Adomas Bukauskas, Renata Jucaitienė, Mindaugas Stoškus, Vilma Valčeckienė, Greta Bušmaitė, Artūras Slobinas, Linas Davainis, Inga Šlepikienė, Igoris Trociukas, Valdas Pečeliūnas, Laimonas Griškevičius, Andrius Žučenka
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However, data on bone marrow (BM)-derived MSC use in biopsy-proven grade III-IV SR-aGVHD with GI involvement, particularly in stage 3-4 cases, remain limited.</p><p><strong>Methods: </strong>This prospective, observational, single-arm, single-center study assessed the efficacy and safety of BM-derived MSC for treating adult patients with biopsy-proven grade III-IV SR-aGVHD with predominant GI involvement. Early (1<sup>st</sup>-2<sup>nd</sup>) passage BM-derived MSC were administered weekly at a target dose of 1x10<sup>6</sup> MSC/kg in two regimens: up to three (MSC3) and six doses (MSC6).</p><p><strong>Results: </strong>Fifty-seven adult patients with biopsy-proven III-IV grade SR-aGVHD (93% with GI involvement) received MSC treatment. The overall response rate (ORR) was 39% and 42% on Days 14 and 28, respectively, with no significant differences between the two MSC groups (Day 28 ORR 38% for MSC3 and 44% for MSC6). In patients with stage 3-4 GI involvement, the ORR was 26% and 36% at the corresponding time points with comparable efficacy between the two MSC groups (Day 28 ORR 31% for MSC3 and 38% for MSC6). Day 14 and Day 28 responders had significantly higher OS compared to non-responders (52% vs. 7%, p=0.000; 54% vs. 5%, p=0.000), with a comparable OS benefit observed in patients with stage 3-4 GI involvement (45% vs. 8%, p=0.005; 42% vs. 6%, p=0.005), respectively. MSC treatment had a favorable safety profile. The one, 5 and 10-year OS rates were 27%, 24%, and 24%, respectively.</p><p><strong>Conclusions: </strong>The grade III-IV SR-aGVHD patients, including cases with biopsy-proven severe GI involvement, had significantly better clinical outcomes if responses to MSC treatment were observed on Days 14 and 28. Intensified MSC administration schedule has failed to improve the clinical outcomes. MSC studies focusing on aGVHD prevention and (or) first-line treatment in combination with other agents should be considered.</p>","PeriodicalId":12622,"journal":{"name":"Frontiers in Immunology","volume":"16 ","pages":"1600019"},"PeriodicalIF":5.7000,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12106019/pdf/","citationCount":"0","resultStr":"{\"title\":\"Mesenchymal stromal cells for steroid-refractory biopsy-proven grade III-IV acute Graft-versus-Host Disease with predominant gastrointestinal involvement.\",\"authors\":\"Adomas Bukauskas, Renata Jucaitienė, Mindaugas Stoškus, Vilma Valčeckienė, Greta Bušmaitė, Artūras Slobinas, Linas Davainis, Inga Šlepikienė, Igoris Trociukas, Valdas Pečeliūnas, Laimonas Griškevičius, Andrius Žučenka\",\"doi\":\"10.3389/fimmu.2025.1600019\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Introduction: </strong>Steroid-refractory acute Graft-versus-Host Disease (SR-aGVHD) is a potentially fatal complication occurring in approximately 60-70% of severe grade III-IV GVHD cases, with a higher incidence in patients with gastrointestinal (GI) involvement. GI aGVHD is associated with poor prognosis, with a 2-year overall survival (OS) rate of only 25% in patients with stage 3-4 GI involvement. Mesenchymal stromal cells (MSC) have emerged as a promising therapeutic option due to their favorable efficacy and safety profile. However, data on bone marrow (BM)-derived MSC use in biopsy-proven grade III-IV SR-aGVHD with GI involvement, particularly in stage 3-4 cases, remain limited.</p><p><strong>Methods: </strong>This prospective, observational, single-arm, single-center study assessed the efficacy and safety of BM-derived MSC for treating adult patients with biopsy-proven grade III-IV SR-aGVHD with predominant GI involvement. 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引用次数: 0
摘要
