Chronic myeloid leukemia (CML) has become a paradigm of targeted therapy success; however, a proportion of patients develop refractory disease, marked by failure or intolerance to multiple TKIs. Optimal management requires integrating molecular, clinical, and patient-related factors into therapeutic decision-making [1,2].

Resistance is commonly mediated by BCR::ABL1 kinase domain mutations. While second-generation TKIs (dasatinib, nilotinib, bosutinib) address many resistant clones, the T315I substitution remains uniquely sensitive to ponatinib [3,4]. Beyond kinase domain changes, clonal evolution with mutations in ASXL1, RUNX1, IKZF1, TP53, and DNMT3A has been increasingly recognized. These lesions, frequently encountered in advanced phases, are associated with poor response to TKIs, higher risk of progression, and inferior survival [5,6].

Ponatinib remains the agent of choice for patients harboring T315I or compound mutations, with careful risk management to mitigate vascular events [4]. Asciminib, a first-in-class STAMP inhibitor targeting the myristoyl pocket of BCR::ABL1, has emerged as a major advance. By restoring kinase autoinhibition, asciminib demonstrated superior efficacy and tolerability over bosutinib in the ASCEMBL trial [3] and has shown promising results in real-world refractory populations.

In clinical practice, TKI selection is guided by a combination of mutational status and comorbidities. Specific mutations confer resistance to certain TKIs, making mutation-directed sequencing essential. At the same time, patient comorbidities such as cardiovascular, pulmonary, or metabolic disease influence drug tolerability and safety, thereby shaping the optimal therapeutic choice [1,7].

For patients failing multiple TKIs, allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains the only potentially curative approach, particularly in younger and high-risk patients [1,2]. Novel strategies under investigation include rational TKI combinations (e.g., asciminib plus ponatinib), immunotherapeutic approaches, and targeted inhibition of epigenetic regulators [8].

Refractory CML reflects the biological and clinical complexity of disease progression beyond BCR::ABL1 dependence. While ponatinib and asciminib have redefined therapeutic opportunities, additional high-risk mutations highlight the need for precision medicine strategies. Tailored TKI sequencing, integration of comorbidity profiles, and timely transplantation remain central pillars, while ongoing translational research promises to expand future options [7,8].