BACKGROUND: STAT5 is a transcriptional factor which when highly expressed in chronic myeloid leukemia (CML) cells stimulate proliferation and mediate resistance from tyrosine kinase inhibitors, resulting in major molecular response (MMR) failure. STAT5 has two isoforms, STAT5A and STAT5B. However, prolonged use of imatinib appears to only upregulate STAT5A pathway. In addition, the resistance conferred by STAT5A does not extend to other drugs such as hydroxyurea. Hence, STAT5A and STAT5B might have different functions in CML cells. AIM: The objective of the study was to determine the association of STAT5A and STAT5B expression with MMR failure in CML patients. METHODS: This was a cross-sectional study of CML patients in chronic phase with age ? 18 years old, receiving IM therapy ? 12 months, and previously given hydroxyurea. MMR status was evaluated and patients were categorized as achieved or failed to achieve MMR. Expression levels of STAT5A and STAT5B were conducted using RT-PCR methods. Associations between STAT5A expression, STAT5B expression, hydroxyurea duration, and imatinib duration with MMR achievement were calculated using logistic regression. RESULTS: A total of 118 patients were analyzed; 71.1% failed to achieve MMR. Multivariate logistic regression analysis showed statistically significant association between high STAT5A expression (odds ratio [OR]: 3.852; 95% confidence interval [CI]: 1.420?10.452; p = 0.008), STAT5A/STAT5B interaction (OR: 0.150; 95% CI: 0.038?0.593; p = 0.007), longer hydroxyurea administration (OR: 3.882; 95% CI: 1.023?14.733; p = 0.046), and shorter imatinib administration (OR: 0.333; 95% CI: 0.132?0.840; p = 0.020) with MMR achievement failure. After adjusting STAT5A expression with STAT5A/STAT5B interaction, high STAT5A expression independently increased the likelihood of MMR achievement failure only in high expression STAT5B patients (OR: 3.852; 95% CI: 1.420?10.452; p = 0.008). CONCLUSION: High STAT5A expression which is induced by high STAT5B is associated with MMR achievement failure of chronic phase CML patients who received hydroxyurea before imatinib. Longer duration of hydroxyurea and shorter duration of IM confound of STAT5A expression to MMR achievement failure. ? 2021 Ikhwan Rinaldi, Anastasia Putri, Melva Louisa, Sukamto Koesnoe.