Rapamycin-Based GvHD Prophylaxis Is Effective in T-Cell Replete Unmanipulated Haploidentical Peripheral Stem Cell Transplantation for Advanced Haematological Malignancies: Results in 46 Patients.
Authors: Peccatori Jacopo , Clerici Daniela , Messina Carlo , Forcina Alessandra , Bondanza Attilio , Crocchiolo Roberto , Stanghellini Maria Teresa Lupo , Assanelli Andrea , Marcatti Magda , Giglio Fabio , Claudiani Simone , Mastaglio Sara , Malato Simona , Crotta Alessandro , Battaglia Manuela , Ronchi Paola , Gattillo Salvatore , Rossini Silvano , Corti Consuelo , Bernardi Massimo , Marktel Sarah , Bernardo Maria Ester , Bonini Chiara , Roncarolo Maria Grazia , Locatelli Franco , Ciceri Fabio 
Published: October 2019

Abstract 666

Background:

Results of haploidentical stem cell transplantation (SCT) after standard extensive T-cell depletion for advanced leukemias are poor (Ciceri et al, 2008). In contrast, significant leukemia-free-survivals are produced after T-cell replete SCT from matched related, unrelated and cord-blood donors, even in advanced phases of disease (Kolb HJ, 2009). New protocols based on T-cell repletion are warrented in patients receiving haplo-SCT, in order to offer to all candidates patients with advanced leukemia the potential of cure of allogeneic SCT.Rapamycin is an immunosuppressive drug that arrests cell cycle in G1 phase through the inhibition of DNA transcription, RNA translation and protein synthesis. Morover, in contrast to calcineurin inhibitors, it promotes the generation and expansion of T regulatory cells (Tregs).

Aim:

We investigated the safety of infusion of T-cell replete unmanipulated peripheral blood stem cells (PBSC) from family haploidentical donor with a combination Rapamycin, Mycophenolate and ATG as GvHD prophylaxis, to preserve early Treg function (TrRaMM study, Eudract 2007-5477-54).

Patients and Methods:

Since 2007, forty-six patients underwent allogeneic transplantation for AML (25 pts), ALL (7 pts), sAML (6 pts), MDS (3 pts), CML-BC (2 pts), NHL (2 pts) or HD (1 pt). The median age was 50 years (range 14-69). At time of transplantation 5 pts were in early phase, and 41 were in advanced phase. Median time from diagnosis to transplantation was 351 days (range 81-1387); 8 patients were enrolled for relapse after allogeneic SCT from MRD or MUD. Median comorbodity index score was 1 (0-5). The conditioning regimen included Treosulfan (14 g/m2 for 3 days), Fludarabine (30 mg/m2 for 5 days) and an in vivo T and B-cell depletion, by ATG-Fresenius (10 mg/kg for 3 times) and Rituximab (a single 500 mg dose). All pts received allogeneic peripheral blood cells from an HLA-haploidentical related donor without any in vitro positive selection of CD34+ cells. GvHD prophylaxis consisted of Rapamycin (target level 8-15 ng/ml, till day +60) and MMF (15 mg/kg tid till day +30).

Results:

All patients engrafted, and all but eight were in disease remission at first marrow evaluation on day +30. Cumulative incidence of grade 2-4 aGvHD was 33% (95% CI: 18-48); cumulative incidence of grade 3-4 aGvHD was 12% (95% CI: 2-22). Interestingly, half of patients with GvHD developed it at immunosuppressive prophylaxis withdrawal for disease relapse. Only six patients developed cGvHD. Cumulative incidence of TRM and relapse incidence were 26% (95% CI: 11-41) and 53% (95% CI: 35-71) respectively. None developed EBV reactivation. Patients experienced an early and sustained immunoreconstitution with a median 221 circulating CD3+cells/μL (range 43-1690) from day 30. The immune-reconstitution was polarized towards central memory cells (CD45RA-CD62L+ cells 32.7% ± 4.8) that produced IL-2 (IL-2+ cells 26.2% ± 5.3). Of interest, at day +90 from transplant, Tregs were significantly expanded (CD4+CD25+CD127-Foxp3+ cells 15.6% ± 4.8 on total CD3+ cells, P<0,05 vs donor controls). After a median follow-up of 6 months, overall survival is 64% (95% CI: 50-78), and projected OS at 1 year is 46% (95% CI: 31-61).

Conclusions:

Rapamycin-Mycophenolate-ATG are effective to prevent GvHD in T-cell replete unmanipulated haploidentical peripheral stem cell transplantation for advanced haematological malignancies. This associates with an early T-cell immunoreconstitution characterized by the in vivo expansion of early-differentiated T cells and Tregs, and translates in promising leukemia-free survival in patients with advanced resistant leukemia. Further studies are warranted to gain insight on the role of rapamycin as platform for exploitation of Tregs in allogeneic HSCT from mismatched donor.

Disclosures:

No relevant conflicts of interest to declare.