Orelabrutinib is a novel and highly selective irreversible Bruton tyrosine kinase (BTK) inhibitor approved in China for the treatment of patients with relapsed/refractory (R/R) chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). We previously reported that orelabrutinib had high bioavailability with ~100% BTK occupancy at 24 hours at 150 mg daily dosing regimen and had demonstrated excellent safety and efficacy profiles in a phase II trial of R/R CLL/SLL. Here we present the long-term result of this study.


This is an open-label, multicenter, phase II study to evaluate the safety and efficacy following 150 mg oral daily administration of orelabrutinib (NCT03493217). Responses were assessed per 2008 IWCLL criteria with modification for PR with lymphocytosis (PR-L) (Hallek 2008, Cheson 2012) or the Lugano Classification (Cheson 2014) for CLL and SLL, respectively.


A total of 80 patients with R/R CLL/SLL were enrolled. All patients received ≥1 prior treatment with median age of 60.0 years. 70% of patients had Rai stage III-IV disease, 22.5% had del(17p) and/or TP53 mutation, 41.3% had unmutated immunoglobulin heavy chain variable region (IGHV) and 23.8% had del(11q). The median follow-up time was 31. 2 months, with 68.8% remaining on study treatment.

The overall response rate (ORR) was 93.8 % (95% CI: 86.01 ~ 97.94%) with 23.8% complete response (CR), 2.5% incomplete marrow recovery (CRi), 56.3% partial response (PR) and 11.3% PR with lymphocytosis (PR-L) by investigators assessed. Median time for achieving first response was 1.84 months. The median duration of response (DOR) and progression-free survival (PFS) were not reached. The estimated 30-month DOR was 70.6%, 30-month PFS was 70.9 % by investigator assessed. The overall response rate was generally consistent across all subgroups analyzed, including those with unfavorable prognostic factors. Comparing to the previous CR/CRi rate of 8.8% reported at median follow up of 14.3 months, the updated CR/CRi rate had achieved 26.3%. Orelabrutinib showed a significant higher CR/CRi rate in R/R CLL/SLL in comparison with other BTK inhibitors at a similar median follow-up period.

Extended follow-up demonstrates no emerging safety concerns. Similar to the previous reported safety results (Xu W 2020), most adverse events (AEs) were mild to moderate. The most frequent AEs (>30% of any grade) were neutropenia, thrombocytopenia, upper respiratory tract infection and urine red blood cells positive. No case of atrial fibrillation nor secondary malignancy was reported, no patient experienced ≥3 grade hypertension and only one patient had ≥3 grade diarrhea. Major hemorrhage was reported in 2 patients, one with intracranial hemorrhage (65-year old patient with >10 years hypertension) and the other with vitreous hemorrhage which was assessed as unlikely related to the treatment of orelabrutinib. There were 2 patients (2.5%) and 5 patients (6.3%) reported treatment related AEs leading to treatment discontinuation or dose reduction, respectively.


This updated study result further confirms that orelabrutinib is efficacious in treating R/R CLL patients with significant higher CR rate than other BTK inhibitors, durable response and improved safety profiles. Orelabrutinib provides a favorable therapeutic choice for patients with R/R CLL/SLL and has great potential to be the best candidate for the combination therapy.


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

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