Mazyar Shadman, MD, MPH, is the Innovators Network Endowed Chair and an associate professor, in theClinical Research Division at Fred Hutchinson Cancer. He is also an associate professor in the Medical Oncology Division at University of Washington School of Medicine.
This presentation shows that the next-generation BTK inhibitor zanubrutinib demonstrates increasingly durable long-term survival and progression-free benefits compared with ibrutinib and acalabrutinib in previously untreated chronic lymphocytic leukemia, supporting its use as a preferred frontline therapy when direct comparative trial data are unavailable.
Dr. Parikh highlights the CLL14 9-year follow-up data as among the most important datasets presented at EHA 2026. The study enrolled treatment-naïve patients with significant comorbidities (high CIRS score) randomized to venetoclax-obinutuzumab versus chlorambucil-obinutuzumab. With 9-year follow-up, the median PFS for venetoclax-obinutuzumab reaches approximately 6 years overall, with a remarkably striking finding for IGHV-mutated patients achieving median PFS of approximately 8.5 to 9 years.
Dr. Marc Hoffmann introduces the program on optimizing CLL treatment strategies, noting that CLL remains the most common adult leukemia in the Western world with approximately 20,000 new annual US diagnoses. The panel includes Drs. Catherine Coombs, Andrew Lipsky, Sameer Parikh, and Mazyar Shadman.
Mazyar Shadman, MD, MPH, discusses data from the phase 1/1b BGB-11417-101 trial of sonrotoclax plus zanubrutinib in frontline CLL/SLL.
Dr. Brander asks about synthesizing comparative analyses and important limitations clinicians should understand when interpreting cross-trial comparisons, including balancing insights with other evidence forms.
Dr. Brander introduces the third analysis comparing zanubrutinib from SEQUOIA with acalabrutinib plus venetoclax from AMPLIFY, representing an anchored analysis with similar comparison arms showing zanubrutinib association with prolonged progression-free survival when adjusting for baseline characteristics.
Dr. Shadman transitions to discussing the second analysis comparing zanubrutinib as continuous therapy versus venetoclax-obinutuzumab fixed-duration regimen, the previously preferred approved fixed-duration option in the United States.
Dr. Brander discusses the comparison of zanubrutinib from the SEQUOIA trial with fixed-duration venetoclax plus ibrutinib from GLOW and CAPTIVATE studies, examining patient populations and study design relevance.
Dr. Mazyar Shadman from the University of Washington and Fred Hutchinson Cancer Center and Dr. Danielle Brander from Duke Cancer Institute introduce their discussion on interpreting matching adjusted indirect comparisons (MIACs) to inform first-line chronic lymphocytic leukemia (CLL) treatment decisions. The focus centers on how recent comparative analyses help clinicians choose between continuous BTK inhibitor therapy versus fixed-duration venetoclax-based therapies in clinical practice.
Dr Shadman discusses an indirect comparison evaluating zanubrutinib vs acalabrutinib plus venetoclax in chronic lymphocytic leukemia.
Mazyar Shadman, MD, MPH, discusses a post hoc analysis that compared data BTK inhibitor–based regimens for treatment-naive chronic lymphocytic leukemia.
Experts discuss advancements in CLL treatment, highlighting pirtobrutinib's role and the potential of CAR T-cells and bispecific therapies.
Experts discuss the role of MRD testing in CLL treatment, emphasizing personalized approaches and the importance of continuity in patient care.
Experts discuss the impact of real-world data on CLL treatment sequencing, highlighting survival outcomes and the importance of targeted therapies.
Explore the latest insights on venetoclax retreatment effectiveness and its impact on patient outcomes in chronic lymphocytic leukemia therapy.
Experts discuss the implications of recent studies on pirtobrutinib, comparing its efficacy and safety against other BTK inhibitors for CLL treatment.
Experts discuss strategies for selecting second-line therapies in CLL, emphasizing treatment history, patient response, and genetic factors.
