Background: AML with NPM1 mutation is the largest subcategory of AML, representing about 35% of AML cases. It is characterized by CD34 negativity, which suggests a relatively differentiated state of the bulk of leukemic blasts. Notably, a significant subset of NPM1-mutated AML cases also exhibit HLA-DR negativity, classifying them as “double-negative”, and mimicking, therefore, the CD34⁻ HLA-DR⁻ immunophenotype of acute promyelocytic leukemia (APL). Objectives: This study focuses on the “acute promyelocytic leukemia-like” (“APL-like”) subset of NPM1-mutated AML, which can be challenging to distinguish from APL at presentation, prior to confirming RARa translocations. We aim to investigate the hematologic and immunophenotypic parameters that may aid to its distinction from APL. Additionally, we explore differences in genetic profile and prognosis between “APL-like” and “non-APL-like” NPM1-mutated AML cases. Methods: We conducted a retrospective evaluation of 77 NPM1-mutated AML cases and 28 APL cases. Results: Morphological characteristics, hematologic parameters (such as DD/WBC and PT/WBC), and specific immunophenotypic markers (including SSC, CD64, and CD4) can assist in the early distinction of “APL-like” NPM1-mutated AML from APL. Regarding differences in genetic profiles and outcomes between “APL-like” and non-“APL-like” NPM1-mutated AML cases, we observed a significantly higher incidence of IDH1/2 /TET2 mutations, along with a significantly lower incidence of DNMT3A mutations in the “APL-like” subset compared to the non-“APL-like” subset. The frequency of Ras-pathway and FLT3 mutations did not differ between these last two groups, nor did their prognoses. Conclusions: Our findings contribute to a comprehensive characterization of NPM1-mutated AML, enhancing diagnostic accuracy and aiding in the detailed classification of the disease. This information may potentially guide targeted therapies or differentiation-based treatment strategies.

Acute leukemias are rare diseases requiring emergency specialized hematological care. However, other specialists may be involved: general practitioners, emergency physicians, internists and intensivists most often. The initial phase of the management of acute leukemia can be marked by the occurrence of complications with a significant impact on morbidity and mortality. The aim of this article is to guide the clinician when facing a suspected acute leukemia for the diagnosis and management of complications that may occur in the first hours. The article reviews the initial assessment, the diagnostic approach and the management of the initial complications of acute leukemia, such as DIC, tumor lysis syndrome, leukostasis syndrome and febrile agranulocytosis, whose outcome is fundamental for the prognosis.