Metabolic reprogramming and plasticity in tyrosine kinase inhibitor persistence and resistance in chronic myeloid leukaemia

Chronic myeloid leukaemia (CML) is driven by the constitutively active BCR::ABL1 fusion tyrosine kinase. Although tyrosine kinase inhibitors (TKIs) have dramatically improved patient survival, therapeutic resistance and the persistence of leukemic stem cells (LSCs) remain major barriers to durable disease control and treatment-free remission. This review examines BCR::ABL1-dependent and independent mechanisms of TKI resistance, with particular emphasis on metabolic reprogramming as an adaptive component of CML persistence. Accumulating evidence indicates that resistant and primitive CML populations do not conform to a single metabolic phenotype. Instead, therapeutic pressure selects and reshapes heterogeneous cell states capable of dynamically redistributing energy production and substrate utilization among glycolysis, oxidative phosphorylation, fatty acid oxidation, glutamine metabolism, and other amino acid pathways. This metabolic plasticity is further influenced by mitochondrial fitness, redox regulation, the bone marrow microenvironment, epigenetic-metabolic interactions, and immunometabolic mechanisms. Single-cell and spatial approaches are beginning to resolve the cellular heterogeneity underlying these adaptive states and their association with treatment response. Metabolic vulnerabilities therefore provide a rationale for combining BCR::ABL1 inhibition, including asciminib, with strategies targeting mitochondrial metabolism, glycolysis, fatty acid oxidation, glutamine utilization, autophagy, or hypoxia-responsive pathways. However, most such combinations remain preclinical, highlighting the need for biomarker-guided patient stratification and prospective clinical validation.