Two Decades of NPM1-Mutated Acute Myeloid Leukemia: From Molecular Insights to Clinical Decision-Making

Abstract

Simple Summary Acute myeloid leukemia with NPM1 mutation (NPM1-mutated AML) is one of the most frequent and clinically relevant subtypes of acute myeloid leukemia. Over the last two decades, major advances in molecular biology have transformed the understanding of this disease and have directly influenced diagnosis, risk stratification, measurable residual disease monitoring, and treatment strategies. This review summarizes the evolution of NPM1-mutated AML from its initial discovery to the present, characterized by precision medicine approaches. We discuss how the identification of co-occurring mutations, the development of molecular monitoring techniques, and the emergence of targeted therapies are reshaping clinical management and improving patient outcomes. We also highlight the limitations of genomic classification alone and discuss emerging approaches aimed at capturing the biological complexity of this AML entity. Indeed, a deeper understanding of disease biology will be essential for developing more personalized and effective therapeutic strategies in the near future.