Efficacy and safety of zanubrutinib monotherapy for chronic lymphocytic leukemia/small lymphocytic lymphoma: A multicenter, real‐world study in <scp>China</scp>
Authors: Jing Luo, Jiaojiao Zhang, Ligen Liu, Rong Wei, Yonghua Yao, Min Xu, Jumei Shi, Jianmin Yang, Jian Hou, Jin Wang, Jian‐Qing Mi
Journal: American Journal of Hematology (2024)

Bruton tyrosine kinase (BTK) inhibitor is now the standard of care for both treatment-naïve (TN) and relapsed/refractory (R/R) chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). Zanubrutinib, a next-generation BTK inhibitor with better BTK specificity and less off-target inhibition, has demonstrated superior efficacy and improved safety profile compared with first-generation BTK inhibitor ibrutinib in large phase III ALPINE study.1 Zanubrutinib is the first next-generation BTK inhibitor approved in China for CLL/SLL in June 2020, and so far, the real-world data of zanubrutinib have not been reported. Thus, we present this multicenter real-world study detailing the efficacy and safety profile of zanubrutinib monotherapy in Chinese patients with CLL/SLL. Chronic lymphocytic leukemia/small lymphocytic lymphoma patients treated with zanubrutinib monotherapy for at least 3 months were enrolled in 9 medical centers in Shanghai, China. The last follow-up time was September 15, 2024. CLL diagnosis, treatment indications, response assessment, and hematologic adverse events were evaluated in accordance with the International Workshop on Chronic Lymphocytic Leukemia 2018 guidelines. Patients switched from ibrutinib to zanubrutinib were not required to meet criteria for initiation of treatment. Imaging and laboratory assessments at zanubrutinib initiation were considered baseline for response assessment. Non-hematologic adverse events were graded according to the Common Terminology Criteria for Adverse Events version 5.0. A total of 138 patients were included. Ninety (65.2%) patients were TN, and 48 (34.8%) were R/R, with their types of prior treatment regimens listed in Table S1. The median age at zanubrutinib initiation was 68 years. Baseline characteristics at zanubrutinib initiation were described in Table S2. Among 109 patients with available data, primary TP53 deletion and/or mutation were detected in 27 (24.8%) patients, and the ratios of TP53 aberration in TN and R/R patients were 21.9% and 30.6%, respectively. Main characteristics of zanubrutinib administration were listed in Table S3. Forty-two (30.4%) patients switched from ibrutinib to zanubrutinib, with a median duration of prior ibrutinib treatment of 12.9 months (IQR, 4.5–22.2 months). Twenty-eight (20.3%) patients had zanubrutinib dose reduction, with a median time to reduction of 2.1 months (IQR, 0.7–10.8 months), and these patients received zanubrutinib 80 mg twice daily after reduction. The median time to discontinuation among the 31 patients was 15.0 months (IQR, 7.4–23.1 months), with 48.4% discontinued due to disease progression. Among 121 efficacy-evaluable patients, the overall response rate (ORR) was 86.0% and 10 (8.3%) patients achieved complete remission (CR). Seventeen patients who achieved CR with prior ibrutinib treatment at the time of zanubrutinib initiation were excluded in the sensitivity analysis of ORR. Among all 138 patients, 20 (14.5%) had progressive disease, including 9 patients with primary TP53 aberration. Mutational analysis of BTK at disease progression was performed in 11 patients, and 4 of whom had BTK C481S mutation, including 3 patients with prior ibrutinib exposure. Five (3.6%) patients had histologically confirmed Richter transformation. With a median follow-up of 36.8 months (95% CI: 34.5–39.1), the median progression free survival (PFS) and overall survival (OS) were not reached (Figure 1A,B). The 36-month PFS and OS rates were 77.7% (95% CI: 70.6–85.5%) and 88.5% (95% CI: 82.9–94.5%) for the entire cohort. When stratified by line of therapy, PFS was significantly shorter in R/R compared with TN setting (p = .004, Figure S1A), and the 36-month PFS rates were 64.8% (95% CI: 51.3–82.0%) for R/R patients and 84.3% (95% CI: 76.7–92.6%) for TN patients. No significant difference in OS was observed (83.0% vs. 92.3%, p = .069). No impact of TP53 aberration on PFS or OS was observed (p = .362, Figure S1B, p = .512, respectively). Notably, patients who had zanubrutinib dose reduction for any reason had significantly inferior PFS and OS (Figure 1C,D) compared with those receiving full dose treatment (p = .005, p = .031, respectively), and were significantly older (t = 2.731, p = .007). Prior treatment and zanubrutinib dose reduction remained to be significantly associated with inferior PFS in multivariate analysis (p = .006, p = .009, respectively, Figure 1E). Gender, age, clinical stage, IGHV mutation status, complex karyotype, 11q deletion and zanubrutinib suspension had no significant impact on PFS or OS. The univariate and multivariate analyses of PFS and OS were presented in Table S4. In total, 117 (84.8%) patients experienced at least one adverse event (AE) of any grade during zanubrutinib treatment. The most common all grade AEs were fatigue (31.2%), infections (29.7%), neutropenia (24.6%) and bleeding events (23.9%). Thirty-six (26.1%) patients had at least one grade 3 or above AE. The most common grade 3 or above AEs were infections (14.5%, mostly pneumonia, 12.3%) and neutropenia (10.1%) (Table S5). Twenty-three (16.7%) patients had at least 1 serious adverse event (SAE). Cardiac adverse events occurred in 7 (5.1%) patients (palpitation, 2.9%; ventricular extrasystole, 1.4%; atrial fibrillation, 0.7%), and no cardiac-related death was reported. Three patients had a history of atrial fibrillation and no recurrence or deterioration of their atrial fibrillation was observed during zanubrutinib treatment. In 61 patients with baseline serologic evidence of hepatitis B virus (HBV) infection, 7 (11.5%) patients had HBV reactivation after zanubrutinib initiation. A total of 21 patients switched to zanubrutinib treatment due to ibrutinib-related intolerance events. The disease control rate, including stable disease or better, was 81.0%. Twenty-one