As targeted therapies continue to transform the treatment landscape of chronic lymphocytic leukemia (CLL), therapeutic goals are evolving beyond long-term disease control toward deeper remissions, fixed-duration treatment strategies, and even the possibility of functional cure. At EHA 2026, several landmark studies provided important evidence supporting this paradigm shift.At the meeting, Oncology Frontier–Hematology Frontier interviewed Prof. Shenmiao Yang from Peking University People’s Hospital to discuss the most significant advances in CLL, with a particular focus on next-generation BTK inhibitors, BCL-2 inhibitor–based combinations, and the future direction of MRD-guided treatment strategies.
Fixed-Duration Therapy and MRD-Guided Treatment Are Shaping the Future of CLL Care
Oncology Frontier–Hematology Frontier: Several important CLL studies were presented at EHA 2026. Which developments do you consider most significant, and how might they influence future treatment strategies?
Prof. Shenmiao Yang: The most important current research focus in CLL centers on fixed-duration combination therapy and treatment duration guided by measurable residual disease (MRD).
Over the past decade, continuous treatment with BTK inhibitors has demonstrated well-established efficacy and safety through extensive clinical experience and long-term follow-up. However, as treatment goals continue to evolve, the field is increasingly focused on achieving deeper remissions, extending disease control after treatment discontinuation, and ultimately moving closer to functional cure.
As a result, identifying rational combinations of agents with complementary mechanisms of action has become a major research priority.
BRUIN CLL-322: Pirtobrutinib-Based Triple Therapy Shows Promising Results
One of the most anticipated late-breaking presentations at EHA 2026 was the BRUIN CLL-322 study.
This trial evaluated the non-covalent BTK inhibitor pirtobrutinib as the treatment backbone in combination with venetoclax and rituximab, compared directly with the standard venetoclax-plus-rituximab (VR) regimen.
Previous studies conducted at MD Anderson Cancer Center had already demonstrated that pirtobrutinib combined with venetoclax and obinutuzumab could achieve remarkably high MRD negativity rates. Encouraging data from these studies were presented at last year’s ASH Annual Meeting.
The decision to combine pirtobrutinib with rituximab in BRUIN CLL-322 was based on strong clinical evidence. The landmark MURANO trial previously established that, in relapsed/refractory CLL, a fixed two-year course of venetoclax plus rituximab significantly outperformed bendamustine-rituximab (BR), producing a median progression-free survival exceeding four years. As a result, VR has become a widely accepted standard treatment option in the relapsed/refractory setting.
Building on this established foundation, the addition of pirtobrutinib is therefore of particular clinical interest.
Although follow-up remains relatively short, early results already demonstrate a separation of progression-free survival (PFS) curves. The addition of pirtobrutinib significantly improved disease control, with two-year PFS exceeding 80%, substantially outperforming the VR regimen alone.
Historically, continuous treatment with either BTK inhibitors or BCL-2 inhibitor–based therapies has typically provided disease control for approximately two years in later-line settings. Combination approaches may potentially extend this duration to approximately three years or beyond.
BTK Inhibitor Plus BCL-2 Inhibitor: The Next Major Question
A key clinical question remains unresolved: when designing combination strategies, should clinicians prioritize anti-CD20 monoclonal antibodies or BTK inhibitors?
Furthermore, if a patient has already received a BTK inhibitor in the frontline setting, is it reasonable to use another BTK inhibitor later in the disease course?
Another notable EHA 2026 study provided important insight into this issue. Data from the combination of zanubrutinib and sonrotoclax (ZS regimen) demonstrated encouraging efficacy in the relapsed/refractory setting.
Importantly, even among patients with prior BTK inhibitor resistance, the ZS regimen produced excellent outcomes, achieving MRD clearance rates of up to 84%.
The regimen has also shown strong potential in frontline treatment. While final results from the ongoing fixed-duration 12-cycle study are not yet available, data from continuous-treatment cohorts have already shown MRD negativity rates reaching 92% after 12 cycles of therapy.
These findings suggest that next-generation BTK inhibitors and next-generation BCL-2 inhibitors may offer substantial synergistic activity when used together, potentially improving outcomes across both frontline and relapsed/refractory treatment settings.
Moving Closer to Functional Cure
Taken together, the studies presented at EHA 2026 highlight a major shift in CLL management.
The field is moving away from indefinite single-agent therapy toward rational combination approaches designed to achieve deep molecular responses and sustained treatment-free remissions. Fixed-duration treatment strategies, MRD-guided decision-making, and highly active combinations of BTK and BCL-2 inhibitors are increasingly viewed as key components of future CLL care.
As more mature follow-up data become available, these approaches may bring patients closer than ever to the long-sought goal of functional cure.
