Overview of First-Line CLL Treatment Strategies

Dr. Mazyar Shadman introduces the program on first-line CLL therapy in the era of BTK inhibition, joined by Dr. Andrew Lipsky. The discussion covers key data shaping early-line therapy, patient and disease-specific factors influencing therapy selection, clinical considerations for BTK inhibitor (BTKi) selection, real-world challenges in long-term management and treatment sequencing, and areas of evolving clinical practice.

Dr. Lipsky outlines the two major therapeutic strategies for frontline CLL in 2026. The first is indefinite continuous therapy with a second-generation covalent BTKi, specifically zanubrutinib or acalabrutinib, representing the most established approach with the longest follow-up data.

The second strategy is time-limited treatment, planned from the outset to stop after a defined number of cycles (typically 12-14). In 2026, time-limited treatment is BCL-2 inhibitor-based with venetoclax as the backbone, combined with either obinutuzumab or a BTKi such as acalabrutinib or zanubrutinib.

Dr. Shadman addresses biomarker testing recommendations, advising testing at diagnosis rather than waiting until treatment is needed. The essential panel includes FISH (fluorescence in situ hybridization), karyotype, IGHV mutational status, and TP53 mutational status via next-generation sequencing. IGHV mutational status is stable over time and requires testing only once, while other markers are dynamic and should be repeated after each line of therapy.

He emphasizes that having molecular data at diagnosis enables understanding of disease prognosis, prediction of time to first treatment, and eligibility for early intervention clinical trials for patients with high-risk disease. At minimum, FISH, karyotype, and molecular studies for IGHV and TP53 mutational status are required before initiating treatment.