Mesenchymal stromal cells in management of steroid refractory acute graft vesrus host disease, systematic review and meta-analysis

Graft versus host disease (GVHD) is a major drawback for haematopoietic stem cell transplant (SCT). Steroids are the main therapy. However, steroid resistance (SR) has poor outcome. Mesenchymal stromal cells (MSCs) had been assessed in several clinical trials but no consistent results. Here we present a systematic review and meta-analysis to explore the potential role of MSCs in steroid refractory acute GVHD (SR-aGVHD). We analysed 16 trials with total of 1301 patients. Primary end points included the safety of MSCs intravenous infusion (IVI), overall response rate (ORR) and overall survival (OS). Secondary end points included complete response rate (CR), relapse rate (RR) and organ specific response. Also, we analysed effect of other variables on outcome such as conditioning intensity, GVHD severity, age of recipients and MSCs related variables. ORR was 0.61 with 95% CI 0.54-0.67, CR rate was 0.29 with a 95% CI 0.23-0.36. Regarding organ specific response, Skin-ORR was 0.73, 95% CI 0.6-0.84, Gut-ORR was 0.62, 95% CI 0.54-0.7 and Liver-ORR was 0.55, 95% CI: 0.37-0.73. No statistically significant difference between the 3 organs ORR. At a median of 12 months, OS was 0.34 with 95% CI 0.29-0.4. However, in the controlled trials OS post MSCs was comparable with the control and ratio was 1.15, 95% CI of 0.81-1.62 and P = 0.4. RR was 0.10, 95% CI 0.06-0.15. Also, RR in controlled trials was comparable between MSCs recepients and control, risk ratio was 0.62, 95% CI of 0.3-1.25 and P = 0.18. Regarding heterogeniety, we assessed effect of conditioning intensity, recepients' age, GVHD severity and MSCs related variables. ORR post "MAC" was comparable with "nMAC", P = 0.7. GVHD grade IV cohorts had ORR of 0.51 while less severe GVHD had ORR 0.66 and P = 0.006. Young age (< 50 ys) was associtaed with better ORR and OS. ORR in "young" was 0.64 while older age had ORR of 0.5 and P = 0.04. And OS in "young" was 0.41 while older cohort had OS 0.25 and P = 0.04. Regarding MSCs related variables, dose of 1 × 10⁶ cell/kg was comparable with [Formula: see text] 2 × 10⁶ cell/kg. However, frequent MSCs infusions " [Formula: see text] 4 IVIs in first 28 days" was associated with ORR 0.64, 95% CI 0.56-0.72 while ORR in the infrequent infusions cohort was 0.47, 95% CI 0.34 - o.62 and P = 0.04. This was also translated to better survival. OS in the "Frequent" cohort was 0.4, 95% CI 0.35-0.45 while OS in the "Infrequent" cohort was 0.22, 95% CI 0.17-0.28 and P < 0.0001. Otherwise, once weekly MSCs infusion was equivalent to twice weekly and ORR post cryopreserved MSCs was comparable with fresh cells. MSCs IVI is a safe effective therapeutic modality for SR-aGVHD. Dose of 1 × 10⁶ cell/kg and frequency of 4 or more IVI within first 4 weeks seem the optimal conditions.