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Safety and efficacy of mesenchymal stromal cell therapy for multi-drug-resistant acute and late-acute graft-versus-host disease following allogeneic hematopoietic stem cell transplantation
Keklik, M., Deveci, B., Celik, S., Deniz, K., Gonen, Z. B., Zararsiz, G., Saba, R., Akyol, G., Ozkul, Y., Kaynar, L., et al
Annals of hematology. 2023
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Editor's Choice
Abstract
Graft versus host disease (GvHD) remains a significant risk for mortality and morbidity following allogeneic hematopoietic stem cell transplantation (HSCT). A growing literature supports successful applications of mesenchymal stromal cells (MSCs) for the treatment of steroid-refractory acute GvHD (aGvHD). However, there is limited knowledge about the effects of MSC treatment on late-acute GvHD (late aGvHD). In this article, we present our multicenter study on the safety and efficacy of MSC therapy for patients with steroid-refractory late aGvHD in comparison to those with aGvHD. The outcome measures include non-relapse mortality (NRM) and survival probability over a 2-year follow-up. The study includes a total of 76 patients with grades III-IV aGvHD (n = 46) or late aGvHD (n = 30), who had been treated with at least two lines of steroid-containing immunosuppressive therapy. Patients received weekly adipose or umbilical cord-derived MSC infusions at a dose of median 1.55 (ranging from 0.84 to 2.56) × 10(6)/kg in the aGvHD group, and 1.64 (ranging from 0.85 to 2.58) × 10(6)/kg in the late aGvHD group. This was an add-on treatment to ongoing conventional pharmaceutical management. In the aGvHD group, 23 patients received one or two infusions, 20 patients had 3-4, and three had ≥ 5. Likewise, in the late aGvHD group, 20 patients received one or two infusions, nine patients had 3-4, and one had ≥ 5. MSC was safe without acute or late adverse effects in 76 patients receiving over 190 infusions. In aGvHD group, 10.9% of the patients had a complete response (CR), 23.9% had a partial response (PR), and 65.2% had no response (NR). On the other hand, in the late aGvHD group, 23.3% of the patients had CR, 36.7% had PR, and the remaining 40% had NR. These findings were statistically significant (p = 0.031). Also, at the 2-year follow-up, the cumulative incidence of NRM was significantly lower in patients with late aGvHD than in patients with aGvHD at 40% (95% CI, 25-62%) versus 71% (95% CI, 59-86%), respectively (p = 0.032). In addition, the probability of survival at 2 years was significantly higher in patients with late aGvHD than in the aGvHD group at 59% (95% CI, 37-74%) versus 28% (95% CI, 13-40%), respectively (p = 0.002). To our knowledge, our study is the first to compare the safety and efficacy of MSC infusion(s) for the treatment of steroid-resistant late aGVHD and aGVHD. There were no infusion-related adverse effects in either group. The response rate to MSC therapy was significantly higher in the late aGvHD group than in the aGvHD group. In addition, at the 2-year follow-up, the survival and NRM rates were more favorable in patients with late aGVHD than in those with aGVHD. Thus, the results are encouraging and warrant further studies to optimize MSC-based treatment for late aGVHD.
PICO Summary
Population
Adults with grades III-IV acute GvHD or late aGvHD from three centres in Turkey (n=76)
Intervention
People with grade III-IV acute GvHD received weekly adipose or umbilical cord-derived mesenchymal stromal cell (MSC) infusions at a dose of median 1.55 (ranging from 0.84 to 2.56) × 10(6)/kg, plus standard care (aGvHD group, n=46)
Comparison
People with late acute GvHD received MSC infusions at a median dose of 1.64 (ranging from 0.85 to 2.58) × 10(6)/kg, plus standard care (late aGvHD, n=30)
Outcome
MSC was safe without acute or late adverse effects in 76 patients receiving over 190 infusions. In aGvHD group, 10.9% of the patients had a complete response (CR), 23.9% had a partial response (PR), and 65.2% had no response (NR). On the other hand, in the late aGvHD group, 23.3% of the patients had CR, 36.7% had PR, and the remaining 40% had NR. These findings were statistically significant (p = 0.031). Also, at the 2-year follow-up, the cumulative incidence of NRM was significantly lower in patients with late aGvHD than in patients with aGvHD at 40% (95% CI, 25-62%) versus 71% (95% CI, 59-86%), respectively (p = 0.032). In addition, the probability of survival at 2 years was significantly higher in patients with late aGvHD than in the aGvHD group at 59% (95% CI, 37-74%) versus 28% (95% CI, 13-40%), respectively.
