Mesenchymal stromal cell infusion to treat steroid-refractory acute GvHD III/IV after hematopoietic stem cell transplantation

Abstract

Acute GvHD (aGvHD) is a life-threatening complication of hematopoietic stem cell transplantation. Frontline therapy for aGvHD consists of corticosteroid administration. However, ∼25% of the patients have a steroid-refractory disease, a sign of poor prognosis. An alternative therapy for steroid-refractory aGvHD is infusion of mesenchymal stromal cells (MSCs). Herein, we report the results of 46 patients treated with MSC infusion as salvage therapy for steroid-refractory aGvHD III/IV (78% grade IV). Patients received a median cumulative dose of MSCs of 6.81 × 10/kg (range, 0.98-29.78 × 10/kg) in a median of 3 infusions (range, 1-7). Median time between the onset of aGvHD and the first MSC infusion was 25.5 days (range, 6-153). Of the patients, 50% (23/46) presented clinical improvement. Of these, 3 patients (13%) had complete response, 14 (61%) had partial response and 6 (26%) had transient partial response. The estimated probability of survival at 2s year was 17.4%. Only 2 patients (4.3%) presented acute transient side effects (nausea/vomiting and blurred vision) during cell infusion. No patient had late or severe side effects because of MSC infusion. These results suggest that this therapeutic modality is safe and should be considered for steroid-refractory aGvHD, especially in countries where other second-line agents are less available.

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).…”

Clinical Use of Mesenchymal Stromal Cells in the Treatment of Acute Graft-versus-Host Disease

“…Bader et al [5] reported a large cohort of patients with refractory aGvHD who received the completely new product “MSC-FFM.” The overall response rate at day +28 as an outcome parameter was 83%. Indeed, these results are very encouraging compared with other aGvHD studies [21, 28, 29, 31, 32]. To our knowledge, so far MSC-FFM offered the best response rates of all MSC preparations in children and especially in adults.…”

“…Ball et al [23] demonstrated a better OS (56%) and lower TRM (17%) in patients who received MSCs between days +5 and +12 after steroid initiation compared with treatment between days +13 and +85 (25 and 53%; p = 0.22 and p = 0.06). Dotoli et al [31], Dalowski et al [32], and also Salmenniemi et al [30] reported considerably lower response rates and OS. Bader et al [5] reported a large cohort of patients with refractory aGvHD who received the completely new product “MSC-FFM.” The overall response rate at day +28 as an outcome parameter was 83%.…”

“…In a multicenter, retrospective study of 3 Brazilian public hospitals, 46 patients were treated with MSCs between October 2007 and March 2015 [31]. Sixteen children and 30 adults with steroid-refractory aGvHD grade III (21.7%) and grade IV (78.3%) were included.…”

Clinical potential of mesenchymal stem/stromal cell-derived extracellular vesicles

“…Dotoli and colleagues published the results of 46 patients treated with MSC infusion as salvage therapy for steroid-refractory acute GvHD III/IV (78% grade IV), recently (41). Patients in this study received a median cumulative dose of 6.81×10 6 MSCs per kg bodyweight in a median of three infusions.…”