From January 16–18, 2026, the CSCO Leukemia, Lymphoma, and Myeloma Expert Committee Working Meeting and the 2026 CSCO Hematologic Oncology Conference were held in Haikou. During the meeting, Professor Wei Xu from Jiangsu Provincial People’s Hospital provided a comprehensive review of key advances in CLL treatment, therapeutic decision-making in high-risk disease, and future research directions, offering valuable insights for optimizing clinical practice.Q1. Treatment selection differs between high-risk CLL patients and standard-risk patients. In your view, what defines the current treatment landscape for high-risk CLL, and how should therapy be tailored according to specific high-risk factors?
Professor Wei Xu: Historically, high-risk CLL has primarily referred to patients harboring TP53 deletion or mutation and unmutated IGHV. Additional genetic abnormalities, such as NOTCH1 and SF3B1 mutations, should also be regarded as adverse prognostic factors.
Since the 2013 iwCLL guidelines, treatment strategies for high-risk CLL have gradually shifted from immunochemotherapy to continuous BTK inhibitor–based therapy. In the chemoimmunotherapy era, high-risk biology was difficult to overcome; however, continuous BTK inhibition has significantly improved survival outcomes in this population.
Currently, fixed-duration therapy has become an important emerging strategy in CLL and is increasingly endorsed by global experts, including the iwCLL panel. Most fixed-duration regimens involve 12 months of treatment. At ASH 2025, the three-year follow-up of the randomized CLL13 trial compared chemoimmunotherapy (CIT), venetoclax-obinutuzumab-ibrutinib (GIV), and two fixed-duration regimens—venetoclax-rituximab (RV) and venetoclax-obinutuzumab (GV). Overall survival did not differ significantly between continuous BTK inhibition and fixed-duration therapy.
However, subgroup analyses revealed that patients with TP53 abnormalities or unmutated IGHV benefited more from continuous BTK inhibitor therapy, reinforcing its role as the preferred frontline strategy in high-risk CLL.
This challenges prior assumptions that high-risk patients require BTK inhibitor plus BCL-2 inhibitor combinations. In fact, venetoclax-based combinations did not outperform BTK inhibitor monotherapy, and in some analyses showed inferior progression-free survival (PFS). Therefore, continuous BTK inhibitor monotherapy remains the recommended first-line approach for patients with TP53 mutation/deletion or unmutated IGHV.
That said, some high-risk patients prefer finite therapy due to concerns about long-term toxicity. The SEQUOIA Cohort D evaluated zanubrutinib plus venetoclax (ZV) in treatment-naïve CLL/SLL, using a minimal residual disease (MRD)-guided stopping strategy rather than a fixed-duration design. Patients discontinued therapy only after achieving complete response and sustained MRD negativity for 12 weeks. Outcomes in high-risk patients were comparable to those in standard-risk patients, supporting MRD-guided finite therapy as a viable alternative.
Additionally, the AMPLIFY trial, which excluded TP53-aberrant patients, compared chemoimmunotherapy, acalabrutinib-venetoclax (AV), and acalabrutinib-venetoclax-obinutuzumab (AVO). In NOTCH1-mutated disease, dual therapy did not overcome poor prognosis, whereas triple therapy produced superior outcomes, suggesting that intensified regimens may be preferable for select high-risk subsets.
In summary:
- If high-risk patients can tolerate long-term therapy, continuous BTK inhibitor monotherapy remains the preferred option
- If finite therapy is desired, MRD-guided treatment is recommended, with cautious discontinuation
- Triple-drug combinations may offer superior efficacy compared with doublet regimens in certain high-risk populations
Q2. With expanding treatment options, how do you view the evolving role of novel agents in CLL? What broader therapeutic trends are emerging?
Professor Wei Xu: Current targeted therapy in CLL focuses primarily on two key pathways: BTK and BCL-2.
Advances in BTK Inhibition
Several covalent BTK inhibitors—including ibrutinib, zanubrutinib, orelabrutinib, and acalabrutinib—are widely used, offering multiple frontline options.
In 2025, non-covalent BTK inhibitors demonstrated major breakthroughs. Pirtobrutinib, for example, showed superior ORR and PFS compared with ibrutinib in the BRUIN CLL-314 trial, and outperformed chemoimmunotherapy in BRUIN CLL-313, highlighting its potential frontline role.
A further innovation is the emergence of fourth-generation BTK inhibitors, such as Lobutinib, developed in China. Lobutinib can bind both wild-type BTK covalently and mutant BTK reversibly. In the ROCK-1 Phase II trial, Lobutinib achieved an IRC-assessed ORR of 63.9% and a median duration of response of 16.46 months in relapsed/refractory CLL, suggesting meaningful activity in resistant disease.
Another promising class is BTK degraders (e.g., NX-5948, APG-3288, BGB-16673), which can overcome resistance to both BTK and BCL-2 inhibitors. These agents have shown high response rates and favorable safety, marking a new mechanistic frontier in CLL therapy.
Overall, BTK-targeted therapy has rapidly evolved from covalent inhibitors → non-covalent inhibitors → dual-binding inhibitors → BTK degraders, demonstrating a clear and accelerating innovation trajectory.
Progress in BCL-2 Inhibition
The approval of venetoclax ushered CLL into the fixed-duration treatment era. In 2025, two additional BCL-2 inhibitors—Lisatoclax and Sotoclax—were approved in China, each showing strong clinical potential.
Notably, sotoclax plus obinutuzumab achieved an undetectable MRD (uMRD4) rate of 94%, reaching unprecedented depth of remission compared with prior combinations. These advances suggest that next-generation BCL-2 inhibitors may enable deeper remissions, longer PFS, and movement toward functional cure.
Q3. What research priorities will shape the future of CLL treatment, particularly for high-risk or relapsed/refractory disease?
Professor Wei Xu: The most pressing challenges lie in optimizing therapy for genetically high-risk patients and overcoming resistance in relapsed/refractory CLL, especially in patients who have failed both BTK and BCL-2 inhibitors.
Frontline treatment will likely continue to center on BTK- and BCL-2–based regimens, including:
- Continuous BTK inhibitor monotherapy, or
- BCL-2–anchored fixed-duration combination therapy
Beyond targeted small molecules, emerging immunotherapies represent key future directions:
- Bispecific antibodies, particularly for Richter transformation
- CAR-T cell therapy for heavily pretreated disease
- ROR-1–targeted therapies and other novel immune targets
These innovative strategies are expected to expand therapeutic boundaries, improve outcomes in poor-prognosis patients, and push CLL closer to durable remission and potential cure.