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Multipotent mesenchymal stromal cells as treatment for poor graft function after allogeneic hematopoietic cell transplantation: A multicenter prospective analysis
Servais, S., Baron, F., Lechanteur, C., Seidel, L., Baudoux, E., Briquet, A., Selleslag, D., Maertens, J., Poire, X., Schroyens, W., et al
Frontiers in immunology. 2023;14:1106464
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Editor's Choice
Abstract
INTRODUCTION Poor graft function (PGF) is a rare but serious complication of allogeneic hematopoietic cell transplantation (alloHCT). Due to their hematopoietic supporting properties and immune regulatory effects, multipotent mesenchymal stromal cells (MSC) could be considered a good candidate to help to restore bone marrow (BM) niches homeostasis and facilitate hematopoiesis after alloHCT. METHODS We prospectively assessed the efficacy and safety of ex-vivo expanded BM-derived MSC from third-party donor in a series of 30 patients with prolonged severe cytopenia and PGF after alloHCT. This multicenter trial was registered at www.clinicaltrials.gov (#NTC00603330). RESULTS Within 90 days post-MSC infusion, 53% (95% CI, 35 - 71%) of patients improved at least one cytopenia (overall response, OR) and 37% (95% CI, 19 - 54%) achieved a complete hematological response (CR: absolute neutrophil count, ANC >0.5 x 10(9)/L, Hb > 80g/L and platelet count > 20 x 10(9)/L with transfusion independence). Corresponding response rates increased to 67% (95% CI, 50 - 84%) OR and 53% (95% CI, 35 - 71%) CR within 180 days after MSC infusion. A significant decrease in red blood cells and platelets transfusion requirement was observed after MSC (median of 30-days transfusion requirement of 0.5 and 0 from d90-120 post-MSC versus 5 and 6.5 before MSC, respectively, p ≤0.001). An increase in ANC was also noted by day +90 and +180, with 3/5 patients with severe neutropenia having recovered an ANC > 1 x 10(9)/L within the 90-120 days after MSC infusion. Overall survival at 1 year post-MSC was 70% (95% CI, 55.4 - 88.5), with all but one of the patients who achieved CR being alive. A single infusion of third-party MSC appeared to be safe, with the exception of one deep vein thrombotic event possibly related to the intervention. DISCUSSION In conclusion, a single i.v. infusion of BM-derived MSC from third party donor seemed to improve hematological function after alloHCT, although spontaneous amelioration cannot be excluded. Comparative studies are warranted to confirm these encouraging results.
PICO Summary
Population
Adults with prolonged severe cytopenia and poor graft function (PGF) after allogeneic transplant in eight centres in Belgium (n=30).
Intervention
Single infusion of third-party donor mesenchymal stromal cells (MSC)
Comparison
None
Outcome
Within 90 days post-MSC infusion, 53% (95% CI, 35 - 71%) of patients improved at least one cytopenia (overall response, OR) and 37% (95% CI, 19 - 54%) achieved a complete hematological response (CR: absolute neutrophil count, ANC >0.5 x 10(9)/L, Hb > 80g/L and platelet count > 20 x 10(9)/L with transfusion independence). Corresponding response rates increased to 67% (95% CI, 50 - 84%) OR and 53% (95% CI, 35 - 71%) CR within 180 days after MSC infusion. A significant decrease in red blood cells and platelets transfusion requirement was observed after MSC (median of 30-days transfusion requirement of 0.5 and 0 from d90-120 post-MSC versus 5 and 6.5 before MSC, respectively). An increase in ANC was also noted by day +90 and +180, with 3/5 patients with severe neutropenia having recovered an ANC > 1 x 10(9)/L within the 90-120 days after MSC infusion. Overall survival at 1 year post-MSC was 70% (95% CI, 55.4 - 88.5), with all but one of the patients who achieved CR being alive.
