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4529 Olverembatinib 30 Mg Versus 40 Mg Every Other Day (QOD) in Patients with Tyrosine Kinase Inhibitor (TKI) Resistant or Intolerant Chronic-Phase Chronic Myeloid Leukemia (CML-CP): A Multi-Center Propensity Score-Matched Analysis

Program: Oral and Poster Abstracts
Session: 632. Chronic Myeloid Leukemia: Clinical and Epidemiological: Poster III
Hematology Disease Topics & Pathways:
Research, Clinical Practice (Health Services and Quality), Clinical Research, CML, Chronic Myeloid Malignancies, Diseases, Real-world evidence, Treatment Considerations, Adverse Events, Myeloid Malignancies
Monday, December 9, 2024, 6:00 PM-8:00 PM

Xiaoshuai Zhang1*, Lu Yu2*, Li Zhou, MD3*, Yanli Zhang, MD4*, Huanling Zhu5*, Bingcheng Liu6,7,8,9*, Xin Du10,11,12*, Xiaodong Wang13*, Linhua Yang, MD14*, Yanping Ma15*, Li Meng, MD16*, Yanqing Zhang, MD17*, Guohui Li, MD18*, Lijie Yang, MD19*, Baohong Wang, MD20*, Xuehong Ran, MD20*, Jian Huang, MD, PhD21,22,23,24,25, Qin Wen, MD26*, Yan Wen, MD27*, Yuxia Zhao, MD28*, Yu Zhu, MD29*, Yanqiu Han, MD30*, Zhenfang Liu, MD31*, Xin Du, PhD32, Jianyu Weng, MD, PhD33* and Qian Jiang, MD34,35,36

1Peking University Peoples Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing, China
2National Clinical Research Center for Hematologic Disease, Peking University People’s Hospital, Peking University Institute of Hematology, Beijing, China
3Ruijin Hospital, Shanghai Jiaotong University School Of Medicine, West Roxbury, MA
4Department of Hematology, Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, China
5Department of Hematology, West China Hospital, Sichuan University, Chengdu, China
6State 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, China
7National Clinical Research Center for Blood Diseases, State Key Laboratory of Experimental Hematology, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences &Peking Union Medical College, Tianjin, China
8State 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, China
9Tianjin Institutes of Health Science, Tianjin, China
10Department of Hematology, The Second People's Hospital of Shenzhen, The First Affiliated Hospital of Shenzhen University, Shenzhen, China
11Department of Hematology, Shenzhen Second People's Hospital, Shenzhen, China
12Department of Hematology and Shenzhen Bone Marrow Transplantation Public Service Platform, Shenzhen Second People's Hospital, The First Affiliated Hospital of Shenzhen University, Shenzhen, China
13Department of Hematology, Sichuan Academy of Medical Sciences Sichuan Provincial, Sichuan, CHN
14Department of Hematology, The Second Affiliated Hospital of Shanxi Medical University, Taiyuan, China
15Department of Hematology, The Second Hospital of Shanxi Medical University, Taiyuan, China
16Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
17Shenzhen Hospital of Southern Medical University, Shenzhen, China
18Xi'an International Medical Center Hospital, Xian, CHN
19Xi'an international Medical Center, Xi'An, China
20Department of Hematology, Weifang People's Hospital, Weifang, CHN
21Zhejiang University Cancer Center, Hangzhou, China
22Department of Hematology, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
23Zhejiang Provincial Clinical Research Center for Hematological disorders, Hangzhou, China
24Department of Hematology, The First Affiliated Hospital, Zhejiang University School of Medicine, YIWU, ZHEJIANG, China
25Zhejiang Provincial Key Lab of Hematopoietic Malignancy, Zhejiang University, Hangzhou, China
26Xinqiao Hospital, Army Medical University, Chongqing, China
27The First People's Hospital of Yunnan Province, Yunnan, China
28Xing'an League People's Hospital, Inner Mongolia, CHN
29Department of Hematology, Jiangsu Provincial People's Hospital, Nanjing, China
30The Affiliated Hospital of Inner Mongolia Medical University, Hohhot, China
31The First Affiliated Hospital of Guangxi Medical University, Nanning, China
32Department of Hematology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, WA, China
33Guangdong Provincial People's Hospital, Guangdong, China
34National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Peking University People’s Hospital, Peking University Institute of Hematology, Beijing, China
35National Clinical Research Center for Hematologic Disease, Peking University People’s Hospital, Peking University Institute of Hematology, Beijing, Beijing, China
36Peking University People’s Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing, China

Background There is limited data comparing the efficacy and safety of olverembatinib in patients with TKI-resistant and/or intolerant CML-CP between 30 mg and 40 mg QOD.

