Mesenchymal stromal cells plus basiliximab, calcineurin inhibitor as treatment of steroid-resistant acute graft-versus-host disease: a multicenter, randomized, phase 3, open-label trial

Ke Zhao, Ren Lin, Zhiping Fan, Xiaoyong Chen, Yu Wang, Fen Huang, Na Xu, Xi Zhang, Xin Zhang, Li Xuan, Shunqing Wang, Dongjun Lin, Lan Deng, Danian Nie, Jianyu Weng, Yonghua Li, Xiaohui Zhang, Yuhua Li, A P Xiang, Qifa Liu, Ke Zhao, Ren Lin, Zhiping Fan, Xiaoyong Chen, Yu Wang, Fen Huang, Na Xu, Xi Zhang, Xin Zhang, Li Xuan, Shunqing Wang, Dongjun Lin, Lan Deng, Danian Nie, Jianyu Weng, Yonghua Li, Xiaohui Zhang, Yuhua Li, A P Xiang, Qifa Liu

Abstract

Background: Steroid-resistant (SR) acute graft-versus-host disease (aGVHD) lacks standard second-line treatment. Mesenchymal stromal cells (MSCs) have potential efficacy in SR aGVHD. We aimed to assess the efficacy and safety of MSCs combined with basiliximab and calcineurin inhibitor as second-line therapy for SR aGVHD.

Methods: A randomized phase 3 trial involved 203 SR aGVHD patients at nine centers in China (September 2014-March 2019). Participants were randomized at a 1:1 ratio to receive second-line therapy with (n = 101) or without (n = 102) MSCs. The primary endpoint was the overall response (OR) at day 28. Secondary and safety endpoints included durable OR at day 56, failure-free survival, overall survival (OS), chronic GVHD (cGVHD), infection, hematological toxicity and relapse.

Results: Of 203 patients, 198 (97.5%; mean age, 30.1 years; 40.4% women) completed the study. The OR at day 28 was higher in the MSC group than the control group (82.8% [82 patients] vs. 70.7% [70]; odds ratio, 2.00; 95% confidence interval [CI], 1.01-3.94; P = 0.043). The durable OR at day 56 was also higher in the MSC group (78.8% [78 patients] vs. 64.6% [64]; odds ratio, 2.02; 95% CI, 1.08-3.83; P = 0.027). The median failure-free survival was longer in the MSC group compared with control (11.3 months vs. 6.0 months; hazard ratio (HR) 0.68; 95% CI, 0.48-0.95, P = 0.024). The 2-year cumulative incidence of cGVHD was 39.5% (95% CI, 29.3-49.4%) and 62.7% (51.4-72.1%) in the MSC and control groups (HR 0.55, 95% CI, 0.36-0.84; P = 0.005). Within 180 days after study treatments, the most common grade 3 and 4 adverse events were infections (65 [65.7%] in the MSC group vs. 78 [78.8%] in the control group) and hematological toxicity (37 [37.4%] vs. 53 [53.5%]). The 3-year cumulative incidence of tumor relapse was 10.1% (95% CI, 5.2-17.1) and 13.5% (7.5-21.2%) in the MSC and control groups, respectively (HR 0.75, 95% CI, 0.34-1.67, P = 0.610).

Conclusions: MSCs plus second-line treatments increase the efficacy of SR aGVHD, decrease drug toxicity of second-line drugs and cGVHD without increasing relapse, and are well-tolerated. MSCs could be recommended as a second-line treatment option for aGVHD patients. Trial registration clinicaltrials.gov identifier: NCT02241018. Registration date: September 16, 2014, https://ichgcp.net/clinical-trials-registry/NCT02241018 .

Keywords: Allogeneic hematopoietic stem cell transplantation; Mesenchymal stromal cell; Second-line treatment; Steroid-resistant acute graft-versus-host disease.

Conflict of interest statement

The authors declare that they have no competing interests.

© 2022. The Author(s).

Figures

Fig. 1
Fig. 1
Treatment plan of SR aGVHD patients in the MSC and control group. CNI calcineurin inhibitor, CR complete response, PR partial response, NR no response
Fig. 2
Fig. 2
Flow of patient enrollment, randomization and follow-up
Fig. 3
Fig. 3
Assessment of response to acute graft-versus-host disease (aGVHD) treatments. A Overall response (OR) at day 28 after randomization, B OR at day 56 after randomization and C Sankey diagram of responses in the MSCs and control groups over time. Steroid-resistant (SR) aGVHD in the MSCs and control groups were shaded baby blue and ultramarine, respectively; the width of each bar represented their relative frequency with the study. Qualities of response at day 28 follow-up (second column from left) and at day 56 follow-up (third column from left) were depicted in red (CR), yellow (PR), and prussian blue (NR). The NR patients in the control group crossed over to receive MSCs treatment was depicted in green
Fig. 4
Fig. 4
Overall survival (OS) and failure-free survival. A OS and B failure-free survival were stratified according to whether patients receiving MSCs post-randomization. And for these analysis, the eight patients in the control group who crossed over to receive MSCs are included in the control group. Failure-free survival was defined as time from randomization to relapse or progression of hematologic disease, non-relapse-related death or the addition of new systemic therapy for aGVHD, and the competing risk was the onset of chronic graft-versus-host disease (cGVHD). *P < 0.05, **P < 0.001
Fig. 5
Fig. 5
Cumulative incidence of overall chronic graft-versus-host disease (cGVHD) (A) and severe cGVHD (B). A, B Stratified according to whether patients receiving MSCs post-randomization. *P < 0.05, **P < 0.001
Fig. 6
Fig. 6
Cumulative incidence of leukemia relapse (A) and non-relapse mortality (NRM) (B). A, B Stratified according to whether patients receiving MSCs post-randomization

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