Abstract
Acute promyelocytic leukemia (APL) evolved from the most lethal to the most curable subtype of acute leukemia today, owing to targeted therapy with all-trans retinoic acid (ATRA) and arsenic trioxide. Despite cure rates exceeding 90% and the rarity of relapse or refractoriness, early death (ED)-occurring within 30 days of diagnosis-remains unacceptably high, reaching up to 30% in population-based studies. ED is the major barrier to universal cure, with fatal hemorrhage as the predominant cause, followed by infection, differentiation syndrome, and thrombosis. Patients who survive the initial month generally achieve excellent long-term outcomes. This review synthesizes data from clinical trials and large real-world cohorts to provide a comprehensive overview of the incidence, causes, and predictors of ED in APL. Higher white blood cell count and older age emerge as the most consistently validated predictors, followed by increased IRB/BICcreatinine, low albumin, thrombocytopenia, and coagulopathy, although their predictive value is not uniform across studies. Risk scores such as the Sanz classification, the Österroos ED model, and dynamic disseminated intravascular coagulation (DIC) assessments represent practical tools for identifying patients at high risk of ED. Importantly, ED rates remain significantly higher in real-world populations than in clinical trials, highlighting the impact of age and comorbidities, delayed diagnosis, and barriers to immediate ATRA initiation and supportive care. Addressing ED in APL requires intensified early supportive strategies, physician awareness and education, and rapid treatment initiation. Refinement and validation of predictive models may guide tailored interventions and inform strategies to finally overcome this persistent unmet need.