Co-infusion of mesenchymal stromal cells to prevent GVHD after allogeneic hematopoietic cell transplantation from HLA-mismatched unrelated donors after reduced-intensity conditioning: a double-blind randomized study and literature review.
[en] [en] BACKGROUND: Mesenchymal stromal cells (MSC) have immunomodulatory and hematopoiesis-supporting properties that could potentially benefit hematopoietic stem cell (HSC) engraftment and decrease the incidence and/or severity of graft-versus-host disease (GVHD).
METHODS: Based on our previous pilot study, we established a multicenter, prospective, randomized, double-blind trial evaluating the efficacy of co-infusing third-party MSC (1.5-3 × 106/kg) versus placebo on the day of HSC transplantation (HCT) to prevent GVHD in recipients of HLA-mismatched unrelated donors after reduced-intensity conditioning.
RESULTS: The study planned to include 120 patients to improve 1-year overall survival (OS) from 55 to 77% but was stopped after 9 years for low recruitment (n = 38). One-year OS was 74% in the MSC group and 80% in the placebo group. In multivariate analysis, the incidence of grade II-IV acute GVHD was significantly lower in patients receiving MSC (HR 0.332, 95% CI 0.124-0.890, p = 0.0284). No difference was observed in the incidences of chronic GVHD, infection or relapse, overall or progression-free survival at 1 year or long-term, or hematopoietic and immune reconstitution.
CONCLUSIONS: Despite premature study closure, the suggested beneficial effect of MSC co-transplantation for the prevention of acute GVHD in HLA-mismatched HCT warrants further investigation.
Disciplines :
Hematology
Author, co-author :
Lombardo, Gérôme ; Centre Hospitalier Universitaire de Liège - CHU > > Service d'hématologie clinique
LECHANTEUR, Chantal ; Centre Hospitalier Universitaire de Liège - CHU > > Laboratoire de thérapie cellulaire et génique (LTCG)
BRIQUET, Alexandra ; Centre Hospitalier Universitaire de Liège - CHU > > Laboratoire de thérapie cellulaire et génique (LTCG)
Seidel, Laurence ; CHU Liège - Central University Hospital of Liege > Center for Biostatistics and Research Methods
Willems, Evelyne ; Centre Hospitalier Universitaire de Liège - CHU > > Service d'hématologie clinique
Servais, Sophie ; Université de Liège - ULiège > Département des sciences cliniques
BAUDOUX, Etienne ; Centre Hospitalier Universitaire de Liège - CHU > > Laboratoire de thérapie cellulaire et génique (LTCG)
Kerre, Tessa; Department of Clinical Hematology, Ghent University Hospital, Ghent, Belgium
Zachee, Pierre; Department of Clinical Hematology, ZNA Stuivenberg, Antwerp, Belgium
HERMAN, Julie ; Centre Hospitalier Universitaire de Liège - CHU > > Service de rhumatologie
JANSSEN, Audrey ; Centre Hospitalier Universitaire de Liège - CHU > > Clinical Trial Center (CTC)
MULLER, Joséphine ; Centre Hospitalier Universitaire de Liège - CHU > > Service d'hématologie clinique
Baron, Frédéric ; Université de Liège - ULiège > Département des sciences cliniques
Beguin, Yves ; Université de Liège - ULiège > Département des sciences cliniques
Co-infusion of mesenchymal stromal cells to prevent GVHD after allogeneic hematopoietic cell transplantation from HLA-mismatched unrelated donors after reduced-intensity conditioning: a double-blind randomized study and literature review.
F.R.S.-FNRS - Fonds de la Recherche Scientifique Fondation contre le Cancer ULiège - Université de Liège CHU Liège - Centre Hospitalier Universitaire de Liège Fonds Léon Fredericq
Funding text :
FB is Senior Research Associate at the Fonds National de la Recherche Scientifique (FNRS). SS was Postdoctoral Researcher at the Belgian Foundation against Cancer (FBC). JH and AJ were supported by the Belgian Hematology Society (BHS). The study was supported by grants of the FNRS, the FBC, the University of Li\u00E8ge, the CHU of Li\u00E8ge and the Fondation L\u00E9on Fr\u00E9d\u00E9ricq. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.The authors thank all the personnel of the Laboratory of Cell and Gene Therapy at the CHU of Li\u00E8ge for their help to the production of MSC.
