ELTS score and early "warning" define a 2-stage risk framework for failure-free survival in chronic-phase CML.

abstractRisk stratification to predict treatment failure in chronic-phase chronic myeloid leukemia (CP-CML) remains an important challenge in the tyrosine kinase inhibitor (TKI) era. We conducted a pooled analysis of 710 patients with newly diagnosed CP-CML enrolled in the prospective Japan Adult Leukemia Study Group CML212 and New TARGET studies, ∼80% of whom received second-generation TKIs (2G-TKIs) as first-line therapy, to identify predictors of failure-free survival (FFS). In this study, we incorporated the European LeukemiaNet 2025-defined "warning" category as an initial adverse state in the definition of FFS events and evaluated transitions to "unfavorable." Within this framework, the EUTOS long-term survival (ELTS) score consistently stratified FFS whether treatment failure included both "warning" and "unfavorable" events or was restricted to "unfavorable." Among patients treated with 2G-TKIs, ELTS demonstrated superior time-dependent discrimination compared with Sokal and remained the baseline predictor of initial treatment failure. Importantly, once "warning" occurred, baseline ELTS no longer predicted deterioration. Instead, the attainment of "warning" within 6 months after TKI initiation independently predicted transition from "warning" to "unfavorable" (hazard ratio, 7.31; 95% confidence interval, 2.94-18.2; P< .001). These findings distinguish baseline risk from postmilestone disease evolution and support a 2-stage risk framework integrating baseline ELTS stratification with "warning" timing to guide dynamic risk-adapted management in CP-CML.