First-Line Zanubrutinib Prolongs PFS in Real-World Study of Chinese Patients With CLL/SLL

Treatment with first-line zanubrutinib (Brukinsa) demonstrated comparable efficacy and safety in the real world vs prior clinical trials, and generated a greater progression-free survival (PFS) benefit for patients with treatment-naive chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) than those with relapsed/refractory CLL/SLL, according to results from a real-world study published in The American Journal of Hematology.

At a median follow-up of 36.8 months (95% CI, 34.5-39.1), the median PFS and overall survival (OS) among all patients with CLL/SLL (n = 138) were not reached. 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%), respectively, for the entire cohort. Notably, PFS was significantly shorter in the relapsed/refractory cohort of patients when stratified by line of therapy (P = .004). The 36-month PFS rates were 64.8% (95% CI, 51.3%-82.0%) for patients with relapsed/refractory disease and 84.3% (95% CI, 76.7%-92.6%) for patients with treatment-naive disease. Additionally, no notable differences in OS were reported, (83.0% vs. 92.3%; P = .069).

Among 121 efficacy-evaluable patients, the overall response rate was 86.0%; 8.3% of patients also achieved complete remission. In the overall study population, 14.5% of patients had progressive disease, including 9 patients with primary TP53 aberrations.

“To the best of our knowledge, this report is the first and largest assessment of outcomes for [patients with] CLL/SLL receiving zanubrutinib monotherapy in a real-world setting. With a median follow-up of 36.8 months, the survival rates were in line with [those observed in] clinical trials, both in previously untreated and relapsed/refractory patients,” study authors wrote in the report. “Patients receiving first-line zanubrutinib had significantly longer PFS than patients [with relapsed/refractory disease], suggesting that early administration of zanubrutinib confers better outcome for [patients].”

Overview of Study Design

BTK inhibitors are the current standard of care for both treatment-naive and relapsed/refractory CLL and SLL. Zanubrutinib, a next-generation BTK inhibitor, provides better BTK specificity and less off-target inhibition compared with other agents in this drug class. The first next-generation BTK inhibitor has previously demonstrated superior efficacy and has a better safety profile compared with the BTK inhibitor ibrutinib in the phase 3 ALPINE study.

These positive data supported the approval of zanubrutinib by China’s National Medical Products Administration for patients with CLL/SLL in June 2020. Accordingly, investigators assessed the efficacy and safety profile of zanubrutinib monotherapy in a real-world population of Chinese patients with CLL/SLL.

Patients with CLL or SLL who had been treated with zanubrutinib monotherapy for at least 3 months were eligible for the study; however, patients who switched from ibrutinib (Imbruvica) to zanubrutinib were not required to meet the criteria for treatment initiation.

The evaluation gathered data from patients across 9 medical centers in Shanghai, China. CLL diagnosis, treatment indications, response assessment, and hematologic adverse effects (AEs) were evaluated in accordance with the International Workshop on Chronic Lymphocytic Leukemia 2018 guidelines. Study authors noted that non-hematologic AEs were graded according to the Common Terminology Criteria for Adverse Events version 5.0.

At the data cutoff date of September 15, 2024, 138 patients were included in the analysis. Of these, 65.2% had treatment-naive CLL/SLL, 34.8% had relapsed/refractory disease, and the median age across both groups was 68 years (interquartile range [IQR], 37-87) at the time of zanubrutinib initiation. Among the 109 patients with available data, 24.8% had detectable TP53 deletions and/or mutations, including 21.9% in the treatment-naive group and 30.6% in the relapsed/refractory group, respectively. A total of 30.4% of patients switched from ibrutinib to zanubrutinib treatment, with a median duration of prior ibrutinib treatment of 12.9 months (IQR, 4.5-22.2).

Although there was a high proportion of patients in this cohort who had TP53 aberrations at zanubrutinib initiation, no significant impact of TP53 aberration on survival was observed. However, investigators noted that evidence is limited for the direct comparison of effectiveness among these subgroups receiving single-agent zanubrutinib due to small sample sizes. Prior data show that TP53 abnormality may not be involved in the onset of resistance in ibrutinib treatment but may be associated with a higher rate of clonal evolution. In total, 45.0% of patients who progressed had primary TP53 aberration, warranting further investigation.