O. Jamy R. Zeiser Y.B. Chen Novel developments in the prophylaxis and treatment of acute GVHD Blood 2023 142 1037 1046 1:CAS:528:DC%2BB3sXhvFKqur%2FF 37471585
R. Zeiser N. von Bubnoff J. Butler M. Mohty D. Niederwieser R. Or et al. Ruxolitinib for glucocorticoid-refractory acute graft-versus-host disease N Engl J Med 2020 382 1800 1810 32320566
Pidala JA, Gooley TA, Luznik L, Blazar BR. Chronic graft-versus-host disease: Unresolved complication or ancient history ? Blood 2024;blood.2023022735.
S. Viswanathan Y. Shi J. Galipeau M. Krampera K. Leblanc I. Martin et al. Mesenchymal stem versus stromal cells: international society for cell & gene therapy (ISCT®) mesenchymal stromal cell committee position statement on nomenclature Cytotherapy 2019 21 1019 1024 1:STN:280:DC%2BB3MrptlejsQ%3D%3D 31526643
J.P. Hauzeur V. De Maertelaer E. Baudoux M. Malaise Y. Beguin V. Gangji Inefficacy of autologous bone marrow concentrate in stage three osteonecrosis: a randomized controlled double-blind trial Int Orthop 2018 42 1429 1435 28988340
N. Van Overstraeten-Schlögel Y. Beguin A. Gothot Role of stromal-derived factor-1 in the hematopoietic-supporting activity of human mesenchymal stem cells Eur J Haematol 2006 76 488 493 16494621
A. Briquet S. Dubois S. Bekaert M. Dolhet Y. Beguin A. Gothot Prolonged ex vivo culture of human bone marrow mesenchymal stem cells influences their supportive activity toward NOD/SCID-repopulating cells and committed progenitor cells of B lymphoid and myeloid lineages Haematologica 2010 95 47 56 19713224
K. Le Blanc D. Mougiakakos Multipotent mesenchymal stromal cells and the innate immune system Nat Rev Immunol 2012 12 383 396 22531326
C. Grégoire C. Lechanteur A. Briquet É. Baudoux F. Baron E. Louis et al. Review article: mesenchymal stromal cell therapy for inflammatory bowel diseases Aliment Pharmacol Ther 2017 45 205 221 27878827
P. Erpicum O. Detry L. Weekers C. Bonvoisin C. Lechanteur A. Briquet et al. Mesenchymal stromal cell therapy in conditions of renal ischaemia/reperfusion Nephrol Dial Transplant 2014 29 1487 1493 24516234
C. Trento M.E. Bernardo A. Nagler S. Kuçi M. Bornhäuser U. Köhl et al. Manufacturing mesenchymal stromal cells for the treatment of graft-versus-host disease: a survey among centers affiliated with the european society for blood and marrow transplantation Biol Blood Marrow Transplant 2018 24 2365 2370 30031938 6299357
C. Lechanteur A. Briquet V. Bettonville E. Baudoux Y. Beguin MSC manufacturing for academic clinical trials: from a clinical-grade to a full GMP-compliant process Cells 2021 10 1320 1:CAS:528:DC%2BB3MXisF2is7rO 34073206 8227789
O. Detry M. Vandermeulen M.H. Delbouille J. Somja N. Bletard A. Briquet et al. Infusion of mesenchymal stromal cells after deceased liver transplantation: a phase I-II, open-label, clinical study J Hepatol 2017 67 47 55 28284916
P. Erpicum L. Weekers O. Detry C. Bonvoisin M.H. Delbouille C. Grégoire et al. Infusion of third-party mesenchymal stromal cells after kidney transplantation: a phase I-II, open-label, clinical study Kidney Int 2019 95 693 707 1:CAS:528:DC%2BC1cXisVGmsLfM 30528263
M. Vandermeulen P. Erpicum L. Weekers A. Briquet C. Lechanteur O. Detry et al. Mesenchymal stromal cells in solid organ transplantation Transplantation 2020 104 923 31929427
