Calcineurin and mTOR Inhibitor–Free Post-Transplantation Cyclophosphamide and Bortezomib Combination for Graft-versus-Host Disease Prevention after Peripheral Blood Allogeneic Hematopoietic Stem Cell Transplantation: A Phase I/II Study

Abstract

Graft-versus-host disease (GVHD) hampers the utility of allogeneic hematopoietic stem cell transplantation (AHSCT). The purpose of this study was to determine the feasibility, safety, and efficacy of a novel combination of post-transplantation cyclophosphamide (PTC) and bortezomib for the prevention of GVHD. Patients undergoing peripheral blood AHSCT for hematological malignancies after reduced-intensity conditioning with grafts from HLA-matched related or unrelated donors were enrolled in a phase I/II clinical trial. Patients received a fixed dose of PTC and an increasing dose of bortezomib in 3 cohorts, from .7 to 1 and then to 1.3 mg/m, administered 6 hours after graft infusion and 72 hours thereafter, during phase I. The study was then extended at the higher dose in phase II for a total of 28 patients. No graft failure and no unexpected grade ≥3 nonhematologic toxicities were encountered. The median times to neutrophil and platelet engraftment were 16 and 27 days, respectively. Day +100 treatment-related mortality was 3.6% (95% confidence interval [CI], .2% to 15.7%). The cumulative incidences of grades II to IV and grades III and IV acute GVHD were 35.9% (95% CI, 18.6% to 53.6%) and 11.7% (95% CI, 2.8% to 27.5%), respectively. The incidence of chronic GVHD was 27% (95% CI, 11.4% to 45.3%). Progression-free survival, overall survival, and GVHD and relapse-free survival rates were 50% (95% CI, 30.6% to 66.6%), 50.8% (95% CI, 30.1% to 68.2%), and 37.7% (95% CI, 20.1% to 55.3%), respectively. Immune reconstitution, measured by CD3, CD4, and CD8 recovery, was prompt. The combination of PTC and bortezomib for the prevention of GVHD is feasible, safe, and yields promising results. The combination warrants further examination in a multi-institutional trial.

Prospective phase 2 trial of ixazomib after nonmyeloablative haploidentical peripheral blood stem cell transplant

“…15 The combination of PTCy and ixazomib was tested in a phase 1/2 clinical study in the context of reduced-intensity matched related or unrelated donor transplantation with promising results. 33 Although overall NRM in this study was low (12% at 3 years posttransplant), NRM seemed higher in patients who received transplants with donors who expressed the more inhibitory KIR A/A haplotype (43% vs 0%). Given the critical importance of the immunoproteasome for CD8 1 T-cell-mediated immune responses against intracellular infections, 34,35 we speculate that more potent NK cells resulting from an activating KIR genotype may be important in controlling early infections posttransplant when using a PI-based GVHD prophylaxis regimen.…”

Current Status and Future Directions in Graft-Versus-Host Disease Prevention Following Allogeneic Blood and Marrow Transplantation in Adults

“…Furthermore, PTC prevented the expansion of donor T-cells and IL-1 β surge, phenomena described after sustained post-transplant administration of proteasome inhibitors. Clinically, the combination of PTC and bortezomib was studied in the setting of RIC and MRD or MUD peripheral blood transplants [ 57 ]. PTC was given in a standard fashion and bortezomib was administered on day 0, 6 hours after the graft infusion and 72 hours thereafter.…”

Post-transplantation Cyclophosphamide: From HLA-Haploidentical to Matched-Related and Matched-Unrelated Donor Blood and Marrow Transplantation

“…The rate of cGvHD was 27% (95% CI 11.4%-45.3%). The 2-year GRFS was 37.7% (95% CI 20.1%-55.3%) (43). When compared to a registry control group the 1-year GRFS was 39% (95% CI 24%-54%) in the study group and 32% (95% CI 27%-38%) in the control group (HR = 0.81, 90% CI 0.52-1.27, p = 0.44) (unpublished data).…”