Bortezomib-based graft-versus-host disease prophylaxis in HLA-mismatched unrelated donor transplantation

Abstract

Purpose: HLA-mismatched unrelated donor (MMUD) hematopoietic stem-cell transplantation (HSCT) is associated with increased graft-versus-host disease (GVHD) and impaired survival. In reduced-intensity conditioning (RIC), neither ex vivo nor in vivo T-cell depletion (eg, antithymocyte globulin) convincingly improved outcomes. The proteasome inhibitor bortezomib has immunomodulatory properties potentially beneficial for control of GVHD in T-cell-replete HLA-mismatched transplantation.

Patients and methods: We conducted a prospective phase I/II trial of a GVHD prophylaxis regimen of short-course bortezomib, administered once per day on days +1, +4, and +7 after peripheral blood stem-cell infusion plus standard tacrolimus and methotrexate in patients with hematologic malignancies undergoing MMUD RIC HSCT. We report outcomes for 45 study patients: 40 (89%) 1-locus and five (11%) 2-loci mismatches (HLA-A, -B, -C, -DRB1, or -DQB1), with a median of 36.5 months (range, 17.4 to 59.6 months) follow-up.

Results: The 180-day cumulative incidence of grade 2 to 4 acute GVHD was 22% (95% CI, 11% to 35%). One-year cumulative incidence of chronic GVHD was 29% (95% CI, 16% to 43%). Two-year cumulative incidences of nonrelapse mortality (NRM) and relapse were 11% (95% CI, 4% to 22%) and 38% (95% CI, 24% to 52%), respectively. Two-year progression-free survival and overall survival were 51% (95% CI, 36% to 64%) and 64% (95% CI, 49% to 76%), respectively. Bortezomib-treated HLA-mismatched patients experienced rates of NRM, acute and chronic GVHD, and survival similar to those of contemporaneous HLA-matched RIC HSCT at our institution. Immune recovery, including CD8(+) T-cell and natural killer cell reconstitution, was enhanced with bortezomib.

Conclusion: A novel short-course, bortezomib-based GVHD regimen can abrogate the survival impairment of MMUD RIC HSCT, can enhance early immune reconstitution, and appears to be suitable for prospective randomized evaluation.

Fig 1.

Bortezomib–mismatched unrelated donor reduced-intensity conditioning hematopoietic stem-cell transplantation. (A) Sustained total donor chimerism at days 30, 100, and 180 after transplantation in patients initially engrafted and without evidence of disease relapse/progression. Triangles indicate patients without sustained donor engraftment (≥ 70% total donor cell chimerism). Of note, donor chimerism analysis was not mandated beyond day 100. (B) Cumulative incidence of nonrelapse mortality (NRM; with relapse/progression as a competing event) and relapse/progression (with death as a competing event). (C) Cumulative incidence of grade 2 to 4 acute graft-versus-host disease (aGVHD) and grade 3 to 4 aGVHD (with relapse/progression and death as competing events). (D) Cumulative incidence of chronic GVHD (cGVHD; with relapse/progression and death as competing events). (E) Overall and progression-free survival. (F) Overall survival for HLA-C mismatched and non–HLA-C mismatched transplantation.

Fig 2.

Bortezomib–mismatched unrelated donor (MMUD) and sirolimus–matched unrelated donor (MUD) cohorts. (A) CD3⁺ total T-cell reconstitution; (B) CD8⁺ T-cell reconstitution; (C) CD4⁺ T-cell reconstitution; (D) natural killer cell reconstitution. Median cell counts (with vertical bars indicating interquartile range). (*) Significant P value.