M. Vandermeulen M. Mohamed-Wais P. Erpicum M.H. Delbouille C. Lechanteur A. Briquet et al. Infusion of allogeneic mesenchymal stromal cells after liver transplantation: a 5-year follow-up Liver Transpl 2022 28 636 34605167
C. Grégoire N. Layios B. Lambermont C. Lechanteur A. Briquet V. Bettonville et al. Bone marrow-derived mesenchymal stromal cell therapy in severe COVID-19: preliminary results of a phase I/II clinical trial Front Immunol 2022 13 35860245 9291273 932360
C. Reenaers R.P. Gillard C. Coimbra R.M. Gillard P. Meunier C. Lechanteur et al. Clinical and MRI evolution after local injection of bone marrow-derived mesenchymal stem cells in perianal fistulae in crohn’s disease: results from a prospective monocentric study J Crohns Colitis 2023 17 728 737 36733215
S. Vieujean J.P. Loly L. Boutaffala P. Meunier C. Reenaers A. Briquet et al. Mesenchymal stem cell injection in crohn’s disease strictures: a phase i-ii clinical study J Crohns Colitis 2022 16 506 510 34473270
K. Le Blanc F. Frassoni L. Ball F. Locatelli H. Roelofs I. Lewis et al. Mesenchymal stem cells for treatment of steroid-resistant, severe, acute graft-versus-host disease: a phase II study Lancet Lond Engl 2008 371 1579 1586
S. Servais F. Baron C. Lechanteur L. Seidel D. Selleslag J. Maertens et al. Infusion of bone marrow derived multipotent mesenchymal stromal cells for the treatment of steroid-refractory acute graft-versus-host disease: a multicenter prospective study Oncotarget 2018 9 20590 20604 29755674 5945536
K. Kelly J.E.J. Rasko Mesenchymal stromal cells for the treatment of graft versus host disease Front Immunol 2021 12 1:CAS:528:DC%2BB38Xps12htbo%3D 34764962 8577186 761616
Y. Li J. Hao Z. Hu Y.G. Yang Q. Zhou L. Sun et al. Current status of clinical trials assessing mesenchymal stem cell therapy for graft versus host disease: a systematic review Stem Cell Res Ther 2022 13 93 1:CAS:528:DC%2BB38Xhs1Cqt74%3D 35246235 8895864
B. Nachmias E. Zimran B. Avni Mesenchymal stroma/stem cells: Haematologists’ friend or foe? Br J Haematol 2022 199 175 189 1:CAS:528:DC%2BB38XhvVWksLzI 35667616 9796884
S.A. Fisher A. Cutler C. Doree S.J. Brunskill S.J. Stanworth C. Navarrete et al. 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 Cochrane Database Syst Rev 2019 1 009768
O. Ringdén G. Moll B. Gustafsson B. Sadeghi Mesenchymal stromal cells for enhancing hematopoietic engraftment and treatment of graft-versus-host disease, hemorrhages and acute respiratory distress syndrome Front Immunol 2022 10.3389/fimmu.2022.839844 36426365 9680556
K. Liu Y. Chen Y. Zeng L. Xu D. Liu H. Chen et al. Coinfusion of mesenchymal stromal cells facilitates platelet recovery without increasing leukemia recurrence in haploidentical hematopoietic stem cell transplantation: a randomized Controlled Clinical Study Stem Cells Dev 2011 20 1679 1685 1:CAS:528:DC%2BC3MXht1Cht73E 21142788
N. Kadri S. Amu E. Iacobaeus E. Boberg K. Le Blanc Current perspectives on mesenchymal stromal cell therapy for graft versus host disease Cell Mol Immunol 2023 20 613 625 1:CAS:528:DC%2BB3sXpsl2rtrk%3D 37165014 10229573
