Efficacy and Safety of Ex Vivo Cultured Adult Human Mesenchymal Stem Cells (Prochymal™) in Pediatric Patients with Severe Refractory Acute Graft-Versus-Host Disease in a Compassionate Use Study

Abstract

Preliminary studies using directed-donor ex vivo expanded human mesenchymal stem cells (hMSCs) have shown promise in the treatment of acute graft-versus-host disease (aGVHD). However, their production is cumbersome and standardization is difficult. We describe the first experience of using a premanufactured, universal donor, formulation of hMSCs (Prochymal) in children (n = 12; 10 boys; 9 Caucasian; age range: 0.4-15 years) with treatment-resistant grade III and IV aGVHD who received therapy on compassionate use basis between July 2005 and June 2007 at 5 transplant centers. All patients had stage III or IV gut (GI) symptoms and half had additional liver and/or skin involvement. Disease was refractory to steroids in all cases and additionally to a median of 3 other immunosuppressive therapies. The hMSCs (8 × 10(6)cells/kg/dose in 2 patients and 2 × 10(6)cells/kg/dose in the rest) were infused intravenously over 1 hour twice a week for 4 weeks. Partial and mixed responders received subsequent weekly therapy for 4 weeks. HLA or other matching was not needed. The hMSCs were started at a median of 98 days (range: 45-237) posttransplant. A total of 124 doses were administered, with a median of 8 doses (range: 2-21) per patient. Overall, 7 (58%) patients had complete response, 2 (17%) partial response, and 3 (25%) mixed response. Complete resolution of GI symptoms occurred in 9 (75%) patients. Two patients relapsed after initial response and showed partial response to retreatment. The cumulative incidence of survival at 100 days from the initiation of Prochymal therapy was 58%. Five of 12 patients (42%) were still alive after a median follow-up of 611 days (range: 427-1111) in surviving patients. No infusional or other identifiable acute toxicity was seen in any patient. Multiple infusions of hMSCs were well tolerated and appeared to be safe in children. Clinical responses, particularly in the GI system, were seen in the majority of children with severe refractory aGVHD. Given the favorable results observed in a patient population with an otherwise grave prognosis, we conclude that hMSCs hold potential for the treatment of aGVHD, and should be further studied in phase III trials in pediatric and adult patients.

Co-transplantation of third-party umbilical cord blood-derived MSCs promotes engraftment in children undergoing unrelated umbilical cord blood transplantation

“…54,55 In the present study, the incidences of acute and chronic GVHD were not different between the two groups. Although a recent study has shown that parental MSCs decreased the grade III-IV acute GVHD, given the immunosuppressive properties of MSCs, which are upregulated in the inflammatory milieu, 56,57 it may be more appropriate to use them for the treatment rather than the prophylaxis of GVHD.…”

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

“…This study included 12 children with III or IV degree of GvHD resistance to other treatments. 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.…”

“…No side effects were documented during and immediately after MSC infusion [22]. Safety application of mesenchymal stem cells from third-party donor is also described in the work of Prasad et al [36]. In this study, patients received MSC contained in the product called 'Prochymal'.…”