Allogeneic Human Mesenchymal Stem Cell Therapy (Remestemcel-L, Prochymal) as a Rescue Agent for Severe Refractory Acute Graft-versus-Host Disease in Pediatric Patients

Abstract

Severe steroid-refractory acute graft-versus-host disease (aGVHD) is related to significant mortality and morbidity after allogeneic stem cell transplantation. Early clinical trials of therapy with human mesenchymal stem cells (hMSCs) in pediatric patients with severe aGVHD resistant to multiple immunosuppressive agents showed promising results. In this study, we evaluated the risk/benefit profile of remestemcel-L (Prochymal), a third-party, off-the-shelf source of hMSCs, as a rescue agent for treatment-resistant aGVHD in pediatric patients. Children with grade B-D aGVHD failing steroids and, in most cases, other immunosuppressive agents were eligible for enrollment. Patients received 8 biweekly i.v. infusions of 2 × 10(6) hMSCs/kg for 4 weeks, with an additional 4 weekly infusions after day +28 for patients who achieved either a partial or mixed response. The enrolled patients compose a very challenging population with severe disease that was nonresponsive to the standard of care, with 88% of the patients experiencing severe aGVHD (grade C or D). Seventy-five patients (median age, 8 yr; 58.7% male; and 61.3% Caucasian) were treated in this study. Sixty-four patients (85.3%) had received an unrelated hematopoietic stem cell graft, and 28 patients (37.3%) had received a cord blood graft. At baseline, the distribution of aGVHD grades B, C, and D was 12.0%, 28.0%, and 60.0%, respectively. The median duration of aGVHD before enrollment was 30 d (range, 2 to 1639 d), and patients failed a median of 3 immunosuppressive agents. Organ involvement at baseline was 86.7% gastrointestinal, 54.7% skin, and 36.0% liver. Thirty-six patients (48.0%) had 2 organs involved, and 11 patients (14.7%) had all 3 organs involved. When stratified by aGVHD grade at baseline, the rate of overall response (complete and partial response) at day +28 was 66.7% for aGVHD grade B, 76.2% for grade C, and 53.3% for grade D. Overall response for individual organs at day +28 was 58.5% for the gastrointestinal system, 75.6% for skin, and 44.4% for liver. Collectively, overall response at day +28 for patients treated for severe refractory aGVHD was 61.3%, and this response was correlated with statistically significant improved survival at day +100 after hMSC infusion. Patients who responded to therapy by day +28 had a higher Kaplan-Meier estimated probability of 100-d survival compared with patients who did not respond (78.1% versus 31.0%; P < .001). Prochymal infusions were generally well tolerated, with no evidence of ectopic tissue formation.

Umbilical cord-derived stem cells (ModulatistTM) show strong immunomodulation capacity compared to adipose tissue-derived or bone marrow-derived mesenchymal stem cells

“…The first stem cells (Prochymal TM ) were BMderivedallogenic MSCs, and were approved in 2012 in Canada. Now, several countries are using Prochymal TM to manage GVHD (Chen et al, 2014;Kurtzberg et al, 2014;Prasad et al, 2011). Recently, another form of MSCs was approved in Japan for GVHD (Konishi et al, 2016).…”

Human Mesenchymal Stem Cell Therapy for Acute Graft Versus Host Disease

“…In the study, Prochymal was administered at two different dose (2 or 8 × 106 cells/kg) with corticosteroid as the first line therapy to the patients with grade II-IV acute GVHD and the overall response rate was 93% (CR, 77%; PR, 16%). Subsequently, several studies of manufactured MSC therapy for steroid-resistant refractory acute GVHD have been reported (summarized in Table 2) [39][40][41][42][43][44]. CR and overall response rate were 24-58% and 60-93%, which were similar to the results of MSC therapy from individual donors.…”

Application of mesenchymal stem cells in paediatrics

“…The results of the study indicate a rather high effectiveness of MSC when used in GvHD [36]. The efficiency and safety of mesenchymal stem cells contained in Prochymal, was also described by Kurtzberg et al in 2014. They treated 75 patients (whose average age was 8) suffering from GvHD affecting the gastrointestinal tract, the skin and/or liver.…”

“…The post-treatment assessment showed satisfactory results in most patients (total or partial remission at day +28 was 66.7% for GVHD grade B, 76.2% for grade C, and 53.3% for grade D). Patients, whose initial respond to the treatment was poor, received additional doses of the cells, which produced good final results [27]. The volume and number of the infusion of MSC in GvHD is still being discussed in literature.…”