Differentiation Syndrome in Acute Myeloid Leukemia: Molecular Mechanisms, Clinical Spectrum, and Emerging Therapeutic Paradigms

Acute Myeloid leukemia (AML) is characterized by differentiation arrest, driving blast proliferation and abnormal blood formation. While differentiation therapy revolu-tionized acute promyelocytic leukemia (APL) with all-trans retinoic acid (ATRA) and arsenic trioxide (ATO), its extension into non-APL AML has been limited until recent targeted agents. This narrative review synthesizes preclinical and clinical evidence in-to differentiation-inducing therapy, with a focus on IDH1/2, FLT3 and menin inhibi-tors. Following SANRA guidelines, we searched pubmed (2010-sep,2025) for clinical trials and key preclinical studies, with particular attention to the molecular mecha-nism of differentiation induction, clinical efficacy and management of differentiation syndrome (DS). IDH1/2 inhibitors (ivosidenib, enasidenib, olutasidenib) yield overall response rate (ORR) of 30-94% in AML with DS in 10-19%. Menin inhibitors (re-vumenib, ziftomenib, enzomenib, bleximenib) achieve an ORR of 33-88% in KMT2A-rearranged or NPM1-mutated AML, with DS in 10-25% and QT prolongation as key toxicities. FLT3-inhibitors (gilteritinib, quizartinib) improve survival in FLT3-mutated AML with DS in 1-5%. Resistance mutations limit durability and com-binations enhance efficacy. Differentiation therapy represents a paradigm shift to-wards non-cytotoxic AML management. Improved recognition of DS and rational combination approaches will be essential to maximize therapeutic benefit. Future re-search should address mechanisms of resistance and biomarkers to achieve cure be-yond APL.