Dr Munir on the Navigation of Continuous BTK Inhibitors in Treatment-Naive CLL

In my mind, the options that we need to give to our patients [with treatment-naive CLL] are still fixed-duration therapy, but also continuous [BTK inhibitor] therapy.

Talha Munir, MBChB, PhD, a consultant hematologist at Leeds Teaching Hospitals NHS Trust in the United Kingdom (UK) and the deputy chair of the UK National Cancer Research Institute Chronic Lymphocytic Leukemia (CLL) Study Group, discussed the implications of an unanchored matching-adjusted indirect comparison (MAIC) comparing zanubrutinib (Brukinsa) vs ibrutinib (Imbruvica) monotherapy in patients with treatment-naive CLL, along with the evolving role of continuous BTK inhibition vs fixed-duration approaches for this patient population.

Findings from the MAIC presented at the 2026 EHA Congress showed that zanubrutinib led to a 56% reduction in the risk of COVID-19–adjusted disease progression or death in the intention-to-treat (ITT) population (n = 352) of the phase 3 SEQUOIA trial (NCT03336333) compared with ibrutinib (n = 301) in the phase 3 CLL17 trial (NCT04608318; HR, 0.44; 95% CI, 0.30-0.64; P < .0001). When the SEQUOIA population was matched with the CLL17 group (n = 91), the PFS benefit with zanubrutinib vs ibrutinib was more pronounced (HR, 0.23; 95% CI, 0.12-0.42; P < .0001).

Although no statistical significance was observed in terms of overall survival outcomes, similar results were observed between the SEQUOIA ITT population and the CLL17 group (HR, 1.17; 95% CI, 0.61-2.25; P = .6369). The population-adjusted estimate following matching trended in favor of zanubrutinib (HR, 0.70; 95% CI, 0.29-1.73; P = .4463).

Although the CLL17 trial established fixed-duration regimens, such as venetoclax (Venclexta) plus obinutuzumab (Gazyva) and venetoclax plus ibrutinib, as noninferior to continuous ibrutinib in patients with treatment-naive CLL, Munir explained that additional evidence is needed to assess second-generation BTK inhibitors like zanubrutinib or acalabrutinib (Calquence) vs fixed-duration therapies in the frontline setting. He explained that although fixed-duration therapy has an established role in the treatment-naive CLL setting, continuous BTK inhibition can also generate favorable long-term outcomes, concluding that both treatment approaches should be considered and discussed with newly diagnosed patients.