First-Line Therapy Decisions & Risk Stratification in CLL

The panel explores the nuances of selecting optimal first-line therapy for CLL, focusing on risk stratification, patient characteristics, and the evolving evidence base. They discuss how IGHV mutation status continues to play an important prognostic role, even though chemoimmunotherapy has largely fallen out of favor. High-risk features, most notably TP53 mutations and 17p deletions, significantly influence treatment decisions, steering clinicians toward BTK-based therapy and away from venetoclax monotherapy or regimens where depth of remission is heavily prioritized.

The panelists describe how covalent BTKi (acalabrutinib and zanubrutinib) have become dominant choices for many frontline patients due to their tolerability, continuous dosing convenience, and favorable long-term progression-free survival data. However, venetoclax-obinutuzumab remains an attractive time-limited treatment approach, especially for younger patients, those desiring fixed-duration therapy, or individuals with cardiovascular concerns that make BTK use more complicated.

The experts emphasize patient preference as a major determinant (continuity versus fixed duration) and how clinicians must be sensitive to lifestyle realities, travel burdens, and comorbidity profiles. Cardiovascular risk remains a key factor, especially in older patients who may be more vulnerable to atrial fibrillation or hypertension associated with BTKi.

They also note that despite the availability of multiple effective frontline options, sequencing strategy increasingly matters, as the selected first-line therapy determines which treatments remain most effective at relapse. The discussion transitions into how these frontline choices later influence second-line and beyond therapy decisions.