Efficacy and safety of human umbilical cord-derived mesenchymal stem cells in the treatment of refractory immune thrombocytopenia: a prospective, single arm, phase I trial

Abstract

Patients with refractory immune thrombocytopenia (ITP) frequently encounter substantial bleeding risks and demonstrate limited responsiveness to existing therapies. Umbilical cord-derived mesenchymal stem cells (UC-MSCs) present a promising alternative, capitalizing on their low immunogenicity and potent immunomodulatory effects for treating diverse autoimmune disorders. This prospective phase I trial enrolled eighteen eligible patients to explore the safety and efficacy of UC-MSCs in treating refractory ITP. The research design included administering UC-MSCs at escalating doses of 0.5 × 10⁶ cells/kg, 1.0 × 10⁶ cells/kg, and 2.0 × 10⁶ cells/kg weekly for four consecutive weeks across three cohorts during the dose-escalation phase, followed by a dose of 2.0 × 10⁶ cells/kg weekly for the dose-expansion phase. Adverse events, platelet counts, and changes in peripheral blood immunity were monitored and recorded throughout the administration and follow-up period. Ultimately, 12 (with an addition of three patients in the 2.0 × 10⁶ cells/kg group due to dose-limiting toxicity) and six patients were enrolled in the dose-escalation and dose-expansion phase, respectively. Thirteen patients (13/18, 72.2%) experienced one or more treatment emergent adverse events. Serious adverse events occurred in four patients (4/18, 22.2%), including gastrointestinal hemorrhage (2/4), profuse menstruation (1/4), and acute myocardial infarction (1/4). The response rates were 41.7% in the dose-escalation phase (5/12, two received 1.0 × 10⁶ cells/kg per week, and three received 2.0 × 10⁶ cells/kg per week) and 50.0% (3/6) in the dose-expansion phase. The overall response rate was 44.4% (8/18) among all enrolled patients. To sum up, UC-MSCs are effective and well tolerated in treating refractory ITP (ClinicalTrials.gov ID: NCT04014166).

Fig. 1

Flow diagram of the study. Twenty-two patients were screened for eligibility, 3 patients were excluded based on the eligibility criteria, and one patient withdrew informed consent. Finally, 18 patients were enrolled in the study. In the dose-escalation phase, 12 patients were enrolled and assigned to the 3-dose group, and 6 patients were subsequently enrolled in the dose-expansion phase

Fig. 2

Treatment response, outcomes and platelet counts over time in all patients. a The best responses, concomitant medications, and rescue therapy of all 18 patients with different infusion doses (0.5 × 10⁶ cells/kg, 1.0 × 10⁶ cells/kg, and 2.0 × 10⁶ cells/kg) are shown in the swimmer plot. GC glucocorticoids, TPO-RA thrombopoietin receptor agonist, R response. b The mean platelet counts of all enrolled patients from baseline to 24 weeks after the completion of UC-MSC administration. Data are the mean ± s.e.m., and different colors represent different infusion doses of UC-MSCs

Fig. 3

The peripheral immune monitoring plan of enrolled patients and the dynamic changes in peripheral blood immune cells after receiving UC-MSC infusion. a Blood samples were collected from all enrolled patients for platelet count and peripheral blood immune subpopulation monitoring at baseline and 2, 4, 8, 12, 16 and 24 weeks after the first infusion (peripheral blood samples at the baseline and 2 week observation points were collected within 2 h before the UC-MSC infusion). b, c Changes in the proportion of CD8+ T cells in peripheral lymphocytes after UC-MSC infusion (n = 8 in the response group, n = 8 in the no response group). d, e Changes in the proportion of suppressor T cells (Tregs, CD8⁺CD28⁻ T cells) after UC-MSC infusion (n = 8 in the response group, n = 10 in the no response group). f, g Dynamic changes in the counts and percentages of CD19⁺ B cells in peripheral blood after UC-MSC infusion (n = 8 in the response group, n = 9 in the no response group). Due to the impact of COVID-19, some follow-up data of enrolled patients were missing. Consequently, for the evaluation of peripheral immune alterations, we consolidated observations at 16 weeks and 24 weeks, presenting them as ≥16 weeks. Data are the mean ± s.e.m., and different colors represent different infusion doses of UC-MSCs in the scatterplots: purple = 0.5 × 10⁶ cells/kg, green = 1.0 × 10⁶ cells/kg, red = 2.0 × 10⁶ cells/kg. Statistical analysis was conducted using independent samples t-tests or Wilcoxon signed-rank test, with a significance level set at p < 0.05. W weeks, R response, NR no response

Fig. 4

Quantitative analysis of plasma cytokine concentrations before and after UC-MSC infusion. The concentrations of 12 kinds of cytokines were measured before (0), during UC-MSC infusion (2 weeks), and after UC-MSC infusion (4 weeks) in the response and no response group, respectively (n = 8 in the response group, n = 10 in the no response group). The levels of plasma IL-1β, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-17A, IFN-α, and TNF-α had significantly increased after the infusion of UC-MSC (all p < 0.05). No significant changes were observed in the response group before and after the UC-MSC infusion. Data are the mean ± s.e.m., circle represents response group, square represents no response group. And different colors represent different infusion doses of UC-MSCs in the scatterplots: purple = 0.5 × 10⁶ cells/kg, green = 1.0 × 10⁶ cells/kg, red = 2.0 × 10⁶ cells/kg. Statistical analysis was conducted using paired t-test or Wilcoxon signed-rank test, with a significance level set at p < 0.05. W weeks, R response, NR no response