PMID- 24897508
OWN - NLM
STAT- MEDLINE
DCOM- 20150406
LR  - 20211021
IS  - 1476-5551 (Electronic)
IS  - 0887-6924 (Linking)
VI  - 29
IP  - 2
DP  - 2015 Feb
TI  - 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.
PG  - 396-405
LID - 10.1038/leu.2014.180 [doi]
AB  - 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.
FAU - Peccatori, J
AU  - Peccatori J
AD  - Hematology and Bone Marrow Transplantation Unit, Division of Regenerative 
      Medicine, Gene Therapy and Stem Cells, IRCCS San Raffaele Scientific Institute, 
      Milan, Italy.
FAU - Forcina, A
AU  - Forcina A
AD  - 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.
FAU - Clerici, D
AU  - Clerici D
AD  - Hematology and Bone Marrow Transplantation Unit, Division of Regenerative 
      Medicine, Gene Therapy and Stem Cells, IRCCS San Raffaele Scientific Institute, 
      Milan, Italy.
FAU - Crocchiolo, R
AU  - Crocchiolo R
AD  - 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.
FAU - Vago, L
AU  - Vago L
AD  - 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.
FAU - Stanghellini, M T L
AU  - Stanghellini MT
AD  - Hematology and Bone Marrow Transplantation Unit, Division of Regenerative 
      Medicine, Gene Therapy and Stem Cells, IRCCS San Raffaele Scientific Institute, 
      Milan, Italy.
FAU - Noviello, M
AU  - Noviello M
AD  - Experimental Hematology Unit, Division of Immunology, Infectious Diseases and 
      Transplants, IRCCS San Raffaele Scientific Institute, Milan, Italy.
FAU - Messina, C
AU  - Messina C
AD  - Hematology and Bone Marrow Transplantation Unit, Division of Regenerative 
      Medicine, Gene Therapy and Stem Cells, IRCCS San Raffaele Scientific Institute, 
      Milan, Italy.
FAU - Crotta, A
AU  - Crotta A
AD  - Hematology and Bone Marrow Transplantation Unit, Division of Regenerative 
      Medicine, Gene Therapy and Stem Cells, IRCCS San Raffaele Scientific Institute, 
      Milan, Italy.
FAU - Assanelli, A
AU  - Assanelli A
AD  - Hematology and Bone Marrow Transplantation Unit, Division of Regenerative 
      Medicine, Gene Therapy and Stem Cells, IRCCS San Raffaele Scientific Institute, 
      Milan, Italy.
FAU - Marktel, S
AU  - Marktel S
AD  - Hematology and Bone Marrow Transplantation Unit, Division of Regenerative 
      Medicine, Gene Therapy and Stem Cells, IRCCS San Raffaele Scientific Institute, 
      Milan, Italy.
FAU - Olek, S
AU  - Olek S
AD  - Epiontis GmbH, Berlin, Germany.
FAU - Mastaglio, S
AU  - Mastaglio S
AD  - Hematology and Bone Marrow Transplantation Unit, Division of Regenerative 
      Medicine, Gene Therapy and Stem Cells, IRCCS San Raffaele Scientific Institute, 
      Milan, Italy.
FAU - Giglio, F
AU  - Giglio F
AD  - Hematology and Bone Marrow Transplantation Unit, Division of Regenerative 
      Medicine, Gene Therapy and Stem Cells, IRCCS San Raffaele Scientific Institute, 
      Milan, Italy.
FAU - Crucitti, L
AU  - Crucitti L
AD  - Hematology and Bone Marrow Transplantation Unit, Division of Regenerative 
      Medicine, Gene Therapy and Stem Cells, IRCCS San Raffaele Scientific Institute, 
      Milan, Italy.
FAU - Lorusso, A
AU  - Lorusso A
AD  - Hematology and Bone Marrow Transplantation Unit, Division of Regenerative 
      Medicine, Gene Therapy and Stem Cells, IRCCS San Raffaele Scientific Institute, 
      Milan, Italy.
FAU - Guggiari, E
AU  - Guggiari E
AD  - Hematology and Bone Marrow Transplantation Unit, Division of Regenerative 
      Medicine, Gene Therapy and Stem Cells, IRCCS San Raffaele Scientific Institute, 
      Milan, Italy.
FAU - Lunghi, F
AU  - Lunghi F
AD  - Hematology and Bone Marrow Transplantation Unit, Division of Regenerative 
      Medicine, Gene Therapy and Stem Cells, IRCCS San Raffaele Scientific Institute, 
      Milan, Italy.
FAU - Carrabba, M
AU  - Carrabba M
AD  - Hematology and Bone Marrow Transplantation Unit, Division of Regenerative 
      Medicine, Gene Therapy and Stem Cells, IRCCS San Raffaele Scientific Institute, 
      Milan, Italy.
FAU - Tassara, M
AU  - Tassara M
AD  - Hematology and Bone Marrow Transplantation Unit, Division of Regenerative 
      Medicine, Gene Therapy and Stem Cells, IRCCS San Raffaele Scientific Institute, 
      Milan, Italy.
FAU - Battaglia, M
AU  - Battaglia M
AD  - San Raffaele Diabetes Research Institute, Division of Immunology, Infectious 
      Diseases and Transplants, IRCCS San Raffaele Scientific Institute, Milan, Italy.
FAU - Ferraro, A
AU  - Ferraro A
AD  - San Raffaele Diabetes Research Institute, Division of Immunology, Infectious 
      Diseases and Transplants, IRCCS San Raffaele Scientific Institute, Milan, Italy.
