Reduced-intensity versus intensive induction in high-risk acute promyelocytic leukemia: A systematic review and meta-analysis.

Abstract

e18521 Background: High-risk acute promyelocytic leukemia (APL), defined by WBC >10×10⁹/L, accounts for 20-30% of cases with increased early mortality. While all-trans retinoic acid (ATRA) + arsenic trioxide (ATO) is standard for standard-risk APL, optimal induction for high-risk disease remains debated. Reduced-intensity regimens combining ATRA+ATO with gemtuzumab ozogamicin (GO) or low-dose anthracycline have emerged as alternatives to intensive chemotherapy. We compared outcomes between these approaches. Methods: Following PRISMA guidelines, we systematically searched PubMed, EMBASE, and Cochrane Library from 2000–2025 (PROSPERO CRD420261293473). We included randomized controlled trials and observational studies reporting high-risk APL outcomes. Reduced-intensity regimens were defined as ATRA+ATO combined with gemtuzumab ozogamicin (GO), low-dose anthracycline (1–2 doses), or hydroxyurea. Intensive regimens consisted of ATRA-based therapy with ≥3 anthracycline doses. Risk of bias was assessed using RoB 2 for RCTs and ROBINS-I for observational studies. Primary endpoints were complete remission (CR) and early mortality (EM); secondary endpoints included event-free survival (EFS) and relapse. We pooled arm-level outcomes using random-effects meta-analysis with logit transformation for proportions and inverse-variance method for hazard ratios, with restricted maximum-likelihood (REML) estimation. Results: Seventeen studies comprising 25 treatment arms (1,234 patients) were included: 11 reduced-intensity arms (360 patients) and 14 intensive arms (874 patients). For CR (17 arms, 840 patients), pooled rates were 92.3% (95% CI 85.9–95.9%; I²=0%) with reduced-intensity versus 89.3% (82.6–93.6%; I²=56%) with intensive therapy (p=0.35). Early mortality (19 arms, 936 patients) was numerically lower with reduced-intensity: 8.8% (4.7–15.9%; I²=37%) versus 10.4% (6.8–15.5%; I²=45%; p=0.62). Pooled hazard ratio for EFS from two RCTs was 0.23 (95% CI 0.07–0.75, p=0.02), representing a 77% reduction in EFS events favoring reduced-intensity therapy. Relapse rates (17 arms, 836 patients) were 3.9% (1.5–9.6%) for reduced-intensity versus 5.5% (2.7–10.7%) for intensive regimens (p=0.49). In prespecified exploratory WBC-stratified analysis (11 arms, 569 patients), reduced-intensity regimens maintained stable CR across WBC strata (91.6% to 92.5%), whereas intensive chemotherapy showed declining efficacy from 96.0% at WBC <30×10⁹/L to 86.6% at WBC ≥30×10⁹/L. Conclusions: Reduced-intensity ATRA+ATO-based induction achieves equivalent complete remission, comparable early mortality, superior event-free survival, and lower relapse compared with intensive chemotherapy in high-risk APL. These findings support ATRA+ATO combined with gemtuzumab ozogamicin or low-dose anthracycline as preferred first-line therapy.