Advances in targeted therapies have transformed the frontline management of patients with chronic lymphocytic leukaemia (CLL). At an industry-sponsored symposium in Hong Kong, Professor Ja Min Byun of the Seoul National University Hospital in Seoul, South Korea, highlighted how evolving evidence is shaping individualized treatment strategies, focusing on next-generation Bruton tyrosine kinase inhibitors (BTKIs), tumour biology and emerging combinations.
Evolving paradigms in frontline CLL treatment
Frontline CLL treatment has shifted away from chemoimmunotherapy toward targeted therapies, including covalent BTKIs and B‑cell lymphoma‑2 inhibitors (BCL2Is). Current guidelines broadly categorize first‑line strategies as either continuous BTKI therapy or time‑limited regimens incorporating a BCL2I such as venetoclax, with regimen choice guided by tumour biology, comorbidities, treatment goals and patient’s preference. [Cancers (Basel) 2025;17:799; NCCN Clinical Practice Guidelines in Oncology, Chronic Lymphocytic Leukaemia/ Small Lymphocytic Lymphoma, version 2.2026; Blood Cancer J 2026;16:19]
“First-line [1L] CLL therapy today is less about identifying one universally preferred regimen, and more about selecting the most appropriate strategy for each patient,” Byun underscored. “This individualized approach takes into consideration each patient’s biological risk factors and clinical context.”
Meanwhile, molecular biomarkers, particularly TP53 mutation or deletion of chromosome 17p (del17p), and immunoglobulin heavy chain variable (IGHV) mutation status, remain central to therapeutic decision‑making because of their strong prognostic and predictive impact. [NCCN Clinical Practice Guidelines in Oncology, Chronic Lymphocytic Leukaemia/Small Lymphocytic Lymphoma, version 2.2026; Ann Oncol 2021;32:23-33]
Zanubrutinib: Durable treatment outcomes
Early fixed‑duration ibrutinib–venetoclax regimens have demonstrated strong efficacy vs chemoimmunotherapy in the phase III GLOW and FLAIR trials, but their uptake is limited due to ibrutinib‑related toxicity and the emergence of better‑tolerated next‑generation BTKIs. [Lancet Oncol 2023;24: 1423-1433; N Engl J Med 2025;393:1177-1190; Cancers (Basel) 2025;17:799]
Zanubrutinib is a next‑generation BTKI designed for sustained BTK occupancy with improved kinase selectivity and is approved as monotherapy for adults with CLL. [Blood 2024;144:2706-2717; Brukinsa Hong Kong Prescribing Information; Lancet Haematol 2023;10:e35-e45]
In the head-to-head phase III ALPINE trial involving adults with relapsed or refractory (R/R) CLL or small lymphocytic lymphoma (SLL), zanubrutinib monotherapy achieved superior progression-free survival (PFS) and higher overall response rates (ORR) vs ibrutinib. At 24 months, investigator-assessed PFS rates were 78.4 percent with zanubrutinib vs 65.9 percent with ibrutinib (hazard ratio [HR], 0.65; 95 percent confidence interval [CI], 0.49–0.86; p=0.002), with sustained benefits beyond 3 years in favour of zanubrutinib. [N Engl J Med 2023;388:319-332; Blood 2024;144:2706-2717]
Real-world persistence advantages with 1L zanubrutinib
Real‑world data suggest that zanubrutinib’s efficacy translates into improved 1L treatment persistence. In a matched cohort study of 414 patients with CLL/SLL treated in US community practices (zanubrutinib, n=138; acalabrutinib, n=276), ongoing treatment rates at 12 months were 81.2 vs 68.8 percent with zanubrutinib vs acalabrutinib, with higher probabilities of avoiding next treatment at both 6 and 12 months. [Hou JZ, et al, ASH 2024, poster abstract 906]
In the larger US nationwide Flatiron electronic health record–derived analysis, 2,515 patients with CLL received 1L BTKIs from January 2020 to August 2024. Results showed that patients receiving 1L zanubrutinib were more likely to remain on initial therapy and less likely to require subsequent treatment vs those receiving acalabrutinib, with higher probabilities of remaining free from treatment discontinuation or next treatment at 6 and 12 months. (Table) [Jacobs R, et al, ASCO 2025, abstract e23264]
These findings suggest that zanubrutinib may enable more sustained 1L treatment and delay the need for subsequent therapy.
