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Mesenchymal stromal cell therapy induces high responses and survival in children with steroid refractory GVHD and poor risk biomarkers
Kasikis, S., Baez, J., Gandhi, I., Grupp, S., Kitko, C. L., Kowalyk, S., Merli, P., Morales, G., Pulsipher, M. A., Qayed, M., et al
Bone marrow transplantation. 2021
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A Phase 3, Single-arm, Prospective Study of Remestemcel-L, Ex-vivo Culture-Expanded Adult Human Mesenchymal Stromal Cells, for the Treatment of Pediatric Patients who Failed to Respond to Steroid Treatment for Acute GVHD
Kurtzberg, J., Abdel-Azim, H., Carpenter, P., Chaudhury, S., Horn, B., Mahadeo, K., Nemecek, E., Neudorf, S., Prasad, V., Prockop, S., et al
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2020
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Editor's Choice
Abstract
Steroid-refractory acute graft-versus-host disease (SR-aGVHD) following hematopoietic cell transplantation (HSCT) is associated with poor clinical outcomes. Currently, there are no safe and effective therapies approved for use in the pediatric population under the age of 12 years. Accordingly, there is an urgent need for new treatments that are safe, well-tolerated and effective in managing this debilitating and potentially fatal complication of HSCT. In early phase clinical trials, Mesenchymal stromal cells (MSCs) have demonstrated efficacy in the treatment of acute GVHD (aGVHD) in pediatric patients. We now report the results of a phase 3, prospective, single arm, multicenter study (NCT02336230) in 54 children with primary SR-aGVHD who were naive to other immunosuppressant therapies (IST) for aGVHD treated with MSC product (remestemcel-L) dosed at 2x10(6) cells/kg twice weekly for four weeks. Remestemcel-L therapy significantly improved day 28 overall response rate (OR) compared to the pre-specified control OR value of 45% (70.4% versus 45%, P =0.0003). The statistically significant OR (70.4%) was sustained through day 100 including an increase in complete response (CR) from 29.6% at day 28 to 44.4% at day 100. Overall survival was 74.1% at day 100 and 68.5% at day 180. Overall response in all participants at day 28 was highly predictive of improved survival through 180 days and survival was significantly greater in day 28 responders compared with non-responders through day 100 (86.8% vs. 47.1% for responders and non-responders, respectively, P=0.0001) and through day 180 (78.9% vs. 43.8%, p=0.003). Remestemcel-L was well-tolerated with no identified infusion-related toxicities or other safety concerns. This study provides robust, prospective evidence of the safety, tolerability and efficacy of remestemcel-L as first-line therapy after initial steroid failure in pediatric SR-aGVHD.
PICO Summary
Population
Children with primary steroid refractory aGVHD, naive to other immunosuppressant therapies (n=54)
Intervention
Mesenchymal stromal cell product (remestemcel-L) dosed at 2x10(6) cells/kg twice weekly for four weeks.
Comparison
None
Outcome
Remestemcel-L therapy significantly improved day 28 overall response rate (OR) compared to the pre-specified control OR value of 45% (70.4% versus 45%). The statistically significant OR (70.4%) was sustained through day 100 including an increase in complete response (CR) from 29.6% at day 28 to 44.4% at day 100. Overall survival was 74.1% at day 100 and 68.5% at day 180. Overall response in all participants at day 28 was highly predictive of improved survival through 180 days and survival was significantly greater in day 28 responders compared with non-responders through day 100 (86.8% vs. 47.1% for responders and non-responders, respectively) and through day 180 (78.9% vs. 43.8%) Remestemcel-L was well-tolerated with no identified infusion-related toxicities or other safety concerns.
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Study 275: Updated Expanded Access Program for Remestemcel-L in Steroid-Refractory Acute Graft-Versus-Host Disease (SR-aGVHD) in Children
Kurtzberg, J., Prockop, S., Chaudhury, S., Horn, B., Nemecek, E., Prasad, V., Satwani, P., Teira, P., Hayes, J., Burke, E.
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2020
Abstract
Clinical outcomes in children with steroid-refractory acute graft-versus-host disease (SR-aGVHD) are generally poor with a high mortality rate and limited therapeutic options. We report here our updated investigational experience with mesenchymal stromal cell therapy (remestemcel-L) used in a multicenter expanded access protocol (NCT00759018) in 241 children with aGVHD who failed to respond to steroids with or without other secondary and tertiary immunosuppressive therapies (IST). A total of 241 children with Grade B-D steroid refractory (SR) aGVHD were enrolled in 50 sites in eight countries and received eight biweekly intravenous infusions of human mesenchymal stromal cells (hMSCs) 2x10(6) per kg for four weeks, with an option for an additional four weekly infusions after day 28 for subjects who achieved either a partial or mixed response. Mean age of subjects was 9.6 years; 39% were female, and 60% were white. Most of the subjects had grade C (30%) or grade D (50%) disease and in most cases, the subjects had failed to respond to other immunosuppressive agents after failing steroids. The primary endpoint was overall response rate (ORR, the sum of complete and partial response) at day 28. Across all subjects, the 28 day ORR, was observed in n=157 (65.1%) with 34 (14.1%) and 123 (51.3%) achieving complete and partial responses, respectively. Stratified by aGVHD grade at baseline, the rate of overall response at day 28 was 72.9% for aGVHD grade B, 67.1% for grade C, and 60.8% for grade D subjects. Survival through day 100, a secondary endpoint of the study was 66.9% (n=160/239). Importantly, survival through day 100 was significantly greater in subjects that achieved a day 28 OR (82.1%) compared with non-responders (38.6%), log rank p<0.001. Remestemcel-L safety was generally well tolerated with no infusional toxicity and no identified safety concerns. In summary, this update to the remestemcel-L EAP confirms the reported clinical and survival benefits of remestemcel-L therapy in children with aGVHD who have exhausted all conventional therapeutic options.
