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

Among NPM1-mutated acute myeloid leukemia (AML) (NPM1 ^mut), a distinct subtype has been described with an immunophenotypic profile resembling acute promyelocytic leukemia (APL-like). In this retrospective multicenter study including 384 NPM1 ^mut 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-like group (30.5% vs. 10.1%, P < 0.001). Notably, a higher cumulative incidence of early death due to vascular complications (within 30 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 NPM1 ^mut 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 all patients 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.