 17 mutations, which favor an active conformation that prevents these TKIs from binding. The ATP-competitive inhibitors, midostaurin and avapritinib, which target the active kinase conformation, were developed to inhibit exon 17-mutant KIT.