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Mesenchymal stromal cells for the prophylaxis and treatment of graft-versus-host disease-a meta-analysis
Morata-Tarifa, C., Macias-Sanchez, M. D. M., Gutierrez-Pizarraya, A., Sanchez-Pernaute, R.
Stem cell research & therapy. 2020;11(1):64
Abstract
BACKGROUND Graft-versus-host disease (GvHD) is the main life-threatening complication of allogeneic hematopoietic stem cell transplantation (HSCT). Thirty to 80% of GvHD patients do not respond to first-line treatment and a second-line treatment is not universally established. Based on their immunomodulatory properties, mesenchymal stromal cells (MSC) have been proposed for the prevention and the treatment of GvHD in patients undergoing HSCT. Unfortunately, previous studies reported conflicting results regarding the prophylactic and therapeutic effects of MSC for GvHD. Consequently, we carried out a meta-analysis to clarify whether MSC administration can improve the dismal outcome of these patients. METHODS We carried out a systematic review and selected studies (2004-2019) reporting data about the administration of allogeneic MSC for the prevention (n = 654 patients) or treatment of acute (n = 943 patients) or chronic (n = 76 patients) GvHD after HSCT. Our primary outcome was overall survival at the last follow-up. The secondary outcomes were the response and development of GvHD. Subgroup analyses included age, MSC dose, first infusion day after HSCT, number of organs and organ-specific involvement, acute GvHD grade (I-IV), and chronic GvHD grade (limited or extensive). RESULTS Patients infused with MSC for GvHD prophylaxis showed a 17% increased overall survival (95% CI, 1.02-1.33) and a reduced incidence of acute GvHD grade IV (RR = 0.22; 95% CI, 0.06-0.81) and chronic GvHD (RR = 0.64; 95% CI, 0.47-0.88) compared with controls. Overall survival of acute GvHD patients (0.50; 95% CI, 0.41-0.59) was positively correlated with MSC dose (P = 0.0214). The overall response was achieved in 67% (95% CI, 0.61-0.74) and was complete in 39% (95% CI, 0.31-0.48) of acute patients. Organ-specific response was higher for the skin. Twenty-two percent (95% CI, 0.16-0.29) of acute patients infused with MSC developed chronic GvHD. Sixty-four percent (95% CI, 0.47-0.80) of chronic patients infused with MSC survived; the overall response was 66% (95% CI, 0.55-0.76) and was complete in 23% (95% CI 0.12-0.34) of patients. CONCLUSIONS Our meta-analysis indicates that allogeneic MSC could be instrumental for the prophylaxis and treatment of GvHD. Future trials should investigate the effect of the administration of MSC as an adjuvant therapy for the treatment of patients with GvHD from the onset of the disease.
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The role of mesenchymal stem cells in hematopoietic stem cell transplantation: prevention and treatment of graft-versus-host disease
Zhao, L., Chen, S., Yang, P., Cao, H., Li, L.
Stem cell research & therapy. 2019;10(1):182
Abstract
BACKGROUND The use and effectiveness of hematopoietic stem cell transplantation (HSCT) are limited by lethal complications, i.e., acute and chronic graft-versus-host disease (aGVHD and cGVHD, respectively), in which immune cells from the donor attack healthy recipient tissues. GVHD presents both prophylactic and therapeutic challenges, and overall survival is poor. Mesenchymal stem cells (MSCs) show considerable promise in the treatment of GVHD because of their potential immunomodulatory activity. Multiple studies have been performed to explore the possible benefit of MSCs in GVHD, but the results of these studies are sometimes conflicting. Therefore, we performed a systematic review and meta-analysis to estimate the effect of MSC infusion on GVHD treatment and prevention. METHODS We systematically searched the MEDLINE (PubMed), Cochrane Library, EMBASE, ClinicalTrials.gov, and SinoMed CBM databases to identify studies published before February 2018 involving patients with hematologic malignancies undergoing HSCT and receiving MSC-based or conventional therapy. We included studies if they reported on the outcomes of interest. RESULTS Ultimately, 10 studies were selected from among 413 candidates. According to our meta-analyses, compared with conventional treatment, MSC therapy demonstrated substantial improvements in terms of complete response (CR) and overall survival for cGVHD. However, MSC therapy did not show substantial improvements in terms of engraftment, the incidence of aGVHD, relapse, death, death due to relapse, or death due to infection. Subgroup analyses showed that MSCs derived from the umbilical cord (U-MSCs) and MSC infusion after HSCT substantially improved engraftment and cGVHD incidence, whereas MSCs derived from bone marrow (B-MSCs) and MSC infusion before HSCT shows no improvement. In addition, B-MSCs and MSC infusion before HSCT tend to prolong engraftment time, as well as increase the rates of relapse and death. CONCLUSIONS MSC infusion can reduce cGVHD but not aGVHD incidence and showed a positive effect in patients who already had aGVHD. For GVHD prevention, the use of U-MSCs and MSC infusion after HSCT were optimal for reducing cGVHD incidence and promoting engraftment, and might help decrease the incidence rate of relapse and death. However, B-MSCs and MSC infusion before HSCT may be harmful to patients and thus require serious consideration. A lack of robust evidence, owing to the small number of studies and small sample sizes, indicates a need for further high-quality clinical trials including large numbers of patients to validate our findings.