Improved CV safety and tolerability
Cardiovascular (CV) toxicity, particularly atrial fibrillation (AF) and other cardiac events, remains a key limitation of first‑generation BTKIs. Next-generation BTKIs were designed to improve kinase selectivity and mitigate these risks. [Cancers (Basel) 2025;17:799; Expert Rev Hematol 2022;15:321-331]
Notably, the overall burden of BTKI‑associated cardiac toxicity appears lower in East Asian patients with CLL than in predominantly Western cohorts. A phase I/II trial reported that among Chinese patients with R/R CLL treated with acalabrutinib, no AF/flutter events occurred, compared with 5.8 percent in an ibrutinib comparator cohort. [Ann Hematol 2025;104:701-712] Similarly, pooled zanubrutinib data showed only rare AF events in Chinese patients vs higher rates in other populations, further suggesting lower BTKI-associated AF risk and discontinuation rates in East Asian vs predominantly Western cohorts. [Blood Adv 2022;6:1296-1308]
In ALPINE, overall cardiac events were less frequent with zanubrutinib vs ibrutinib (25.9 vs 35.5 percent), with substantially lower rates of AF/flutter (7.1 vs 17.0 percent), fewer discontinuations due to cardiac events (0.9 vs 4.9 percent), and no cardiac deaths in the zanubrutinib arm vs six with ibrutinib. [Blood 2024;144:2706-2717]
These findings indicate that while BTKI‑related CV adverse events are relatively infrequent in Asian patients, the use of next‑generation, more selective BTKIs further reduces cardiac risk, making them valid options when long‑term therapy is anticipated. [Haematologica 2022;107:1335-1346; Ann Hematol 2025;104:701-712; Blood Adv 2022;6:1296-1308; J Clin Oncol 2021;39:3441-3452]
Continuous BTKI for durable disease control
Continuous BTKI therapy remains a cornerstone of CLL management, providing sustained B‑cell receptor pathway inhibition and durable disease control, particularly in biologically higher‑risk disease. [Cancers (Basel) 2025;17:799] In ALPINE, zanubrutinib maintained a PFS advantage over ibrutinib in patients with del17p/TP53 mutation (HR, 0.51; 95 percent CI, 0.33– 0.78), supporting its use when long‑term disease suppression is a key objective. [Blood 2024;144:2706-2717]
Long-term follow-up analyses and cross-trial comparisons revealed durable PFS with continuous BTKI therapy. This was demonstrated in matching-adjusted indirect comparisons between the phase III SEQUOIA trial (which evaluated frontline continuous zanubrutinib vs six cycles of bendamustine plus rituximab) and the phase III GLOW trial (which assessed fixed-duration ibrutinib plus venetoclax vs chlorambucil plus obinutuzumab). Similar deep, time-limited responses were also observed in the phase II CAPTIVATE trial with ibrutinib plus venetoclax. [Munir T, et al, EHA 2024, abstract P702; Br J Haematol 2026;208:321-324; NCT03336333]
Importantly, available evidence suggests that continuous BTKI therapy provides durable disease control across high-risk subgroups, including del17p and TP53 mutations, supporting its role as a key treatment strategy in patients where sustained disease suppression is an important objective. [Munir T, et al, EHA 2024, abstract P702; Br J Haematol 2026;208:321-324; Cancers (Basel) 2025;17:799]
Future prospects
“Future strategies in frontline CLL treatment are increasingly focused on novel fully oral combinations, including next‑generation BCL2Is such as sonrotoclax partnered with BTKIs,” shared Byun. [Shadman M, et al, ASCO 2024, abstract TPS7087] “Next‑generation BTKIs, particularly zanubrutinib, with its durable efficacy and favourable safety profile, are emerging as key 1L backbones on which these future regimens are likely to build.”