Infusion of bone marrow derived multipotent mesenchymal stromal cells for the treatment of steroid-refractory acute graft-versus-host disease: a multicenter prospective study

Abstract

The prognosis of steroid-refractory acute graft-versus-host disease (aGVHD) remains poor and better treatments are urgently needed. Multipotent mesenchymal stromal cell (MSC)-based therapy emerged as a promising approach but response rates were highly variable across studies. We conducted a multicenter prospective study assessing the efficacy of 1–2 infusion(s) of cryopreserved, third-party donor bone marrow-derived MSCs for treating grade II-IV steroid-refractory or -dependent aGVHD in a series of 33 patients. MSCs were produced centrally and distributed to 8 hospitals throughout Belgium to be infused in 2 consecutive cohorts of patients receiving 1–2 or 3–4 × 106 MSCs/kg per dose, respectively. All patients received MSCs as the first rescue therapy after corticosteroids, with the exception for one patient who received prior treatment with mycophenolate mofetil (that was still ongoing by the time of MSC therapy). In these conditions, MSC therapy resulted in at least a partial response in 13 patients (40.6%) at day 30 and in 15 patients (46%) within 90 days after first MSC infusion. The corresponding complete response rates were 21.6% (7 patients) and 30% (10 patients), respectively. Only 5 patients achieved a sustained complete response, lasting for at least 1 month. The 1-year overall survival was 18.2% (95% CI: 8.82–37.5%). Higher response and survival rates were observed among patients receiving 3–4 × 106 MSCs/kg for first infusion, as compared with patients receiving 1–2 × 106 MSCs/ kg. Response and survival with MSC therapy for SR/SD-aGVHD remains to be optimized.

Mesenchymal stromal cells for acute graft‐versus‐host disease: response at 1 week predicts probability of survival

“…However, the obtainment of any kind of response (either PR or CR) was sufficient to affect OS. This is consistent with previous studies in patients who, like ours, were refractory to several lines of treatment (Resnick et al, 2013;Kurtzberg et al, 2014;von Dalowski et al, 2016;Muroi et al, 2016;Dotoli et al, 2017;Servais et al, 2018). In contrast, other groups have reported that, when MSCs were administered soon after steroids, only CR are associated with improved OS (Le Blanc et al, 2008;Kebriaei et al, 2009;S anchez-Guijo et al, 2014).…”

“…This observation is in contrast with other reports (Ball et al, 2013;von Dalowski et al, 2016) but the discrepancy could be ascribed to the fact that, in those studies, the dose ranges were too narrow and the number of patients too small to identify any correlation between response and dose. Our data have been confirmed by a recent multicentre prospective study, in which patients who received doses of 3-4x10 6 /kg body-weight had better responses and longer survival rates than those who received 1-2 9 10 6 /kg bodyweight (Servais et al, 2018). Our study confirms that patient age and the affected organ significantly affect responses to MSCs (Resnick et al, 2013;S anchez-Guijo et al, 2014).…”

Mesenchymal Stromal Cells for Graft Versus Host Disease: Mechanism-Based Biomarkers

“…Furthermore, an important consequence of these observations is that, although MSCs remain the necessary starting point for therapeutic immunosuppression, patient-derived cells play a crucial role in delivering such an immunosuppression. This new perspective, in line with clinical data whereby MSCs from the same donor can give different responses in different patients ( 72 – 74 , 76 , 78 , 79 , 150 ), may significantly affect the Research and Development sector of MSC manufacturing. In the last decades, much efforts have been spent on the identification of the most clinically effective MSC preparations.…”

“…Albeit not strikingly biomarkers by definition, there have been several associative factors which can seemingly influence MSC responses among aGvHD patients. Dosage of MSC infusion, age of MSC recipients and organ involvement have been reported as affecting responses in aGvHD patients (72,77,78,82,84,85,130). Briefly, patients who received higher MSC doses (78,85), younger patients (72,82,84,85), or patients with gut or/and skin involvement seem to achieve a better response to MSCs (77,85,130).…”

“…Dosage of MSC infusion, age of MSC recipients and organ involvement have been reported as affecting responses in aGvHD patients ( 72 , 77 , 78 , 82 , 84 , 85 , 130 ). Briefly, patients who received higher MSC doses ( 78 , 85 ), younger patients ( 72 , 82 , 84 , 85 ), or patients with gut or/and skin involvement seem to achieve a better response to MSCs ( 77 , 85 , 130 ). However, these results have not been confirmed in other studies ( 73 , 79 , 131 ), and should be considered with caution.…”