Early predictors of MR4.5 attainment and eligibility for TKI discontinuation in CML treated with second-generation TKIs

ABSTRACT: Among patients with chronic myeloid leukemia (CML) aiming for tyrosine kinase inhibitor (TKI) discontinuation, second-generation TKIs (2G-TKIs) are used as one of the first-line therapy options because they induce faster and deeper molecular responses (MR) than imatinib. However, predictors of attaining and sustaining MR4.5 (BCR::ABL1 International Scale [IS] ≤0.0032%) during 2G-TKI therapy remain undefined. We analyzed 431 patients enrolled in the phase 3 Japan Adult Leukemia Study Group CML212 trial comparing nilotinib at 300 mg twice daily (n = 218) and dasatinib at 100 mg once daily (n = 213) as first-line therapy. The objective was to identify predictors of MR4.5 attainment and TKI discontinuation eligibility (TDE). Candidate variables assessed within 6 months included the European Treatment and Outcome Study (EUTOS) Long-Term Survival (ELTS) score; BCR::ABL1 IS at baseline, 3 months, and 6 months; and IS-derived halving times (HT), HT (0-3) and HT (3-6). TDE was defined as ≥3 years of TKI therapy with ≥2 consecutive years of sustained MR4.5. With a median follow-up of 3.0 years, the cumulative incidence of MR4.5 was 46.6%, and 36.3% of patients achieving MR4.5 met TDE criteria. In multivariable models, HT (0-3) (subdistribution hazard ratio [HR], 2.23; 95% confidence interval [CI], 1.09-4.55) and the 6-month IS value (HR, 0.38; 95% CI, 0.31-0.47) were independent predictors of MR4.5 attainment, whereas only the 6-month IS value predicted TDE (odds ratio, 0.37; 95% CI, 0.24-0.56). This study demonstrates that MR at 6 months after TKI initiation has important clinical value in early stratification of MR4.5 attainment and TDE in patients receiving 2G-TKI therapy.