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, A P Xiang, Yu Wang, Qifa Liu
{"title":"在接受间充质间质细胞治疗的激素抵抗性aGVHD患者中，cGVHD的发病率和死亡率降低：一项随机3期试验的长期随访","authors":"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, A P Xiang, Yu Wang, Qifa Liu","doi":"10.1186/s40164-025-00687-8","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>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><p><strong>Methods: </strong>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><p><strong>Results: </strong>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.</p><p><strong>Conclusions: </strong>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><p><strong>Trial registration: </strong>clinicaltrials.gov identifier: NCT02241018. Registration date: 16 September 2014, https://clinicaltrials.gov/ct2/show/NCT02241018 .</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"14 1","pages":"95"},"PeriodicalIF":9.4000,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12243361/pdf/","citationCount":"0","resultStr":"{\"title\":\"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.\",\"authors\":\"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, A P Xiang, Yu Wang, Qifa Liu\",\"doi\":\"10.1186/s40164-025-00687-8\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>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><p><strong>Methods: </strong>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><p><strong>Results: </strong>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.</p><p><strong>Conclusions: </strong>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><p><strong>Trial registration: </strong>clinicaltrials.gov identifier: NCT02241018. Registration date: 16 September 2014, https://clinicaltrials.gov/ct2/show/NCT02241018 .</p>\",\"PeriodicalId\":12180,\"journal\":{\"name\":\"Experimental Hematology & Oncology\",\"volume\":\"14 1\",\"pages\":\"95\"},\"PeriodicalIF\":9.4000,\"publicationDate\":\"2025-07-09\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12243361/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Experimental Hematology & Oncology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1186/s40164-025-00687-8\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"HEMATOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Experimental Hematology & Oncology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1186/s40164-025-00687-8","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"HEMATOLOGY","Score":null,"Total":0}
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.
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.
期刊介绍：
Experimental Hematology & Oncology is an open access journal that encompasses all aspects of hematology and oncology with an emphasis on preclinical, basic, patient-oriented and translational research. The journal acts as an international platform for sharing laboratory findings in these areas and makes a deliberate effort to publish clinical trials with 'negative' results and basic science studies with provocative findings.
Experimental Hematology & Oncology publishes original work, hypothesis, commentaries and timely reviews. With open access and rapid turnaround time from submission to publication, the journal strives to be a hub for disseminating new knowledge and discussing controversial topics for both basic scientists and busy clinicians in the closely related fields of hematology and oncology.
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