Bukauskas Adomas, Jucaitienė Renata, Stoškus Mindaugas, Valčeckienė Vilma, Bušmaitė Greta, Slobinas Artūras, Davainis Linas, Šlepikienė Inga, Trociukas Igoris, Pečeliūnas Valdas, Griškevičius Laimonas, Žučenka Andrius
Hematology, Oncology and Transfusion Medicine Center, Vilnius University Hospital Santaros Klinikos, Vilnius, Lithuania.
Department of Hematology and Oncology, Institute of Clinical Medicine, Faculty of Medicine, Vilnius University, Vilnius, Lithuania.
Front Immunol. 2025 May 13;16:1600019. doi: 10.3389/fimmu.2025.1600019. eCollection 2025.
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.
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 (1-2) passage BM-derived MSC were administered weekly at a target dose of 1x10 MSC/kg in two regimens: up to three (MSC3) and six doses (MSC6).
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.
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.
类固醇难治性急性移植物抗宿主病（SR-aGVHD）是一种潜在致命的并发症，约60%-70%的重度III-IV级移植物抗宿主病（GVHD）病例会出现该并发症，在有胃肠道（GI）受累的患者中发生率更高。胃肠道急性移植物抗宿主病（GI aGVHD）与预后不良相关，3-4期胃肠道受累患者的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已成为一种有前景的治疗选择。然而，关于骨髓（BM）来源的MSC用于经活检证实的III-IV级SR-aGVHD且有胃肠道受累，尤其是3-4期病例的数据仍然有限。
这项前瞻性、观察性、单臂、单中心研究评估了BM来源的MSC治疗经活检证实为III-IV级SR-aGVHD且以胃肠道受累为主的成年患者的疗效和安全性。早期（1-2）代BM来源的MSC以1x10 MSC/kg的目标剂量每周给药，分两种方案：最多3剂（MSC3）和6剂（MSC6）。
57例经活检证实为III-IV级SR-aGVHD的成年患者（93%有胃肠道受累）接受了MSC治疗。第14天和第28天的总缓解率（ORR）分别为39%和42%，两个MSC组之间无显著差异（第28天，MSC3组的ORR为38%，MSC6组为44%）。在3-级胃肠道受累患者中，相应时间点的ORR分别为26%和36%，两个MSC组的疗效相当（第28天，MSC3组的ORR为31%，MSC6组为38%）。与无反应者相比，第14天和第28天有反应者的总生存率显著更高（52%对7%，p=0.000；54%对5%，p=0.000）；在3-4期胃肠道受累患者中也观察到了类似的总生存获益（分别为45%对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年的总生存率分别为27%、24%和24%。
III-IV级SR-aGVHD患者，包括经活检证实有严重胃肠道受累的病例，如果在第14天和第28天观察到对MSC治疗有反应，临床结局会显著更好。强化的MSC给药方案未能改善临床结局。应考虑开展侧重于预防急性移植物抗宿主病和（或）与其他药物联合进行一线治疗的MSC研究。
