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Background <p>Our open-label, multicenter, randomized, phase 3 trial showed that the incidence and severity of chronic graft-versus-host disease (cGVHD) reduced in steroid-resistant acute graft-versus-host disease (aGVHD) patients who underwent mesenchymal stromal cells (MSCs) treatments, but survival benefit was not received. Here, we present a post-hoc analysis of the 5-year follow-up to explore long-term survival and its underlying mechanism.</p> Methods <p>This long-term follow-up trial included steroid-resistant aGVHD patients, who were randomly assigned (1:1) to receive MSCs (MSC group) (1 × 10<sup>6</sup> cells/kg once weekly for 4 consecutive weeks, 8 doses at most) or without MSCs treatment (control group). For this updated analysis, the 5-year endpoints were cumulative incidence of cGVHD, overall survival, cGVHD-free, relapse-free survival (CRFS), and relapse. To explore the mechanism, We investigated the changes in T, B cells, and signal joint T cell receptor excision DNA circles (sjTRECs).</p> Results <p>Between September 2014 and March 2019, 198 patients were randomly assigned to the MSC group (<i>n</i> = 99) or the control group (<i>n</i> = 99). Extended follow-up showed the lower 5-year cumulative incidence of cGVHD (42.0% [95%CI 32.2–51.5] vs. 67.1% [55.6–76.3]; hazard ratio [HR] 2.19, 95%CI 1.47–3.27; <i>P</i> &lt; 0.001), improved 5-year overall survival (60.4% [50.8–70.0] vs. 41.7% [31.9–51.5]; 0.63, 0.42–0.94; <i>P</i> = 0.023), CRFS (33.9% [24.5–43.3] vs. 20.9% [12.9–28.9]; 0.67, 0.48–0.93; <i>P</i> = 0.017) and no increase on relapse (13.6% [7.6–21.3] vs. 16.0% [9.5–23.9]; 1.24, 0.60–2.56; <i>P</i> = 0.568) for patients in MSC group compared with the control group. Clinical improvement of MSCs was accompanied by significant increases in regulatory T cells, CD4 + CD45RA + CD31 + naïve T, CD19 + CD27 + IgD- memory B cells, and sjTRECs.</p> Conclusions <p>With extended follow-up, MSCs reduced the morbidity of cGVHD in aGVHD patients and improved overall survival and CRFS. Mechanistically, MSCs reduced cGVHD by thymus pathway.</p> Trial registration <p>clinicaltrials.gov identifier: NCT02241018. Registration date: 16 September 2014, <a href="https://clinicaltrials.gov/ct2/show/NCT02241018">https://clinicaltrials.gov/ct2/show/NCT02241018</a>.</p>

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Reduced morbidity and mortality of cGVHD in patients who received treatment with mesenchymal stromal cells for steroid-resistant aGVHD: long-term follow-up of a randomized phase 3 trial

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  • 发表日期：

    2025年7月9日

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  • Ke Zhao,
  • Ren Lin,
  • Zhiping Fan,
  • Zhen Li,
  • Xiaoyong Chen,
  • Li Xuan,
  • Fen Huang,
  • Na Xu,
  • Xiuli Wu,
  • Shaohua Chen,
  • Jing Sun,
  • Xi Zhang,
  • Jianyu Weng,
  • Yonghua Li,
  • Yuhua Li,
  • Dongjun Lin,
  • Danian Nie,
  • Shunqing Wang,
  • Xiaojun Xu,
  • Xiaohui Zhang,
  • Yangqiu Li,
  • AP Xiang,
  • Yu Wang,
  • Qifa Liu

摘要

Background

Our open-label, multicenter, randomized, phase 3 trial showed that the incidence and severity of chronic graft-versus-host disease (cGVHD) reduced in steroid-resistant acute graft-versus-host disease (aGVHD) patients who underwent mesenchymal stromal cells (MSCs) treatments, but survival benefit was not received. Here, we present a post-hoc analysis of the 5-year follow-up to explore long-term survival and its underlying mechanism.

Methods

This long-term follow-up trial included steroid-resistant aGVHD patients, who were randomly assigned (1:1) to receive MSCs (MSC group) (1 × 106 cells/kg once weekly for 4 consecutive weeks, 8 doses at most) or without MSCs treatment (control group). For this updated analysis, the 5-year endpoints were cumulative incidence of cGVHD, overall survival, cGVHD-free, relapse-free survival (CRFS), and relapse. To explore the mechanism, We investigated the changes in T, B cells, and signal joint T cell receptor excision DNA circles (sjTRECs).

Results

Between September 2014 and March 2019, 198 patients were randomly assigned to the MSC group (n = 99) or the control group (n = 99). Extended follow-up showed the lower 5-year cumulative incidence of cGVHD (42.0% [95%CI 32.2–51.5] vs. 67.1% [55.6–76.3]; hazard ratio [HR] 2.19, 95%CI 1.47–3.27; P < 0.001), improved 5-year overall survival (60.4% [50.8–70.0] vs. 41.7% [31.9–51.5]; 0.63, 0.42–0.94; P = 0.023), CRFS (33.9% [24.5–43.3] vs. 20.9% [12.9–28.9]; 0.67, 0.48–0.93; P = 0.017) and no increase on relapse (13.6% [7.6–21.3] vs. 16.0% [9.5–23.9]; 1.24, 0.60–2.56; P = 0.568) for patients in MSC group compared with the control group. Clinical improvement of MSCs was accompanied by significant increases in regulatory T cells, CD4 + CD45RA + CD31 + naïve T, CD19 + CD27 + IgD- memory B cells, and sjTRECs.

Conclusions

With extended follow-up, MSCs reduced the morbidity of cGVHD in aGVHD patients and improved overall survival and CRFS. Mechanistically, MSCs reduced cGVHD by thymus pathway.

Trial registration

clinicaltrials.gov identifier: NCT02241018. Registration date: 16 September 2014, https://clinicaltrials.gov/ct2/show/NCT02241018.