Clinical Perspectives: A 45-Year-Old Man With R/R CML

This case illustrates the clinical complexity of managing CML in a younger patient who initially responded well to frontline therapy but later presented with signs of disease progression. The initial symptoms of fatigue, weight loss, splenomegaly, and leukocytosis, along with the presence of the BCR::ABL1 fusion gene, confirmed the CML diagnosis. The patient achieved molecular milestones on imatinib, suggesting good early disease control. However, years later, he returned with elevated blasts, cytopenias, and rising transcript levels, all pointing to disease relapse and possible progression to accelerated phase.

A key turning point in this case was the inappropriate selection of second-line therapy. The patient was empirically switched to dasatinib despite having a history of asthma and smoking—both risk factors for pulmonary complications. This decision overlooked the known pulmonary toxicities associated with dasatinib and may have contributed to suboptimal outcomes. Upon lack of response and worsening blood counts, further evaluation confirmed continued disease progression, and next-generation sequencing revealed the T315I mutation, which is known to confer resistance to all first- and second-generation TKIs.

At this stage, treatment options become significantly limited. The T315I mutation narrows therapeutic choices to agents specifically effective against this mutation, such as ponatinib or the allosteric inhibitor asciminib. These therapies may offer better disease control, but their use requires careful assessment of risks and benefits. This case highlights the importance of molecular testing at the time of suspected relapse, careful TKI selection considering comorbidities, and ongoing monitoring to promptly identify resistance and adapt treatment strategies accordingly.