Acalabrutinib Maleate and Bortezomib for Patients With HLA Antibodies

Summary

Platelet transfusion refractoriness (PTR) is a common complication in patients with hematological malignancies. It not only prolongs the duration of platelet transfusion dependence and significantly increases the risk of bleeding, but is also strongly associated with graft failure and reduced survival after transplantation. HLA class I antibody-mediated alloimmunization is recognized as the most important immunological cause of PTR. HLA antibodies are directly secreted by plasma cells, which are derived from B cells. Therefore, targeting B cells to reduce antibody production is a crucial step in eliminating HLA antibodies. Bruton's tyrosine kinase (BTK) is expressed throughout B cell development from the pre-B cell stage to maturity and supports B cell development, maturation, survival, proliferation, and antibody production by acting as a downstream kinase in the B cell receptor signaling pathway. Bortezomib, a proteasome inhibitor, can selectively induce apoptosis in long-lived plasma cells. The investigators' preliminary exploratory use of a BTK inhibitor in the treatment of PTR with HLA antibodies significantly reduced the mean fluorescence intensity (MFI) of HLA antibodies, improved platelet transfusion outcomes, and demonstrated a favorable safety profile. Based on these findings, the investigators are conducting a prospective, multicenter, randomized controlled two-arm study to investigate the efficacy and safety of acalabrutinib and bortezomib in eliminating HLA antibodies in hematological malignancies patients with PTR.

Timeline

Start

2026-06-01

Primary completion

2029-01-01

Completion

2029-05-31

Publications

• Background Pan Y, Zuo Y, Cui Q, Liu S, Dai H, Wu D, Jiang M, Tang X. Treatment outcome and efficacy of desensitization strategies for immunized-PTR in hematological malignancies before hematopoietic stem cell transplantation. Bone Marrow Transplant. 2026 Apr;61(4):437-444. doi: 10.1038/s41409-025-02749-1. Epub 2026 Jan 28.
• Background Van Osch TLJ, Oosterhoff JJ, Bentlage AEH, Nouta J, Koeleman CAM, Geerdes DM, Mok JY, Heidt S, Mulder A, Van Esch WJE, Kapur R, Porcelijn L, Van der Schoot CE, De Haas M, Wuhrer M, Voorberg J, Vidarsson G. Fc galactosylation of anti-platelet human IgG1 alloantibodies enhances complement activation on platelets. Haematologica. 2022 Oct 1;107(10):2432-2444. doi: 10.3324/haematol.2021.280493.
• Background Couvidou A, Rojas-Jimenez G, Dupuis A, Maitre B. Anti-HLA Class I alloantibodies in platelet transfusion refractoriness: From mechanisms and determinants to therapeutic prospects. Front Immunol. 2023 Feb 9;14:1125367. doi: 10.3389/fimmu.2023.1125367. eCollection 2023.
• Background Boothby AB, Tanner MK, Alswied A, Youngs D, Bribiesca Rodriguez J, Bikkani T, Cha N, Gernsheimer T, Gimferrer I, Hess JR, Sokol-Hessner L, Marivada S, Nash MG, Flegel WA, Vassallo RR, Stroncek DF, Tsang HC, Panch SR. Cumulative donor-specific antibody threshold predicts platelet transfusion response in HLA-alloimmunized patients. Blood Adv. 2024 Sep 10;8(17):4689-4699. doi: 10.1182/bloodadvances.2024014143.

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