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Mesenchymal stromal cells as treatment or prophylaxis for acute or chronic graft-versus-host disease in haematopoietic stem cell transplant (HSCT) recipients with a haematological condition
Fisher, S. A., Cutler, A., Doree, C., Brunskill, S. J., Stanworth, S. J., Navarrete, C., Girdlestone, J.
The Cochrane database of systematic reviews. 2019;1:Cd009768
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Abstract
BACKGROUND Recipients of allogeneic haematopoietic stem cell transplants (HSCT) can develop acute or chronic, or both forms of graft-versus-host disease (a/cGvHD), whereby immune cells of the donor attack host tissues. Steroids are the primary treatment, but patients with severe, refractory disease have limited options and a poor prognosis. Mesenchymal stromal cells (MSCs) exhibit immunosuppressive properties and are being tested in clinical trials for their safety and efficacy in treating many immune-mediated disorders. GvHD is one of the first areas in which MSCs were clinically applied, and it is important that the accumulating evidence is systematically reviewed to assess whether their use is favoured. OBJECTIVES To determine the evidence for the safety and efficacy of MSCs for treating immune-mediated inflammation post-transplantation of haematopoietic stem cells. SEARCH METHODS We searched for randomised controlled trials (RCTs) in the Cochrane Central Register of Controlled Trials (CENTRAL, the Cochrane Library 2018, Issue 12), MEDLINE (from 1946), Embase (from 1974), CINAHL (from 1937), Web of Science: Conference Proceedings Citation Index-Science (CPCI-S) (from 1990) and ongoing trial databases to 6 December 2018. No constraints were placed on language or publication status. SELECTION CRITERIA We included RCTs of participants with a haematological condition who have undergone an HSCT as treatment for their condition and were randomised to MSCs (intervention arm) or no MSCs (comparator arm), to prevent or treat GvHD. We also included RCTs which compared different doses of MSCs or MSCs of different sources (e.g. bone marrow versus cord). We included MSCs co-transplanted with haematopoietic stem cells as well as MSCs administered post-transplantation of haematopoietic stem cells. DATA COLLECTION AND ANALYSIS We used standard methodological procedures expected by Cochrane.We employed a random-effects model for all analyses due to expected clinical heterogeneity arising from differences in participant characteristics and interventions. MAIN RESULTS We identified 12 completed RCTs (879 participants), and 13 ongoing trials (1532 enrolled participants planned). Of 12 completed trials, 10 compared MSCs versus no MSCs and two compared different doses of MSCs. One trial was in people with thalassaemia major, the remaining trials were for haematological malignancies. Seven trials administered MSCs to prevent GvHD, whereas five trials gave MSCs to treat GvHD.In the comparison of MSCs with no MSCs, cells were administered at a dose of between 10(5) and 10(7) cells/kg in either a single dose (six trials) or in multiple doses (four trials) over a period of three days to four months. The dose-comparison trials compared 2 x 10(6) cells/kg with 8 x 10(6) cells/kg in two infusions, or 1 x 10(6) cells/kg with 3 x 10(6) cells/kg in a single infusion.The median duration of follow-up in seven trials which administered MSCs prophylactically ranged from 10 to 60 months. In three trials of MSCs as treatment for aGvHD, participants were followed up for 90 or 100 days. In two trials of MSCs as treatment for cGvHD, the mean duration of follow-up was 13.4 months (MSC group) and 23.6 months (control group) in one trial, and 56 weeks in the second trial. Five trials included adults only, six trials included adults and children, and one trial included children only. In eight trials which reported the gender distribution, the percentage of females ranged from 20% to 59% (median 35.8%).The overall quality of the included studies was low: randomisation methods were poorly reported and several of the included studies were subject to a high risk of performance bias and reporting bias. One trial which started in 2008 has not been published and the progress of this trial in unknown, leading to potential publication bias. The quality of evidence was therefore low or very low for all outcomes due to a high risk of bias as well as imprecision due to the low number of overall participants, and in some cases evidence based on a single study. We found that MSCs may make little or no difference