背景:对于患有类固醇难治性急性移植物抗宿主病(SR-aGVHD)的患者,迫切需要有效的二线治疗方案。过去,间充质基质细胞(MSC)已被用作SR-aGVHD的抢救方案。然而,临床试验和对MSCs联合巴利昔单抗治疗SR-aGVHD的分子机制的总体了解有限,尤其是在单倍体相合造血干细胞移植(HIDHSCT)中。
方法:此多中心的主要终点,随机化,对照试验是SR-aGVHD的4周完全缓解(CR)率。总共130名SR-aGVHD患者以1:1的随机时间表分配到MSC组(接受巴利昔单抗加MSC)或对照组(单独接受巴利昔单抗)(NCT04738981)。
结果:大多数入组患者(96.2%)接受HIDHSCT。MSC组SR-aGVHD4周CR率明显优于对照组(83.1%vs.55.4%,P=0.001)。然而,对于第4周的总体缓解率,两组具有可比性.对照组中有更多患者使用≥6剂量的巴利昔单抗(4.6%vs.20%,P=0.008)。我们收集了19例连续患者的血液样本,并评估了MSC来源的免疫抑制细胞因子,包括HO1、GAL1、GAL9、TNFIA6、PGE2、PDL1、TGF-β和HGF。与MSC输注前的水平相比,MSC输注后1天,HO1(P=0.0072)和TGF-β(P=0.0243)水平显着增加。在MSC输注后7天,HO1、GAL1、TNFIA6和TGF-β水平有升高的趋势;差异无统计学意义。尽管MSC组cGVHD的52周累积发生率与对照组相当,MSC组较少患者发生cGVHD累及≥3个器官(14.3%vs.43.6%,P=0.006)。MSCs耐受性良好,两组间未发生输液相关不良事件(AE),其他AE也具有可比性.然而,MSC组恶性血液病患者52周无病生存率高于对照组(84.8%vs.65.9%,P=0.031)。
结论:对于allo-HSCT后的SR-aGVHD,尤其是HIDHSCT,MSCs和巴利昔单抗联合作为二线治疗方案,其4周CR率显著优于单用巴利昔单抗.添加MSC不仅没有增加毒性,而且提供了存活益处。
BACKGROUND: For patients with steroid-refractory acute graft-versus-host disease (SR-aGVHD), effective second-line regimens are urgently needed. Mesenchymal stromal cells (MSCs) have been used as salvage regimens for SR-aGVHD in the past. However, clinical trials and an overall understanding of the molecular mechanisms of MSCs combined with basiliximab for SR-aGVHD are limited, especially in haploidentical haemopoietic stem cell transplantation (HID HSCT).
METHODS: The primary endpoint of this multicentre, randomized, controlled trial was the 4-week complete response (CR) rate of SR-aGVHD. A total of 130 patients with SR-aGVHD were assigned in a 1:1 randomization schedule to the MSC group (receiving basiliximab plus MSCs) or control group (receiving basiliximab alone) (NCT04738981).
RESULTS: Most enrolled patients (96.2%) received HID HSCT. The 4-week CR rate of SR-aGVHD in the MSC group was obviously better than that in the control group (83.1% vs. 55.4%, P = 0.001). However, for the overall response rates at week 4, the two groups were comparable. More patients in the control group used ≥ 6 doses of basiliximab (4.6% vs. 20%, P = 0.008). We collected blood samples from 19 consecutive patients and evaluated MSC-derived immunosuppressive cytokines, including HO1, GAL1, GAL9, TNFIA6, PGE2, PDL1, TGF-β and HGF. Compared to the levels before MSC infusion, the HO1 (P = 0.0072) and TGF-β (P = 0.0243) levels increased significantly 1 day after MSC infusion. At 7 days after MSC infusion, the levels of HO1, GAL1, TNFIA6 and TGF-β tended to increase; however, the differences were not statistically significant. Although the 52-week cumulative incidence of cGVHD in the MSC group was comparable to that in the control group, fewer patients in the MSC group developed cGVHD involving ≥3 organs (14.3% vs. 43.6%, P = 0.006). MSCs were well tolerated, no infusion-related adverse events (AEs) occurred and other AEs were also comparable between the two groups. However, patients with malignant haematological diseases in the MSC group had a higher 52-week disease-free survival rate than those in the control group (84.8% vs. 65.9%, P = 0.031).
CONCLUSIONS: For SR-aGVHD after allo-HSCT, especially HID HSCT, the combination of MSCs and basiliximab as the second-line therapy led to significantly better 4-week CR rates than basiliximab alone. The addition of MSCs not only did not increase toxicity but also provided a survival benefit.