EASIX-guided risk stratification of severe coagulopathy and early mortality among newly diagnosed acute myeloid leukaemia with APL-like phenotype Free

Introduction: Acute promyelocytic leukemia (APL)-like is a unique subgroup of non-M3 acute myeloid leukemia (AML), with a special CD34 and HLA-DR double-negative immunophenotype that resembles APL and common genomic alteration of NPM1 mutation. It is characterized by remarkable risk of early death (ED) that is mainly attributed to common coagulation abnormalities of the subset.

Endothelial Activation and Stress Index (EASIX) is a marker of endothelial dysfunction that has been increasingly used in clinical practice. Studies have proved endothelial damage as a crucial mechanism of bleeding in APL. Thus, our study aimed to investigate whether EASIX can guide prediction of severe coagulapathy and elevated ED risk of APL-like AML (APLL), particularly in the era of venetoclax (VEN).

Methods: In this study, consecutive newly diagnosed AML patients at 3 centers in Eastern China between July 2018 and April 2025 were investigated. APLL patients enrolled in the study constitued 3 independent cohorts of training, validation1 and validation2 cohort according to institutions and periods of diagnosis. EASIX score was calculated by the formula of [lactate dehydrogenase (LDH, U/L) x creatinine (mg/dL)/ platelets (PLT, 10⁹/L)] based on the laboratory data on the day of initial diagnosis and was converted to a log2 form (log2-EASIX) for analyses.

Results: Median log2-EASIX of APLL (N=275) was 3.050, indicating no significant difference with APL (N=140, median: 3.064, P=0.347), but was significantly higher than other AML (N=1494, median: 2.822, P<0.001). Within NPM1-mutated (NPM1c) subgroup, NPM1c APLL also presented a significantly higher log2-EAISX level than other NPM1c AML (2.940 vs 2.452, P=0.005).

Overt disseminated intravascular coagulation (DIC) rate at onset was 37.9% in training cohort and 44.9% in validation1 cohort. Cumulative incidence of major bleeding event (MBE) and thrombotic event (MTE) within 60 days was 15.3% and 4.0% respectively in training cohort, as well as 17.3% and 8.2% respectively in validation1 cohort. Median of log2-EASIX for patients with overt DIC at onset was significantly higher than those without DIC in both cohorts (P<0.001). Similar results were found in those with MBE (P<0.001), but there was no significant difference of EASIX level regarding the occurrence of MTE.

Integrating comprehensive clinical variables, it was found in training cohort that ECOG score>2 (OR: 7.660, P<0.001), high log2-EASIX level (OR: 4.111, P=0.002) and CD56 expression (OR: 3.394, P=0.002) served as independent risk factors of MBE. Utilizing coefficents, a weighted score was assigned to design a predictive scoring index of MBE: 2 to ECOG score>2, 1 to high log2-EASIX and CD56 expression. Patients scoring≥2 were stratified as high-risk APLL of MBE. The scoring index showed decent performance in validation1 cohort. High-risk APLL showed significantly higher cumulative incidence of MBE in training and validation1 cohort (P<0.001).

ED rate was 16.9% in training cohort and 16.3% in validation1 cohort, among whom 66.7% and 81.3% were due to MBE, respectively. It was revealed that high-risk APLL patients showed significantly poorer ED rate in training (42.5% vs 10.2%, P<0.001) and validation1 (40.9% vs 9.2%, P<0.001) cohort.

Surprisingly, the predictive index showed specifically excellent performance of ED in APLL patients receiving VEN plus hypomethylating agents (HMA) regimen comparing intensive regimens. Under standard VEN dose, high-risk APLL showed inferior ED rate in training (41.2% vs 12.5%, P=0.011) and validation1 (50.0% vs 6.3%, P=0.001) cohort. In validation2 cohort, in which APLL patients were initiated with different VEN doses, no significant difference between reduced and standard VEN doses was identified of ED rate in low-risk APLL (P=1.000), while it was found in high-risk APLL that reduced VEN doses showed significantly improved ED rate (P=0.015). Also, when integrating APLL in training and validation1 cohort, reduced VEN initiation doses specifically improve early outcomes among high-risk APLL patients (P =0.041).

Conclusion: Our study suggests that EASIX is a robust marker of severe coagulopathy and ED of APLL. In addition, an EASIX-based MBE risk stratification index was established, which could also predict ED of APLL, particularly those undergoing VEN-HMA regimen. Reduced VEN initiation dose could specifically improve early outcomes of high-risk APLL patients.