Graft-versus-host disease (GVHD), both acute and chronic, is still a leading cause of nonrelapse mortality after transplantation. 1 Highdose, posttransplantation cyclophosphamide (PTCy) is an attractive approach for in vivo allodepletion across the HLA barrier in allogeneic hematopoietic stem cell transplantation (HSCT), aimed at inducing a state of immunologic tolerance and preventing GVHD. 2 This clinical platform was demonstrated first in the reduced-intensity conditioning, haploidentical allogeneic HSCT setting3, 4 and later as single-agent GVHD prophylaxis after myeloablative conditioning and HLA-matched-related or-unrelated bone marrow allografting. 5 Moreover, we have recently reported encouraging results in a haploidentical setting with the combination of PTCy and sirolimus as GVHD prophylaxis (Sir-PTCy), 6 with a potential reduced transplant-related mortality (TRM) and GVHD incidence over a GVHD prophylaxis based on sirolimus–antithymocyte globulin. 7 PTCy has been widely investigated in in the haploidentical context, with bone marrow as a source and in association with calcineurin inhibitors (CNIs), 4, 8-10 but limited series have been reported after HLA-matched HSCT with peripheral blood as a source or CNI-free GVHD prophylaxis. 11 Mielcarek et al recently reported their experience on PTCy followed by cyclosporine in HLA-matched mobilized blood cell grafts. 12, 13 Here, we describe the use of PTCy and sirolimus as GVHD prophylaxis after HLA-matched peripheral blood HSCT, aiming to increase its feasibility by reducing TRM, as recently obtained by our group in the haploidentical setting. 6 We report 28 consecutive patients, treated from 2014 to 2016, according to a Sir-PTCy6 GVHD prophylaxis schedule with an allogeneic HSCT from a matched-related donor (MRD; n 5 15) or a matched-unrelated volunteer donor (MUD; n513). All patients were treated according to current institutional programs upon written informed consent for transplant procedures. HLA compatibility among donor-recipient pairs was assessed by 10 loci molecular typing (HLA-A,-B,-C,-DRB1,-DQB1) at the allelic level; MUDs were matched at 10 of 10 loci in 11 patients and 9 of 10 loci in 2 patients. Comorbidities were evaluated according to the Comorbidity-Age Index. 14 Immune reconstitution was evaluated by flow cytometry and analyzed with FCS Express software (De Novo Software). Neutrophil engraftment was defined as achievement of an absolute neutrophil count. 500 cells/mm3 for 3 consecutive days. Acute and chronic GVHD were defined and scored according to the Glucksberg and National Institutes of Health consensus criteria, respectively. 15-17 TRM was defined as death from any cause without evidence of relapse or progression of the original disease. Progressionfree survival (PFS) was defined as the interval from HSCT to either relapse or progression or death in remission (whichever came first). Overall survival (OS) was defined as the interval from HSCT to death from any cause. The probabilities of PFS and OS were estimated using the Kaplan-Meier estimator. Cumulative incidences (CIs) were estimated for engraftment, GVHD, TRM, and relapse to accommodate competing risks. 18 Univariate comparisons of survival curves were made using the log-rank test, whereas the Gray test was used for univariate comparisons of CI functions. 19 The type I error rate wasfixed at 0.05 for determination of factors associated with time to event. Statistical analyses were performed with R (R Development Core Team, Vienna, Austria) software packages. Patients, donors, and graft characteristics are provided in Table 1. Median age at HSCT was 46 …