Understanding the Impact of Toxicity and Dose Reductions on Real-World Outcomes

A total of 21 patients crossed over to treatment with zanubrutinib due to ibrutinib-related intolerance events, which comprised non-hematological AEs. These intolerance events did not recur in 53.8% of patients or recurred at a lower grade during zanubrutinib treatment in 42.3% of patients. Notably, 2 patients experienced ibrutinib-related arrhythmia, including premature atrial contractions and premature ventricular contractions, though neither patient had recurrence while taking zanubrutinib.

Regarding safety, 84.8% of participants experienced at least 1 AE of any grade during treatment, including fatigue (31.2%), infections (29.7%), neutropenia (24.6%) and bleeding events (23.9%). A total of 26.1% of patients had at least 1 grade 3 or higher AE including infections (14.5%; pneumonia, 12.3%) and neutropenia (10.1%). Notably, 16.7% of patients had at least 1 serious AE.

Cardiac AEs occurred in 5.1% of patients and included palpitations (2.9%), ventricular extrasystole (1.4%), and atrial fibrillation (0.7%); no cardiac-related deaths were reported. There were no fatal cardiac AEs. Investigators noted that in the 3 patients with a history of atrial fibrillation, there was no recurrence or deterioration of their atrial fibrillation during treatment. Among patients with baseline serologic evidence of hepatitis B virus (HBV) infection (n = 61), 11.5% of patients had HBV reactivation following zanubrutinib treatment.

According to the study authors, the toxicity profile of zanubrutinib was similar to that seen in previously reported studies. Additionally, a lower proportion of patients had HBV reactivation in clinical trials compared with this cohort (5.3% vs 11.5%). Given the prevalence of HBV infection in Chinese patients older than 50 years, its management throughout the course of zanubrutinib treatment is crucial.

Zanubrutinib dose reductions were needed for 20.3% of patients, with a median time to reduction of 2.1 months (IQR, 0.7-10.8); these patients received zanubrutinib at 80 mg twice daily after reduction. However, multivariate analysis showed that patients who underwent dose reduction had a significantly shorter PFS than those treated with the full dose of zanubrutinib, making it difficult for patients to achieve a deep remission. This was particularly notable in older patients.

“Zanubrutinib dose reduction significantly compromised patients’ survival, highlighting the importance of continuous exposure to zanubrutinib at full doses to maximize its antileukemia activity,” study authors stated. “Thus, recognition and management of [AEs] during continuous zanubrutinib monotherapy is of great importance. Oncologists should consider resuming zanubrutinib at the full dose once AEs have been adequately improved following a dose reduction.”

Investigators added that previous studies of ibrutinib showed mixed results with dose reduction. Some studies reported worse survival outcomes with reduced dose intensity or prolonged dose interruptions, but other studies showed comparable survival benefit for patients who underwent dose reduction vs those who did not. However, there are factors that act as confounders when interpreting the effect of dose reduction on survival in some of these studies.

Overall, results from this real-world analysis demonstrated the importance of continuous zanubrutinib treatment at full doses and developing better treatment strategies to improve treatment tolerability and outcomes for these patients.

“For the first time, this study [has] demonstrated comparable efficacy and toxicity between real-world data and published trials in [patients with] CLL/SLL receiving zanubrutinib monotherapy,” study authors concluded. “In addition, our results showed that zanubrutinib is an effective option for ibrutinib-intolerant patients to maintain efficacy and minimize ibrutinib-related [AEs] in clinical practice.”

Reference

Luo J, Zhang J, Liu L, et al. Efficacy and safety of zanubrutinib monotherapy for chronic lymphocytic leukemia/small lymphocytic lymphoma: A multicenter, real-world study in China. Am J Hematol. Published online October 19, 2024. doi:10.1002/ajh.27519