S. Hashmi M. Ahmed M.H. Murad M.R. Litzow R.H. Adams L.M. Ball et al. Survival after mesenchymal stromal cell therapy in steroid-refractory acute graft-versus-host disease: systematic review and meta-analysis Lancet Haematol 2016 3 e45 52 26765648
S. Servais F. Baron C. Lechanteur L. Seidel E. Baudoux A. Briquet et al. Multipotent mesenchymal stromal cells as treatment for poor graft function after allogeneic hematopoietic cell transplantation: a multicenter prospective analysis Front Immunol 2023 10.3389/fimmu.2023.1106464 36817464 9929549
T. Lin Y. Yang X. Chen A review of the application of mesenchymal stem cells in the field of hematopoietic stem cell transplantation Eur J Med Res 2023 28 268 37550742 10405442
M. Kallekleiv L. Larun Ø. Bruserud K.J. Hatfield Co-transplantation of multipotent mesenchymal stromal cells in allogeneic hematopoietic stem cell transplantation: a systematic review and meta-analysis Cytotherapy 2016 18 172 185 26794711
C. Morata-Tarifa M. del Macías-Sánchez A. Gutiérrez-Pizarraya R. Sanchez-Pernaute Mesenchymal stromal cells for the prophylaxis and treatment of graft-versus-host disease—a meta-analysis Stem Cell Res Ther 2020 11 64 1:CAS:528:DC%2BB3cXks1Glt7Y%3D 32070420 7027118
T. Li C. Luo J. Zhang L. Wei W. Sun Q. Xie et al. Efficacy and safety of mesenchymal stem cells co-infusion in allogeneic hematopoietic stem cell transplantation: a systematic review and meta-analysis Stem Cell Res Ther 2021 12 246 33879242 8056684
R. Li J. Tu J. Zhao H. Pan L. Fang J. Shi Mesenchymal stromal cells as prophylaxis for graft-versus-host disease in haplo-identical hematopoietic stem cell transplantation recipients with severe aplastic anemia?-a systematic review and meta-analysis Stem Cell Res Ther 2021 12 106 33541414 7860635
F. Baron C. Lechanteur E. Willems F. Bruck E. Baudoux L. Seidel et al. Cotransplantation of mesenchymal stem cells might prevent death from graft-versus-host disease (GVHD) without abrogating graft-versus-tumor effects after HLA-mismatched allogeneic transplantation following nonmyeloablative conditioning Biol Blood Marrow Transplant 2010 16 838 847 20109568
C. Lechanteur A. Briquet O. Giet O. Delloye E. Baudoux Y. Beguin Clinical-scale expansion of mesenchymal stromal cells: a large banking experience J Transl Med 2016 14 145 27207011 4875672
P. Armand H.T. Kim B.R. Logan Z. Wang E.P. Alyea M.E. Kalaycio et al. Validation and refinement of the disease risk index for allogeneic stem cell transplantation Blood 2014 123 3664 3671 1:CAS:528:DC%2BC2cXps12qtbo%3D 24744269 4047501
M.L. Sorror B.M. Sandmaier B.E. Storer M.B. Maris F. Baron D.G. Maloney et al. Comorbidity and disease status-based risk stratification of outcomes among patients with acute myeloid leukemia or myelodysplasia receiving allogeneic hematopoietic cell transplantation J Clin Oncol 2007 25 4246 4254 17724349
A. Kumar T. Reljic M. Hamadani M. Mohty M.A. Kharfan-Dabaja Antithymocyte globulin for graft-versus-host disease prophylaxis: an updated systematic review and meta-analysis Bone Marrow Transplant 2019 54 1094 1106 1:CAS:528:DC%2BC1cXit1ChtLfI 30446739
F. Bruck L. Belle C. Lechanteur L. de Leval M. Hannon S. Dubois et al. Impact of bone marrow-derived mesenchymal stromal cells on experimental xenogeneic graft-versus-host disease Cytotherapy 2013 15 267 279 1:CAS:528:DC%2BC3sXht1yktr3F 23265769
