Insights About Mesenchymal Stromal Cells As Therapeutic Option In Refractory Graft Versus Host Disease.
 

Background: Graft versus host disease (GVHD) is a major drawback for haematopoietic stem cell transplant (SCT). Steroids are the main therapy. However, steroid resistance has poor outcome. Mesenchymal stromal cells (MSCs) had been assessed in several clinical trials but no consistent results.

Methods and results: Here, we present a meta-analysis to explore the potential role of MSCs in steroid refractory acute GVHD (SR-aGVHD). We analysed 15 trials with total of 1084 patients. Primary end points were the safety of MSCs IVI and overall response rate. Secondary end points included complete response rate (CR), overall survival (OS) and relapse rate. Also, we analysed effect of other variables on outcome such as the GVHD severity, age of recipients and cell related variables.

Most trials reported safe MSCs IVI. Overall response rate (ORR) was 0.61 and complete cure rate (CR) was 0.28. The overall survival (OS) was 0.33 and relapse rate was 0.11 at median 14 and 12 months respectively. Severity of GVHD correlated negatively with ORR.

Age of the recipients did not incur any significant difference. Dose of 1x106 cell/kg was equivalent to higher doses. Frequency of MSCs IVI showed significant effect. Four or more IVIs within 28 days correlated with better ORR and OS. ORR and OS were comparable between cryopreserved MSCs and fresh cells. 

Conclusion: MSCs IVI is a safe effective therapeutic modality for SR-aGVHD. Dose of 1x106 cell/kg and frequency of 4 or more IVI within first 4 weeks seem the optimal conditions. This is likely related to in-vivo enhanced MSCs apoptosis and cell death with short durability. Therefore, repeated infusions are needed to prolong efficacy.

ORR post MSCs in SR-aGVHD. The mean effect size is the ORR. ORR was 0.61 with 95% CI 0.53-0.7 with PI 0.27 – 0.9.

ORR: overall response rate, MSCs: Mesenchymal stromal cells, CI: confidence interval, PI: prediction interval.