Aims To compare the efficacy and safety of olverembatinib at initial doses of 30 mg versus 40 mg QOD in CML patients.

Methods Data from patients with TKI-resistant and/or intolerant CML-CP receiving olverembatinib 30 mg or 40 mg QOD from 33 hospital in China were retrospectively interrogated. Propensity-score matching (PSM) analyses were performed to compare the efficacy and safety between the 30 mg and 40 mg cohorts. Cox model was utilized to identify co-variates associated with treatment responses and outcomes. Plasma concentrations of patients from Peking University People’s Hospital, who had been receiving olverembatinib therapy regularly for at least one month, were measured using the UHPLC-MS/MS method before dosing (C0) and 6 hours after dosing (C6).

Results 282 patients with CML-CP receiving olverembatinib 30 mg (n = 66) or 40 mg (n = 216) QOD were included in the study. Of these, 145 patients (51%) were enrolled from clinical trials, while 137 patients (49%) were from real-world post-marketing settings. Median age at the start of olverembatinib therapy was 39 years (IQR, 25-46 years). 130 (46%) received ≥ 3 prior TKIs. Median duration of prior TKI-therapy was 47 months (IQR, 25-80 months). BCR::ABL kinase domain mutations were detected by Sanger sequencing, revealing that 161 (57%) patients harbored the single T315I mutation. There were no significant differences in baseline co-variates between the two dose cohorts, except for better prior TKI-therapy responses (p = 0.04) in the 30 mg cohort. Median follow-up period were 25 months (IQR: 8-75 months) in the 30 mg cohort and 23 months (IQR: 7-54 months) in the 40 mg cohort. There were no significant differences in the 4-year cumulative incidences of MCyR (p = 0.43), CCyR (p = 0.46), MMR (p = 0.45) and MR4 (p = 0.17), as well as PFS (p = 0.99) and survival (p = 0.56) between the 2 dose cohorts. Multi-variable Cox analyses further confirmed that the dose of olverembatinib was not significantly associated with treatment responses and outcomes.

During treatment, 36 patients (55%) in the 30 mg cohort and 99 patients (46%) in the 40 mg cohort temporarily reduced their dose or discontinued treatment due to treatment-related adverse events (TRAEs) (p = 0.22). However, the proportion of patients still receiving the original dose at the last follow-up was significantly higher in the 30 mg cohort compared to the 40 mg cohort (67% versus 46%, p = 0.003). Additionally, the proportion of patients who reduced dose or permanently discontinued treatment due to TRAEs in the 30 mg cohort was significantly lower than that in the 40 mg cohort (18% versus 39%, p = 0.002). During the treatment, there was no significant differences in the prevalence of hematologic (≥ 3 grade) and non-hematologic (any grade) TRAEs between the 30mg and 40mg cohorts: severe thrombocytopenia, 50% versus 44% (p = 0.36); skin pigmentation, 65% versus 61% (p = 0.57); hypertriglyceridemia, 40% versus 37% (p = 0.71); sexual dysfunction, 23% versus 16% (p = 0.17). For the cardiovascular and cerebrovascular TRAEs of interest, there was still no difference between the 2 cohorts: hypertension,11% versus 18% (p = 0.24); sinus tachycardia,11% versus 7% (p = 0.28); arterial and/or venous obstructive events, 5% versus 7% (p = 0.72); pericardial effusion, 3% versus 2% (p = 0.66); atrial fibrillation, 2% versus 2% (p = 0.66), sinus bradycardia, 2% versus 2% (p = 0.99). However, no cases of pulmonary arterial hypertension were observed in the 30mg cohort, while 2 cases were reported in the 40mg cohort. PSM analyses further validated these results. Sensitivity analyses were performed in the clinical trial and the real-world cohorts, respectively, which did not alter these results.

Plasma concentrations at C0 and C6 were measured in 96 patients regularly receiving olverembatinib (30 mg cohort, n = 64; 40 mg cohort, n = 32). The C0 (p = 0.001) and C6 (p < 0.001) levels in the 40 mg cohort were significantly higher than those in the 30 mg cohort.

Conclusions Olverembatinib 30 mg QOD as an initial dose demonstrated equivalent effectiveness but better safety and tolerability compared to 40 mg QOD in TKI-resistant and/or intolerant patients with chronic-phase CML. This conclusion needs to be further validated in the longer-observation studies or randomized controlled trials.

Disclosures: No relevant conflicts of interest to declare.

*signifies non-member of ASH