title: Sirolimus-based graft-versus-host disease prophylaxis promotes the in vivo expansion of regulatory T cells and permits peripheral blood stem cell transplantation from haploidentical donors.
abstract: Hematopoietic stem cell transplantation (HSCT) from human leukocyte antigen (HLA) haploidentical family donors is a promising therapeutic option for high-risk hematologic malignancies. Here we explored in 121 patients, mostly with advanced stage diseases, a sirolimus-based, calcineurin-inhibitor-free prophylaxis of graft-versus-host disease (GvHD) to allow the infusion of unmanipulated peripheral blood stem cell (PBSC) grafts from partially HLA-matched family donors (TrRaMM study, Eudract 2007-5477-54). Conditioning regimen was based on treosulfan and fludarabine, and GvHD prophylaxis on antithymocyte globulin Fresenius (ATG-F), rituximab and oral administration of sirolimus and mycophenolate. Neutrophil and platelet engraftment occurred in median at 17 and 19 days after HSCT, respectively, and full donor chimerism was documented in patients' bone marrow since the first post-transplant evaluation. T-cell immune reconstitution was rapid, and high frequencies of circulating functional T-regulatory cells (Treg) were documented during sirolimus prophylaxis. Incidence of acute GvHD grade II-IV was 35%, and occurrence and severity correlated negatively with Treg frequency. Chronic GvHD incidence was 47%. At 3 years after HSCT, transpant-related mortality was 31%, relapse incidence 48% and overall survival 25%. In conclusion, GvHD prophylaxis with sirolimus-mycophenolate-ATG-F-rituximab promotes a rapid immune reconstitution skewed toward Tregs, allowing the infusion of unmanipulated haploidentical PBSC grafts.
authors.affiliation: Hematology and Bone Marrow Transplantation Unit, Division of Regenerative Medicine, Gene Therapy and Stem Cells, IRCCS San Raffaele Scientific Institute, Milan, Italy.
authors.forename: J
authors.initials: J
authors.lastname: Peccatori
authors.affiliation: 1] Hematology and Bone Marrow Transplantation Unit, Division of Regenerative Medicine, Gene Therapy and Stem Cells, IRCCS San Raffaele Scientific Institute, Milan, Italy [2] Experimental Hematology Unit, Division of Immunology, Infectious Diseases and Transplants, IRCCS San Raffaele Scientific Institute, Milan, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Forcina
authors.affiliation: Hematology and Bone Marrow Transplantation Unit, Division of Regenerative Medicine, Gene Therapy and Stem Cells, IRCCS San Raffaele Scientific Institute, Milan, Italy.
authors.forename: D
authors.initials: D
authors.lastname: Clerici
authors.affiliation: 1] Hematology and Bone Marrow Transplantation Unit, Division of Regenerative Medicine, Gene Therapy and Stem Cells, IRCCS San Raffaele Scientific Institute, Milan, Italy [2] Humanitas Cancer Center, Rozzano, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Crocchiolo
authors.affiliation: 1] Hematology and Bone Marrow Transplantation Unit, Division of Regenerative Medicine, Gene Therapy and Stem Cells, IRCCS San Raffaele Scientific Institute, Milan, Italy [2] Unit of Molecular and Functional Immunogenetics, Division of Regenerative Medicine, Gene Therapy and Stem Cells, IRCCS San Raffaele Scientific Institute, Milan, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Vago
authors.affiliation: Hematology and Bone Marrow Transplantation Unit, Division of Regenerative Medicine, Gene Therapy and Stem Cells, IRCCS San Raffaele Scientific Institute, Milan, Italy.
