Efficacy and safety of human umbilical cord-derived mesenchymal stem cells versus placebo added to second-line therapy in patients with steroid-refractory acute graft-versus-host disease: a multicentre, randomized, double-blind, phase 2 trial

Abstract

Background: Failure of systemic corticosteroid therapy is 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 potentially effective second-line therapy for steroid-refractory aGVHD (SR-aGVHD); however, well-designed, prospective, controlled studies are lacking.

Methods: This multicentre, randomized, double-blind, placebo-controlled, exploratory phase 2 study enrolled patients with SR-aGVHD above grade II from 7 centres. Patients were randomized 1:1 to receive umbilical cord-derived MSCs or placebo added to one centre's choice of second-line agents (except for ruxolitinib). The agents were infused twice weekly. Patients with complete response (CR), no response (NR), or progression of disease (PD) at d28 received 8 infusions, and those with partial response (PR) received the above infusions for another 4 weeks. The per-protocol population consisted of patients who received ≥ 8 infusions. The primary endpoint was the overall response rate (ORR, CR + PR) at d28, analyzed in the per-protocol and intention-to-treat populations.

Results: Seventy-eight patients (median age 38, range 13-62) were enrolled: 40 in the MSC group and 38 in the control. Patients in the MSC group received a median of 8 doses, with a median response time of 14 days. In intention-to-treat analysis, ORR at d28 was 60% for MSC group and 50% for control group (p = 0.375). The 2-year cumulative incidence of moderate to severe cGVHD was marginally lower in the MSC group than in the control (13.8% vs. 39.8%, p = 0.067). The 2-year failure-free survival was similar between the MSC and control groups (52.5% vs. 44.4%, p = 0.43). In per-protocol analysis (n = 62), ORR at d28 was significantly greater in the MSC group than in the control group (71.9% vs. 46.7%, p = 0.043). Among patients with gut involvement, ORR at d28 was significantly greater in the MSC group than in the control (66.7% vs. 33.3%, p = 0.031). The adverse events incidences were similar between groups.

Conclusions: In this exploratory study, there was no superior ORR at d28 demonstrated in the MSC group compared with the control. However, MSCs showed a gradual treatment effect at a median of 2 weeks. Patients who completed 8 infusions may benefit from adding MSCs to one conventional second-line agent, especially those with gut involvement. MSCs was well tolerated in patients with SR-aGVHD.

Trial registration: chictr.org.cn ChiCTR2000035740.

Keywords: Acute graft-versus-host disease; Haematopoietic stem cell transplantation; Mesenchymal stem cells; Steroid-refractory.

Fig. 1

Flowchart of the study procedure

Fig. 2

Efficacy between the MSC group and the control group in all patients. A ORR at d28 in the ITT set; B ORR at d56 in the ITT set; (C) DCR rate in the ITT set; D ORR at d28 in the per-protocol set; E ORR at d56 in the per-protocol set; F DCR rate in the per-protocol set. MSC mesenchymal stem cell, ORR overall response rate, DCR durable complete response, ITT intention-to-treat

Fig. 3

Comparison of outcomes between the MSC group and the control group in the ITT set. A Cumulative incidence of cGVHD between two arms in the ITT set; B cumulative incidence of moderate to severe cGVHD between two arms in the ITT set; C FFS between two arms in the ITT set; D OS between two arms in the ITT set. cGVHD chronic graft-versus-host disease, ITT intention-to-treat, FFS failure-free survival, OS overall survival