Gradual treatment effect from mesenchymal stem cell on steroid-refractory aGVHD in patients receiving above 8 infusions and with gut involvement: a multicenter, randomized, double-blind, placebo-controlled phase 2 trial

Abstract Background Failure of systemic corticosteroid therapy is quite common in patients with newly diagnosed acute graft-versus-host disease (aGVHD) above grade II. Mesenchymal stem cells (MSCs) have been used as a tolerable and potential effective second-line therapy for steroid-refractory aGVHD (SR-aGVHD) for decades, however, well-designed perspective, controlled studies are lacking.Methods This multicenter, randomized, double-blind, placebo-controlled phase 2 study enrolled patients with SR-aGVHD above grade II from 7 centers. Patients were randomized 1:1 to receive MSCs or placebo added to one center’s choice of second-line agents except for ruxolitinib. Study agents were infused twice weekly. Patients who were CR (complete response), NR (no response), and PD (progression of disease) at d28 received 8 infusions and those who were PR (partial response) at d28 received the above infusions for another 4 weeks. The per-protocol population consisted of patients who received ≥ 8 study agent infusions. The primary endpoint was overall response rate (ORR, CR + PR) at d28, and was analyzed in the per-protocol and intention-to-treat populations.Results Seventy-eight patients with a median age of 38 (range, 13–62) years were enrolled, 40 in the MSC group and 38 in the control. Patients in MSC group received a median of 8 doses with a median response time of 14 days. In per-protocol analysis (n = 62), ORR at d28 was significantly higher in the MSC group than in the control (71.9% vs. 46.7%, p = 0.043). Among patients with gut involvement, ORR at d28 was significantly higher in the MSC group than in the control (66.7% vs. 33.3%, p = 0.031). The 2-year cumulative incidence of moderate or severe cGVHD was marginally lower in the MSC group compared to the control (16.5% vs. 46.7%, p = 0.056). In intention-to-treat analysis, the main endpoint was not met (p = 0.375). The incidences of adverse events were comparable between the two groups.Conclusions Adding MSCs to one conventional second-line agent for SR-aGVHD had a gradual treatment effect at a median of 2 weeks in adult patients who completed 8 infusions and with gut involvement. The toxicities were comparable between two groups.Trial registration chictr.org.cn ChiCTR2000035740