authors.forename: M T L
authors.initials: MT
authors.lastname: Stanghellini
authors.affiliation: Experimental Hematology Unit, Division of Immunology, Infectious Diseases and Transplants, IRCCS San Raffaele Scientific Institute, Milan, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Noviello
authors.affiliation: Hematology and Bone Marrow Transplantation Unit, Division of Regenerative Medicine, Gene Therapy and Stem Cells, IRCCS San Raffaele Scientific Institute, Milan, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Messina
authors.affiliation: Hematology and Bone Marrow Transplantation Unit, Division of Regenerative Medicine, Gene Therapy and Stem Cells, IRCCS San Raffaele Scientific Institute, Milan, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Crotta
authors.affiliation: Hematology and Bone Marrow Transplantation Unit, Division of Regenerative Medicine, Gene Therapy and Stem Cells, IRCCS San Raffaele Scientific Institute, Milan, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Assanelli
authors.affiliation: Hematology and Bone Marrow Transplantation Unit, Division of Regenerative Medicine, Gene Therapy and Stem Cells, IRCCS San Raffaele Scientific Institute, Milan, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Marktel
authors.affiliation: Epiontis GmbH, Berlin, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Olek
authors.affiliation: Hematology and Bone Marrow Transplantation Unit, Division of Regenerative Medicine, Gene Therapy and Stem Cells, IRCCS San Raffaele Scientific Institute, Milan, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Mastaglio
authors.affiliation: Hematology and Bone Marrow Transplantation Unit, Division of Regenerative Medicine, Gene Therapy and Stem Cells, IRCCS San Raffaele Scientific Institute, Milan, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Giglio
authors.affiliation: Hematology and Bone Marrow Transplantation Unit, Division of Regenerative Medicine, Gene Therapy and Stem Cells, IRCCS San Raffaele Scientific Institute, Milan, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Crucitti
authors.affiliation: Hematology and Bone Marrow Transplantation Unit, Division of Regenerative Medicine, Gene Therapy and Stem Cells, IRCCS San Raffaele Scientific Institute, Milan, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Lorusso
authors.affiliation: Hematology and Bone Marrow Transplantation Unit, Division of Regenerative Medicine, Gene Therapy and Stem Cells, IRCCS San Raffaele Scientific Institute, Milan, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Guggiari
authors.affiliation: Hematology and Bone Marrow Transplantation Unit, Division of Regenerative Medicine, Gene Therapy and Stem Cells, IRCCS San Raffaele Scientific Institute, Milan, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Lunghi
authors.affiliation: Hematology and Bone Marrow Transplantation Unit, Division of Regenerative Medicine, Gene Therapy and Stem Cells, IRCCS San Raffaele Scientific Institute, Milan, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Carrabba
authors.affiliation: Hematology and Bone Marrow Transplantation Unit, Division of Regenerative Medicine, Gene Therapy and Stem Cells, IRCCS San Raffaele Scientific Institute, Milan, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Tassara
authors.affiliation: San Raffaele Diabetes Research Institute, Division of Immunology, Infectious Diseases and Transplants, IRCCS San Raffaele Scientific Institute, Milan, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Battaglia
authors.affiliation: San Raffaele Diabetes Research Institute, Division of Immunology, Infectious Diseases and Transplants, IRCCS San Raffaele Scientific Institute, Milan, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Ferraro
authors.affiliation: Experimental Hematology Unit, Division of Immunology, Infectious Diseases and Transplants, IRCCS San Raffaele Scientific Institute, Milan, Italy.
authors.forename: M R
authors.initials: MR
authors.lastname: Carbone
authors.affiliation: Experimental Hematology Unit, Division of Immunology, Infectious Diseases and Transplants, IRCCS San Raffaele Scientific Institute, Milan, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Oliveira
authors.affiliation: 1] Pediatric Immunology, Hematology and Bone Marrow Transplantation Unit, Division of Regenerative Medicine, Gene Therapy and Stem Cells, IRCCS San Raffaele Scientific Institute, Milan, Italy [2] San Raffaele Telethon Institute for Gene Therapy (HSR-TIGET), Division of Regenerative Medicine, Gene Therapy and Stem Cells, San Raffaele Scientific Institute, Milan, Italy [3] 'Vita-Salute' San Raffaele University, Milan, Italy.
