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

J. Peccatori, A. Forcina, D. Clerici, R. Crocchiolo, L. Vago, M. T L Stanghellini, M. Noviello, C. Messina, A. Crotta, A. Assanelli, S. Marktel, S. Olek, S. Mastaglio, F. Giglio, L. Crucitti, A. Lorusso, E. Guggiari, F. Lunghi, M. Carrabba, M. TassaraM. Battaglia, A. Ferraro, M. R. Carbone, G. Oliveira, M. G. Roncarolo, S. Rossini, M. Bernardi, C. Corti, M. Marcatti, F. Patriarca, M. Zecca, F. Locatelli, C. Bordignon, K. Fleischhauer, A. Bondanza, C. Bonini, F. Ciceri

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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.

Original languageEnglish
Pages (from-to)396-405
Number of pages10
JournalLeukemia
Volume29
Issue number2
DOIs
Publication statusPublished - Feb 7 2015

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Peripheral Blood Stem Cell Transplantation
Graft vs Host Disease
Regulatory T-Lymphocytes
Sirolimus
Tissue Donors
Hematopoietic Stem Cell Transplantation
Antilymphocyte Serum
treosulfan
HLA Antigens
Transplants
Incidence
Chimerism
Hematologic Neoplasms
Oral Administration
Neutrophils
Blood Platelets
Bone Marrow
T-Lymphocytes
Recurrence
Survival

ASJC Scopus subject areas

  • Hematology
  • Cancer Research
  • Anesthesiology and Pain Medicine
  • Medicine(all)

Cite this

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. / Peccatori, J.; Forcina, A.; Clerici, D.; Crocchiolo, R.; Vago, L.; Stanghellini, M. T L; Noviello, M.; Messina, C.; Crotta, A.; Assanelli, A.; Marktel, S.; Olek, S.; Mastaglio, S.; Giglio, F.; Crucitti, L.; Lorusso, A.; Guggiari, E.; Lunghi, F.; Carrabba, M.; Tassara, M.; Battaglia, M.; Ferraro, A.; Carbone, M. R.; Oliveira, G.; Roncarolo, M. G.; Rossini, S.; Bernardi, M.; Corti, C.; Marcatti, M.; Patriarca, F.; Zecca, M.; Locatelli, F.; Bordignon, C.; Fleischhauer, K.; Bondanza, A.; Bonini, C.; Ciceri, F.

In: Leukemia, Vol. 29, No. 2, 07.02.2015, p. 396-405.

Research output: Contribution to journalArticle

Peccatori, J, Forcina, A, Clerici, D, Crocchiolo, R, Vago, L, Stanghellini, MTL, Noviello, M, Messina, C, Crotta, A, Assanelli, A, Marktel, S, Olek, S, Mastaglio, S, Giglio, F, Crucitti, L, Lorusso, A, Guggiari, E, Lunghi, F, Carrabba, M, Tassara, M, Battaglia, M, Ferraro, A, Carbone, MR, Oliveira, G, Roncarolo, MG, Rossini, S, Bernardi, M, Corti, C, Marcatti, M, Patriarca, F, Zecca, M, Locatelli, F, Bordignon, C, Fleischhauer, K, Bondanza, A, Bonini, C & Ciceri, F 2015, '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', Leukemia, vol. 29, no. 2, pp. 396-405. https://doi.org/10.1038/leu.2014.180
Peccatori, J. ; Forcina, A. ; Clerici, D. ; Crocchiolo, R. ; Vago, L. ; Stanghellini, M. T L ; Noviello, M. ; Messina, C. ; Crotta, A. ; Assanelli, A. ; Marktel, S. ; Olek, S. ; Mastaglio, S. ; Giglio, F. ; Crucitti, L. ; Lorusso, A. ; Guggiari, E. ; Lunghi, F. ; Carrabba, M. ; Tassara, M. ; Battaglia, M. ; Ferraro, A. ; Carbone, M. R. ; Oliveira, G. ; Roncarolo, M. G. ; Rossini, S. ; Bernardi, M. ; Corti, C. ; Marcatti, M. ; Patriarca, F. ; Zecca, M. ; Locatelli, F. ; Bordignon, C. ; Fleischhauer, K. ; Bondanza, A. ; Bonini, C. ; Ciceri, F. / 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. In: Leukemia. 2015 ; Vol. 29, No. 2. pp. 396-405.
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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.",
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T1 - 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

AU - Peccatori, J.

AU - Forcina, A.

AU - Clerici, D.

AU - Crocchiolo, R.

AU - Vago, L.

AU - Stanghellini, M. T L

AU - Noviello, M.

AU - Messina, C.

AU - Crotta, A.

AU - Assanelli, A.

AU - Marktel, S.

AU - Olek, S.

AU - Mastaglio, S.

AU - Giglio, F.

AU - Crucitti, L.

AU - Lorusso, A.

AU - Guggiari, E.

AU - Lunghi, F.

AU - Carrabba, M.

AU - Tassara, M.

AU - Battaglia, M.

AU - Ferraro, A.

AU - Carbone, M. R.

AU - Oliveira, G.

AU - Roncarolo, M. G.

AU - Rossini, S.

AU - Bernardi, M.

AU - Corti, C.

AU - Marcatti, M.

AU - Patriarca, F.

AU - Zecca, M.

AU - Locatelli, F.

AU - Bordignon, C.

AU - Fleischhauer, K.

AU - Bondanza, A.

AU - Bonini, C.

AU - Ciceri, F.

PY - 2015/2/7

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N2 - 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.

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