Efficacy and safety of ATRA plus arsenic trioxide versus ATRA plus chemotherapy in newly diagnosed acute promyelocytic leukemia: a grade-assessed systematic review and meta-analysis

Acute promyelocytic leukemia (APL) is an aggressive malignancy. Although recent advancements in therapy have improved outcomes, differing toxicity profiles remain. The optimal choice between all-trans retinoic acid plus arsenic trioxide (ATRA + ATO) and ATRA plus chemotherapy, in newly diagnosed APL remains uncertain. A systematic literature search was conducted across databases PubMed (n = 812), Embase (n = 975), Scopus (n = 894), and the Cochrane Library (n = 300) for studies comparing ATRA + ATO with ATRA+chemotherapy in newly diagnosed APL. Of 2,981 records found, 681 duplicates were removed, leaving 2,300 records for screening. After a full-text review of 100 reports, 12 studies met the inclusion criteria. Data were analyzed using random- and fixed-effects models, with subgroup and sensitivity analyses performed to assess heterogeneity. The certainty of evidence for each outcome was assessed using the GRADE framework. Findings from RCTs are primary basis for conclusion. In RCTs, ATRA + ATO significantly improved complete remission rates (risk ratio [RR] 1.04, 95% CI 1.02–1.06), disease-free survival (RR 1.22, 95% CI 1.11–1.34), event-free survival (RR 1.25, 95% CI 1.20–1.29) and overall survival (RR 1.07, 95% CI 1.03–1.12) compared with ATRA+chemotherapy.observational studies showed showed consistent findings supporting real world generalizability. A trend toward lower gastrointestinal toxicity was observed with ATRA + ATO (RR 0.28, 95% CI 0.07–1.18), but it was not statistically significant. There were no significant differences in hepatic toxicity, differentiation syndrome or thrombocytopenia. ATRA + ATO was associated with an increased risk of QTc prolongation (RR 3.79, 95% CI 1.00–14.36, p = 0.05). The under-reporting in the primary studies limits the ability to draw a definitive conclusion on the difference in reported cardiac event rates in the clinics. Compared with ATRA plus chemotherapy, ATRA + ATO is associated with superior remission and survival outcomes in newly diagnosed APL, with lower gastrointestinal toxicity but higher risk of QTc prolongation. These findings support the preferential clinical use of ATRA + ATO with close cardiac monitoring. The systematic review was registered with the International Prospective Register Of Systematic Reviews (PROSPERO Registration No. CRD420251164171).