Acalabrutinib Maleate and Bortezomib for Patients With HLA Antibodies

Официальное название

Acalabrutinib Maleate Monotherapy or in Combination With Bortezomib for Eliminating HLA Antibodies in Patients With Hematologic Malignancies and Platelet Transfusion Refractoriness: a Multicenter, Randomized Controlled Study

Обзор

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.

Вмешательства

• Препарат Acalabrutinib maleate
  100mg twice a day
• Препарат bortezomib
  1.3mg/m2, d1,4,8,11
• Другое HLA-matched or crossmatched irradiated platelets
  Transfusion HLA-matched or crossmatched irradiated platelets 10U if platelet count lower than 10\*109/L
• Препарат human immune globulin
  0.4g/kg.d for 5 days

Первичные конечные точки

• The response rate for anti-HLA antibody clearance [Срок оценки: 4 weeks after intervention]
• CCI (corrected count increments) [Срок оценки: 4 weeks after intervention]
• PPR (percentage platelet recovery) [Срок оценки: 4 weeks after intervention]

Вторичные конечные точки (2)

• The incidence of bleeding events [Срок оценки: The study period (8 weeks after the initiation of intervention)]
• The overall survival rate [Срок оценки: 1 year]

Критерии участия

Критерии включения

• Patients with hematological malignancies and platelet transfusion refractoriness (24-hour CCI < 4.5×10⁹/L or PPR < 20%), and with the highest MFI of HLA antibodies > 8000 ;
• Age 18-65 years, both male and female;
• ECOG performance status 0-3;
• Expected survival > 6 months;
• Patients must be able to understand and be willing to participate in this study, and sign an informed consent form.

Критерии исключения

• Hypersensitivity to acalabrutinib, bortezomib, or excipients;
• Major organ bleeding (central nervous system, lung, intestines) or grade ≥3 bleeding;
• Hypersplenism;
• Concurrent use of drugs that may cause excessive platelet consumption (amphotericin B, vancomycin, ATG, interferon, etc.);
• Disseminated intravascular coagulation, microangiopathic hemolytic anemia;
• Underlying diseases of vital organs: such as malignant arrhythmia, myocardial infarction, chronic cardiac insufficiency, decompensated liver insufficiency, renal insufficiency, severe coagulation abnormalities, etc.; persistent fever (>38.0°C) for more than 3 days; clinically uncontrolled active infection (including bacterial, fungal, or viral infections), but patients under effective drug therapy are not excluded;
• Concurrent other progressive malignancies;
• Patients with cardiac insufficiency: ejection fraction (EF) <30%, NYHA class ≥III cardiac insufficiency;
• Pregnant or lactating women;
• Expected survival <60 days;
• Currently participating in other clinical drug trials.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Рандомизированное

Модель

Параллельные группы

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

Список центров уточняется — проверьте первичный протокол.

Публикации

• 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. PMID 41606225
• 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. PMID 35354253
• 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. PMID 36845153
• 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.2 PMID 39028936

Идентификаторы

NCT: NCT07635511 · XFH2026-05

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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