Human Umbilical Cord Derived Mesenchymal Stromal Cells for Treatment of Steroid-resistant and Therapy-refractory III-IV Acute Gastrointestinal Graft-versus-host Disease: An Open-label, Single-center, Self-control and Phase I/II Study

Background: Acute graft-versus-host disease (aGVHD) is a life-threatening complication after allogeneic hematopoietic stem cell transplantation. First-line treatment of aGVHD is corticosteroid. Second-line therapy mainly comprises immunosuppressants. However, ∼ 25% of the patients have a steroid-resistant and therapy-refractory disease, which is associated with a very poor prognosis. An alternative therapy option for steroid-refractory and therapy-refractory aGVHD is the use of mesenchymal stromal cells (MSCs). Here, we report the results of 88 patients with grade III-IV aGVHD treated with human umbilical cord derived mesenchymal stromal cells (UC-MSC). Methods: There were 18 children and 70 adults with grade III/ IV aGVHD (82% grade IV). These patients were either resistant to steroids or refractory to 1–5 additional immunosuppressants. UC-MSCs were transfused at a median dose of 1 × 106 cells/kg with a median of 4 times (range, 1 to 16). Results: Median time between the onset of aGVHD and the first infusion of UC-MSC was 7 days (range, 3–88). The day 28 overall response rate was 51.14%, of these, 24 patients (27.27%) showed complete remission (CR), 21 (23.86%) showed partial remission (PR). The estimated survival probability at 100 days was 43.3%. And after a median follow-up of 66 months (26–122 months), the survival rate was approximately 33% (29/88). Patients developed acute gastrointestinal (GI) tract and liver GVHD showed worse overall response in day 28 than patients only with acute GI GVHD (21% vs. 58%; p= 0.037). No patient had severe side effects. Conclusions: These results suggest that UC-MSC treatment was safe and effective in children and adults, and should be considered for treating steroid-refractory aGVHD. Trial registration: ClinicalTrials: NCT01754454. Registered 21 December 2012 - Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT01754454?cond=msc+gvhd&draw=2&rank=8