patients reported 26 ibrutinib-related intolerance events. All events were non-hematological AEs, mostly hemorrhages. Fourteen (53.8%) and 11 (42.3%) of intolerance events did not recur or recurred at a lower grade during zanubrutinib treatment (Figure S2). Two patients experienced ibrutinib-related arrhythmia (premature atrial contractions and premature ventricular contractions, one for each), neither recurred while taking zanubrutinib. To the best of our knowledge, this report is the first and largest assessment of outcomes for CLL/SLL patients receiving zanubrutinib monotherapy in a real-world setting. With a median follow up time of 36.8 months, the survival rates were in line with clinical trials, both in previously untreated and relapsed/refractory patients.1, 2 Patients receiving first line zanubrutinib had significantly longer PFS than R/R patients, suggesting that early administration of zanubrutinib confers better outcome for CLL/SLL patients. A relatively high proportion of patients in our cohort had TP53 aberration (deletion and/or mutation) at zanubrutinib initiation (21.9% in TN patients, 30.6% in R/R patients). However, we did not find a significant impact of TP53 aberration on survival. The relatively small sample size may partly explain this noninferior survival. In the context of TP53 aberration, evidence is now limited for the direct comparison of effectiveness among these subgroups receiving single-agent zanubrutinib. Studies on ibrutinib resistance indicated that TP53 abnormality may not be involved in the onset of resistance, but may have a higher rate of clonal evolution due to genomic instability, and concurrent mutations in other genes or pathways ultimately lead to ibrutinib failure.3 Notably, 9 of 20 (45.0%) progressed patients in our cohort had primary TP53 aberration, a rate higher than the entire cohort (24.8%). Therefore, the impact of TP53 abnormality during zanubrutinib treatment warrants further investigation. Patients who had zanubrutinib dose reduction had significantly shorter PFS in multivariate cox-regression model. All patients received 50% zanubrutinib dose intensity (80 mg twice daily) after reduction in this study, and the median time from zanubrutinib initiation to dose reduction was only 2.1 months, which was too short for most patients to get a relatively deep remission. Besides, patients with dose reduction were older compared with patients receiving full doses. Previous studies of ibrutinib reported mixed results. Some studies showed a worse survival with reduced dose intensity or prolonged dose interruptions,4 whereas other studies showed similar survival.5 Notably, patient-related characteristics, disease burden at dose reduction and dose intensity after reduction varied in these reported studies, suggesting these factors may act as confounders when interpreting the effect of dose reduction on survival. Consequently, the extent to which interruptions in zanubrutinib dosing may influence long-term outcomes requires further investigation. Our results demonstrated the importance of continuous zanubrutinib treatment at full doses and exploring better treatment strategies such as combined targeted therapy to improve the tolerability and outcomes of these patients. The toxicity spectrum was similar to reported data. A similar low rate of cardiac adverse events (5.1%) was confirmed in this study. No fatal cardiac adverse event was observed. Furthermore, a higher proportion of patients had HBV reactivation in our cohort compared with clinical trials (11.5% vs. 5.3%).6 Given the high prevalence of HBV infection in Chinese population over the age of 50, management of HBV is crucial during zanubrutinib treatment. It is worth noticing that patients receiving zanubrutinib <3 months were excluded from this study and the safety evaluation of these patients needs further study. In conclusion, for the first time, this study demonstrated comparable efficacy and toxicity profile between real-world data and published trials in CLL/SLL patients receiving zanubrutinib monotherapy. In addition, our results showed that zanubrutinib is an effective option for ibrutinib-intolerant patients to maintain efficacy and minimize ibrutinib-related side effects in clinical practice. Zanubrutinib dose reduction significantly compromised patients' survival, highlighting the importance of continuous exposure of zanubrutinib at full doses to maximize its antileukemia activity. Thus, recognition and management of adverse events during continuous zanubrutinib monotherapy are of great importance. Oncologists should consider resuming zanubrutinib at the full dose once adverse events have been adequately improved following a dose reduction. This study was funded by grants from the National Key R&D Program of China (2023YFC2508900), the Innovation Program of Shanghai Science and Technology Committee (23141903000) and the Innovative Research Team of High-level Local Universities in Shanghai. The authors declare no conflict of interests. A waiver of informed consent was granted due to the nature of a retrospective study. This study did not reproduce any other protected material. Not applicable. Data are available upon reasonable requests. Requests for data review should be submitted to the corresponding author. Figure S1: Subgroup analysis of progression free survival. Progression free survival by (A) line of therapy (treatment-naïve vs. relapsed/refractory) and (B) TP53 status (with or without TP53 aberration). Figure S2: Recurrence and changes in severity of ibrutinib related intolerant events after switching to zanubrutinib treatment. ALT, alanine aminotransferase; AST, aspartate aminotransferase. Table S1: Types of treatment regimens before zanubrutinib initiation in relapsed/refractory patients. Table S2: Baseline characteristics at zanubrutinib initiation. Table S3: Zanubrutinib administration characteristics. Table S4: The univariate and multivariate analysis of progression free survival and overall survival for the entire cohort. Table S5: Any grade adverse event during zanubrutinib treatment. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.