Genetic Analysis of Imatinib Resistance in CML: The Role of T315I and E255K

Background and Aims Imatinib mesylate is a small molecule inhibitor targeting the BCR‐ABL tyrosine kinase. However, some CML patients develop resistance to imatinib. This resistance is commonly associated with mutations in the kinase domain of BCR‐ABL, notably the prevalent T315I and E255K mutations. We evaluated the frequency of E255K and T315I mutations in CML patients who do not respond to imatinib therapy. Methods Twenty imatinib‐resistant CML patients were selected from a total cohort of 100 CML patients undergoing regular follow‐up. Genomic screening for the T315I and E255K mutations was carried out using a two‐step molecular approach: initial reverse transcription‐PCR (RT‐PCR) amplification of the ABL kinase domain, followed by restriction fragment length polymorphism (RFLP) analysis. The subsequent clinical management and outcomes for patients harboring these mutations were meticulously tracked and analyzed. Results The T315I and E255K mutations were present in 20% (4/20) and 10% (2/20) of the imatinib‐resistant patients, respectively. All patients required an immediate switch to second‐line tyrosine kinase inhibitors. Notably, one patient with the T315I mutation secured ponatinib and achieved remission, while three other patients underwent allogeneic stem cell transplantation. Two patients carrying the E255K mutation ultimately progressed to blast crisis and died, highlighting the particularly dire prognosis associated with this mutation. Conclusion The T315I and E255K mutations are significant contributors to imatinib resistance in our patient population and are linked to an aggressive clinical course. These findings underscore the critical importance of integrating routine mutation screening into clinical practice to enable early treatment modification, facilitate access to advanced therapies, and ultimately improve patient outcomes.