Chronic Myeloid Leukemia (CML) is a hematological malignancy distinguished by the
presence of the BCR-ABL1 fusion gene, resulting from the Philadelphia chromosome
translocation. This fusion leads to constitutive tyrosine kinase activity, driving unregulated cell
proliferation and survival. Tyrosine kinase inhibitors (TKIs) have revolutionized CML
management by specifically targeting the BCR-ABL1 protein, altering the natural history of
the disease and providing near-normal life expectancy for many patients.
Imatinib, the first-generation TKI, set the foundation for targeted therapy in CML,
demonstrating remarkable efficacy in achieving hematologic, cytogenetic, and molecular
responses. Despite its success, resistance and suboptimal responses prompted the development
of second-generation TKIs like Dasatinib and Nilotinib. These agents, with enhanced potency
and ability to target resistant BCR-ABL1 mutations, including some imatinib-resistant cases,
have further improved therapeutic outcomes.
Pharmacokinetics and pharmacodynamics of TKIs highlight their ability to penetrate
hematopoietic cells and maintain effective intracellular concentrations, while safety profiles
emphasize the need to balance efficacy with manageable adverse effects. Common adverse
events include cytopenias, cardiovascular toxicities, and metabolic disturbances, varying
among TKIs.
Emerging strategies focus on overcoming resistance due to mutations, such as T315I, through
third-generation TKIs like Ponatinib and allosteric inhibitors like Asciminib. Advances in
combination therapies, gene editing technologies, and immunotherapeutic approaches offer
promising avenues. Future research aims at achieving treatment-free remission and
personalized medicine, optimizing therapies to individual patient profiles. These next-
generation approaches are poised to further redefine the treatment paradigm of CML,
addressing resistance and unmet clinical needs.
Keywords: CML, TKIs, Imatinib, Dasatinib, Nilotinib, Drug Resistance
Publication date: 01/05/2026
https://www.ijbpas.com/pdf/2026/May/MS_IJBPAS_2026_10156.pdf
Download PDF
https://doi.org/10.31032/IJBPAS/2026/15.5.10156
