Dr. Marc Hoffmann from University of Kansas moderated a comprehensive discussion with Drs. Catherine Coombs, Andrew Lipsky, Sameer Parikh, and Mazyar Shadman on optimizing CLL treatment strategies in 2026. The program covered the two dominant frontline strategies: continuous covalent BTK inhibitor therapy (zanubrutinib or acalabrutinib) and fixed-duration venetoclax-based combinations including venetoclax-obinutuzumab and the recently approved acalabrutinib-venetoclax. Patient preference, molecular risk features (TP53 aberrations, IGHV mutational status), comorbidities, disease bulk, and logistical considerations collectively guide individualized treatment selection. Key data highlights included CLL14 9-year follow-up showing median progression-free survival of approximately 6 years overall and 8.5 to 9 years for IGHV-mutated patients, SEQUOIA 6-year zanubrutinib data, and the CLL17 trial confirming non-inferiority of fixed-duration regimens versus continuous ibrutinib. Sonrotoclax's emerging 98% undetectable MRD rates in combination with zanubrutinib generated substantial discussion about potential paradigm shifts. BTK degraders, CAR-T therapy, and Richter's transformation management represent exciting pipeline developments.
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.
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. Shadman reviews SEQUOIA 6-year follow-up data, highlighting that zanubrutinib monotherapy continues demonstrating high efficacy regardless of del(17p) status. Key outcomes include 74% PFS at 6 years for del(17p)-negative patients (Arm A) and 64% for del(17p)-positive patients (Arm C, 111 patients representing the largest prospective BTK inhibitor cohort in this high-risk population).
Dr. Lipsky separates high-risk biomarkers conceptually, emphasizing TP53 aberrations and IGHV unmutated status should be considered distinctly rather than aggregated. TP53 aberrations—encompassing del(17p) and/or TP53 mutation—represent the highest-risk adverse predictive biomarkers across all CLL treatment strategies.
Dr. Hoffmann frames long-term adherence as a practical challenge in continuous BTK inhibitor therapy.
Dr. Parikh summarizes the CLL17 trial: a 3-arm comparison of continuous ibrutinib, ibrutinib-venetoclax doublet, and venetoclax-obinutuzumab, all with approximately 3-year median follow-up showing no significant PFS difference between fixed-duration regimens and continuous ibrutinib.
Dr. Coombs frames sequencing philosophy around patient age and disease trajectory.
Dr. Shadman introduces sonrotoclax as a next-generation selective BCL-2 inhibitor approved for mantle cell lymphoma, with emerging CLL data in combination with zanubrutinib.
Dr. Lipsky outlines different conceptual frameworks for evaluating the 2 CELESTIAL trials.
The panel emphasizes MRD testing is not a current standard of care requirement, advising community oncologists not to feel obligated to order it outside clinical trials or high-risk treatment extension decisions.
The panel addresses two important areas not fully covered earlier.
