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Mesenchymal Stem Cells for Prophylaxis of Chronic Graft-vs-Host Disease After Haploidentical Hematopoietic Stem Cell Transplant: An Open-Label Randomized Clinical Trial
Huang, R., Chen, T., Wang, S., Wang, J., Su, Y., Liu, J., Zhang, Y., Ma, X., Wen, Q., Kong, P., et al
JAMA oncology. 2023
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Abstract
IMPORTANCE Chronic graft-vs-host disease (GVHD) limits the long-term benefit of haploidentical hematopoietic stem cell transplant (HSCT). This clinical trial evaluated repeated infusions of umbilical cord mesenchymal stem cells (MSCs) during the early stage (45 days and 100 days) after haplo-HSCT to prevent chronic GVHD. OBJECTIVE To determine whether repeated infusions of MSCs during the early stage after haplo-HSCT decreases the incidence of severe chronic GVHD. DESIGN, SETTING, AND PARTICIPANTS This open-label, multicenter, parallel randomized clinical trial was conducted from April 2016 to January 2022. Eligibility criteria included a diagnosis of acute leukemia and having a haploidentical, suitable related donor for HSCT. The median (range) follow-up time was 39.0 (1.5-67.0) months. INTERVENTIONS The enrolled patients with a haploidentical relative for HSCT received the modified busulfan/cyclophosphamide + antithymocyte globulin modified regimen and standard GVHD prophylaxis. Patients were randomly chosen to receive MSCs (the MSC group) (1 × 106 cells/kg, every 2 weeks, starting from 45 days after transplant, 4 times total) or regular prophylaxis (control group). MAIN OUTCOME AND MEASURE The cumulative incidence of severe chronic GVHD. RESULTS Of 158 patients, 58 (36.7%) were female individuals; the median (range) age for the MSC and control groups was 28 (18-60) years and 28 (18-56) years, respectively. A total of 158 patients were screened, and 148 patients were randomly assigned to the MSC group (n = 74) or control group (n = 74) 1 day before MSCs infusion. The estimated 2-year cumulative incidence of severe chronic GVHD was 5.4% (95% CI, 1.8%-14.0%) in the MSC group and 17.4% (95% CI, 10.1%-28.5%) in the control group (hazard ratio [HR], 0.29; 95% CI, 0.10-0.88; P = .03). There was no difference between the MSC and control groups in the cumulative incidence of leukemia relapse (HR, 1.17; 95% CI, 0.55-2.47; P = .68). The cumulative incidence of stage II to IV acute GVHD in the MSC group was significantly lower than that in the control group (HR, 0.25; 95% CI, 0.09-0.67; P = .01). The MSC group had better GVHD-free and relapse-free survival rates than the control group (HR, 0.62; 95% CI, 0.39-0.98; P = .04). CONCLUSIONS AND RELEVANCE The results of this randomized clinical trial show that early repeated infusions of MSCs decreased the incidence and severity of chronic GVHD, and the incidence and severity of acute GVHD manifested as a better GVHD-free and relapse-free survival rate for patients after haplo-HSCT. TRIAL REGISTRATION Chinese Clinical Trial Registry: ChiCTR-IIR-16007806.
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T-cell and cytokine dynamics in the blood of patients after hematopoietic stem cell transplantation and multipotent mesenchymal stromal cells administration
Petinati, N., Davydova, Y., Nikiforova, K., Bigildeev, A., Belyavsky, A., Arapidi, G., Drize, N., Kuzmina, L., Parovichnikova, E., Savchenko, V.
Transplantation and cellular therapy. 2022
Abstract
BACKGROUND Multipotent mesenchymal stromal cells (MSCs) are currently under intense investigation for treatment and prevention of graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT), owing to their substantial immunomodulatory properties. The responses of recipients to MSC infusion following allo-HSCT are not yet well understood. T-cells are central to the adaptive immune system, protecting organism from infection and malignant cells. Memory T-cells with different phenotypes, gene expression profiles and functional properties are critical for immune processes regulation. OBJECTIVE The aim of this work was to study the dynamics of memory T-cells subpopulations and cytokines in blood of allo-HSCT patients after MSCs administration. STUDY DESIGN In clinical trial NCT01941394 patients after allo-HSCT were randomized into two groups: the one receiving standard GVHD prophylaxis and another one receiving additionally MSCs infusion on the day of recovery of leukocytes to 1000 cells/μl (engraftment, day E0). The blood samples of patients from both groups were analyzed on days E0, E+3 and E+30. Subpopulations of T-cells were studied by flow cytometry and concentration of cytokines was evaluated by the Bio-Plex Pro Human Cytokine Panel. RESULTS Administration of MSCs to patients on day E0 did not affect the overall dynamics of restoration of absolute numbers and the proportion of T and B lymphocytes after 3 and 30 days. Three days after MSCs injection, only the numbers of CD8+ effector cells (CD8+TE, CD8+TM, CD8+EM) were found to increase significantly. Significant increase in a number of CD4+ cells after 30 days compared to day E0 was observed only in patients who received MSCs, which indicates a faster recovery of CD4+ cell population following MSC injection. Increase in CD8+ cell number by day E+30 was significant regardless of MSC administration. To characterize the immune status of patients following allo-HSCT in more detail, changes in the cytokine concentration in the peripheral blood of patients on days E0, E+3 and E+30 after the administration of MSCs were investigated. On day E+30, significant increase in the number of CD4+CM and activated CD4+CD25+ cells was observed. The concentration of pro- and anti-inflammatory cytokines IL-6, IL-8, IL-17, TNF-α and IFN-γ, significantly increased in patients injected with MSCs. Analysis of the growth factor levels showed that in the group of patients who received MSCs, the concentration of G-CSF, CM-CSF, PDGFbb, FGFb and IL-5 increased by day E+30. Among the cytokines involved in the regulation of the immune response, the concentration of IL-9, Eotaxin, IP-10, MCP-1, and MIP-1a increased after 30 days, regardless of the MSCs administration. CONCLUSION The administration of MSCs exerts a positive effect on restoration of T-cell subpopulations and recovery of immune system of patients after allo-HSCT.
