Mesenchymal stem cells added to second-line therapy improve response and failure-free survival in steroid-refractory acute graft-versus-host disease after allogeneic hematopoietic stem cell transplantation: a meta-analysis of randomized controlled trials

Man Xiao¹Yinghu Yan²Rui Zhang²Dan Wang³Li Wang³Jinhong Yang^1*

• ¹Shandong Second Medical University, Weifang, China
• ²Chinese People's Liberation Army Rocket Force Characteristic Medical Center, Beijing, China
• ³Sunshine Union Hospital, Weifang, China

Background: Steroid-refractory acute graft-versus-host disease (aGVHD) remains a major cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (allo-HSCT), with limited effective treatment options. Mesenchymal stem cells (MSCs) have emerged as a promising therapeutic approach due to their immunomodulatory and tissue-repair properties. However, inconsistent results existed. Methods: A systematic literature search was conducted in PubMed, Embase, and the Cochrane Central Register of Controlled Trials up to May 2025. Randomized controlled trials (RCTs) evaluating MSCs plus second-line therapy versus second-line therapy alone in patients with steroid-refractory aGVHD were included. Meta-analysis was performed using random-effects models to pool risk ratios (RR) or hazard ratios (HR) with 95% confidence intervals (CIs). Results: Four RCTs comprising 650 patients were included. MSC administration significantly improved overall response (RR: 1.13, 95% CI: 1.03-1.23, P = 0.007) and complete response rates (RR: 1.43, 95% CI: 1.19-1.70, P < 0.001). Subgroup analysis showed consistent benefits in patients with skin or gut involvement, multiorgan disease, and adults. MSC treatment also reduced the incidence of chronic GVHD (HR: 0.60, 95% CI: 0.42-0.86, P = 0.005) and improved failure-free survival (HR: 0.72, 95% CI: 0.54-0.95, P = 0.022), though no significant overall survival benefit was observed. The safety profile was comparable to controls. Conclusions: The addition of MSCs to second-line therapy significantly improves treatment response, reduces chronic GVHD incidence, and prolongs failure-free survival in patients with steroid-refractory aGVHD, with a favorable safety profile. These findings support MSC-based therapy as a promising strategy for this high-risk population.