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Mesenchymal stem cells provide prophylaxis against acute graft-versus-host disease following allogeneic hematopoietic stem cell transplantation: A meta-analysis of animal models.

ABSTRACT: A meta-analysis of animal models was conducted to evaluate the prophylactic effects of mesenchymal stem cells (MSCs) on acute graft-versus-host disease (aGVHD) after allogeneic hematopoietic stem cell transplantation. A total of 50 studies involving 1848 animals were included. The pooled results showed that MSCs significantly reduced aGVHD-associated mortality (risk ratio = 0.70, 95% confidence interval 0.62 to 0.79, P = 2.73×10-9) and clinical scores (standardized mean difference = -3.60, 95% confidence interval -4.43 to -2.76, P = 3.61×10-17). In addition, MSCs conferred robust favorable prophylactic effects on aGVHD across recipient species, MSC doses, and administration times, but not MSC sources. Our meta-analysis showed that MSCs significantly prevented mortality and alleviated the clinical manifestations of aGVHD in animal models. These data support further clinical trials aimed at evaluating the efficacy of using MSCs to prevent aGVHD.

SUBMITTER: Wang L

PROVIDER: S-EPMC5308689 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

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Mesenchymal stem cells provide prophylaxis against acute graft-versus-host disease following allogeneic hematopoietic stem cell transplantation: A meta-analysis of animal models.

Wang Li L Zhang Haiyan H Guan Lixun L Zhao Shasha S Gu Zhenyang Z Wei Huaping H Gao Zhe Z Wang Feiyan F Yang Nan N Luo Lan L Li Yonghui Y Wang Lili L Liu Daihong D Gao Chunji C

Oncotarget 20160901 38

A meta-analysis of animal models was conducted to evaluate the prophylactic effects of mesenchymal stem cells (MSCs) on acute graft-versus-host disease (aGVHD) after allogeneic hematopoietic stem cell transplantation. A total of 50 studies involving 1848 animals were included. The pooled results showed that MSCs significantly reduced aGVHD-associated mortality (risk ratio = 0.70, 95% confidence interval 0.62 to 0.79, P = 2.73×10-9) and clinical scores (standardized mean difference = -3.60, 95% c ...[more]

PMID: 27528221

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Project description:Chronic graft-versus-host disease (cGVHD) is major cause of morbidity and mortality following allogeneic hematopoietic cell transplantation (HCT). Ixazomib is an oral, second-generation, proteasome inhibitor that has been shown in preclinical models to prevent GVHD. We conducted a phase I/II trial in 57 patients to evaluate the safety and efficacy of ixazomib administration for cGVHD prophylaxis in patients undergoing allogeneic HCT. Oral ixazomib was administered on a weekly basis for a total of 4 doses, beginning days +60 through +90, to recipients of matched related donor (MRD, n = 25) or matched unrelated donor (MUD, n = 26) allogeneic HCT in phase II portion of the study, once the recommended phase II dose of 4 mg was identified in phase I (n = 6). All patients received peripheral blood graft and standard GVHD prophylaxis of tacrolimus and methotrexate. Ixazomib administration was safe and well tolerated, with thrombocytopenia, leukopenia, gastrointestinal complaints, and fatigue the most common adverse events (>10%). In phase II (n = 51), the cumulative incidence of cGVHD at 1 year was 36% (95% confidence interval [CI], 19% to 54%) in the MRD cohort and 39% (95% CI, 21% to 56%) in the MUD cohort. One-year cumulative incidence of nonrelapse mortality (NRM) and relapse was 0% and 20% (95% CI, 8% to 36%) in the MRD cohort, respectively. In the MUD cohort, the respective NRM and relapse rates were 4% (0% to 16%) and 34% (17% to 52%). The outcomes on the study were compared post hoc with contemporaneous matched Center for International Blood and Marrow Transplant Research (CIBMTR) controls. This post hoc analysis showed no significant improvement in cGVHD rates in both the MRD (hazard ratio [HR] = 0.85, P = .64) or MUD cohorts (HR = 0.68, P = .26) on the study compared with CIBMTR controls. B cell activating factor plasma levels were significantly higher after ixazomib dosing in those who remained cGVHD free compared with those developed cGVHD. This study shows that the novel strategy of short-course oral ixazomib following allogeneic HCT is safe but did not demonstrate significant improvement in cGVHD incidence in recipients of MRD and MUD transplantation compared with matched CIBMTR controls. This study is registered at www.clinicaltrials.gov as NCT02250300.

Project description:BackgroundMesenchymal stem cells (MSCs) have been broadly used experimentally in various clinical contexts. The addition of MSCs to initial steroid therapy for acute graft-versus-host disease (aGVHD) may improve patient outcomes. However, investigations regarding prognostic factors affecting the efficacy of MSC therapy for steroid-refractory aGVHD remain controversial. We thus conducted a systematic review and meta-analysis of published clinical trials to determine possible prognostic factors affecting the efficacy of MSCs in treating steroid-refractory aGVHD.Methods and findingsClinical trials using MSC therapy for steroid-refractory aGVHD were identified by searching PubMed and EMBASE databases. A total of 6,963 citations were reviewed, and 13 studies met the inclusion criteria. A total of 301 patients from thirteen studies were included. Of these, 136 patients showed a complete response (CR), and 69 patients displayed a partial (PR) or mixed response (MR). In total, 205 patients exhibited overall response (ORR). Patients with skin steroid-refractory aGVHD showed a better clinical response than gastrointestinal (CR: odds ratio [OR] = 1.93, 95% confidence interval [95%CI]: 1.05-3.57, p < 0.05) and liver (CR: OR = 2.30, 95%CI: 1.12-4.69, p < 0.05, and ORR: OR = 2.93, 95%CI: 1.06-8.08, p < 0.05) steroid-refractory aGVHD. Those with grade II steroid-refractory aGVHD exhibited a better clinical response following MSC therapy than recipients with grade III-IV (CR: OR = 3.22, 95%CI: 1.24-8.34, p < 0.05). Completion therapy may improve the CR but reduce ORR compared with induction therapy (CR: OR = 0.20, 95%CI: 0.09-0.44, p < 0.05; ORR: OR = 2.18, 95%CI: 1.17-4.05, p = 0.01). There was also a trend towards a better clinical response in children compared with adults (CR: OR = 2.41, 95%CI: 1.01-5.73, p = 0.05).ConclusionsAge, skin involvement, lower aGVHD grade, and the number of infusions are the main prognostic factors affecting the efficacy of MSC therapy for steroid-refractory aGVHD.

Dataset Information

Mesenchymal stem cells provide prophylaxis against acute graft-versus-host disease following allogeneic hematopoietic stem cell transplantation: A meta-analysis of animal models.

Publications

Mesenchymal stem cells provide prophylaxis against acute graft-versus-host disease following allogeneic hematopoietic stem cell transplantation: A meta-analysis of animal models.

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