C. Grégoire C. Ritacco M. Hannon L. Seidel L. Delens L. Belle et al. Comparison of mesenchymal stromal cells from different origins for the treatment of graft-vs.-host-disease in a humanized mouse model Front Immunol 2019 10.3389/fimmu.2019.00619 31749798 6842949
I.N. Shipounova N.A. Petinati A.E. Bigildeev E.A. Zezina N.I. Drize L.A. Kuzmina et al. Analysis of results of acute graft-versus-host disease prophylaxis with donor multipotent mesenchymal stromal cells in patients with hemoblastoses after allogeneic bone marrow transplantation Biochem Biokhimiia 2014 79 1363 1370 1:CAS:528:DC%2BC2cXitVyhurvP
X. Wang M. Zhang P. He 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 J Int Med Res 2020 48 0300060520920438 1:CAS:528:DC%2BB3cXht1OnsbzM 32363972 7221479
H. Ning F. Yang M. Jiang L. Hu K. Feng J. Zhang et al. The correlation between cotransplantation of mesenchymal stem cells and higher recurrence rate in hematologic malignancy patients: outcome of a pilot clinical study Leukemia 2008 22 593 599 1:STN:280:DC%2BD1c7nsVOktw%3D%3D 18185520
L. Gao Y. Zhang B. Hu J. Liu P. Kong S. Lou et al. Phase II multicenter, randomized, double-blind controlled study of efficacy and safety of umbilical cord-derived mesenchymal stromal cells in the prophylaxis of chronic graft-versus-host disease after HLA-haploidentical stem-cell transplantation J Clin Oncol 2016 34 2843 2850 1:CAS:528:DC%2BC28XhvFOrsrnP 27400949
R. Huang X. Zhang Umbilical cord-derived mesenchymal stromal cells for prevention of chronic graft-vs-host disease—reply JAMA Oncol 2024 10 987 988 38814587
K.H. Wu C. Tsai H.P. Wu M. Sieber C.T. Peng Y.H. Chao Human application of ex vivo expanded umbilical cord-derived mesenchymal stem cells: enhance hematopoiesis after cord blood transplantation Cell Transplant 2013 22 2041 2051 24165586
T. Rostami N. Maleki A. Kasaeian M. Nikbakht A. Kiumarsi S. Asadollah Mousavi et al. 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 Pediatr Transplant 2021 25 1:CAS:528:DC%2BB3MXptVKjt7k%3D 33179398 e13905
M.E. Bernardo L.M. Ball A.M. Cometa H. Roelofs M. Zecca M.A. Avanzini et al. Co-infusion of ex vivo-expanded, parental MSCs prevents life-threatening acute GVHD, but does not reduce the risk of graft failure in pediatric patients undergoing allogeneic umbilical cord blood transplantation Bone Marrow Transplant 2011 46 200 207 1:STN:280:DC%2BC3M7nvFajtA%3D%3D 20400983
S.H. Lee M.W. Lee K.H. Yoo D.S. Kim M.H. Son K.W. Sung et al. Co-transplantation of third-party umbilical cord blood-derived MSCs promotes engraftment in children undergoing unrelated umbilical cord blood transplantation Bone Marrow Transplant 2013 48 1040 1045 1:STN:280:DC%2BC3szntVWgug%3D%3D 23396407
L. Ding D.M. Han X.L. Zheng H.M. Yan M. Xue J. Liu et al. Infusion of haploidentical hematopoietic stem cells combined with mesenchymal stem cells for treatment of severe aplastic anemia in adult patients yields curative effects Cytotherapy 2022 24 205 212 1:CAS:528:DC%2BB38XmtVagu7g%3D 34799271
L. Ding D.M. Han H.M. Yan J.X. Zhou X.L. Zheng L. Zhu et al. Infusion of haploidentical HSCs combined with allogenic MSCs for the treatment of ALL patients Bone Marrow Transplant 2022 57 1086 1094 1:CAS:528:DC%2BB38XhsVOls7vO 35468947
