Steroid-resistant and therapy-refractory aGVHD is still the main cause of allogeneic HSCT related mortality. The 2-year nonrelapse mortalities of these patients were up to 84%(30). Since the first report of MSC administration to treat a child with refractory steroid-resistant aGVHD(7), numerous studies confirmed the potential benefit of this therapy to steroid-refractory aGVHD. However, there are not many of clinical trails to treat aGVHD with UC-MSCs(26, 27). Compare to BM, UC is an abundant source of MSCs (24, 25) since it is a kind of “waste” after delivery. Besides, the harvesting procedure of UC-MSC is non-invasive, and has no ethical issues. What’s more, UC-MSCs revealed higher potential of immunomodulatory capacity than BM-MSCs(31). To the best of our knowledge, this is the results of so far the largest single-center cohorts of 88 patients receiving UC-MSCs to treat steroid-resistant and therapy-refractory acute GI GVHD. Though the findings have some limitations as it is a single-center retrospective study and there is no control group, it can be viewed as a real-world scenario to assess the therapeutic effect of UC-MSCs. In our study, no patients showed any adverse effects due to UC-MSC infusions, the application of UC-MSCs was confirmed to be safe.
Our results showed that UC-MSC infusion to treat steroid-resistant and therapy-refractory acute GI GVHD has led to an overall response rate (OR) of 51.14% (45 of 88 patients) by day 28. Le Blanc et al. reported an overall response rate of 71% (39 of 55 patients), 84% in children and 60% in adults(8). However, the response of the treatment was assessed at a median of 18 days (3–63 days) after the first MSC infusion. In our study, we used day 28 response as an outcome parameter, according to updated recommendations(32). Kaipe et al(33) summarized the data of 190 patients with aGVHD treated with MSCs of published studies and found a CR of 52% and PR of 23% (75% OR) after 4 weeks of MSCs infusion. A possible explanation for the inferior results we reported could be the disease severity of our patients: in our study, most of our patients (82%) had grade IV aGVHD. This is a more severely disease cohort than in most published series. Besides, the only prospective, randomized, double-blind phase III placebo-controlled trial of an industrial third-party BMSC product (Prochymal) for treating steroid-refractory GVHD reported no significant differences in effects between BMSC and placebo-treated groups. This indicates the complex of this disease and the difficulty to value a single treatment in supplement with other second-line immunosuppressive therapies ---- most of our patients had received more than two additional treatments before UC-MSC infusion. Still, these results we obtained with such a highly challenging patient cohort (18% grade III and 82% IV) suggests the advantage of the treatment of aGVHD with UC-MSC.
Liver involvement along with GI aGVHD is associated with a worse response in our study. This probably cannot be regarded as a MSC-specific predictor since it has been frequently identified in non-MSC approaches.
We did not observe any difference in response rates between children and adults (P = 0.76) and this disagrees with most of the studies demonstrated a trend towards a better clinical response in children(11, 12,). Our pediatric cohort demonstrated an OR of 46%, which in inferior to that reported by Introna et al(10) of 66.7%. However, in their patient cohort, only 25% of the patients exhibited aGVHD over grade III, whereas in our cohort, 23.5% of the patients exhibited grade III aGVHD and 76.5% grade IV, this may be a possible explanation for our finding.
In addition, MSC infusion frequency, once a week or twice a week, has not been shown to affect response rates. Among the final survivors, 14 patients received UC-MSCs once a week, 13 patients twice a week, and 2 patients only received UC-MSCs for one time. And from our experience, the UC-MSCs will be announced invalid after 4-week treatment.
The survival at the last follow-up in July 2020 in our cohort, with a median follow-up of 66 months (26–122 months) from the onset of aGVHD, was approximately 33% (29/88), better than that of a previous report with an OS of 22% for their MSC-treated patients with GVHD after a median follow-up of 767 days (range 74–1270 days)(34). To be more specific, the survival rate was 25.7% in our adult cohort, which was similar with the result of von Dalowski et al.(35), while 61.1% in the child cohort. In our study, children have significant better survival rate than adults.