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Mesenchymal stromal cells plus basiliximab, calcineurin inhibitor as treatment of steroid-resistant acute graft-versus-host disease: a multicenter, randomized, phase 3, open-label trial
Zhao, K., Lin, R., Fan, Z., Chen, X., Wang, Y., Huang, F., Xu, N., Zhang, X., Zhang, X., Xuan, L., et al
Journal of hematology & oncology. 2022;15(1):22
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Editor's Choice
Abstract
BACKGROUND Steroid-resistant (SR) acute graft-versus-host disease (aGVHD) lacks standard second-line treatment. Mesenchymal stromal cells (MSCs) have potential efficacy in SR aGVHD. We aimed to assess the efficacy and safety of MSCs combined with basiliximab and calcineurin inhibitor as second-line therapy for SR aGVHD. METHODS A randomized phase 3 trial involved 203 SR aGVHD patients at nine centers in China (September 2014-March 2019). Participants were randomized at a 1:1 ratio to receive second-line therapy with (n = 101) or without (n = 102) MSCs. The primary endpoint was the overall response (OR) at day 28. Secondary and safety endpoints included durable OR at day 56, failure-free survival, overall survival (OS), chronic GVHD (cGVHD), infection, hematological toxicity and relapse. RESULTS Of 203 patients, 198 (97.5%; mean age, 30.1 years; 40.4% women) completed the study. The OR at day 28 was higher in the MSC group than the control group (82.8% [82 patients] vs. 70.7% [70]; odds ratio, 2.00; 95% confidence interval [CI], 1.01-3.94; P = 0.043). The durable OR at day 56 was also higher in the MSC group (78.8% [78 patients] vs. 64.6% [64]; odds ratio, 2.02; 95% CI, 1.08-3.83; P = 0.027). The median failure-free survival was longer in the MSC group compared with control (11.3 months vs. 6.0 months; hazard ratio (HR) 0.68; 95% CI, 0.48-0.95, P = 0.024). The 2-year cumulative incidence of cGVHD was 39.5% (95% CI, 29.3-49.4%) and 62.7% (51.4-72.1%) in the MSC and control groups (HR 0.55, 95% CI, 0.36-0.84; P = 0.005). Within 180 days after study treatments, the most common grade 3 and 4 adverse events were infections (65 [65.7%] in the MSC group vs. 78 [78.8%] in the control group) and hematological toxicity (37 [37.4%] vs. 53 [53.5%]). The 3-year cumulative incidence of tumor relapse was 10.1% (95% CI, 5.2-17.1) and 13.5% (7.5-21.2%) in the MSC and control groups, respectively (HR 0.75, 95% CI, 0.34-1.67, P = 0.610). CONCLUSIONS MSCs plus second-line treatments increase the efficacy of SR aGVHD, decrease drug toxicity of second-line drugs and cGVHD without increasing relapse, and are well-tolerated. MSCs could be recommended as a second-line treatment option for aGVHD patients. Trial registration clinicaltrials.gov identifier: NCT02241018. Registration date: September 16, 2014, https://clinicaltrials.gov/ct2/show/NCT02241018 .
PICO Summary
Population
Patients with steroid resistant (SR) acute graft-versus-host-disease in 9 centres in China (n=203)
Intervention
Second-line GvHD therapy with mesenchymal stromal cells (n=101)
Comparison
Second-line GvHD therapy without mesenchymal stromal cells (n=102)
Outcome
Of 203 patients, 198 (97.5%; mean age, 30.1 years; 40.4% women) completed the study. The OR at day 28 was higher in the MSC group than the control group (82.8% [82 patients] vs. 70.7% [70]; odds ratio, 2.00; 95% confidence interval [CI], 1.01-3.94). The durable OR at day 56 was also higher in the MSC group (78.8% [78 patients] vs. 64.6% [64]; odds ratio, 2.02; 95% CI, 1.08-3.83). The median failure-free survival was longer in the MSC group compared with control (11.3 months vs. 6.0 months; hazard ratio (HR) 0.68; 95% CI, 0.48-0.95). The 2-year cumulative incidence of cGVHD was 39.5% (95% CI, 29.3-49.4%) and 62.7% (51.4-72.1%) in the MSC and control groups (HR 0.55, 95% CI, 0.36-0.84). Within 180 days after study treatments, the most common grade 3 and 4 adverse events were infections (65 [65.7%] in the MSC group vs. 78 [78.8%] in the control group) and hematological toxicity (37 [37.4%] vs. 53 [53.5%]). The 3-year cumulative incidence of tumor relapse was 10.1% (95% CI, 5.2-17.1) and 13.5% (7.5-21.2%) in the MSC and control groups, respectively (HR 0.75, 95% CI, 0.34-1.67).
