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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

2014; Springer Nature; Volume: 29; Issue: 2 Linguagem: Inglês

10.1038/leu.2014.180

1476-5551

Jacopo Peccatori, Alessandra Forcina, Daniela Clerici, Roberto Crocchiolo, Luca Vago, Maria Teresa Lupo Stanghellini, Maddalena Noviello, Chiara Messina, Alessandro Crotta, Andrea Assanelli, Sarah Marktel, Sven Olek, Sara Mastaglio, Fabio Giglio, Lara Crucitti, Alessandro Lorusso, Elena Guggiari, Francesca Lunghi, Matteo Giovanni Carrabba, Michela Tassara, Manuela Battaglia, Alessandra M. Ferraro, Maria Carbone, Giacomo Oliveira, Maria Grazia Roncarolo, Silvano Rossini, Massimo Bernardi, Consuelo Corti, Magda Marcatti, Francesca Patriarca, Marco Zecca, Franco Locatelli, Claudio Bordignon, Katharina Fleischhauer, Attilio Bondanza, Chiara Bonini, Fabio Ciceri,

Immune Cell Function and Interaction

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.