A multicenter, randomized phase III trial of hetrombopag: a novel thrombopoietin receptor agonist for the treatment of immune thrombocytopenia

Springer Science and Business Media LLC - 2021
Heng Mei1, Xiaofan Liu, Yan Li2, Hu Zhou3, Yong Feng4, Guangxun Gao5, Cheng Pan6, Ruibin Huang7, Linhua Yang8, Jianda Hu9, Ming Hou10, Yazhou Yao11, Li Liu12, Yi Wang13, Depei Wu14, Liansheng Zhang15, Changcheng Zheng16, Xu-Liang Shen17, Qi Hu18, Jing Liu19, Jie Jin20, Jianmin Luo21, Yun Zeng22, Sujun Gao23, Xiaohui Zhang24, Xin Zhou25, Qin Shi26, Ruixiang Xia27, Xian-Jin Xie28, Zhongxing Jiang29, Li Gao30, Yuansong Bai31, Junye Xiong32, Runzi Li32, Jianjun Zou32, Ting Niu33, Renchi Yang, Yu Hu34
1Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science & Technology , Wuhan, Hubei 430022, China.
2Department of Hematology, Institute of Hematology, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China.
3Department of Hematology, Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, China.
4Department of Hematopathology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
5The Blood Internal Medicine, The First Affiliated Hospital of Air Force Medical University, Xi'an, China
6Hematology Department, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
7Hematology Department The First Affiliated Hospital of Nanchang University Nanchang China
8Department of Hematology, The Second Hospital of Shanxi Medical University, Taiyuan, China
9Fujian Medical University Union Hospital, Fuzhou, China
10Department of Hematology, Qilu Hospital, Shandong University, Jinan, China
11Hematology Department, Baoji Central Hospital, Baoji, China.
12Department of Hematopathology, The Second Affiliated Hospital of Air Force Medical University, Xi’an, China
13Department of Hematopathology, Shaanxi Provincial People's Hospital, Xi'an, China.
14Hematology Department, The First Affiliated Hospital of Soochow University, Suzhou, China
15Hematology Department, Lanzhou University Second Hospital, Lanzhou, China.
16Hematology Department, The First Affiliated Hospital of USTC, Hefei, China
17Department of Hematology, Heping Hospital Affiliated to Changzhi Medical College, Changzhi, China
18Department of Hematology, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai, China
19The Third Xiangya Hospital of Central South University, Changsha, China
20Department of Hematology, The First Affiliated Hospital, Zhejiang University College of Medicine, Hangzhou, China
21Department of Hematology, the Second Hospital of Hebei Medical University, Shijiazhuang, China
22Department of Hematology, First Affiliated Hospital of Kunming Medical University, Kunming, China.
23The First Hospital of Jilin University, Changchun, China
24Department of Hematology, Peking University People’s Hospital, Beijing, China
25Hematology Department, Wuxi People's Hospital, Wuxi, China.
26Hematology Department, The Second Affiliated Hospital of Nanchang University, Nanchang, China.
27Hematology Department, The First Affiliated Hospital of Anhui Medical University, Hefei, China.
28Hematology Department, The First People's Hospital of Changzhou, Changzhou, China.
29Department of Hematology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
30Department of Hematology, The Second Affiliated Hospital of Military Medical University PLA, Chongqing, China.
31Hematology & Oncology China–Japan Union Hospital of Jilin University Changchun China
32Clinical Research & Development, Jiangsu Hengrui Medicine Co., Ltd, Shanghai, China
33Department of Hematology, Institute of Hematology, West China Hospital, Sichuan University, Chengdu, China
34Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Hubei, China

