APL‐like subset within NPM1‐mutated AML: A distinct immunophenotype correlating with early vascular complications

Among NPM1‐mutated acute myeloid leukemia (AML) (NPM1mut), a distinct subtype has been described with an immunophenotypic profile resembling acute promyelocytic leukemia (APL‐like). In this retrospective multicenter study including 384 NPM1mut AML patients, we identified 95 (24.7%) cases exhibiting an APL‐like immunophenotype. This subset was characterized by significant abnormalities in coagulopathy markers (D‐dimer, D‐dimer/fibrinogen ratio, and disseminated intravascular coagulation [DIC] score).The cumulative incidence of vascular events at 30 days was significantly higher in the APL‐like group compared to the non‐APL‐likegroup (30.5% vs. 10.1%, P < 0.001). Notably, a higher cumulative incidence of early death due to vascular complications (within30 days) was observed in the APL‐like group (6.3% vs. 0.35% in controls; P = 0.00015). In multivariate analysis, the APL‐like immunophenotype was the only significant factor associated with vascular‐related early death (hazard ratio [HR] = 19, P = 0.0063).There was a significantly higher rate of IDH1/2 mutations in APL‐like (68.3%) compared to non‐APL‐like (18.3%, P < 0.001) cases.We validated these clinical and molecular findings in an independent validation cohort of 302 NPM1mut patients enrolled in the acute myeloid leukemia study group (AMLSG) 09‐09 clinical trial, which included the administration of all‐trans retinoic acid (ATRA) to al lpatients and a randomization for gemtuzumab ozogamicin. In this cohort, the APL‐like immunophenotype was associated with events occurring within the first 15 days but did not influence mortality, likely due to protocol‐driven patient selection. Our findings have important clinical implications that warrant the development of studies exploring disease‐tailored clinical measures to mitigate the risk of early vascular events, as in current APL management