Efficacy of Mesenchymal Stem Cell Therapy for Steroid-Refractory Acute Graft-Versus-Host Disease following Allogeneic Hematopoietic Stem Cell Transplantation: A Systematic Review and Meta-Analysis

Abstract

BackgroundMesenchymal stem cells (MSCs) have been broadly used experimentally in various clinical contexts. The addition of MSCs to initial steroid therapy for acute graft-versus-host disease (aGVHD) may improve patient outcomes. However, investigations regarding prognostic factors affecting the efficacy of MSC therapy for steroid-refractory aGVHD remain controversial. We thus conducted a systematic review and meta-analysis of published clinical trials to determine possible prognostic factors affecting the efficacy of MSCs in treating steroid-refractory aGVHD.Methods and FindingsClinical trials using MSC therapy for steroid-refractory aGVHD were identified by searching PubMed and EMBASE databases. A total of 6,963 citations were reviewed, and 13 studies met the inclusion criteria. A total of 301 patients from thirteen studies were included. Of these, 136 patients showed a complete response (CR), and 69 patients displayed a partial (PR) or mixed response (MR). In total, 205 patients exhibited overall response (ORR). Patients with skin steroid-refractory aGVHD showed a better clinical response than gastrointestinal (CR: odds ratio [OR] = 1.93, 95% confidence interval [95%CI]: 1.05–3.57, p < 0.05) and liver (CR: OR = 2.30, 95%CI: 1.12–4.69, p < 0.05, and ORR: OR = 2.93, 95%CI: 1.06–8.08, p < 0.05) steroid-refractory aGVHD. Those with grade II steroid-refractory aGVHD exhibited a better clinical response following MSC therapy than recipients with grade III–IV (CR: OR = 3.22, 95%CI: 1.24–8.34, p < 0.05). Completion therapy may improve the CR but reduce ORR compared with induction therapy (CR: OR = 0.20, 95%CI: 0.09–0.44, p < 0.05; ORR: OR = 2.18, 95%CI: 1.17–4.05, p = 0.01). There was also a trend towards a better clinical response in children compared with adults (CR: OR = 2.41, 95%CI: 1.01–5.73, p = 0.05).ConclusionsAge, skin involvement, lower aGVHD grade, and the number of infusions are the main prognostic factors affecting the efficacy of MSC therapy for steroid-refractory aGVHD.

Clinical Use of Mesenchymal Stromal Cells in the Treatment of Acute Graft-versus-Host Disease

“…However, children showed a trend towards better CR compared with adults [25, 28]. Certain factors, including skin involvement and lower aGvHD grade, yielded a higher response rate to MSC application [25].…”

“…However, children showed a trend towards better CR compared with adults [25, 28]. Certain factors, including skin involvement and lower aGvHD grade, yielded a higher response rate to MSC application [25]. Possibly, inconsistent results of clinical studies are attributable to different or inconsistent pharmacological quality of MSCs resulting from the lack of a standardized methodology for MSC generation, dosing, and interdonor heterogeneity [5, 24].…”

Acute Graft Versus Host Disease: A Comprehensive Review

“…Median time to resolution of aGVHD is 30-42 days. in patients who respond to initial therapy, short-term tapering treatment with prednisone to a cumulative dose of 2,000 mg/m 2 is effective and expected to minimize steroid-related complications (71,72).…”

Clinical potential of mesenchymal stem/stromal cell-derived extracellular vesicles

“…Chen and colleagues summarized the results of 13 studies with a total of 301 pediatric and adult patients and report an overall response rate (complete and partial remissions) after MSC treatment for steroid-refractory acute GvHD in 205 patients (66%) (45). According to these review patients with skin steroid refractory acute GvHD showed a better response than patients with gastrointestinal (P<0.05) or hepatic (P<0.05) steroidrefractory acute GvHD.…”