Olverembatinib (HQP1351), a well-tolerated and effective tyrosine kinase inhibitor for patients with T315I-mutated chronic myeloid leukemia: results of an open-label, multicenter phase 1/2 trial
机构：[1]National Clinical Research Center for Hematologic Disease, Peking University People’s Hospital, Peking University Institute of Hematology, No. 11 South Street of Xizhimen, Xicheng District, Beijing 100044, China.[2]Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei, China.华中科技大学同济医学院附属协和医院[3]Department of Hematology, Nanfang Hospital, Southern Medical University, 1838 Guangzhou N Ave, Baiyun, Guangzhou 510515, Guangdong Province, China.[4]State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300020, China.[5]Department of Hematology, The Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer Hospital, Zhengzhou 450008, Henan, China.河南省肿瘤医院[6]Department of Hematology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei, China.华中科技大学同济医学院附属同济医院[7]Department of Hematology, West China Hospital of Sichuan University, No. 37 Guoxue Alley, Wuhou District, Chengdu City 610000, Sichuan Province, China.四川大学华西医院[8]Division of Hematology, Shenzhen Second People’s Hospital, The First Affiliated Hospital of Shenzhen University, 3002 Sungang W Rd, Futian District, Shenzhen 518000, Guangdong Province, China.深圳市第二人民医院深圳医学信息中心[9]National Clinical Research Center for Hematologic Diseases, The First Affiliated Hospital of Soochow University, Jiangsu Institute of Hematology, Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China.[10]State Key Laboratory of Oncology in South China, Department of Hematologic Oncology, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, 651 Dongfeng Road East, Guangzhou 510060, Guangdong Province, China.[11]Guangzhou Healthquest Pharma Co. Ltd., Room F314, GIBI, No. 3 Lanyue Road, Guangzhou 510663, China.[12]Ascentage Pharma Group Inc., 800 King Farm Blvd Suite 300, Rockville, MD 20850, USA.[13]Ascentage Pharma (Suzhou) Co., Ltd, 218 Xinghu St, Bldg B7, 7th Floor, Suzhou Industrial Park, Suzhou 215000, Jiangsu, China.[14]State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, 651 Dongfeng Road East, Guangzhou 510060, Guangdong Province, China.[15]Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, No. 11 South Street of Xizhimen, Xicheng District, Beijing 100044, China.[16]Peking- Tsinghua Center for Life Sciences, No. 11 South Street of Xizhimen, Xicheng District, Beijing 100044, China.[17]Academy for Advanced Interdisciplinary Studies, Peking University, No. 11 South Street of Xizhimen, Xicheng District, Beijing 100044, China.
Background BCR-ABL1(T315I) mutations confer resistance to tyrosine kinase inhibitors (TKIs) in chronic myeloid leukemia (CML). Olverembatinib is a new potent BCR-ABL1 TKI with preclinical activity against T315I-mutated CML. In phase 1/2 studies, we explored the safety and efficacy of olverembatinib in Chinese adults with TKI-resistant CML in the chronic phase (CML-CP) and accelerated phase (CML-AP). Methods In the phase 1 study, olverembatinib was orally administered once every other day in 28-day cycles at 11 dose cohorts ranging from 1 to 60 mg, and we evaluated the maximum tolerated dose, recommended phase 2 dose (RP2D), safety, efficacy, and pharmacokinetics of olverembatinib. In the phase 2 studies, olverembatinib was administered at the RP2D of 40 mg orally on alternate days for 28-day cycles. The primary outcome measure is major cytogenetic response (MCyR) and major hematologic response by the end of Cycle 12 in CML-CP and CML-AP, respectively. Fine and Gray's hazard models were used to identify covariates associated with responses. Results A total of 165 patients (> 80.0% of whom had received >= 2 TKIs) were enrolled in this study. Among 127 patients with CML-CP, the 3-year cumulative incidences of achieving MCyR, complete cytogenetic response (CCyR), major molecular response (MMR), MR4.0, and MR4.5 were 79.0, 69.0, 56.0, 44.0 and 39.0%, respectively. The highest response rates were observed in patients with a single T315I mutation. Among 38 patients with CML-AP, the 3-year cumulative incidences of achieving MCyR, CCyR, MMR, MR4.0, and MR4.5 were 47.4%, 47.4%, 44.7%, 39.3%, and 32.1%, respectively. In multivariate analyses, baseline BCR-ABL1 mutation status was significantly associated with cytogenetic and molecular responses. Common treatment-related adverse events included skin hyperpigmentation, hypertriglyceridemia, proteinuria, and severe thrombocytopenia. Conclusions Olverembatinib was well tolerated, with significant antileukemic activity in adults with TKI-resistant CML-CP and CML-AP, especially those with the T315I mutation. Trial registration: The phase 1 trial is registered at CTR20220566, and the two single-arm, open-label phase 2 studies are registered at ClinicalTrials.gov: NCT03883087 (CML-CP) and NCT03883100 (CML-AP).
基金：
This work was supported partially by National Science and Technology Major
Project (No. 2018ZX09301021-005), National Key Research and Development
Program of China (No. 2017YFA0104500), Innovative Research Groups of the
National Natural Science Foundation of China (No. 81621001), Key Program of
the National Natural Science Foundation of China (No. 81530046, 81930004),
National Nature Science Foundation of China (No. 81770161, No. 81970140),
and Ascentage Pharma Group Corp Ltd (Hong Kong).
第一作者机构：[1]National Clinical Research Center for Hematologic Disease, Peking University People’s Hospital, Peking University Institute of Hematology, No. 11 South Street of Xizhimen, Xicheng District, Beijing 100044, China.
通讯作者：
通讯机构：[1]National Clinical Research Center for Hematologic Disease, Peking University People’s Hospital, Peking University Institute of Hematology, No. 11 South Street of Xizhimen, Xicheng District, Beijing 100044, China.[15]Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, No. 11 South Street of Xizhimen, Xicheng District, Beijing 100044, China.[16]Peking- Tsinghua Center for Life Sciences, No. 11 South Street of Xizhimen, Xicheng District, Beijing 100044, China.[17]Academy for Advanced Interdisciplinary Studies, Peking University, No. 11 South Street of Xizhimen, Xicheng District, Beijing 100044, China.
推荐引用方式(GB/T 7714)：
Jiang Qian,Li Zongru,Qin Yazhen,et al.Olverembatinib (HQP1351), a well-tolerated and effective tyrosine kinase inhibitor for patients with T315I-mutated chronic myeloid leukemia: results of an open-label, multicenter phase 1/2 trial[J].JOURNAL OF HEMATOLOGY & ONCOLOGY.2022,15(1):doi:10.1186/s13045-022-01334-z.
APA：
Jiang, Qian,Li, Zongru,Qin, Yazhen,Li, Weiming,Xu, Na...&Huang, Xiaojun.(2022).Olverembatinib (HQP1351), a well-tolerated and effective tyrosine kinase inhibitor for patients with T315I-mutated chronic myeloid leukemia: results of an open-label, multicenter phase 1/2 trial.JOURNAL OF HEMATOLOGY & ONCOLOGY,15,(1)
MLA：
Jiang, Qian,et al."Olverembatinib (HQP1351), a well-tolerated and effective tyrosine kinase inhibitor for patients with T315I-mutated chronic myeloid leukemia: results of an open-label, multicenter phase 1/2 trial".JOURNAL OF HEMATOLOGY & ONCOLOGY 15..1(2022)
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