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46 Efficacy and Safety of Orelabrutinib in Relapsed/Refractory Waldenstrom’s Macroglobulinemia Patients

Program: Oral and Poster Abstracts
Type: Oral
Session: 623. Mantle Cell, Follicular, and Other B-Cell Lymphomas: Clinical and Epidemiological: Targeted Therapy in Low Grade Lymphoma
Hematology Disease Topics & Pathways:
Clinical Trials, Biological, Adults, Lymphomas, Clinical Research, B Cell Lymphoma, Diseases, Immunotherapy, Lymphoid Malignancies, Study Population
Saturday, December 11, 2021: 10:15 AM

Daobin Zhou, MD1*, Jie Jin, MD, PhD2, Zheng-zheng Fu3*, Shuhua Yi, MD4*, Wei Li Zhao, MD5, Zimin Sun6*, Wei Yang, MD7*, Dengju Li, MD8*, Guohui Cui9*, Jianda Hu, M.D. & Ph.D.10, Ting Liu, MD, PhD11, Yongping Song12*, Bing Xu, MD, PhD13*, Zunmin Zhu, MD14*, Wei Xu15, Mingzhi Zhang, MD16, Yamin Tian, MD, PhD17*, Huaqiang Zhu, MD17*, Bin Zhang, PhD17*, Renbin Zhao, PhD17* and Xiang-Yang Zhang, MD, PhD17*

1Department of Hematology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
2Department of Hematology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
3Department of Hematology,, First Affiliated Hospital of Soochow University, Suzhou, China
4National Clinical Research Center for Blood Diseases, State Key Laboratory of Experimental Hematology, Blood Diseases Hospital & Institute of Hematology, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
5Department of Hematology, Shanghai Rui Jin Hospital, Shanghai, China
6Hematology department, Anhui provincial hospital, Hefei, China
7Shengjing Hospital of China Medical University, Shenyang, China
8Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
9Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
10Department of Hematology, Union Hospital, Fujian Institute of Hematology, Fuzhou, China
11Department of Hematology, West China Hospital of Sichuan University, Chengdu, China
12Department Hematology, Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, China
13Department of Hematology, The First Affiliated Hospital of Xiamen University and Institute of Hematology, School of Medicine, Xiamen University, Xiamen, China
14Institute of Hematology, Henan Provincial People's Hospital, Zhengzhou, China
15Department of Hematology, the First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, China
16Department of Oncology, Institution of Clinical Medicine, Zhengzhou, Henan, China
17Beijing InnoCare Pharma Tech Co., Ltd, Beijing, China


Waldenstrom’s Macroglobulinemia (WM) is a B-cell disorder characterized primarily by bone marrow infiltration with lymphoplasmacytic cells, along with immunoglobulin M (IgM) monoclonal gammopathy. Bruton's tyrosine kinase (BTK) plays a key role in signaling pathways for the survival of WM clone, particular in patients harboring MYD88L265P mutations. However, due to target selectivity issue, Clinical uses of early BTK inhibitors are still compromised with off-target activities to many other kinases besides BTK. Orelabrutinib is a novel, highly potent small molecule inhibitor of BTK with superior selectivity for B-cell malignancies and autoimmune diseases. Preliminary efficacy and safety data of ICP-CL-00105 in relapsed/refractory WM patients are presented here.


ICP-CL-00105 is a single arm, multiple centers, open label, phase 2 study in clinical and histopathological confirmed patients with R/R WM requiring treatment per IWWM-7. MYD88 and CXCR4 mutations were assessed in bone marrow samples at baseline. Orelabrutinib at a daily dose of 150mg was administered orally until disease progression or unacceptable toxicity. Blood samples for IgM were assessed at baseline and every cycle for 6 cycles and every 3 cycles thereafter by central lab. Responses were assessed in accordance with IWWM-6 and NCCN guidelines. The primary endpoint was major response rate (MRR) as assessed by IRC. Key secondary endpoints were MRR as assessed by investigator, overall response rate (ORR), duration of major response (DOMR), progression-free survival (PFS), OS, changes in IgM levels from baseline, improvement on hemoglobin levels and safety. Treatment-emergent adverse events (TEAEs) and treatment-related adverse events (TRAEs) were assessed according to NCI CTCAE v4.03.


As of June 1, 2021, for the 47 patients the median follow-up duration was 10.5 months. The median age was 63 years (range, 56-68 years), 40 patients (85.1%) were male. 87.2% of patients were at intermediate or high risk according to the Prognostic Scores (IPSS). The proportion of patients with MYD88L265PCXCR4wildtype was 83% at baseline. With a median duration of treatment of 9.2 months, MRR was 74.5% as assessed by investigator. ORR was 87.2% with 97.9% patients achieved disease control. The estimated 12-month DOMR were 89.5%. The estimated 12-month PFS and OS were 88.0% and 92.3%, respectively. The median PFS and median OS have not been reached. The MRR was higher in patients with MYD88L265PCXCR4wildtype (79.5%). The median IgM level was 30.3g/L at baseline. The decline in the serum IgM levels from baseline were observed with a median reduction by 79.0% (IQR: -89.4, -57.2). The median hemoglobin level at baseline was 102g/L. Durable improvement in hemoglobin levels was found in 83% of patients with a median maximal improvement of 40g/L (IQR: 24.0, 62.0).

Safety data were summarized by the cutoff date of June 1, 2021. The most commonly reported AEs were thrombocytopenia (27.7%),neutropenia (14.9%), leukopenia (10.6%), upper respiratory infection (14.9%),weight increased (14.9%), influenza-like disease (12.8%) and rash (10.6%). Most reported AEs (89.5%) were grade 1-2. 16 patients (34.0%) reported grade ≥ 3 TEAE while 9 patients (19.1%) reported grade ≥ 3 TRAE. There was no reported grade ≥3 atrial fibrillation and/or atrial flutter, or grade ≥3 diarrhea. Only One TRAE (2.1%) resulted in drug discontinuation.


Orelabrutinib has demonstrated substantial efficacy in treating r/r WM patients under short-term follow-up. It has shown favorable safety and tolerability profile with limited off-target adverse effects. It has the potential to be a promising treatment option for r/r WM patients.

Disclosures: Hu: Astellas Pharma, Inc.: Research Funding. Tian: Innocare pharma: Current Employment. Zhu: Innocare pharma: Current Employment. Zhang: Innocare pharma: Current Employment. Zhao: Innocare pharma: Current Employment. Zhang: Innocare pharma: Current Employment.

*signifies non-member of ASH