Deciphering elevated risk of life-threatening hemorrhage and early death in acute myeloid leukemia with APL-like phenotype: independent role of endothelial injury and implications of EASIX-based risk stratification in a multicenter study

BACKGROUND: Early hemorrhagic mortality remains the major cause of elevated early death (ED) incidence in acute promyelocytic leukemia (APL)-like subgroup of acute myeloid leukemia (AML). The underlying mechanisms remain unknown and risk-adapted management strategies are not well established. We aimed to investigate the significance of endothelial injury in major bleeding event (MBE) and ED of APL-like AML (APLL) using endothelial activation and stress index (EASIX), and to develop an EASIX-based risk stratification with translational implications on APLL in venetoclax (VEN) era. METHODS: This multicenter study investigated newly diagnosed AML patients from three Chinese institutions between January 2017 and September 2025. Propensity score matching (PSM) and prospective thrombomodulin (TM) measurements were applied to validate EASIX utility in APLL. The APLL cohort was divided into development and validation cohorts based on diagnostic institutions to establish an MBE risk stratification using logistic regression. RESULTS: Of 344 APLL, 212 APL, and 1596 'Other AML' in the analysis, log2-EASIX of APLL was comparable to APL but significantly higher than 'Other AML' (3.777 vs. 2.692, P < 0.001), which was sustained after PSM (4.022 vs. 2.904, P < 0.001). Significant correlation was further validated between log2-EASIX and TM (r = 0.80, P < 0.001). Within APLL, high log2-EASIX (OR: 5.611, 95% CI: 2.212-14.233, P < 0.001), overt DIC at diagnosis (OR: 2.929, 95% CI: 1.127-7.616, P = 0.027) and CD56 + blasts (OR: 3.697, 95% CI: 1.691-8.082, P = 0.001) emerged as independent MBE risk factors, setting foundation for a novel risk stratification. High-risk APLL exhibited significantly higher cumulative ED incidence in both development and validation cohorts, particularly when treated with standard VEN combining hypomethylating agent (HMA) regimen (P < 0.05 in both cohorts). However, modified VEN-HMA regimen with reduced VEN initiation dose specifically improved early outcomes of high-risk APLL (P = 0.036) in an independent, real-world implementation cohort. CONCLUSIONS: APLL is characterized by significant endothelial damage, which is quantifiable by EASIX to independently contribute to the elevated MBE risk. The EASIX-based stratification can be utilized to rapidly identify high-risk APLL, who may benefit from an optimized VEN-HMA induction strategy to reduce ED risk.