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Mesenchymal Stromal Cells for Treating Steroid-Resistant Acute and Chronic Graft Versus Host Disease: A Multicenter Compassionate Use Experience
Macías-Sánchez, M. D. M., Morata-Tarifa, C., Cuende, N., Cardesa-Gil, A., Cuesta-Casas, MÁ, Pascual-Cascon, M. J., Pascual, A., Martín-Calvo, C., Jurado, M., Perez-Simón, J. A., et al
Stem cells translational medicine. 2022
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Editor's Choice
Abstract
Graft versus host disease (GVHD) is a severe complication after allogenic hematopoietic cell transplantation (HSCT). Several clinical trials have reported the use of mesenchymal stromal cells (MSCs) for the treatment of GVHD. In March 2008, the Andalusian Health Care System launched a compassionate use program to treat steroid-resistant GVHD with MSC. Clinical-grade MSC were obtained under GMP conditions. MSC therapy was administered intravenously in four separate doses of 1 × 106 cells/kg. Sixty-two patients, 45 males (7 children) and 17 females (2 children), received the treatment. Patients had a median age of 39 years (range: 7-66) at the time of the allogenic HSCT. The overall response was achieved in 58.7% of patients with acute (a)GVHD. Two years' survival for aGVHD responders was 51.85%. The overall response for patients with chronic (c)GVHD was 65.50% and the 2-year survival rate for responders was 70%. Age at the time of HSCT was the only predictor found to be inversely correlated with survival in aGVHD. Regarding safety, four adverse events were reported, all recovered without sequelae. Thus, analysis of this compassionate use experience shows MSC to be an effective and safe therapeutic option for treating refractory GVHD, resulting in a significant proportion of patients responding to the therapy.
PICO Summary
Population
Adults and children with graft versus host disease after allogeneic transplant (n=62)
Intervention
Mesenchymal stromal cells (MSCs) administered intravenously in four separate doses of 1 × 106 cells/kg.
Comparison
None
Outcome
The overall response was achieved in 58.7% of patients with acute (a)GVHD. Two years' survival for aGVHD responders was 51.85%. The overall response for patients with chronic (c)GVHD was 65.50% and the 2-year survival rate for responders was 70%. Age at the time of HSCT was the only predictor found to be inversely correlated with survival in aGVHD. Four adverse events were reported, all recovered without sequelae.
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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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Mesenchymal stromal cells for acute graft-versus-host disease: response at 1 week predicts probability of survival
Galleu, A., Milojkovic, D., Deplano, S., Szydlo, R., Loaiza, S., Wynn, R., Marks, D. I., Richardson, D., Orchard, K., Kanfer, E., et al
British journal of haematology. 2019
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Abstract
Mesenchymal stromal cells (MSCs) have been successfully used for the treatment of steroid-resistant graft-versus-host-disease (GvHD). However, the lack of early predictors of clinical responses impacts on the time at which to add further treatment and consequently the design of informative clinical trials. Here, we present the UK experience of one of the largest cohorts of GvHD patients undergoing MSC infusions so far reported. We show that clinical responses assessed as early as 1 week after MSC infusion predict patients' overall survival. In our cohort, cell dose, patients' age and type of organ involvement are crucial factors associated with clinical responses.
PICO Summary
Population
60 steroid‐resistant aGvHD patients treated with bone marrow‐derived MSCs at several Centres in the UK
Intervention
Mesenchymal stromal cells (single dose in 34 patients, up to 4 doses for others)
Comparison
None
Outcome
Clinical responses assessed as early as 1 week after MSC infusion predict patients' overall survival. Cell dose, patients' age and type of organ involvement are associated with clinical responses.
