{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T01:57:15Z","timestamp":1789091835622,"version":"build-2803163510"},"reference-count":28,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,9,9]],"date-time":"2021-09-09T00:00:00Z","timestamp":1631145600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Oncol."],"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>The objective of this study was to evaluate the safety and efficacy of sirolimus (SRL) in the prevention of graft-<jats:italic>versus<\/jats:italic>-host disease (GVHD) in recipients following allogeneic hematopoietic stem cell transplantation (allo-HSCT).<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Randomized controlled trials (RCTs) evaluating the safety and efficacy of SRL-based prophylaxis regimens in patients receiving allo-HSCT were obtained from PubMed, Embase, and the Cochrane database. Following specific inclusion and exclusion criteria, studies were selected and screened by two independent reviewers who subsequently extracted the study data. The Cochrane risk bias evaluation tool was used for quality evaluation, and RevMan 5.3 software was used for statistical analysis comparing the effects of SRL-based and non\u2013SRL-based regimens on acute GVHD, chronic GVHD, overall survival (OS), relapse rate, non-relapse mortality (NRM), thrombotic microangiopathy (TMA), and veno-occlusive disease (VOD).<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Seven studies were included in this meta-analysis, with a total sample size of 1,673 cases, including 778 cases of patients receiving SRL-based regimens and 895 cases in which patients received non-SRL-based regimens. Our data revealed that SRL containing prophylaxis can effectively reduce the incidence of grade II\u2013IV acute GVHD (RR\u00a0= 0.75, 95% CI: 0.68\u223c0.82, <jats:italic>p<\/jats:italic> &amp;lt; 0.0001). SRL-based prophylaxis was not associated with an improvement of grade III\u2013IV acute GVHD (RR = 0.78, 95% CI: 0.59\u223c1.03, <jats:italic>p<\/jats:italic> = 0.08), chronic GVHD (<jats:italic>p<\/jats:italic> = 0.89), OS (<jats:italic>p<\/jats:italic> = 0.98), and relapse rate (<jats:italic>p<\/jats:italic> = 0.16). Despite its immunosuppressant effects, SRL-based regimens did not increase bacterial (<jats:italic>p<\/jats:italic> = 0.68), fungal (<jats:italic>p<\/jats:italic> = 0.70), or CMV (<jats:italic>p<\/jats:italic> = 0.10) infections. However, patients receiving SRL-based regimens had increased TMA (<jats:italic>p<\/jats:italic> &amp;lt; 0.00001) and VOD (<jats:italic>p<\/jats:italic> &amp;lt; 0.00001).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>This meta-analysis indicates that addition of sirolimus is an effective alternative prophylaxis strategy for II\u2013IV aGVHD but may cause endothelial cell injury and result in secondary TMA or VOD events.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fonc.2021.683263","type":"journal-article","created":{"date-parts":[[2021,9,9]],"date-time":"2021-09-09T11:36:19Z","timestamp":1631187379000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":13,"title":["The Addition of Sirolimus to GVHD Prophylaxis After Allogeneic Hematopoietic Stem Cell Transplantation: A Meta-Analysis of Efficacy and Safety"],"prefix":"10.3389","volume":"11","author":[{"given":"Xiaoli","family":"Chen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hengrui","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaniel","family":"Cassady","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shijie","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ting","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongju","family":"Yan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xi","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yimei","family":"Feng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,9,9]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbmt.2009.10.032","article-title":"HLA-Haploidentical Stem Cell Transplantation for Hematologic Malignancies","volume":"16","author":"Fuchs","year":"2010","journal-title":"Biol Blood Marrow Transplant"},{"key":"B2","doi-asserted-by":"publisher","first-page":"112391","DOI":"10.1016\/j.ejmech.2020.112391","article-title":"Targeting Mtor for Fighting Diseases: A Revisited Review of mTOR Inhibitors","volume":"199","author":"Xu","year":"2020","journal-title":"Eur J Med Chem"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.3389\/fmed.2020.00110","article-title":"Sirolimus