Tóm tắt

Abstract Background Hetrombopag, a novel thrombopoietin receptor agonist, has been found in phase I studies to increase platelet counts and reduce bleeding risks in adults with immune thrombocytopenia (ITP). This phase III study aimed to evaluate the efficacy and safety of hetrombopag in ITP patients. Methods Patients who had not responded to or had relapsed after previous treatment were treated with an initial dosage of once-daily 2.5 or 5 mg hetrombopag (defined as the HETROM-2.5 or HETROM-5 group) or with matching placebo in a randomized, double-blind, 10-week treatment period. Patients who received placebo and completed 10 weeks of treatment switched to receive eltrombopag, and patients treated with hetrombopag in the double-blind period continued hetrombopag during the following open-label 14-week treatment. The primary endpoint was the proportion of responders (defined as those achieving a platelet count of ≥ 50 × 109/L) after 8 weeks of treatment. Results The primary endpoint was achieved by significantly more patients in the HETROM-2.5 (58.9%; odds ratio [OR] 25.97, 95% confidence interval [CI] 9.83–68.63; p < 0.0001) and HETROM-5 (64.3%; OR 32.81, 95% CI 12.39–86.87; p < 0.0001) group than in the Placebo group (5.9%). Hetrombopag was also superior to placebo in achieving a platelet response and in reducing the bleeding risk and use of rescue therapy throughout 8 weeks of treatment. The durable platelet response to hetrombopag was maintained throughout 24 weeks. The most common adverse events were upper respiratory tract infection (42.2%), urinary tract infection (17.1%), immune thrombocytopenic purpura (17.1%) and hematuria (15%) with 24-week hetrombopag treatment. Conclusions In ITP patients, hetrombopag is efficacious and well tolerated with a manageable safety profile. Trial registration Clinical trials.gov NCT03222843, registered July 19, 2017, retrospectively registered.

Từ khóa


Tài liệu tham khảo

Rodeghiero F, Stasi R, Gernsheimer T, et al. Standardization of terminology, definitions and outcome criteria in immune thrombocytopenic purpura of adults and children: report from an international working group. Blood. 2009;113(11):2386–93.

Arnold DM. Bleeding complications in immune thrombocytopenia. Hematol Am Soc Hematol Educ Program. 2015;2015:237–42.

McCrae K. Immune thrombocytopenia: no longer “idiopathic.” Cleve Clin J Med. 2011;78(6):358–73.

Neunert C, Terrell DR, Arnold DM, et al. American Society of Hematology 2019 guidelines for immune thrombocytopenia. Blood Adv. 2019;3(23):3829–66.

Provan D, Arnold DM, Bussel JB, et al. Updated international consensus report on the investigation and management of primary immune thrombocytopenia. Blood Adv. 2019;3(22):3780–817.

Liu X-G, Bai X-C, Chen F-P, et al. Chinese guidelines for treatment of adult primary immune thrombocytopenia. Int J Hematol. 2018;107(6):615–23.

Lambert MP, Gernsheimer TB. Clinical updates in adult immune thrombocytopenia. Blood. 2017;129(21):2829–35.

Ghanima W, Cooper N, Rodeghiero F, Godeau B, Bussel JB. Thrombopoietin receptor agonists: ten years later. Haematologica. 2019;104(6):1112–23.

Bussel JB, Kuter DJ, Aledort LM, et al. A randomized trial of avatrombopag, an investigational thrombopoietin-receptor agonist, in persistent and chronic immune thrombocytopenia. Blood. 2014;123(25):3887–94.

Jurczak W, Chojnowski K, Mayer J, et al. Phase 3 randomised study of avatrombopag, a novel thrombopoietin receptor agonist for the treatment of chronic immune thrombocytopenia. Br J Haematol. 2018;183(3):479–90.

Xie C, Zhao H, Bao X, Fu H, Lou L. Pharmacological characterization of hetrombopag, a novel orally active human thrombopoietin receptor agonist. J Cell Mol Med. 2018;22(11):5367–77.

Thiele J, Kvasnicka HM, Facchetti F, Franco V, van der Walt J, Orazi A. European consensus on grading bone marrow fibrosis and assessment of cellularity. Haematologica. 2005;90(8):1128–32.

Bussel JB, Provan D, Shamsi T, et al. Effect of eltrombopag on platelet counts and bleeding during treatment of chronic idiopathic thrombocytopenic purpura: a randomised, double-blind, placebo-controlled trial. Lancet. 2009;373(9664):641–8.

Tomiyama Y, Miyakawa Y, Okamoto S, et al. A lower starting dose of eltrombopag is efficacious in Japanese patients with previously treated chronic immune thrombocytopenia. J Thromb Haemost. 2012;10(5):799–806.

