Catherine C. Coombs, MD, is a hematologist-oncologist and associate clinical professor in the Department of Medicine of the Division of Hematology/Oncology at University of California Irvine Health.

Nicole Lamanna, MD, is a hematologic oncologist at the Herbert Irving Comprehensive Cancer Center at NewYork-Presbyterian/Columbia University Irving Medical Center

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.

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 

 mutation status continues to play an important prognostic role, even though chemoimmunotherapy has largely fallen out of favor. High-risk features, most notably 

 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.

Videos

Experts discuss evolving treatment strategies for CLL, highlighting the balance between time-limited and continuous therapies for optimal patient outcomes.

Introductions & Framework for CLL Treatment

The moderator introduces the faculty panel, experts in the management of CLL, and outlines the session’s agenda, which centers on evolving frontline treatment strategies, sequencing considerations after relapse, and future directions. The panelists begin by grounding the discussion in the core principles that drive therapeutic decisions for newly diagnosed patients with CLL.

Early dialogue emphasizes the need to evaluate a combination of biologic, genetic, and patient-specific factors before initiating therapy. Clinicians describe how markers such as 

 disruption, cytogenetic risk features, and overall disease tempo shape initial treatment choices. They also highlight the importance of balancing efficacy with tolerability, particularly in older adults or those with comorbidities. Concepts of time-limited versus continuous therapy are introduced as a central theme.

The panel addresses the major frontline classes, including covalent BTK inhibitors (BTKis) and venetoclax-based regimens, discussing how each may be favored depending on the patient’s lifestyle, cardiovascular risk profile, and preference for daily therapy versus finite treatment. They note that as evidence accumulates, clinicians increasingly incorporate real-world experience to refine the selection of optimal first-line therapy. There is also reference to the declining role of chemoimmunotherapy, setting the stage for the deeper exploration that follows in later segments.

CLL is now treated with sophisticated targeted approaches that must be personalized. Understanding frontline decision-making is essential, as choices made at diagnosis strongly influence outcomes and available pathways for subsequent treatment lines.

Explore the evolving treatment landscape for Chronic Lymphocytic Leukemia, focusing on BTK and BCL2 inhibitor strategies and biomarker testing insights.

Daniel Ermann, MD

Articles

First-Line Therapy Decisions & Risk Stratification in CLL

Introductions & Framework for CLL Treatment