as Rescue Therapy for Refractory\/Relapsed Immune Thrombocytopenia: Results of a Single-Center, Prospective, Single-Arm Study","volume":"7","author":"Feng","year":"2020","journal-title":"Front Med"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2020.611690","article-title":"The Role of Mtor Inhibitors in Hematologic Disease: From Bench to Bedside","volume":"10","author":"Feng","year":"2021","journal-title":"Front Oncol"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1038\/bmt.2011.104","article-title":"Sirolimus and Mycophenolate Mofetil as GVHD Prophylaxis in Myeloablative, Matched-Related Donor Hematopoietic Cell Transplantation","volume":"47","author":"Johnston","year":"2012","journal-title":"Bone Marrow Transplant"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbmt.2008.02.009","article-title":"Sirolimus in Combination With Cyclosporine or Tacrolimus Plus Methotrexate for Prevention of Graft-Versus-Host Disease Following Hematopoietic Cell Transplantation From Unrelated Donors","volume":"14","author":"Furlong","year":"2008","journal-title":"Biol Blood Marrow Transplant"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbmt.2005.04.007","article-title":"Sirolimus and Thrombotic Microangiopathy After Allogeneic Hematopoietic Stem Cell Transplantation","volume":"11","author":"Cutler","year":"2005","journal-title":"Biol Blood Marrow Transplant"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1038\/bmt.2014.17","article-title":"Risk Factors for Thrombotic Microangiopathy in Allogeneic Hematopoietic Stem Cell Recipients Receiving GVHD Prophylaxis With Tacrolimus Plus MTX or Sirolimus","volume":"49","author":"Labrador","year":"2014","journal-title":"Bone Marrow Transplant"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1002\/sim.1186","article-title":"Quantifying Heterogeneity in a Meta-Analysis","volume":"21","author":"Higgins","year":"2002","journal-title":"Stat Med"},{"key":"B10","doi-asserted-by":"publisher","first-page":"96","DOI":"10.1111\/bjh.13931","article-title":"The Addition of Sirolimus to the Graft-Versus-Host Disease Prophylaxis Regimen in Reduced Intensity Allogeneic Stem Cell Transplantation for Lymphoma: A Multicentre Randomized Trial","volume":"173","author":"Armand","year":"2016","journal-title":"Br J Haematol"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2013-10-534297","article-title":"The Addition of Sirolimus to Tacrolimus\/Methotrexate GVHD Prophylaxis in Children With ALL: A Phase 3 Children\u2019s Oncology Group\/Pediatric Blood and Marrow Transplant Consortium Trial","volume":"123","author":"Pulsipher","year":"2014","journal-title":"Blood"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2014-04-567164","article-title":"Tacrolimus\/Sirolimus vs Tacrolimus\/Methotrexate as GVHD Prophylaxis After Matched, Related Donor Allogeneic HCT","volume":"124","author":"Cutler","year":"2014","journal-title":"Blood"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1038\/bmt.2017.63","article-title":"Predictors of Overall Survival Among Patients Treated With Sirolimus\/Tacrolimus vs Methotrexate\/Tacrolimus for GvHD Prevention","volume":"52","author":"Khimani","year":"2017","journal-title":"Bone Marrow Transplant"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.3324\/haematol.2015.123588","article-title":"Prolonged Sirolimus Administration After Allogeneic Hematopoietic Cell Transplantation Is Associated With Decreased Risk for Moderate-Severe Chronic Graft-Versus-Host Disease","volume":"100","author":"Pidala","year":"2015","journal-title":"Haematologica"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1016\/S2352-3026(19)30088-2","article-title":"Addition of Sirolimus to Standard Cyclosporine Plus Mycophenolate Mofetil-Based Graft-Versus-Host Disease Prophylaxis for Patients After Unrelated Non-Myeloablative Haemopoietic Stem Cell Transplantation: A Multicentre, Randomised, Phase 3 Trial","volume":"6","author":"Sandmaier","year":"2019","journal-title":"Lancet Haematol"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.3324\/haematol.2014.108340","article-title":"A Randomized Phase II Trial of Tacrolimus, Mycophenolate Mofetil and Sirolimus After Non-Myeloablative Unrelated Donor Transplantation","volume":"99","author":"Kornblit","year":"2014","journal-title":"Haematologica"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2011.10.909","article-title":"In-Stent Neoatherosclerosis: A Final Common Pathway