Three generations of targeted therapies in chronic myeloid leukemia: Molecular advances, adverse effects, therapeutic challenges, and future perspectives

Abstract

Introduction: The therapeutic landscape of chronic myeloid leukemia (CML) represents a paradigm of precision oncology, evolving across multiple generations of targeted breakpoint cluster region–Abelson murine leukemia viral oncogene homolog 1 tyrosine kinase inhibitors. As survival approaches that of the general population, long-term care requires balancing drug efficacy with safety, sequencing optimization, and survivorship considerations. Objectives: This review aims to evaluate modern CML management strategies, including drug mechanisms, resistance mutations, toxicity profiles, treatment sequencing, and criteria for treatment discontinuation. Methods: Literature was retrieved up to June 2026 using databases indexing landmark phase I–III trials, European LeukemiaNet guidelines, and regulatory data. Evidence was synthesized thematically across adult chronic-phase CML management strategies to evaluate drug mechanisms, resistance mutations, organ-specific toxicities, and treatment discontinuation criteria. Results: First-generation imatinib provides a well-characterized safety profile but is associated with slower response kinetics. Second-generation agents (e.g., dasatinib, nilotinib, bosutinib) achieve deeper molecular responses but present distinct, non-overlapping toxicities—including pleural, vascular, metabolic, and gastrointestinal complications—and remain vulnerable to the T315I gatekeeper mutation. Third-generation ponatinib and the newly approved allosteric inhibitor asciminib, which specifically targets the ABL myristoyl pocket, provide effective options for salvage-resistant disease, though they necessitate proactive cardiovascular and metabolic risk mitigation. Standardized molecular monitoring remains essential to distinguish true resistance from nonadherence and to guide mutation-directed sequencing. Conclusion: Modern CML management has transitioned from uniform kinase inhibition toward highly individualized survivorship. Optimizing long-term quality of life relies on aligning tyrosine kinase inhibitor selection with patient-specific comorbidities, implementing response-adjusted dosing, and utilizing well-defined clinical parameters to safely evaluate candidates for treatment-free remission.