Experts discuss the balance of safety, efficacy, and logistics in treatment choices, highlighting the evolving landscape of BTK inhibitors and patient preferences.
Experts discuss the importance of patient-specific factors and preferences in selecting first-line treatments for CLL.
Experts discuss evolving treatment strategies for CLL, highlighting the balance between time-limited and continuous therapies for optimal patient outcomes.
Explore the evolving treatment landscape for Chronic Lymphocytic Leukemia, focusing on BTK and BCL2 inhibitor strategies and biomarker testing insights.
Mazyar Shadman, MD, MPH, details the rationale for investigating the combination of zanubrutinib and venetoclax in treatment-naive CLL/SLL.
Panelists discuss how sequencing therapy after covalent Bruton tyrosine kinase (BTK) inhibitor progression involves choosing between noncovalent BTK inhibitors like pirtobrutinib or venetoclax-based therapy, with the traditional approach favoring venetoclax second-line followed by pirtobrutinib third-line based on available data, while acknowledging that current studies reflect heavily pretreated patients and may not represent the superior outcomes expected in earlier-line settings, and highlight promising early results from zanubrutinib plus venetoclax combinations showing 96% overall response rates and high undetectable minimal residual disease rates in phase 1 studies.
Panelists discuss how Bruton tyrosine kinase (BTK) resistance mutation testing is routinely performed at disease progression, but currently doesn’t change treatment decisions because pirtobrutinib shows comparable efficacy regardless of mutation status. However, high-level mutations (C481S or L528W) might favor venetoclax-based therapy over pirtobrutinib in second-line treatment. The panelists also emphasize the importance of patient education; approximately one-third of progressive patients lack detectable resistance mutations yet still require treatment changes based on clinical progression rather than molecular findings.
Panelists discuss how early data from the REVENGE trial show encouraging results for venetoclax retreatment in patients who relapsed more than 2 years after completing fixed-duration venetoclax-obinutuzumab therapy, with most patients achieving excellent responses, including undetectable minimal residual disease, while acknowledging that treatment approaches after progression on oral acalabrutinib-venetoclax doublets remain a “data-free zone” requiring extrapolation from existing venetoclax retreatment studies and resistance mutation testing to guide therapeutic decisions.
Panelists discuss how biomarker retesting at relapse should include cytogenetics and fluorescence in situ hybridization to detect clonal evolution, Bruton tyrosine kinase (BTK) resistance mutations in patients progressing on BTK inhibitors, and molecular panels to identify new mutations that may predict transformation risk. Real-world registry data demonstrate that venetoclax-based therapy remains highly effective after BTK inhibitor progression, with progression-free survival of 30 to 35 months, providing crucial benchmarks for treatment sequencing decisions in the absence of prospective clinical trial data.
Panelists discuss how managing chronic low-grade BTK inhibitor (BTKi) toxicities like myalgias and palpitations requires individualized decision-making that considers the patient’s response quality, treatment duration, and quality-of-life impact, with options including treatment holidays (given median time to next therapy of over 2 years after stopping), switching to different second-generation BTKi if on ibrutinib, or transitioning to venetoclax-based therapy for patients who cannot tolerate continued BTK inhibition despite achieving good responses.
Panelists discuss how real-world data from retrospective studies show that second-generation Bruton tyrosine kinase inhibitors (BTKi) have lower rates of hypertension compared with ibrutinib, and surprisingly reveal that patients treated with venetoclax-obinutuzumab continue to experience serious infections requiring hospitalization at rates of approximately 10% even 12 to 36 months after completing fixed-duration therapy, which is higher than the 6% rate seen in patients on continuous BTKi therapy and challenges assumptions about infection risk resolution after treatment completion.
Mazyar Shadman, MD, MPH discusses future research avenues based on findings from arm D of the SEQUOIA trial in CLL/SLL.
