Four Decades of Molecular Innovation in Chronic Myeloid Leukemia: From Antisense Targeting to Treatment-Free Remission

Background: Chronic myeloid leukemia (CML) is a paradigm of targeted therapy, driven by the BCR::ABL1 fusion kinase. Over the past four decades, therapeutic strategies have evolved from early molecular targeting approaches and interferon-α to tyrosine kinase inhibitors (TKIs), dramatically improving survival and transforming CML into a largely controllable disease. Methods: We performed a narrative review of the literature, focusing on key milestones in CML therapy, including antisense strategies, interferon-based treatment, first-, second-, and third-generation TKIs, and the development of allosteric inhibitors. Current management strategies, treatment-free remission (TFR), and emerging therapies were also analyzed. Results: The introduction of imatinib established proof of principle for oncogene-targeted therapy, leading to sustained survival improvements. Second- and third-generation TKIs further enhanced response depth and addressed resistance, including the T315I mutation. The development of the allosteric inhibitor asciminib introduced a novel mechanism of action and expanded therapeutic options for pretreated patients. Deep molecular responses have enabled TFR in approximately 40–60% of selected patients, redefining treatment goals toward functional cure. Emerging agents, including next-generation ATP-competitive and allosteric inhibitors, are showing promising activity in resistant disease and may further improve outcomes. Conclusions: CML represents a unique model of translational oncology, demonstrating how mechanistic insight can drive therapeutic innovation. Future strategies will focus on increasing TFR rates, overcoming resistance, targeting leukemic stem cells, and improving global access to therapy and monitoring, with the ultimate aim of achieving functional cure in the majority of patients.