T. Goto M. Murata T. Nishida S. Terakura S. Kamoshita Y. Ishikawa et al. Phase I clinical trial of intra-bone marrow cotransplantation of mesenchymal stem cells in cord blood transplantation Stem Cells Transl Med 2021 10 542 553 33314650
Z. Liu X. Wu S. Wang L. Xia H. Xiao Y. Li et al. Co-transplantation of mesenchymal stem cells makes haploidentical HSCT a potential comparable therapy with matched sibling donor HSCT for patients with severe aplastic anemia Ther Adv Hematol 2020 11 2040620720965411 1:CAS:528:DC%2BB3MXjtVCltA%3D%3D 33194162 7605036
X.F. Sheng H. Li L.L. Hong H. Zhuang Combination of haploidentical hematopoietic stem cell transplantation with umbilical cord-derived mesenchymal stem cells in patients with severe aplastic anemia: a retrospective controlled study Turk J Haematol Off J Turk Soc Haematol 2022 39 117 129 1:CAS:528:DC%2BB38XitFKmu7bI
Y. Zhang H. Zheng J. Ren X. Luo Z. Zheng J. Zheng et al. Mesenchymal stem cells enhance the impact of KIR receptor-ligand mismatching on acute graft-versus-host disease following allogeneic hematopoietic stem cell transplantation in patients with acute myeloid leukemia but not in those with acute lymphocytic leukemia Hematol Oncol 2021 39 380 389 1:CAS:528:DC%2BB38Xmt1yltA%3D%3D 33848027
K.H. Wu J.N. Sheu H.P. Wu C. Tsai M. Sieber C.T. Peng et al. Cotransplantation of umbilical cord-derived mesenchymal stem cells promote hematopoietic engraftment in cord blood transplantation: a pilot study Transplantation 2013 95 773 23274973
R. Gonzalo-Daganzo C. Regidor T. Martín-Donaire M.A. Rico G. Bautista I. Krsnik et al. Results of a pilot study on the use of third-party donor mesenchymal stromal cells in cord blood transplantation in adults Cytotherapy 2009 11 278 288 1:CAS:528:DC%2BD1MXlt1Kms7o%3D 19308773
A.K. Singh P. Prasad J.A. Cancelas Mesenchymal stromal cells, metabolism, and mitochondrial transfer in bone marrow normal and malignant hematopoiesis Front Cell Dev Biol 2023 11 1325291 38169927 10759248
H. Afkhami G. Mahmoudvand A. Fakouri A. Shadab M. Mahjoor M.T. Komeili New insights in application of mesenchymal stem cells therapy in tumor microenvironment: pros and cons Front Cell Dev Biol 2023 11 1255697 37849741 10577325
M. Thompson S.H.J. Mei D. Wolfe J. Champagne D. Fergusson D.J. Stewart et al. Cell therapy with intravascular administration of mesenchymal stromal cells continues to appear safe: An updated systematic review and meta-analysis ClinicalMedicine 2020 19 100249
M. Rizk M. Monaghan R. Shorr N. Kekre C.N. Bredeson D.S. Allan Heterogeneity in studies of mesenchymal stromal cells to treat or prevent graft-versus-host disease: a scoping review of the evidence Biol Blood Marrow Transplant 2016 22 1416 1423 27130504
L.S. Kean L.J. Burns T.D. Kou R. Kapikian K. Lozenski A. Langston et al. Abatacept for acute graft-versus-host disease prophylaxis after unrelated donor hematopoietic cell transplantation Blood 2024 144 1834 1845 1:CAS:528:DC%2BB2cXitlamtr3I 39028876
D.M. Han Z.D. Wang X.L. Zheng L. Ding H.M. Yan M. Xue et al. Co-infusion of mesenchymal stromal cells has no effect on relapse and infection in patients with leukemia undergoing haploidentical hematopoietic stem cell transplant Leuk Lymphoma 2015 56 2965 2968 25721754