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Co-transplantation of bone marrow-derived mesenchymal stem cells with hematopoietic stem cells does not improve transplantation outcome in class III beta-thalassemia major: A prospective cohort study with long-term follow-up
Rostami, T., Maleki, N., Kasaeian, A., Nikbakht, M., Kiumarsi, A., Asadollah Mousavi, S., Ghavamzadeh, A.
Pediatric transplantation. 2020;:e13905
Abstract
Bone marrow transplantation is the only curative treatment for beta-thalassemia major. Data on the co-transplantation of MSCs with HSCs in beta-thalassemia major patients are scarce. We aimed to investigate the outcomes of thalassemia major patients who underwent bone marrow-derived MSC co-transplantation with HSCs compared with those who only received HSCs. This prospective randomized study included patients with class III thalassemia major undergoing HSCT divided randomly into two groups: Thirty-three patients underwent co-transplantation of bone marrow-derived MSCs with HSCs, and 26 patients only received HSCs. Five-year OS, TFS, TRM, graft rejection rate, and GVHD were estimated. The 5-year OS was 66.54% (95% CI, 47.8% to 79.9%) in patients who underwent co-transplantation of MSCs with HSCs vs 76.92% (95% CI, 55.7% to 88.9%) in patients who only received HSCs (P = .54). No significant difference was observed in the 5-year TFS between the two groups (59.1% vs 69.2%; P = .49). The 5-year cumulative incidence of TRM was not statistically significant among patients who underwent co-transplantation of MSCs with HSCs (27.27%) vs those who only received HSCs (19.23%; P = .61). There was no statistically significant difference in graft rejection, acute GvHD, and chronic GvHD between the two groups. Based on our findings, the co-transplantation of MSCs and HSCs to class III thalassemia major patients does not alter their transplantation outcomes including OS, TFS, rejection rate, transplant-related mortality, and GvHD.
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Pre-infusion single-dose mesenchymal stem cells promote platelet engraftment and decrease severe acute graft versus host disease without relapse in haploidentical peripheral blood stem cell transplantation
Wang, X., Zhang, M., He, P.
The Journal of international medical research. 2020;48(5):300060520920438
Abstract
BACKGROUND Mesenchymal stem cells (MSCs) may be used to treat steroid-refractory graft versus host disease (GVHD). However, the effects of MSCs in haploidentical peripheral blood stem cell transplantation (haplo-PBSCT) have not been confirmed in randomized studies. METHODS We conducted a randomized clinical study to investigate the effects of pre-infusion (1 x 10(6) cells/kg) MSCs on hematopoietic recovery, Epstein-Barr and cytomegalovirus infection, GVHD, and relapse in patients undergoing haplo-PBSCT. Fifty patients with acute leukemia or myelodysplastic syndrome were randomly divided into an MSC group administered 1 x 10(6) MSCs/kg 4 to 6 hours before infusion of peripheral stem cells and a control group without MSCs. RESULTS Mean platelet engraftment time was significantly faster in the MSC compared with the control group (12.28 vs 13.29 days). The mean neutrophil engraftment time was comparable in both groups (10.76 +/- 2.40 vs. 10.29 +/- 1.72 days). Grade II or above acute GVHD was significantly decreased in the MSC compared with the control group (12% vs. 36%). There were no significant differences in relapse rate or overall survival between the groups. CONCLUSION These results suggest that pre-infusion single-dose MSCs promote platelet engraftment and decrease severe acute GVHD without increasing relapse rate.
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Analysis of multipotent mesenchymal stromal cells used for acute graft-versus-host disease prophylaxis
Kuzmina, L. A., Petinati, N. A., Shipounova, I. N., Sats, N. V., Bigildeev, A. E., Zezina, E. A., Popova, M. D., Drize, N. J., Parovichnikova, E. N., Savchenko, V. G.
European Journal of Haematology. 2016;96(4):425-34
Abstract
BACKGROUND Multipotent mesenchymal stromal cells (MSCs) are used for prophylaxis of acute graft-versus-host disease (aGvHD) after allogeneic hematopoietic cell transplantation (allo-HCT). Not all samples of MSC are efficient for aGvHD prevention. The suitability of MSCs for aGvHD prophylaxis was studied. METHODS MSCs were derived from the bone marrow (BM) of HCT donor and cultivated for no more than three passages. The characteristics of donor BM samples including colony-forming unit fibroblast (CFU-F) concentration, growth parameters of MSCs, and the relative expression levels (REL) of different genes were analyzed. MSCs were injected intravenously precisely at the moment of blood cell reconstitution. RESULTS MSCs infusion induced a significant threefold decrease in aGvHD development and improved overall survival compared with the standard prophylaxis group. In ineffective MSC samples (9.4%), a significant decrease in total cell production and the REL of CSF1, FGFR1, and PDGFRB was observed. In all studied BM samples, the cumulative MSC production and CFU-F concentrations decreased with age. The expression levels of FGFR2, PPARG, and VEGF differed by age. CONCLUSIONS A universal single indicator for the prediction of MSC eligibility for aGvHD prophylaxis was not identified. A multiparameter mathematical model for selecting MSC samples effective for the prevention of aGvHD was proposed. Copyright © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.