Bortezomib-based antibody depletion for refractory autoimmune hematological diseases

Abstract

Certain patients with antibody-mediated autoimmune disease exhibit poor responses to conventional immunosuppression, including B-cell depletion with rituximab. Proteasome inhibitors such as bortezomib demonstrate pleiotropic immunomodulatory effects, including direct toxicity to antibody-producing cells. Here, we report preliminary evidence for the efficacy of bortezomib as salvage therapy for refractory autoimmune hematological disease. Thirteen treatment episodes in 10 patients with autoimmune hematological phenomena (autoimmune hemolytic anemia [AIHA; n = 8], acquired hemophilia (n = 1), immune thrombocytopenia (n = 1), and thrombotic thrombocytopenic purpura [TTP; n = 3]) and a median of 5 (range, 3-12) prior lines of therapy demonstrated an overall response rate of 77% (10 of 13) including 38% (5 of 13) complete remissions. The majority of clinical improvements were rapid, correlated with biomarkers of autoantibody reduction, and were associated with an acceptable safety profile. Responses appeared durable following treatment of TTP and acquired hemophilia; AIHA responses were more limited with a pattern of relapse following bortezomib cessation. These data provide proof of concept for the utility of proteasome inhibition as antibody depletion therapy in autoimmune disease.

Conflict of interest statement

Conflict-of-interest disclosure: In the majority of cases, part funding of bortezomib drug costs was provided by Janssen through a compassionate access program. J.V.C. has participated in advisory boards for Roche, Gilead, and Celgene. The remaining authors declare no competing financial interests.

Figures

Graphical abstract

Figure 1.

Representative clinical responses to bortezomib. (A) Time course for laboratory indices in a TTP patient (case #8) with drug treatments administered as indicated. Concurrent frequency of PEX and ADAMTS13 inhibitory activity (in Bethesda units) is annotated beneath. (B) Time course for laboratory indices in a patient with cold AIHA (case #1). Bortezomib was initiated twice weekly (dark shading) and then transitioned to weekly maintenance therapy (gray shading). B, bortezomib; BU, Bethesda unit; LDH, lactate dehydrogenase; ND, not done; R, rituximab; RBC, red blood cell.