Bortezomib, tacrolimus, and methotrexate for prophylaxis of graft-versus-host disease after reduced-intensity conditioning allogeneic stem cell transplantation from HLA-mismatched unrelated donors

Abstract

Graft-versus-host disease (GVHD) is a significant complication of allogeneic stem cell transplantation (alloSCT). The proteasome inhibitor bortezomib has immunomodulatory properties of potential benefit for GVHD control. We undertook a phase 1 trial of bortezomib, tacrolimus, and methotrexate for GVHD prophylaxis after reduced-intensity conditioning alloSCT using human leukocyte antigen-mismatched unrelated donors. Twenty-three patients were enrolled. Bortezomib dose levels of 1, 1.3, and 1.5 mg/m2 were evaluated with 5, 3, and 5 patients, respectively. Ten additional patients were accrued at the 1.3 mg/m2 bortezomib dose level. Bortezomib-related toxicity was minimal. With a 12-month median follow-up, grade II-IV acute GVHD occurred in 3 patients, a 180-day cumulative incidence of 13%. Chronic GVHD occurred in 9 patients, a 1-year cumulative incidence of 41%. At 1-year, the nonrelapse mortality was zero, cumulative incidence of relapse/progression was 29%, and overall, progression-free, and event-free survival were 75%, 64%, and 59%, respectively. Bortezomib is a promising novel immunomodulatory agent in allogeneic transplantation. This study was registered at http://www.clinicaltrials.gov as #NCT00369226.

Figures

Figure 1

Phase 1 trial outcomes. (A) Total donor chimerism at days +30, +100, and +180 after transplantation in patients without evidence of disease relapse/progression. Donor chimerism analysis was not mandated beyond day +100. The 2 patients with low initial donor chimerism of 54% and 0% had MPD. The protocol was subsequently amended to exclude MPD. (B) Cumulative incidence of grade II-IV acute GVHD and chronic GVHD with graft failure, relapse/progression, and death as competing events. (C) Overall and event-free survival (N = 23). Events include graft failure, relapse/progression, and death. (D) Cumulative incidence of graft failure and relapse/progression with death as a competing event.