in the risk of all-cause mortality in either prophylactic trials (HR 0.85, 95% CI 0.50 to 1.42; participants = 301; studies = 5; I(2) = 34% ; low-quality evidence) or therapeutic trials (HR 1.12, 95% CI 0.80 to 1.56; participants = 244; studies = 1; very low-quality evidence), and no difference in the risk of relapse of malignant disease (prophylactic trials: RR 1.08, 95% CI 0.73 to 1.59; participants = 323; studies = 6; I(2) = 0%; low-quality evidence) compared with no MSCs. MSCs were well-tolerated, no infusion-related toxicity or ectopic tissue formation was reported. No study reported health-related quality of life. In prophylactic trials, MSCs may reduce the risk of chronic GvHD (RR 0.66, 95% CI 0.49 to 0.89; participants = 283; studies = 6; I(2) = 0%; low-quality evidence). This means that only 310 (95% CI 230 to 418) in every 1000 patients in the MSC arm are expected to develop chronic GvHD compared to 469 in the control arm. However, MSCs may make little or no difference to the risk of aGvHD (RR 0.86, 95% CI 0.63 to 1.17; participants = 247; studies = 6; I(2) = 0%; low-quality evidence). In GvHD therapeutic trials, we are very uncertain whether MSCs improve complete response of either aGvHD (RR 1.16, 95% CI 0.79 to 1.70, participants = 260, studies = 1; very low-quality evidence) or cGvHD (RR 5.00, 95%CI 0.75 to 33.21, participants = 40, studies = 1; very low-quality evidence).In two trials which compared different doses of MSCs, we found no evidence of any differences in outcomes. AUTHORS' CONCLUSIONS MSCs are an area of intense research activity, and an increasing number of trials have been undertaken or are planned. Despite a number of reports of positive outcomes from the use of MSCs for treating acute GvHD, the evidence to date from RCTs has not supported the conclusion that they are an effective therapy. There is low-quality evidence that MSCs may reduce the risk of cGvHD. New trial evidence will be incorporated into future updates of this review, which may better establish a role for MSCs in the prevention or treatment of GvHD.
PICO Summary
Population
Adults and children with haematological malignancies (11 trials) or thalassaemia (1 trial) undergoing allogeneic stem cell transplantation, or suffering from GvHD.
Intervention
Mesenchymal stromal cells
Comparison
No MSCs (10 trials) or different dose of MSCs (2 trials)
Outcome
MSCs were well-tolerated, no infusion-related toxicity or ectopic tissue formation was reported. In prophylactic trials, MSCs may reduce the risk of chronic GvHD. However, MSCs may make little or no difference to the risk of aGvHD. In GvHD therapeutic trials, it is very uncertain whether MSCs improve complete response of either aGvHD or cGvHD. In two trials which compared different doses of MSCs, no evidence was found of any differences in outcomes.
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Remestemcel-L for the treatment of graft versus host disease
Locatelli, F., Algeri, M., Trevisan, V., Bertaina, A.
Expert Review of Clinical Immunology. 2017;13(1):43-56
Abstract
INTRODUCTION Remestemcel-L, a third-party, off-the-shelf preparation of bone-marrow derived mesenchymal stromal cells (MSCs), has been developed for experimental use in acute graft-versus-host disease (aGvHD) and other immune-mediated conditions. Several preclinical and clinical studies have indeed suggested the potential of human mesenchymal stromal cells (MSCs) as an effective treatment for steroid-refractory aGvHD. However, an unambiguous demonstration of efficacy is still lacking. Areas covered: This review critically examines the biologic rationale supporting MSCs use in aGvHD and analyzes the results of published clinical trials in this setting, with a particular focus on the potential benefits and drawbacks of Remestemcel-L. For this purpose, a systematic literature search was performed in PubMed using the following keywords: 'mesenchymal stromal cells', 'mesenchymal progenitor cells', 'multipotent stromal cells', 'mesenchymal cells', 'MSC', 'Remestemcel-L', 'Prochymal', and 'graft-versus-host disease' or 'GvHD'. Expert commentary: Remestemcel-L represents a promising alternative to second-line immunosuppressive agents for the treatment of steroid-refractory aGvHD. Despite the safety and the favorable risk/benefit profile of this cell product, which has been demonstrated in several phase I-II studies, large and prospective randomized trials are required to confirm its efficacy in aGvHD and to define the optimal schedule of administration in terms of infusion timing, cell dose and pharmacological synergism.
