Clinical Significance of the S348l Mutation in BCR-ABL as a Dominant Variant in Indonesian CML Patients Under Tyrosine Kinase Inhibitor Therapy: A Cohort Study.

[OBJECTIVE] Chronic myeloid leukemia (CML) is characterized by the translocation of chromosomes 9 and 22, resulting in the BCR-ABL fusion gene. Tyrosine kinase inhibitors (TKIs) have markedly improved CML outcomes. Yet, resistance may develop due to mutations in the BCR-ABL kinase domain, particularly in the ATP-binding loop (P-loop), activation loop (A-loop), catalytic domain, and direct binding site. This study aimed to evaluate the relationship between BCR-ABL kinase domain mutations, hematological response, and overall survival among CML patients receiving TKI therapy at Wahidin Sudirohusodo General Hospital, Makassar.

[METHODS] A prospective cohort study was conducted from March 2022 to July 2023 at the Hematology-Oncology outpatient clinic. Among 312 patients, 22 were classified as non-responders (no hematological response within three months) and 290 as responders. Forty-four patients (22 responders and 22 non-responders) underwent mutation analysis, and survival outcomes were compared. Statistical analysis was performed using SPSS.

[RESULTS] Of the 44 patients, 11 harbored BCR-ABL mutations: S348L (n=6), T315I (n=4), and Y253F (n=1). All mutations were identified exclusively in the non-responder group. Mortality was significantly higher in non-responders than responders (p<0.05), and among non-responders with mutations compared to those without (p<0.01). Six-month survival rates were 65% for S348L, 50% for T315I, and 0% for Y253F, though survival differences between mutation types were not statistically significant (p=0,641).

[CONCLUSION] CML patients achieving early hematological response to TKI therapy had significantly better survival outcomes. In contrast, non-responders, particularly those harboring BCR-ABL kinase domain mutations, demonstrated poorer survival. The S348L mutation was the most common variant in this cohort. Early mutation detection may help guide therapeutic adjustments and improve outcomes in TKI-resistant CML.