China-Europe Dialogue | Dr. Shenmiao Yang in Conversation with Dr. Stephan Stilgenbauer Fixed-Duration Therapy Gains Traction in CLL, with New Considerations in Combination Strategies and Resistance Management

Editor’s Note: At the 31st European Hematology Association (EHA) Congress in 2026, the FOCUS Clinical Scientists brought together Dr. Stephan Stilgenbauer from University Hospital Ulm, Germany, and Dr. Shenmiao Yang from Peking University People’s Hospital, China, for an in-depth dialogue. Their discussion covered the evolving paradigm of first-line therapy for chronic lymphocytic leukemia (CLL), optimization strategies for targeted combination regimens, clinical decision-making after BTK inhibitor resistance, the underlying reasons for differences in MRD negativity rates across regimens, and future breakthrough directions as well as prospects for China-Europe research collaboration.

 

FOCUS Clinical Scientists: In recent years, first-line CLL therapy has entered an era dominated by BTK and BCL-2 inhibitors. In light of data presented at EHA 2026, where do you see the future of first-line treatment heading—toward continuous therapy or fixed-duration regimens? What are the key drivers behind this shift?

Dr. Stephan Stilgenbauer: Both BTK inhibitors and BCL-2 inhibitors have fundamentally transformed the treatment landscape for CLL, with clear efficacy as monotherapies. The all-oral combination of a BTK inhibitor plus a BCL-2 inhibitor represents a highly promising future direction, and one that will push CLL further toward fixed-duration therapy.

Such all-oral regimens are more convenient for both patients and healthcare systems, and they eliminate the infusion-related reactions associated with CD20 antibodies. The lead-in phase with a BTK inhibitor also facilitates the ramp-up of the BCL-2 inhibitor, reducing the risk of tumor lysis syndrome. As data mature for combinations involving next-generation BTK inhibitors and next-generation BCL-2 inhibitors, the population eligible for fixed-duration therapy will continue to expand.

Dr. Shenmiao Yang: Some studies are now exploring triplet regimens combining a BTK inhibitor, a BCL-2 inhibitor, and a CD20 antibody for CLL—for example, the PVO regimen, which has achieved MRD clearance down to 10⁻⁶. However, there is a view that excessive B-cell depletion may not necessarily benefit patients. What is your perspective on the clinical value of triplet therapy? Is there a routine need to add a CD20 antibody in clinical practice?

Dr. Stephan Stilgenbauer: The triplet regimen PVO (pirtobrutinib + venetoclax + obinutuzumab) reported by MD Anderson Cancer Center is still in the clinical trial phase. It is based on a single-center, small-sample study, and while the data are promising, they still require validation.

More broadly, clinical experience from the COVID-19 and other infectious contexts suggests that CD20 antibodies do not always provide a net benefit and may actually increase infection risk. Therefore, the added clinical value of incorporating a CD20 antibody on top of a two-drug BTK+BCL-2 inhibitor backbone is likely to diminish over time.

The upcoming randomized controlled trial comparing PVR (pirtobrutinib + venetoclax + rituximab) with VR (venetoclax + rituximab) will provide important reference data. The VR regimen was the first approved fixed-duration regimen in the relapsed CLL setting. In real-world practice, however, many clinicians tend to omit the CD20 antibody and use the PV doublet alone.

Furthermore, different CD20 antibodies have distinct efficacy and toxicity profiles. Overall, obinutuzumab appears to have stronger antitumor clearance activity, but under comparable conditions, it also carries a relatively higher risk of infection-related adverse events. Clinicians must therefore weigh the risk–benefit balance based on each patient’s immune status.

Dr. Shenmiao Yang: For patients who progress after prior BTK inhibitor-based combination therapy, to reduce the risk of rapid disease flare upon discontinuation, we often continue the BTK inhibitor while adding a BCL-2 inhibitor. Once disease progression is controlled—essentially, when the patient is deriving benefit from the two-drug combination—should we then stop the BTK inhibitor to which the patient had previously become resistant?

