Format

Send to

Choose Destination
Leukemia. 2015 Feb;29(2):396-405. doi: 10.1038/leu.2014.180. Epub 2014 Jun 4.

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.

Author information

1
Hematology and Bone Marrow Transplantation Unit, Division of Regenerative Medicine, Gene Therapy and Stem Cells, IRCCS San Raffaele Scientific Institute, Milan, Italy.
2
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.
3
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.
4
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.
5
Experimental Hematology Unit, Division of Immunology, Infectious Diseases and Transplants, IRCCS San Raffaele Scientific Institute, Milan, Italy.
6
Epiontis GmbH, Berlin, Germany.
7
San Raffaele Diabetes Research Institute, Division of Immunology, Infectious Diseases and Transplants, IRCCS San Raffaele Scientific Institute, Milan, Italy.
8
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.
9
Immunohematology and Transfusion Medicine Service, Division of Regenerative Medicine, Gene Therapy and Stem Cells, IRCCS San Raffaele Scientific Institute, Milan, Italy.
10
Clinica Ematologica, Policlinico Universitario, Udine, Italy.
11
Policlinico San Matteo, Pavia, Italy.
12
IRCCS Ospedale Bambino Gesù, Roma, Italy.
13
1] 'Vita-Salute' San Raffaele University, Milan, Italy [2] MolMed SpA, Milan, Italy.
14
Unit of Molecular and Functional Immunogenetics, Division of Regenerative Medicine, Gene Therapy and Stem Cells, IRCCS San Raffaele Scientific Institute, Milan, Italy.
15
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.

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.

PMID:
24897508
DOI:
10.1038/leu.2014.180
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Nature Publishing Group
Loading ...
Support Center