FAU - Carbone, M R
AU  - Carbone MR
AD  - Experimental Hematology Unit, Division of Immunology, Infectious Diseases and 
      Transplants, IRCCS San Raffaele Scientific Institute, Milan, Italy.
FAU - Oliveira, G
AU  - Oliveira G
AD  - Experimental Hematology Unit, Division of Immunology, Infectious Diseases and 
      Transplants, IRCCS San Raffaele Scientific Institute, Milan, Italy.
FAU - Roncarolo, M G
AU  - Roncarolo MG
AD  - 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.
FAU - Rossini, S
AU  - Rossini S
AD  - Immunohematology and Transfusion Medicine Service, Division of Regenerative 
      Medicine, Gene Therapy and Stem Cells, IRCCS San Raffaele Scientific Institute, 
      Milan, Italy.
FAU - Bernardi, M
AU  - Bernardi M
AD  - Hematology and Bone Marrow Transplantation Unit, Division of Regenerative 
      Medicine, Gene Therapy and Stem Cells, IRCCS San Raffaele Scientific Institute, 
      Milan, Italy.
FAU - Corti, C
AU  - Corti C
AD  - Hematology and Bone Marrow Transplantation Unit, Division of Regenerative 
      Medicine, Gene Therapy and Stem Cells, IRCCS San Raffaele Scientific Institute, 
      Milan, Italy.
FAU - Marcatti, M
AU  - Marcatti M
AD  - Hematology and Bone Marrow Transplantation Unit, Division of Regenerative 
      Medicine, Gene Therapy and Stem Cells, IRCCS San Raffaele Scientific Institute, 
      Milan, Italy.
FAU - Patriarca, F
AU  - Patriarca F
AD  - Clinica Ematologica, Policlinico Universitario, Udine, Italy.
FAU - Zecca, M
AU  - Zecca M
AD  - Policlinico San Matteo, Pavia, Italy.
FAU - Locatelli, F
AU  - Locatelli F
AD  - IRCCS Ospedale Bambino Gesu, Roma, Italy.
FAU - Bordignon, C
AU  - Bordignon C
AD  - 1] 'Vita-Salute' San Raffaele University, Milan, Italy [2] MolMed SpA, Milan, 
      Italy.
FAU - Fleischhauer, K
AU  - Fleischhauer K
AD  - Unit of Molecular and Functional Immunogenetics, Division of Regenerative 
      Medicine, Gene Therapy and Stem Cells, IRCCS San Raffaele Scientific Institute, 
      Milan, Italy.
FAU - Bondanza, A
AU  - Bondanza A
AD  - 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.
FAU - Bonini, C
AU  - Bonini C
AD  - Experimental Hematology Unit, Division of Immunology, Infectious Diseases and 
      Transplants, IRCCS San Raffaele Scientific Institute, Milan, Italy.
FAU - Ciceri, F
AU  - Ciceri F
AD  - Hematology and Bone Marrow Transplantation Unit, Division of Regenerative 
      Medicine, Gene Therapy and Stem Cells, IRCCS San Raffaele Scientific Institute, 
      Milan, Italy.
LA  - eng
PT  - Clinical Trial, Phase II
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20140604
PL  - England
TA  - Leukemia
JT  - Leukemia
JID - 8704895
RN  - 0 (Antibodies, Monoclonal, Murine-Derived)
RN  - 0 (Antilymphocyte Serum)
RN  - 0 (HLA Antigens)
RN  - 0 (Immunosuppressive Agents)
RN  - 4F4X42SYQ6 (Rituximab)
RN  - CO61ER3EPI (treosulfan)
RN  - FA2DM6879K (Vidarabine)
RN  - G1LN9045DK (Busulfan)
RN  - HU9DX48N0T (Mycophenolic Acid)
RN  - P2K93U8740 (fludarabine)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Administration, Oral
MH  - Adolescent
MH  - Adult
MH  - Aged
MH  - Antibodies, Monoclonal, Murine-Derived/therapeutic use
MH  - Antilymphocyte Serum/therapeutic use
MH  - Blood Platelets/cytology
MH  - Busulfan/analogs & derivatives/therapeutic use
MH  - Child
MH  - Female
MH  - Graft vs Host Disease/*immunology/*prevention & control
MH  - HLA Antigens/*immunology
MH  - Humans
MH  - Immunosuppressive Agents/therapeutic use
MH  - Male
MH  - Middle Aged
MH  - Mycophenolic Acid/analogs & derivatives/therapeutic use
MH  - Neutrophils/cytology
MH  - *Peripheral Blood Stem Cell Transplantation
MH  - Prospective Studies
MH  - Rituximab
MH  - Sirolimus/*therapeutic use
MH  - T-Lymphocytes/immunology
MH  - T-Lymphocytes, Regulatory/*immunology
MH  - Tissue Donors
MH  - Transplantation Conditioning
MH  - Treatment Outcome
MH  - Vidarabine/analogs & derivatives/therapeutic use
MH  - Young Adult
EDAT- 2014/06/05 06:00
MHDA- 2015/04/07 06:00
CRDT- 2014/06/05 06:00
PHST- 2013/12/24 00:00 [received]
PHST- 2014/04/14 00:00 [revised]
PHST- 2014/05/19 00:00 [accepted]
PHST- 2014/06/05 06:00 [entrez]
PHST- 2014/06/05 06:00 [pubmed]
PHST- 2015/04/07 06:00 [medline]
AID - leu2014180 [pii]
AID - 10.1038/leu.2014.180 [doi]
PST - ppublish
SO  - Leukemia. 2015 Feb;29(2):396-405. doi: 10.1038/leu.2014.180. Epub 2014 Jun 4.