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Heterogeneity in Studies of Mesenchymal Stromal Cells to Treat or Prevent Graft-versus-Host Disease: A Scoping Review of the Evidence
Rizk, M., Monaghan, M., Shorr, R., Kekre, N., Bredeson, C. N., Allan, D. S.
Biology of Blood & Marrow Transplantation. 2016;22(8):1416-23
Abstract
Effective treatments are lacking for the treatment of steroid-refractory graft-versus-host disease (GVHD), a major cause of morbidity and mortality after allogeneic hematopoietic cell transplantation. Mesenchymal stromal cells (MSCs) have demonstrated promise but there is uncertainty regarding their clinical effectiveness. A systematic scoping review of the literature was performed to characterize the heterogeneity of published studies and identify opportunities for standardization. Thirty studies were identified, including 19 studies (507 patients) addressing the treatment of acute or chronic GVHD and 11 prevention studies (277 patients). Significant heterogeneity was observed in the age and diagnoses of study subjects, intensity and specifics of the conditioning regimens, degree of HLA matching, and source of hematopoietic cells. MSCs were derived from bone marrow (83% of studies), cord blood (13%), or adipose tissue (3%) and were cryopreserved from third-party allogeneic donors in the majority of studies (91% of prevention studies and 63% of treatment studies). Culture conditions and media supplements were highly variable and characterization of MSCs did not conform to all International Society for Cellular Therapy criteria in any study. MSCs were harvested from cell culture at passage 1 to 7 and the dosage of MSCs ranged from 0.3 to 10 x 10(6)/kg, using varying schedules of administration. Treatment response criteria were not standardized and effectiveness in controlled treatment studies (5 studies) was unconvincing. Details of actively recruiting trials suggest heterogeneity still persists with only 53% of registered trials describing the use of standard GVHD response criteria and few detailing methods of MSC manufacturing. Future studies will need to make substantial coordinated efforts to reduce study heterogeneity and clarify the role of MSCs in GVHD. Copyright © 2016 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.
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The Potential of Mesenchymal Stromal Cells as Treatment for Severe Steroid-Refractory Acute Graft-Versus-Host Disease: A Critical Review of the Literature
Munneke, J. M., Spruit, M. J., Cornelissen, A. S., van Hoeven, V., Voermans, C., Hazenberg, M. D.
Transplantation. 2016;100(11):2309-2314
Abstract
BACKGROUND Acute graft-versus-host disease (GvHD) is a major complication after allogeneic hematopoietic stem cell transplantation which causes high morbidity and mortality among patients who do not respond to steroid treatment. Mesenchymal stromal cells (MSCs) have immune modulatory abilities and earned their place in the treatment of GvHD after a pediatric patient remarkably recovered from steroid-refractory acute GvHD with MSC salvage therapy. Large, prospective clinical trials evaluating the potency of MSCs have however not been published. METHODS To evaluate the therapeutic potential of MSCs in the treatment of steroid-refractory acute GvHD, we conducted a systematic literature search. We included all studies that focused on MSC treatment of adult allogeneic hematopoietic stem cell transplantation recipients with grades III to IV steroid-refractory acute GvHD and were transparent about their methods and patient selection criteria. RESULTS From a total of 255 articles, 9 articles met the quality criteria for this study. The proportion of patients achieving complete resolution of all symptoms (complete response, CR) varied between 8% and 83%. Four of the 9 studies reported CR rates above 50%. The GvHD grade at the time of treatment was identified as a predictor of clinical response. Interestingly, complete response but not partial response to MSCs was associated with overall survival. No serious side effects of MSC therapy were reported. CONCLUSIONS MSC treatment does improve the outcome in steroid-refractory acute GvHD patients but well-designed, prospective randomized clinical trials are needed to confirm the potential of MSCs as salvage therapy for steroid-refractory GvHD and to identify those patients that will benefit most.