Yang R, Li J, Jin J, et al. Multicentre, randomised phase III study of the efficacy and safety of eltrombopag in Chinese patients with chronic immune thrombocytopenia. Br J Haematol. 2017;176(1):101–10.

Bussel JB, Cheng G, Saleh MN, et al. Eltrombopag for the treatment of chronic idiopathic thrombocytopenic purpura. N Engl J Med. 2007;357(22):2237–47.

Cheng G, Saleh MN, Marcher C, et al. Eltrombopag for management of chronic immune thrombocytopenia (RAISE): a 6-month, randomised, phase 3 study. Lancet. 2011;377(9763):393–402.

Bussel JB, Kuter DJ, George JN, et al. AMG 531, a thrombopoiesis-stimulating protein, for chronic ITP. N Engl J Med. 2006;355(16):1672–81.

González-Porras JR, Mingot-Castellano ME, Andrade MM, et al. Use of eltrombopag after romiplostim in primary immune thrombocytopenia. Br J Haematol. 2015;169(1):111–6.

González-Porras JR, Godeau B, Carpenedo M. Switching thrombopoietin receptor agonist treatments in patients with primary immune thrombocytopenia. Ther Adv Hematol. 2019;10:2040620719837906.

Webster ML, Sayeh E, Crow M, et al. Relative efficacy of intravenous immunoglobulin G in ameliorating thrombocytopenia induced by antiplatelet GPIIbIIIa versus GPIbalpha antibodies. Blood. 2006;108(3):943–6.

Peng J, Ma SH, Liu J, et al. Association of autoantibody specificity and response to intravenous immunoglobulin G therapy in immune thrombocytopenia: a multicenter cohort study. J Thromb Haemost. 2014;12(4):497–504.

Zeng Q, Zhu L, Tao L, et al. Relative efficacy of steroid therapy in immune thrombocytopenia mediated by anti-platelet GPIIbIIIa versus GPIbα antibodies. Am J Hematol. 2012;87(2):206–8.

Li J, van der Wal DE, Zhu G, et al. Desialylation is a mechanism of Fc-independent platelet clearance and a therapeutic target in immune thrombocytopenia. Nat Commun. 2015;6:7737.

Tao L, Zeng Q, Li J, et al. Platelet desialylation correlates with efficacy of first-line therapies for immune thrombocytopenia. J Hematol Oncol. 2017;10(1):46.

Chow L, Aslam R, Speck ER, et al. A murine model of severe immune thrombocytopenia is induced by antibody- and CD8+ T cell-mediated responses that are differentially sensitive to therapy. Blood. 2010;115(6):1247–53.

Olsson B, Andersson PO, Jernås M, et al. T-cell-mediated cytotoxicity toward platelets in chronic idiopathic thrombocytopenic purpura. Nat Med. 2003;9(9):1123–4.

Di Buduo CA, Currao M, Pecci A, Kaplan DL, Balduini CL, Balduini A. Revealing eltrombopag’s promotion of human megakaryopoiesis through AKT/ERK-dependent pathway activation. Haematologica. 2016;101(12):1479–88.

Xu M, Li J, Neves MAD, et al. GPIbα is required for platelet-mediated hepatic thrombopoietin generation. Blood. 2018;132(6):622–34.

Kapur R, Aslam R, Speck ER, Rebetz JM, Semple JW. Thrombopoietin receptor agonist (TPO-RA) treatment raises platelet counts and reduces anti-platelet antibody levels in mice with immune thrombocytopenia (ITP). Platelets. 2020;31(3):399–402.

Bao W, Bussel JB, Heck S, et al. Improved regulatory T-cell activity in patients with chronic immune thrombocytopenia treated with thrombopoietic agents. Blood. 2010;116(22):4639–45.

Liu XG, Liu S, Feng Q, et al. Thrombopoietin receptor agonists shift the balance of Fcγ receptors toward inhibitory receptor IIb on monocytes in ITP. Blood. 2016;128(6):852–61.

Thông tin
Thông tin xuất bản

Springer Science and Business Media LLC

Thông tin tác giả