Dr. Stephan Stilgenbauer: The combination of a BTK inhibitor and a BCL-2 inhibitor retains clinical value even in patients who have failed prior BTK inhibitor therapy, and it can achieve good outcomes in the relapsed setting. This makes it a worthwhile option.

The core reason lies in their completely distinct mechanisms of action. BTK inhibitors have a relatively moderate effect—slow to achieve response but durable, requiring continuous administration. BCL-2 inhibitors, in contrast, act rapidly and can eliminate large tumor burdens within days. The two agents have clear synergistic effects; even in patients resistant to one agent alone, the combination can still exert antitumor activity. 

Regarding whether to stop after progression: if a patient progresses on a BTK inhibitor, I do not recommend abrupt discontinuation, as this may trigger rapid disease flare. The proper approach is to initiate subsequent therapy (e.g., a BCL-2 inhibitor) while continuing the BTK inhibitor. If the patient achieves a good response on the combination and tolerates it well, it is reasonable to maintain the two-drug regimen, as the patient can continue to benefit from the synergistic effect.

 

FOCUS Clinical Scientists: Currently, MRD negativity rates vary considerably across different BCL-2 inhibitor–based regimens—for example, only 34% with the AV regimen versus 92% with the SZ regimen. What do you believe are the core reasons for this disparity? And will this difference translate into meaningful gaps in progression-free survival (PFS)?

Dr. Stephan Stilgenbauer: First, it is important to recognize that cross-trial indirect comparisons have inherent limitations and should not be interpreted as head-to-head equivalence. The data for the two regimens come from entirely different sources: the AV regimen (acalabrutinib + venetoclax) is based on the large, multicenter, phase ⅢAMPLIFY trial, which includes a broader range of centers and more diverse patient baselines. In contrast, the high MRD negativity rates reported for the SZ regimen (zanubrutinib + sonrotoclax) largely derive from phase Ⅱ studies conducted at a small number of specialized centers. Differences in trial design, baseline patient characteristics, and center execution standards are major contributors to the observed data gap.

However, even accounting for cross-trial biases, it does appear from indirect comparisons that there are real differences in PFS and MRD negativity across regimens. For instance, the AV regimen seems to show somewhat weaker PFS and MRD outcomes compared with the IV regimen (ibrutinib + venetoclax).

At this point, we cannot definitively conclude that differences in MRD will fully translate into significant long-term PFS disparities; longer follow-up data are needed. We look forward to the updated AMPLIFY results at the ASH annual meeting in December this year, as more mature follow-up should provide clearer validation of the regimen’s long-term value.

 

FOCUS Clinical Scientists: Over the next five years, which direction holds the greatest promise for breakthrough advances in CLL therapy? In what key areas could China and Europe deepen collaboration in basic CLL research, translational science, and international multicenter clinical trials?

Dr. Stephan Stilgenbauer: International collaboration has always been a vital driver of progress in hematologic oncology, enabling the integration of patient resources, pooling of technological expertise, and acceleration of research. Currently, the collaborative landscape between China and Europe in CLL is quite positive.

On the basic and translational research front, we need to further deepen our understanding of disease genetics, particularly resistance mechanisms following targeted therapy. Through analysis of relapsed samples and model systems, we can work toward overcoming resistance.

In terms of therapeutic agents, the BTK inhibitor plus BCL-2 inhibitor combination will remain a core future direction, with next-generation agents expected to further enhance efficacy. Beyond that, BTK degraders represent a highly promising class with a completely novel mechanism of action. Their mode of action differs from conventional kinase inhibitors, and they have already shown encouraging activity in patients who have failed kinase inhibitors. Moving degraders into earlier lines of therapy or combining them with BCL-2 inhibitors and other agents could herald new therapeutic breakthroughs.

 

Expert Profile

Dr. Shenmiao Yang

Peking University People's Hospital

Specializes in CLL and malignant lymphoma.

Dr. Stephan Stilgenbauer

University Hospital Ulm, Germany

Research focuses on high-risk CLL biology and therapy, particularly del(17p)/TP53-mutated disease.