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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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A Phase 3 randomized study of Remestemcel-L versus placebo added to second line therapy in patients with steroid refractory acute graft versus host disease
Kebriaei, P., Hayes, J., Daly, A., Uberti, J., Marks, D. I., Soiffer, R., Waller, E. K., Burke, E., Skerrett, D., Shpall, E., et al
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2019
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Editor's Choice
Abstract
BACKGROUND Uncontrolled studies have suggested that bone marrow-derived mesenchymal stem cells (MSC) may be effective against acute graft-versus-host disease (aGvHD). We conducted a multicenter, randomized study to assess the efficacy of using ex vivo cultured adult human MSC (remestemcel-L) in addition to second-line therapy to treat steroid refractory aGvHD (NCT00366145). METHODS Two-hundred sixty patients, 6 months to 70 years of age, were enrolled from August 2006 to May 2009, and were randomized 2:1 to receive 8 intravenous infusions of remestemcel-L or placebo, given over 4 weeks, in addition to second-line therapy according to institutional standards. Four additional infusions over 4 weeks were indicated for patients with incomplete response at Day 28. Randomization was stratified by aGVHD grade. Efficacy and safety were assessed through 180 days of follow-up, with the primary endpoint being durable complete response (DCR), defined as complete resolution of aGvHD symptoms for any period of at least 28 days after beginning treatment. FINDINGS Remestemcel-L did not meet the primary endpoint of greater DCR in the intent-to-treat population (35% vs. 30%; p=0.42). In post-hoc analyses patients with liver involvement who received at least one infusion of remestemcel-L had a higher DCR, and higher overall complete or partial response rate (OR) than those who received placebo (29% vs. 5%; p=0.047). Furthermore, pediatric patients had a higher OR with MSC compared with placebo (64% vs. 23%; p=0.05). Similar rates of adverse events were observed between treatment groups. INTERPRETATION Remestemcel-L was safe and well-tolerated. Results of this study did not demonstrate superior DCR compared to placebo when added to standard of care. The favorable clinical responses seen in some patient subsets may warrant further investigation.
PICO Summary
Population
Patients with steroid-refractory GvHD (n=260)
Intervention
Ex vivo cultured adult human mesenchymal stromal cells (remestemcel-L), alongside second-line therapy (n=173)
Comparison
Placebo, alongside second-line therapy (n=87)
Outcome
Remestemcel-L did not meet the primary endpoint of greater durable complete response (DCR) in the intent-to-treat population (35% vs. 30%). In post-hoc analyses patients with liver involvement who received at least one infusion of remestemcel-L had a higher DCR, and higher overall complete or partial response rate (OR) than those who received placebo (29% vs. 5%). Furthermore, pediatric patients had a higher OR with MSC compared with placebo (64% vs. 23%). Similar rates of adverse events were observed between treatment groups.
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Infusion of bone marrow derived multipotent mesenchymal stromal cells for the treatment of steroid-refractory acute graft-versus-host disease: a multicenter prospective study
Servais, S., Baron, F., Lechanteur, C., Seidel, L., Selleslag, D., Maertens, J., Baudoux, E., Zachee, P., Van Gelder, M., Noens, L., et al
Oncotarget. 2018;9(29):20590-20604
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Editor's Choice
Abstract
The prognosis of steroid-refractory acute graft-versus-host disease (aGVHD) remains poor and better treatments are urgently needed. Multipotent mesenchymal stromal cell (MSC)-based therapy emerged as a promising approach but response rates were highly variable across studies. We conducted a multicenter prospective study assessing the efficacy of 1-2 infusion(s) of cryopreserved, third-party donor bone marrow-derived MSCs for treating grade II-IV steroid-refractory or -dependent aGVHD in a series of 33 patients. MSCs were produced centrally and distributed to 8 hospitals throughout Belgium to be infused in 2 consecutive cohorts of patients receiving 1-2 or 3-4 x 10(6) MSCs/kg per dose, respectively. All patients received MSCs as the first rescue therapy after corticosteroids, with the exception for one patient who received prior treatment with mycophenolate mofetil (that was still ongoing by the time of MSC therapy). In these conditions, MSC therapy resulted in at least a partial response in 13 patients (40.6%) at day 30 and in 15 patients (46%) within 90 days after first MSC infusion. The corresponding complete response rates were 21.6% (7 patients) and 30% (10 patients), respectively. Only 5 patients achieved a sustained complete response, lasting for at least 1 month. The 1-year overall survival was 18.2% (95% CI: 8.82-37.5%). Higher response and survival rates were observed among patients receiving 3-4 x 10(6) MSCs/kg for first infusion, as compared with patients receiving 1-2 x 106 MSCs/ kg. Response and survival with MSC therapy for SR/SD-aGVHD remains to be optimized.