From fatal disease to functional cure: 25 years of tyrosine kinase inhibition in chronic myeloid leukemia

Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm characterized by the presence of the Philadelphia chromosome, which results from a translocation between chromosomes 9 and 22. This alteration gives rise to the BCR::ABL1 fusion oncogene, whose constitutive tyrosine kinase activity promotes uncontrolled proliferation and survival of leukemic cells. The discovery of this molecular driver laid the foundation for the development of tyrosine kinase inhibitors (TKIs), which transformed CML management from treatment with non-specific modalities to establishing a new paradigm for precision oncology with targeted therapies. Imatinib, the first TKI, demonstrated unprecedented hematologic, cytogenetic, and molecular responses, rapidly becoming the standard of care in CML. Subsequent generations of TKIs were developed to overcome resistance and intolerance to imatinib. These advances improved survival in CML, bringing life expectancy close to that of the general population for the patients who respond to treatment, and shifting treatment goals towards quality of life and the possibility of treatment-free remission (TFR). Landmark discontinuation studies showed that approximately half of eligible patients can maintain TFR. Despite these achievements, important challenges remain, including TKI resistance, safety considerations, and the relatively low proportion of patients who achieve and maintain TFR. Newer-generation TKIs, combination strategies, immunomodulatory approaches, and emerging treatment modalities such as degraders offer promising avenues to further improve outcomes, expand TFR eligibility, ensure optimal quality of life, address resistance mechanisms, and render therapy available and affordable to all patients with CML worldwide.