Mesenchymal stromal cells plus basiliximab improve the response of steroid-refractory acute graft-versus-host disease as a second-line therapy: a multicentre, randomized, controlled trial

Abstract

Background: For patients with steroid-refractory acute graft-versus-host disease (SR-aGVHD), effective second-line regimens are urgently needed. Mesenchymal stromal cells (MSCs) have been used as salvage regimens for SR-aGVHD in the past. However, clinical trials and an overall understanding of the molecular mechanisms of MSCs combined with basiliximab for SR-aGVHD are limited, especially in haploidentical haemopoietic stem cell transplantation (HID HSCT).

Methods: The primary endpoint of this multicentre, randomized, controlled trial was the 4-week complete response (CR) rate of SR-aGVHD. A total of 130 patients with SR-aGVHD were assigned in a 1:1 randomization schedule to the MSC group (receiving basiliximab plus MSCs) or control group (receiving basiliximab alone) (NCT04738981).

Results: Most enrolled patients (96.2%) received HID HSCT. The 4-week CR rate of SR-aGVHD in the MSC group was obviously better than that in the control group (83.1% vs. 55.4%, P = 0.001). However, for the overall response rates at week 4, the two groups were comparable. More patients in the control group used ≥ 6 doses of basiliximab (4.6% vs. 20%, P = 0.008). We collected blood samples from 19 consecutive patients and evaluated MSC-derived immunosuppressive cytokines, including HO1, GAL1, GAL9, TNFIA6, PGE2, PDL1, TGF-β and HGF. Compared to the levels before MSC infusion, the HO1 (P = 0.0072) and TGF-β (P = 0.0243) levels increased significantly 1 day after MSC infusion. At 7 days after MSC infusion, the levels of HO1, GAL1, TNFIA6 and TGF-β tended to increase; however, the differences were not statistically significant. Although the 52-week cumulative incidence of cGVHD in the MSC group was comparable to that in the control group, fewer patients in the MSC group developed cGVHD involving ≥3 organs (14.3% vs. 43.6%, P = 0.006). MSCs were well tolerated, no infusion-related adverse events (AEs) occurred and other AEs were also comparable between the two groups. However, patients with malignant haematological diseases in the MSC group had a higher 52-week disease-free survival rate than those in the control group (84.8% vs. 65.9%, P = 0.031).

Conclusions: For SR-aGVHD after allo-HSCT, especially HID HSCT, the combination of MSCs and basiliximab as the second-line therapy led to significantly better 4-week CR rates than basiliximab alone. The addition of MSCs not only did not increase toxicity but also provided a survival benefit.

Keywords: Acute graft-versus-host disease; Haemopoietic stem cell transplantation; Haploidentical; Mesenchymal stromal cells; Second-line therapy; Steroid-refractory.

Fig. 1

Treatment protocol for eligible patients. Patients randomly assigned to the MSC group received MSCs plus basiliximab, and the control group received basiliximab alone. MSCs were administered once a week for 4 weeks as a cycle. Further administrations of MSCs were given if the patients achieved PR at week 4. Basiliximab was administered twice in the first week and once a week until aGVHD was reduced to grade < II. MSCs, mesenchymal stromal cells; CR, complete response; PR, partial response; NR, no response

Fig. 2

Flowchart of patients

Fig. 3

Response rates of SR-aGVHD after 4 weeks of treatment. Patients in the MSC group (using MSCs plus basiliximab) achieved superior responses compared to outcomes in the control group (using basiliximab alone) stratified according to a all enrolled patients, b patients with grade 3–4 SR-aGVHD, c patients with skin SR-GVHD, d patients with gut SR-GVHD, e patients with liver SR-GVHD, and f patients with SR-GVHD involving ≥2 organs

Fig. 4

Changes in MSC-derived immunosuppressive cytokines after MSC infusion. A–H The levels of the MSC-derived immunosuppressive cytokines HO1, GAL1, GAL9, TNFIA6, PGE2, PDL1, TGF-β and HGF were assessed before and 1 day and 7 days after MSC infusion. Compared to the levels before MSC infusion, HO1 (A) and TGF-β (G) increased significantly 1 day after MSC infusion. At 7 days after MSC infusion, there was a trend towards increased levels of HO1 (A), GAL1 (B), TNFIA6 (D) and TGF-β (G), although the differences were not statistically significant

Fig. 5

The 52-week disease-free survival (DFS) in patients with malignant haematological diseases after enrolment stratified according to the MSC group and control group