类固醇难治性急性移植物抗宿主病（SR-aGVHD）是一种潜在的致命并发症，发生在大约60-70%的严重III-IV级移植物抗宿主病病例中，在胃肠道（GI）受累者中发病率更高。GI aGVHD与不良预后相关，3-4期GI受累患者的2年总生存率（OS）仅为25%。间充质基质细胞（MSC）因其良好的疗效和安全性而成为一种有前景的治疗选择。然而，关于骨髓（BM）来源的MSC在活检证实的III-IV级SR-aGVHD伴胃肠道的应用的数据仍然有限，特别是在3-4期病例中。方法：这项前瞻性、观察性、单臂、单中心研究评估了脑转移性骨髓间充质干细胞治疗活检证实的III-IV级SR-aGVHD（主要累及胃肠道）成人患者的有效性和安全性。早期（1 -2）传代bm来源的MSC每周以1x106 MSC/kg的靶剂量分两种方案给药：最多三剂（MSC3）和六剂（MSC6）。结果：57例活检证实为III-IV级SR-aGVHD的成年患者（93%伴有GI受累）接受了MSC治疗。在第14天和第28天，总缓解率（ORR）分别为39%和42%，两组间无显著差异（第28天，MSC3的ORR为38%，MSC6的ORR为44%）。在3-4期胃肠道受累的患者中，两个MSC组在相应时间点的ORR分别为26%和36%，疗效相当（MSC3和MSC6的第28天ORR分别为31%和38%）。第14天和第28天的应答者的OS明显高于无应答者(52% vs. 7%, p=0.000；54% vs. 5%, p=0.000)，在3-4期胃肠道受累患者中观察到类似的OS获益(45% vs. 8%, p=0.005；42%对6%，p=0.005)。MSC治疗具有良好的安全性。1年、5年和10年的OS率分别为27%、24%和24%。结论：III-IV级SR-aGVHD患者，包括活检证实严重GI受累的病例，如果在第14天和第28天观察对MSC治疗的反应，其临床结果明显更好。强化骨髓间充质干细胞给药计划未能改善临床结果。应该考虑关注aGVHD预防和（或）与其他药物联合一线治疗的MSC研究。
Mesenchymal stromal cells for steroid-refractory biopsy-proven grade III-IV acute Graft-versus-Host Disease with predominant gastrointestinal involvement.
Introduction: Steroid-refractory acute Graft-versus-Host Disease (SR-aGVHD) is a potentially fatal complication occurring in approximately 60-70% of severe grade III-IV GVHD cases, with a higher incidence in patients with gastrointestinal (GI) involvement. GI aGVHD is associated with poor prognosis, with a 2-year overall survival (OS) rate of only 25% in patients with stage 3-4 GI involvement. Mesenchymal stromal cells (MSC) have emerged as a promising therapeutic option due to their favorable efficacy and safety profile. However, data on bone marrow (BM)-derived MSC use in biopsy-proven grade III-IV SR-aGVHD with GI involvement, particularly in stage 3-4 cases, remain limited.
Methods: This prospective, observational, single-arm, single-center study assessed the efficacy and safety of BM-derived MSC for treating adult patients with biopsy-proven grade III-IV SR-aGVHD with predominant GI involvement. Early (1st-2nd) passage BM-derived MSC were administered weekly at a target dose of 1x106 MSC/kg in two regimens: up to three (MSC3) and six doses (MSC6).
Results: Fifty-seven adult patients with biopsy-proven III-IV grade SR-aGVHD (93% with GI involvement) received MSC treatment. The overall response rate (ORR) was 39% and 42% on Days 14 and 28, respectively, with no significant differences between the two MSC groups (Day 28 ORR 38% for MSC3 and 44% for MSC6). In patients with stage 3-4 GI involvement, the ORR was 26% and 36% at the corresponding time points with comparable efficacy between the two MSC groups (Day 28 ORR 31% for MSC3 and 38% for MSC6). Day 14 and Day 28 responders had significantly higher OS compared to non-responders (52% vs. 7%, p=0.000; 54% vs. 5%, p=0.000), with a comparable OS benefit observed in patients with stage 3-4 GI involvement (45% vs. 8%, p=0.005; 42% vs. 6%, p=0.005), respectively. MSC treatment had a favorable safety profile. The one, 5 and 10-year OS rates were 27%, 24%, and 24%, respectively.
Conclusions: The grade III-IV SR-aGVHD patients, including cases with biopsy-proven severe GI involvement, had significantly better clinical outcomes if responses to MSC treatment were observed on Days 14 and 28. Intensified MSC administration schedule has failed to improve the clinical outcomes. MSC studies focusing on aGVHD prevention and (or) first-line treatment in combination with other agents should be considered.
期刊介绍：
Frontiers in Immunology is a leading journal in its field, publishing rigorously peer-reviewed research across basic, translational and clinical immunology. This multidisciplinary open-access journal is at the forefront of disseminating and communicating scientific knowledge and impactful discoveries to researchers, academics, clinicians and the public worldwide.
Frontiers in Immunology is the official Journal of the International Union of Immunological Societies (IUIS). Encompassing the entire field of Immunology, this journal welcomes papers that investigate basic mechanisms of immune system development and function, with a particular emphasis given to the description of the clinical and immunological phenotype of human immune disorders, and on the definition of their molecular basis.
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