Efficacy and safety of orelabrutinib monotherapy in patients with chronic lymphocytic leukemia: A retrospective real-world study

Abstract

Abstract Introduction: Chronic lymphocytic leukaemia (CLL), a hematologic malignancy of B cells, is one of the most frequent types of leukemia (Lancet 2024:404:694-706). Recently, Bruton's tyrosine kinase inhibitors (BTKis) have become a standard first-line treatment for patients (pts) with CLL, showing remarkable clinical efficacy compared to traditional chemoimmunotherapy (J Hematol Oncol 2021:14:69). However, first-generation BTKis are associated with limited target selectivity, which may result in off-target effects and serious adverse events (Haematologica 2018:103:874-879). Given the safety concerns, there is an urgent need for next-generation BTKis with enhanced selectivity and improved safety profiles. Orelabrutinib is a novel, orally administered, and highly selective irreversible BTKi (Blood 2024:144:4399). Its improved target selectivity contributes to a more favorable safety profile. Orelabrutinib has been approved in China for the treatment of pts with relapsed or refractory CLL (Blood 2021:138:2638). This retrospective study was conducted to assess the clinical efficacy and safety of orelabrutinib in pts with CLL. Methods: Between November 1, 2021, and May 28, 2024, we retrospectively reviewed CLL pts who received orelabrutinib monotherapy (150 mg orally once daily). Patient baseline characteristics, response data (overall response rate [ORR]), survival outcomes (progression-free survival [PFS] and overall survival [OS]), and safety data (incidence and severity of adverse events [AEs]) were descriptively analyzed. Results: As of the cut-off date (July 30, 2025), 30 pts were included; 28 were still receiving treatment, and 2 had discontinued. The median age was 66.5 years (IQR 54.0-71.0), with 18 (60.0%) males. Of these pts, all had an ECOG performance status of ≤1; 12 (40.0%) Binet stage C; 18 (60.0%) Rai stage I-IV. Based on CLL-IPI, 16.7% (5/30) of pts were classified as low-risk, 3.3% (1/30) intermediate-risk, and 23.3% (7/30) high-risk. Comorbidities were present in 11 pts, including 7 with hypertension, 2 with diabetes mellitus, 2 with hyperlipidemia, and 1 with heart disease. IGHV mutation was detected in 71.4% (10/14) of tested pts, while TP53 mutation was identified in 33.3% (4/12) of tested pts. Five pts had a history of BTKi treatment (ibrutinib, n=3; Zanubrutinib, n=2), all of whom switched due to inadequate efficacy or AEs. Orelabrutinib was administered to 4 pts in first-line and 26 pts in second- or later-line settings. Among all pts, 28 (93.3%) achieved an objective response, including 4 (13.3%) complete responses (CR) and 24 (80.0%) partial responses (PR). One patient (3.3%) had stable disease (SD), and 1 (3.3%) experienced progressive disease (PD), resulting in a disease control rate (DCR) of 96.7% (29/30). At a median follow-up of 28.0 months (IQR, 24.6-33.7), median PFS and OS were not reached. The 36-month PFS and OS rates were both 96.7% (95% CI, 90.5%-100.0%). Patients receiving first-line orelabrutinib achieved both an ORR and DCR of 100% (4/4). Among those treated in the second- or later-line setting, ORR and DCR were 92.3% (24/26) and 96.2% (25/26), respectively, with the 36-month PFS and OS rates of 96.2%. In the TP53-mutated subgroup, ORR was 50.0% (2/4) in mutated pts versus 100.0% in wild-type (8/8). When analyzed by IGHV-mutated subtype, ORR was observed in 10 (100.0%) pts with IGHV mutation and 2 (50.0%) pts without IGHV mutation. In the subgroup by prior BTKi exposure, the ORR was 100.0% (5/5) in pts with prior BTKi exposure and 92.0% (23/25) in those without. Notably, among 3 pts who switched from ibrutinib to orelabrutinib, 2 achieved an improved response, upgrading from SD to PR, and 1 patient maintained a PR. Additionally, 1 patient who switched from zanubrutinib to orelabrutinib also exhibited an improved response from SD to PR. Among these 5 pts, one experienced improvement in bleeding severity (grade 2 to 1), and another recovered from grade 2 thrombocytopenia to normal platelet counts following orelabrutinib treatment. In the total of 30 pts, any-grade AEs were reported in 20 (66.7%), with grade ≥3 anemia occurring in 1 (3.3%). AEs related to BTKi off-target activity were not observed. Conclusion: This real-world study suggested that orelabrutinib monotherapy showed promising efficacy and a favorable safety profile in pts with CLL, both as first-line and subsequent therapy. Further prospective investigations are needed to validate the observations.