of Late Stent Failure","volume":"59","author":"Park","year":"2012","journal-title":"J Am Coll Cardiol"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1161\/01.HYP.0000257914.80918.72","article-title":"FK506 Binding Protein 12\/12.6 Depletion Increases Endothelial Nitric Oxide Synthase Threonine 495 Phosphorylation and Blood Pressure","volume":"49","author":"Long","year":"2007","journal-title":"Hypertension"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2005-05-2004","article-title":"Hematopoietic Cell Transplantation (HCT)-Specific Comorbidity Index: A New Tool for Risk Assessment Before Allogeneic HCT","volume":"106","author":"Sorror","year":"2005","journal-title":"Blood"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1111\/ejh.13529","article-title":"Ex Vivo T-Cell Depletion vs Post-Transplant Cyclophosphamide, Sirolimus, and Mycophenolate Mofetil as Graft-vs-Host Disease Prophylaxis for Allogeneic Hematopoietic Stem Cell Transplantation","volume":"106","author":"Montoro","year":"2021","journal-title":"Eur J Haematol"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1038\/bmt.2015.50","article-title":"Pre-Transplant Sirolimus Might Improve the Outcome of Haploidentical Peripheral Blood Stem Cell Transplantation With Post-Transplant Cyclophosphamide for Patients With Severe Aplastic Anemia","volume":"50","author":"Jaiswal","year":"2015","journal-title":"Bone Marrow Transplant"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1016\/j.trim.2017.07.004","article-title":"T Cell Costimulation Blockade Promotes Transplantation Tolerance in Combination With Sirolimus and Post-Transplantation Cyclophosphamide for Haploidentical Transplantation in Children With Severe Aplastic Anemia","author":"Jaiswal","year":"2017","journal-title":"Transpl Immunol"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbmt.2020.05.005","article-title":"CTLA4Ig in an Extended Schedule Along With Sirolimus Improves Outcome With a Distinct Pattern of Immune Reconstitution Following Post-Transplantation Cyclophosphamide-Based Haploidentical Transplantation for Hemoglobinopathies","volume":"26","author":"Jaiswal","year":"2020","journal-title":"Biol Blood Marrow Transplant"},{"key":"B24","doi-asserted-by":"publisher","first-page":"298","DOI":"10.1016\/j.bbmt.2012.10.006","article-title":"Thrombotic Microangiopathy Associated With Sirolimus Level After Allogeneic Hematopoietic Cell Transplantation With Tacrolimus\/Sirolimus-Based Graft-Versus-Host Disease Prophylaxis","volume":"19","author":"Shayani","year":"2013","journal-title":"Biol Blood Marrow Transplant"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1038\/sj.bmt.1703615","article-title":"The Effect of Modulation of Glutathione Cellular Content on Busulphan-Induced Cytotoxicity on Hematopoietic Cells In Vitro and In Vivo","volume":"30","author":"Hassan","year":"2002","journal-title":"Bone Marrow Transplant"},{"key":"B26","doi-asserted-by":"publisher","first-page":"490","DOI":"10.1182\/blood-2007-01-069294","article-title":"Sirolimus-Based Graft-Versus-Host Disease Prophylaxis Protects Against Cytomegalovirus Reactivation After Allogeneic Hematopoietic Stem Cell Transplantation: A Cohort Analysis","volume":"110","author":"Marty","year":"2007","journal-title":"Blood"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1097\/MOT.0b013e3283186ba9","article-title":"Epstein-Barr Virus, Rapamycin, and Host Immune Responses","volume":"13","author":"Krams","year":"2008","journal-title":"Curr Opin Organ Transplant"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.7164\/antibiotics.28.721","article-title":"Rapamycin (AY-22,989), a New Antifungal Antibiotic. I. Taxonomy of the Producing Streptomycete and Isolation of the Active Principle","volume":"28","author":"Vezina","year":"1975","journal-title":"J Antibiot (Tokyo)"}],"container-title":["Frontiers in Oncology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fonc.2021.683263\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,9,9]],"date-time":"2021-09-09T11:36:22Z","timestamp":1631187382000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fonc.2021.683263\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,9,9]]},"references-count":28,"alternative-id":["10.3389\/fonc.2021.683263"],"URL":"https:\/\/doi.org\/10.3389\/fonc.2021.683263","relation":{},"ISSN":["2234-943X"],"issn-type":[{"value":"2234-943X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,9,9]]},"article-number":"683263"}}