Reduced-intensity ATRA plus arsenic with GO or low-dose anthracycline improves event-free survival in high-risk APL

BackgroundHigh-risk acute promyelocytic leukemia (APL) [white blood cell (WBC) count >10 × 109/L) accounts for 20%–30% of cases with early mortality of 15%–25%. Optimal induction with reduced-intensity all-trans retinoic acid plus arsenic trioxide (ATRA+ATO) versus intensive chemotherapy remains debated.MethodsFollowing the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines (PROSPERO CRD420261293473), we searched PubMed and Cochrane Library (2000–2025). Reduced-intensity: ATRA+ATO with gemtuzumab ozogamicin (GO; 6–9 mg/m2), low-dose idarubicin (one to two doses of 12 mg/m2), or hydroxyurea; intensive: ATRA-based therapy with three or more anthracycline doses. Random-effects meta-analysis used logit transformation and inverse variance weighting. RoB 2 and ROBINS-I were used to assess risk of bias.ResultsA total of 17 studies (1,323 patients, 11 on the reduced-intensity arm and 14 on the intensive arm) were included. Complete remission (CR) was 92.3% (95%CI = 85.9–95.9%, I2 = 0%) versus 89.3% (82.6%–93.6%, I2 = 56%, p = 0.35). Early mortality was 8.8% versus 10.4% (p = 0.62). Event-free survival (EFS) from two randomized controlled trials (RCTs) favored reduced-intensity induction (HR = 0.23, 95%CI= 0.07–0.76, p = 0.015). Relapse was 3.9% versus 5.5% (p = 0.49). WBC-stratified CR remained stable at 91.6%–92.5% with reduced-intensity induction, while intensive CR declined from 96.0% to 86.6% at WBC ≥30 × 109/L.ConclusionsReduced-intensity ATRA+ATO-based induction achieves equivalent CR, comparable early mortality, superior EFS (HR = 0.23, p = 0.015), and lower relapse, supporting ATRA+ATO with GO or low-dose anthracycline as the preferred first-line therapy for high-risk APL.Systematic Review Registrationhttps://www.crd.york.ac.uk/prospero/, identifier CRD420261293473.