This up-to-date meta-analysis comprehensively examined the published literature to evaluate the efficacy of co-transplantation of MSCs and haplo-HSCT in patients with SAA. To the best of our knowledge, this is the first meta-analysis to compare the clinical outcomes of MSCs with no MSCs in haplo-HSCT in patients with SAA. The results of our study are partially consistent with previous a meta-analysis examining the effects of MSCs post-transplantation of haplo-HSCT in haematological malignancies15.
Our study demonstrated no significant difference with regard to the pooled incidences of GVHD between MSCs and no MSCs group. It’s well known that GVHD remains the common and life-threatening complication limiting the widespread use of haplo-HSCT, as it associates with a high mortality and morbidity58. Since there were no controlled studies, we compared the incidence of aGVHD, grade II-IV aGVHD and cGVHD in MSCs group and no MSCs group. Although the incidence of aGVHD was higher than no MSCs group, the incidences of grade II-IV aGVHD and cGVHD were lower than the pooled results in no MSCs group. But no significant differences were found between these two groups pooled results. Which is different from previous studies supported a role of MSCs in reducing the incidence of GVHD. Despite these previous studies showing that MSCs are effective in GVHD prophylaxis or treatment, most of them were conducted in vitro or in haematological malignancies. Moreover, the conclusions were drawn in HSCT area without highlighting on haplo-HSCT59–61. Hence, MSCs may make little or no difference to the risk of GVHD compared to no MSCs in haplo-HSCT for SAA patients.
Among MSCs group, four of eight studies achieved 100% hematopoietic reconstitution and full donor chimerism after the application of MSCs in haplo-HSCT, which is higher than no MSCs group (4/17). Although MSCs were higher than no MSCs group with regard to the pooled results of 2-year OS and engraftment rates in our report, no statistically significant differences were found. Furthermore, it’s reported that infections are the other major causes of death after haplo-HSCT in addition to GVHD62. We calculated the rates of death due to infection. The pooled result was 9.5% (95% CI, 5.8–13.1%) in the included studies in MSCs group, which was much lower than those reported by Center for International Blood and Marrow Transplant Research (CIBMTR), for all haplo-HSCT transplants conducted between 2009 and 2010 (infection: 13–18%)63. CMV infections are opportunistic infections caused by low immune function. A reduction in CMV infection after allo-HSCT can be achieved by hastening post-transplant immune reconstitution. Therefore, co-transplantation of MSCs and haplo-HSCT seemed like making no contribution to immune reconstitution in SAA patients.
It’s reported that MSCs produce growth factors to aid tissue regeneration and accelerate the haematologic reconstitution64. The median post-HSCT times to neutrophil greater than 0.5 × 109 /L and platelet greater than 20 × 109 /L were summarized and listed in Table 1–2. The shortest and longest median time to achieve neutrophil engraftment and platelet engraftment were (11–14 days) and (13–21 days) respectively in MSCs group; (10–19 days) and (13–28 days) respectively in no MSCs group. Remarkably, all studies in MSCs group reported results descriptively and stated that they observed either rapid engraftment 37 or a similar speed of engraftment after adding MSCs31, 32, which may demonstrate a role for MSCs in the enhancement of engraftment in SAA patients who underwent haplo-HSCT.
According to the published papers, the treatment efficacy of MSCs varies among clinical trials, and MSCs source might influence this65. The studies included in this meta-analysis used only BM-MSCs or UC-MSCs. Therefore, we conducted a subgroup meta-analysis for GVHD prevention according to MSC source. Consequently, the incidence of GVHD shows no significant difference with regard to the use of UC-MSCs versus BM-MSCs. Besides, we conducted “influence analysis” in Stata to explore the source of heterogeneity in no MSCs group. We could reasonably infer that studies (Jennifer et al39 and Gao et al40) were one of the most important sources resulting in the heterogeneity of aGVHD and cGVHD respectively. Both of them were conducted in earlier years with different conditioning regimes and prophylaxis measures.
There are some limitations in our meta-analysis. First, there may be a risk of confounding biases because various baseline characteristics or co-interventions including age, gender, donor type, conditioning regimen and MSCs originals may affect the treatment outcomes in SAA patients after haplo-HSCT, they were not fully controlled in this study. In addition, patients in no MSCs group usually had high heterogeneity. Although we tried to decrease the bias through statistical methods, sometimes errors were unavoidable. Second, because SAA is a rare disorder, few prospective control trails between the MSCs and no MSCs group are available so far, and all the included studies had small sample sizes. Besides, all were single-arm studies and case series that lacked a control group and likely suffered from a high risk of selection bias. Last but not least, we could not assess publication bias using funnel plots because we only had single-arm studies and case series.
In conclusion, our meta-analysis indicates that the prophylactic use of MSCs co-transplantation does not reduce the incidence of GVHD and improve 2-year OS in patients with SAA undergoing haplo-HSCT. Hence, the general co-transplantation of MSCs in routine clinical practice for SAA haplo-HSCT recipients is not recommended. However, since there is no direct evidence from comparative study to support this conclusion, more prospective, randomized controlled trials (RCTs) are needed to confirm whether MSCs convey a definite benefit for haplo-HSCT for SAA patients.