authors.forename: M G
authors.initials: MG
authors.lastname: Roncarolo
authors.affiliation: Immunohematology and Transfusion Medicine Service, Division of Regenerative Medicine, Gene Therapy and Stem Cells, IRCCS San Raffaele Scientific Institute, Milan, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Rossini
authors.affiliation: Hematology and Bone Marrow Transplantation Unit, Division of Regenerative Medicine, Gene Therapy and Stem Cells, IRCCS San Raffaele Scientific Institute, Milan, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Bernardi
authors.affiliation: Hematology and Bone Marrow Transplantation Unit, Division of Regenerative Medicine, Gene Therapy and Stem Cells, IRCCS San Raffaele Scientific Institute, Milan, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Corti
authors.affiliation: Hematology and Bone Marrow Transplantation Unit, Division of Regenerative Medicine, Gene Therapy and Stem Cells, IRCCS San Raffaele Scientific Institute, Milan, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Marcatti
authors.affiliation: Clinica Ematologica, Policlinico Universitario, Udine, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Patriarca
authors.affiliation: Policlinico San Matteo, Pavia, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Zecca
authors.affiliation: IRCCS Ospedale Bambino Gesù, Roma, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Locatelli
authors.affiliation: 1] 'Vita-Salute' San Raffaele University, Milan, Italy [2] MolMed SpA, Milan, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Bordignon
authors.affiliation: Unit of Molecular and Functional Immunogenetics, Division of Regenerative Medicine, Gene Therapy and Stem Cells, IRCCS San Raffaele Scientific Institute, Milan, Italy.
authors.forename: K
authors.initials: K
authors.lastname: Fleischhauer
authors.affiliation: 1] Hematology and Bone Marrow Transplantation Unit, Division of Regenerative Medicine, Gene Therapy and Stem Cells, IRCCS San Raffaele Scientific Institute, Milan, Italy [2] Leukemia Immunotherapy Group, Division of Regenerative Medicine, Gene Therapy and Stem Cells, IRCCS San Raffaele Scientific Institute, Milan, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Bondanza
authors.affiliation: Experimental Hematology Unit, Division of Immunology, Infectious Diseases and Transplants, IRCCS San Raffaele Scientific Institute, Milan, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Bonini
authors.affiliation: Hematology and Bone Marrow Transplantation Unit, Division of Regenerative Medicine, Gene Therapy and Stem Cells, IRCCS San Raffaele Scientific Institute, Milan, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Ciceri
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000368:Aged; D058846:Antibodies, Monoclonal, Murine-Derived / Q000627:therapeutic use; D000961:Antilymphocyte Serum / Q000627:therapeutic use; D001792:Blood Platelets / Q000166:cytology; D002066:Busulfan / Q000031:analogs & derivatives / Q000627:therapeutic use; D002648:Child; D005260:Female; D006086:Graft vs Host Disease / Q000276:immunology* / Q000517:prevention & control*; D006680:HLA Antigens / Q000276:immunology*; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D009173:Mycophenolic Acid / Q000031:analogs & derivatives / Q000627:therapeutic use; D009504:Neutrophils / Q000166:cytology; D036102:Peripheral Blood Stem Cell Transplantation; D011446:Prospective Studies; D000069283:Rituximab; D020123:Sirolimus / Q000627:therapeutic use*; D013601:T-Lymphocytes / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D014019:Tissue Donors; D019172:Transplantation Conditioning; D016896:Treatment Outcome; D014740:Vidarabine / Q000031:analogs & derivatives / Q000627:therapeutic use; D055815:Young Adult
chemical_list: D058846:Antibodies, Monoclonal, Murine-Derived; D000961:Antilymphocyte Serum; D006680:HLA Antigens; D007166:Immunosuppressive Agents; D000069283:Rituximab; C018404:treosulfan; D014740:Vidarabine; D002066:Busulfan; D009173:Mycophenolic Acid; C024352:fludarabine; D020123:Sirolimus