ELTS Score and Early "Warning" Define a Two-Stage Risk Framework for Failure-Free Survival in Chronic-Phase CML

Risk 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 newly diagnosed CP-CML patients enrolled in the prospective JALSG CML212 and New TARGET studies, approximately 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 ELN 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, attainment of "Warning" within 6 months after TKI initiation independently predicted transition from "Warning" to "Unfavorable" (HR 7.31, 95% CI 2.94-18.2; p<0.001). These findings distinguish baseline risk from post-milestone disease evolution and support a two-stage risk framework integrating baseline ELTS stratification with "Warning" timing to guide dynamic risk-adapted management in CP-CML.