Chronic Myeloid Leukemia Beyond BCR::ABL1 Inhibition: Resistance Mechanisms and Emerging Therapeutic Modalities

The BCR::ABL1 fusion oncoprotein is the molecular hallmark and principal oncogenic driver of chronic myeloid leukemia (CML). Tyrosine kinase inhibitors (TKIs) have transformed CML into a largely manageable chronic disease, yet acquired resistance, persistence of leukemic stem cells (LSCs), and disease progression remain important therapeutic challenges. This narrative review examines the molecular and cellular determinants of TKI resistance and their implications for current and emerging therapeutic strategies. Resistance involves both BCR::ABL1-dependent and -independent mechanisms, ranging from kinase-domain mutations to adaptive signaling, altered drug transport, microenvironmental protection, metabolic reprogramming, and epigenetic dysregulation. Increasing understanding of these processes has yielded therapeutic strategies with growing clinical relevance, including next-generation TKIs, dual-site BCR::ABL1 inhibition, as well as rational combination approaches targeting alternative signaling and other survival dependencies. At the experimental frontier, PROTAC-mediated protein degradation, siRNA-based gene silencing, and CAR-based cellular immunotherapies are being explored as innovative approaches for targeting resistant leukemic populations. Nanotechnology-based delivery systems further provide opportunities for targeted delivery of TKIs and nucleic-acid therapeutics. In parallel, molecular monitoring and multi-omic profiling offer opportunities to better define disease evolution and guide individualized treatment. The continued translation of these advances into clinically applicable therapeutic strategies may help address the unmet therapeutic needs in CML, especially in the setting of advanced and blast-phase disease.