Identification and Management of Differentiation Syndrome in Emergency Settings: A Narrative Review

Background: Differentiation therapy is a cornerstone in treating hematologic malignancies, particularly acute myeloid leukemia (AML). Differentiation agents target molecular defects blocking myeloid differentiation. However, rapid differentiation can precipitate a life-threatening complication, differentiation syndrome (DS). DS manifests with fever, pulmonary infiltrates, pleural or pericardial effusions, hypotension, and organ dysfunction, often mimicking sepsis or infection. Early recognition in the emergency department (ED) is critical to mitigate morbidity and mortality. This review aims to provide emergency clinicians with practical strategies for the timely identification and management of DS in patients undergoing differentiation therapy. Discussion: Suspicion for DS should be heightened in patients with acute promyelocytic leukemia (M3 AML) who recently started induction chemotherapy, including all-trans retinoic acid or arsenic trioxide, and in those with non-M3 AML receiving differentiation agents (i.e., isocitrate dehydrogenase inhibitors, menin inhibitors, FMS-like tyrosine kinase 3 inhibitors). Imaging can identify pulmonary infiltrates, effusions, and other cardiopulmonary manifestations. Laboratory workups should include complete blood counts with differentials, serum chemistries, cardiac biomarkers, and sepsis panels to exclude infection. Electrocardiography is advised for patients on QT-prolonging agents. Management emphasizes prompt initiation of high-dose corticosteroids and supportive measures such as blood pressure support, intravascular volume optimization, and oxygen therapy or ventilatory support. Multidisciplinary coordination with oncology, hematology, and critical care teams is important to tailor plans and monitor complications. Conclusions: DS represents a diagnostic challenge in the ED due to its nonspecific presentation and mimicry of infection. A high index of suspicion, combined with targeted imaging, laboratory evaluation, and early corticosteroid therapy, can improve outcomes.