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Children and Adults with Refractory Acute Graft-versus-Host Disease Respond to Treatment with the Mesenchymal Stromal Cell Preparation "MSC-FFM"-Outcome Report of 92 Patients
Bonig, H., Kuci, Z., Kuci, S., Bakhtiar, S., Basu, O., Bug, G., Dennis, M., Greil, J., Barta, A., Kallay, K. M., et al
Cells. 2019;8(12)
Abstract
(1) Background: Refractory acute graft-versus-host disease (R-aGvHD) remains a leading cause of death after allogeneic stem cell transplantation. Survival rates of 15% after four years are currently achieved; deaths are only in part due to aGvHD itself, but mostly due to adverse effects of R-aGvHD treatment with immunosuppressive agents as these predispose patients to opportunistic infections and loss of graft-versus-leukemia surveillance resulting in relapse. Mesenchymal stromal cells (MSC) from different tissues and those generated by various protocols have been proposed as a remedy for R-aGvHD but the enthusiasm raised by initial reports has not been ubiquitously reproduced. (2) Methods: We previously reported on a unique MSC product, which was generated from pooled bone marrow mononuclear cells of multiple third-party donors. The products showed dose-to-dose equipotency and greater immunosuppressive capacity than individually expanded MSCs from the same donors. This product, MSC-FFM, has entered clinical routine in Germany where it is licensed with a national hospital exemption authorization. We previously reported satisfying initial clinical outcomes, which we are now updating. The data were collected in our post-approval pharmacovigilance program, i.e., this is not a clinical study and the data is high-level and non-monitored. (3) Results: Follow-up for 92 recipients of MSC-FFM was reported, 88 with GvHD ≥ degrees III, one-third only steroid-refractory and two-thirds therapy resistant (refractory to steroids plus ≥2 additional lines of treatment). A median of three doses of MSC-FFM was administered without apparent toxicity. Overall response rates were 82% and 81% at the first and last evaluation, respectively. At six months, the estimated overall survival was 64%, while the cumulative incidence of death from underlying disease was 3%. (4) Conclusions: MSC-FFM promises to be a safe and efficient treatment for severe R-aGvHD.
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Effective treatment of steroid and therapy-refractory acute graft-versus-host disease with a novel mesenchymal stromal cell product (MSC-FFM)
Bader, P., Kuci, Z., Bakhtiar, S., Basu, O., Bug, G., Dennis, M., Greil, J., Barta, A., Kallay, K. M., Lang, P., et al
Bone marrow transplantation. 2018
Abstract
The inability to generate mesenchymal stromal cells (MSCs) of consistent potency likely is responsible for inconsistent clinical outcomes of patients with aGvHD receiving MSC products. We developed a novel MSC manufacturing protocol characterized by high in vitro potency and near-identity of individual doses, referred to as "MSC-Frankfurt am Main (MSC-FFM)". Herein, we report outcomes of the 69 patients who have received MSC-FFM. These were 51 children and 18 adults with refractory aGvHD grade II (4%), III (36%) or IV (59%). Patients were refractory either to frontline therapy (steroids) (29%) or to steroids and 1-5 additional lines of immunosuppressants (71%) were given infusions in four weekly intervals. The day 28 overall response rate was 83%; at the last follow-up, 61% and 25% of patients were in complete or partial remission. The median follow-up was 8.1 months. Six-month estimate for cumulative incidence of non-relapse mortality was 27% (range, 16-38); leukemia relapse mortality was 2% (range, 0-5). This was associated with a superior six-month overall survival (OS) probability rate of 71% (range, 61-83), compared to the outcome of patients not treated with MSC-FFM. This novel product was effective in children and adults, suggesting that MSC-FFM represents a promising therapy for steroid refractory aGvHD.
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Mesenchymal Stem Cell Treatment for Steroid Refractory Graft-versus-Host Disease in Children: A Pilot and First Study from Turkey
Erbey, F., Atay, D., Akcay, A., Ovali, E., Ozturk, G.
Stem Cells International. 2016;2016:1641402
Abstract
This study evaluated the efficacy of mesenchymal stem cells (MSCs) from bone marrow of a third-party donor for refractory aGVHD. We report the first experience using MSCs to treat refractory aGVHD in 33 pediatric patients undergoing allogeneic HSCT from Turkey. Totally, 68 doses of bone marrow derived MSCs were infused. The median dose of MSC was 1.18 x 10(6) cells per kg body weight. Overall, complete response (CR) was documented in 18 patients, partial response (PR) was documented in 7 patients, and no response (NR) was documented in 8 patients. The 2-year estimated probability of overall survival (OS) for patients achieving CR and PR/NR was 63.8% and 29.4%, respectively (p = 0.0002). While the cumulative incidence of transplant related mortality (TRM) at day 100 after first MSC infusion was 46.6% in PR/NR patients, there was no any TRM at day 100 after first MSC infusion in CR patients (p = 0.001). Twelve patients developed chronic GVHD (cGVHD); eight of them were alive, with five having extensive disease and three having limited disease. In conclusion, MSCs appear to be safe and effective treatment option for pediatric patients with steroid refractory aGVHD. But the efficacy of MSCs on cGVHD in aGVHD patients treated with MSCs seems to be limited.