Mesenchymal stem cells for treating gastrointestinal-involved steroid-refractory acute graft-versus-host disease: A multicenter, single-arm, pivotal clinical Trial

Abstract Background: Steroid-refractory acute graft-versus-host disease (SR-aGVHD) is the predominant cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (allo-HSCT), in which SR-gastrointestinal-aGVHD (SR-GI-aGVHD) remains one of the major obstacles. We designed a multicenter, single-arm, pivotal clinical trial to assess the efficacy and safety of hUC-MSC PLEB001, a human umbilical cord-derived mesenchymal stem cells (MSCs) product, as second-line therapy for SR-GI-aGVHD. Methods: This study is a multi-center, single-arm pivotal clinical trial in which eligible patients received hUC-MSC PLEB001 therapy plus one second-line treatment conducted per institution for SR-GI-aGVHD of grade Ⅱ or above. All eligible patients received hUC-MSC PLEB001 infusion with a dose of 106 cell/kg and frequency of twice weekly for consecutive 4 weeks. The day of first administration was set as day 1 and all subjects underwent efficacy assessment on day 28. If a patient's response is CR, progressive disease (PD) or no response (NR), the treatment is concluded; if the response is PR, the treatment will continue for additional 4 weeks with the same dose and frequency. The primary endpoint of the study is the overall response rate (ORR) at day 28 after the first administration. Secondary and safety endpoints included complete response (CR) at day 28, ORR at day 56, CR at day 56, 28-day durable complete response rate (DCR), overall survival (OS), ECOG score, non-relapse mortality (NRM), failure-free survival (FFS), and adverse events. Results: Fifty-four patients with a median age of 43(range: 14, 68) years were enrolled. The number of Grade II-Ⅳ SR-aGVHD patients was 21, 16, 17, respectively. Thirty-seven patients were GI-involved only, 15 patients were GI and skin involved, and 2 patients were GI and liver involved. The overall ORR at day 28 was 63.0% (95% CI: 48.74%, 75.71%). The CR rate at day 28 was 55.6% (41.40%, 69.08%). The 28-day DCR rate was 51.9% (37.84%, 65.66%). The ORR and CR rate at day 56 was 51.9% (37.84%, 65.66%) and 50.0% (36.08%, 63.92%), respectively. The OS for full analysis set (FAS) at day 28, 56, 100, 360 for the entire cohort were 94.4% (83.8%, 98.2%), 88.9% (76.9%, 94.9%), 79.6% (66.2%, 88.2%), 65.8% (51.1%, 77.0%) respectively. The median FFS was 65.5 days (95%CI: 44, 180). The incidence of chronic GVHD (cGVHD) and moderate-to-severe cGVHD at day 360 was 33.3% (21.1%, 46.1%) and 29.6% (18.0%, 42.2%), respectively. Fifty-three patients were reported to have experienced 1712 adverse events. No infusion toxicity adverse event was reported. Conclusions: This study suggests the efficacy and good tolerance of hUC-MSC PLEB001 in SR-GI-aGVHD patients, based on which hUC-MSC PLEB001 (Amimestrocel) became the first approved MSC product by Chinese NMPA.