Safety and Efficacy of Zanubrutinib in Chronic Lymphocytic Leukemia/Small Lymphocytic Leukemia: A Systematic Review and Meta-Analysis
Authors: Qureshi Zaheer , Jamil Abdur , Siddique Rimsha , Altaf Faryal , Ahmed Gulrayz , Selene Insija 
Published: December 2024

Introduction
Chronic lymphocytic leukemia (CLL) is a B-cell malignancy that has been considered a separate clinical entity since the early 20th century. However, in the past decades, it has been integrated with small lymphocytic leukemia (SLL) and considered different manifestations of the same disease. Bruton kinase inhibitors (BTKi) have been the mainstay targeted therapies that have revolutionized the field of CLL/SLL management. Zanubrutinib is a BTki that the FDA recently approved for treating CLL/SLL. Therefore, a summary of current evidence on the efficacy of zanubrutinib in managing CLL/SLL is required.
Methods
The authors conducted a comprehensive electronic literature search on three electronic databases, i.e., PubMed, CENTRAL, and ScienceDirect, for records published until May 2024. Randomized and non-randomized trials evaluating zanubrutinib as an intervention in managing CLL/SLL patients were included in the review. The results were pooled using Comprehensive Meta-Analysis (CMA) version 3 and Review Manager (RevMan) 5.4 statistical software and presented using forest plots. The primary outcomes of the study were the overall survival (OS), the progression-free survival (PFS), and the objective response rate (ORR). The secondary outcome was the incidence of adverse events. A subgroup analysis was further conducted to establish the outcomes of patients with different baseline characteristics.
Results
Our online search yielded 666 articles, of which only five studies, including two randomized controlled trials (RCTs) and three non-randomized trials, were included in the analysis after an assessment based on the inclusion criteria. A pooled analysis of the results showed that the PFS was significantly increased in patients who received zanubrutinib compared to controls (HR 0.467; 95% CI [0.33, 0.63] p &lt; 0.000001). Further subgroup analysis according to the baseline patients' characteristics found that the PFS of patients with IGHV mutation receiving zanubrutinib therapy was comparable to that of controls (HR 0.65; 95% CI [ 0.41, 1.03] P =0.07). On the other hand, the PFS was significantly increased in patients without IGHV mutation (HR 0.52; 95% CI [ 0.38, 0.70] P &lt; 0.0001), those with TP53 mutation/ del (17p) (HR 0.58; 95% CI [ 0.35, 0.97] p=0.04), and those without TP53 mutation/ del (17p) (HR 0.55; 95% CI [ 0.43, 0.70] p &lt; 0.00001). However, the OS was comparable between patients receiving zanubrutinib and controls (HR 0.80; 95% CI [0.58, 1.09] p=0.16). Furthermore, the analysis showed that the overall response rate of CLL/SLL patients to zanubrutinib was (86.9%; 95% CI [83.6%, 90.3%] p=0.05). Safety analysis found that grade ≥ 3 adverse events (AEs) occurred in about (62.5%; 95% CI [58.0%, 66.7%] p &lt; 0.05) of the patients. Further analysis found that the incidence of serious AEs was significantly reduced in patients receiving zanubrutinib compared to the control group (OR 0.66; 95% CI [0.52, 0.84] P = 0.0007). However, the incidence of neutropenia, thrombocytopenia, and anemia was comparable between both groups (OR 0.41; 95% CI [0.05, 3.32] P=0.40), (OR 0.43; 95% CI [0.15, 1.21] p=0.11) and (OR 0.41; 95% CI [0.10, 1.63] p=0.20) respectively.
Discussion
Zanubrutinib was approved for treating CLL/SLL after demonstrating superior efficacy to ibrutinib or bendamustine-rituximab regarding OS and PFS. The findings of our study indicate that zanubrutinib is more effective than above in preventing disease progression in CLL/SLL patients but has comparable efficacy in preventing death. An analysis of the response rate of CLL/SLL patients to zanubrutinib showed that about 87% of the patients treated with zanubrutinib were responders. Although significantly high, this response rate to zanubrutinib was not compared to other treatment modalities due to the limited number of studies. Regarding safety, the results from the phase III trials showed that the safety profile of zanubrutinib was better than that of ibrutinib and bendamustine/rituximab. Our pooled analysis found that these AEs occurred in about 62.5% of the patients, and the incidence of serious AEs was lower in patients receiving zanubrutinib than in the controls. The results of our study, however, were based on a limited number of RCTs and non-randomized trials; thus, the quality of evidence was low. Therefore, further phase III RCTs are required to establish the comparative efficacy of zanubrutinib in managing CLL/SLL patients.