Post-transplantation Cyclophosphamide and Sirolimus after Haploidentical Hematopoietic Stem Cell Transplantation Using a Treosulfan-based Myeloablative Conditioning and Peripheral Blood Stem Cells

Abstract

Haploidentical hematopoietic stem cell transplantation (HSCT) performed using bone marrow (BM) grafts and post-transplantation cyclophosphamide (PTCy) has gained much interest for the excellent toxicity profile after both reduced-intensity and myeloablative conditioning. We investigated, in a cohort of 40 high-risk hematological patients, the feasibility of peripheral blood stem cells grafts after a treosulfan-melphalan myeloablative conditioning, followed by a PTCy and sirolimus-based graft-versus-host disease (GVHD) prophylaxis (Sir-PTCy). Donor engraftment occurred in all patients, with full donor chimerism achieved by day 30. Post-HSCT recovery of lymphocyte subsets was broad and fast, with a median time to CD4 > 200/μL of 41 days. Cumulative incidences of grade II to IV and III-IV acute GVHD were 15% and 7.5%, respectively, and were associated with a significant early increase in circulating regulatory T cells at day 15 after HSCT, with values < 5% being predictive of subsequent GVHD occurrence. The 1-year cumulative incidence of chronic GVHD was 20%. Nonrelapse mortality (NRM) at 100 days and 1 year were 12% and 17%, respectively. With a median follow-up for living patients of 15 months, the estimated 1-year overall and disease-free survival (DFS) was 56% and 48%, respectively. Outcomes were more favorable in patients who underwent transplantation in complete remission (1-year DFS 71%) versus patients who underwent transplantation with active disease (DFS, 34%; P = .01). Overall, myeloablative haploidentical HSCT with peripheral blood stem cells (PBSC) and Sir-PTCy is a feasible treatment option: the low rates of GVHD and NRM as well as the favorable immune reconstitution profile pave the way for a prospective comparative trial comparing BM and PBSC in this specific transplantation setting.

The impact of HLA matching on outcomes of unmanipulated haploidentical HSCT is modulated by GVHD prophylaxis

“…Despite this, over recent years, clinical protocols for unmanipulated T-cell-replete haplo-HSCT have been successfully developed, using either posttransplant cyclophosphamide (PTCy) or antithymocyte globulin (ATG) as alternative platforms to harness alloreactivity to the mismatched HLA haplotype. [21][22][23][24][25][26][27] Although haploidentical donors are referred to as HLA-haplotypemismatched, some recipients who share an HLA haplotype with their donor are also matched for 1 or more HLA antigens on the unshared haplotype. Until now, scarce evidence existed on the relative role of optimal HLA mismatching on the unshared haplotype in haplo-HSCT.…”

Posttransplantation cyclophosphamide and sirolimus for prevention of GVHD after HLA-matched PBSC 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 setting 3,4 and later as single-agent GVHD prophylaxis after myeloablative conditioning and HLAmatched-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. …”

“…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.…”

“…2 This clinical platform was demonstrated first in the reduced-intensity conditioning, haploidentical allogeneic HSCT setting 3,4 and later as single-agent GVHD prophylaxis after myeloablative conditioning and HLAmatched-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][9][10] but limited series have been reported after HLAmatched HSCT with peripheral blood as a source or CNI-free GVHD prophylaxis.…”

“…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-PTCy 6 GVHD prophylaxis schedule with an allogeneic HSCT from a matched-related donor (MRD; n 5 15) or a matched-unrelated volunteer donor (MUD; n 5 13). All patients were treated according to current institutional programs upon written informed consent for transplant procedures.…”