Acute graft-versus-host disease (aGVHD) significantly affects quality of life and outcomes in patients post-haploidentical haematopoietic stem cell transplantation (haplo-HSCT). Methotrexate (MTX) is commonly used to prevent aGVHD but can lead to complications like delayed haematological recovery and oral mucositis (OM). This study investigates the efficacy of anti-CD25 monoclonal antibody (mAb) as a potential MTX alternative. Participants were divided into two cohorts: a single-dose group (25 mg/day anti-CD25 mAb with MTX) and a double-dose group (50 mg/day anti-CD25 mAb without MTX). The primary end-point was the cumulative incidence (CI) of severe aGVHD by day 100. The double-dose cohort demonstrated a significantly lower CI of total aGVHD (23.53% vs. 42.11%, p = 0.009) and grade 3-4 aGVHD (7.35% vs. 18.42%, p = 0.047). After inverse probability of treatment weighting adjustment, the adjusted HR of double-dose compared with single-dose cohort for total aGVHD was 0.47 (95% CI 0.26-0.86
p = 0.015), 0.42(95% CI 0.15-1.22
p = 0.110) for grade III-IV aGVHD, 0.45 (95% CI 0.26-0.77
p = 0.004) for total cGVHD and 0.36 (95% CI 0.18-0.72
p = 0.004) for the moderate to severe cGVHD. Additionally, this double-dose regimen significantly reduced the incidence of oral mucositis and demonstrated lower rates of infections and haemorrhagic cystitis. These findings suggest that a double-dose anti-CD25 mAb regimen without MTX is a promising strategy for aGVHD prophylaxis in haplo-HSCT (ChiCTR2200060184).