Bortezomib-based antibody depletion for refractory autoimmune hematological diseases

Sumita Ratnasingam, Patricia A. Walker, Huy Tran, Zane S. Kaplan, James McFadyen, Huyen Tran, Tse-Chieh Teh, Shaun Fleming, John V. Catalano, Sanjeev D. Chunilal, Anna Johnston, Stephen S. Opat, Jake Shortt

Research output: Contribution to journalArticleResearchpeer-review

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.
Original languageEnglish
Pages (from-to)31-35
Number of pages5
JournalBlood Advances
Volume1
Issue number1
DOIs
Publication statusPublished - 22 Nov 2016

Cite this

@article{a4eb7701e172484eba6094423acf2873,
title = "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.",
author = "Sumita Ratnasingam and Walker, {Patricia A.} and Huy Tran and Kaplan, {Zane S.} and James McFadyen and Huyen Tran and Tse-Chieh Teh and Shaun Fleming and Catalano, {John V.} and Chunilal, {Sanjeev D.} and Anna Johnston and Opat, {Stephen S.} and Jake Shortt",
year = "2016",
month = "11",
day = "22",
doi = "10.1182/bloodadvances.2016001412",
language = "English",
volume = "1",
pages = "31--35",
journal = "Blood Advances",
issn = "2473-9529",
publisher = "American Society of Hematology",
number = "1",

}

Bortezomib-based antibody depletion for refractory autoimmune hematological diseases. / Ratnasingam, Sumita; Walker, Patricia A.; Tran, Huy; Kaplan, Zane S.; McFadyen, James; Tran, Huyen; Teh, Tse-Chieh; Fleming, Shaun; Catalano, John V.; Chunilal, Sanjeev D.; Johnston, Anna; Opat, Stephen S.; Shortt, Jake.

In: Blood Advances, Vol. 1, No. 1, 22.11.2016, p. 31-35.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - Bortezomib-based antibody depletion for refractory autoimmune hematological diseases

AU - Ratnasingam, Sumita

AU - Walker, Patricia A.

AU - Tran, Huy

AU - Kaplan, Zane S.

AU - McFadyen, James

AU - Tran, Huyen

AU - Teh, Tse-Chieh

AU - Fleming, Shaun

AU - Catalano, John V.

AU - Chunilal, Sanjeev D.

AU - Johnston, Anna

AU - Opat, Stephen S.

AU - Shortt, Jake

PY - 2016/11/22

Y1 - 2016/11/22

N2 - 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.

AB - 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.

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SN - 2473-9529

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