Dr Coombs on the Need for Consensus to Define High-Risk CLL

“It's important to develop consensus related to what is high risk CLL because that affects how we monitor our patients going forward. Often, the highest-risk patients are those [who]…I would consider for a clinical trial in the early intervention setting.”

Catherine C. Coombs, MD, a hematologist-oncologist and an associate clinical professor in the Division of Hematology/Oncology of the Department of Medicine at University of California Irvine Health, discusses the importance of developing a consensus definition for high-risk chronic lymphocytic leukemia (CLL) and how this classification influences treatment strategies and patient monitoring.

Defining high-risk CLL is critical for determining optimal surveillance and therapeutic approaches, particularly in the context of early intervention and clinical trial enrollment, Coombs begins. She highlights several key molecular markers associated with high-risk disease, including deletion 17p (del[17p]) and TP53 mutations, which remain the strongest predictors of aggressive disease biology and inferior responses to chemoimmunotherapy. Additionally, patients with unmutated IGHV status are considered high risk, as they often experience shorter remission durations despite advancements in targeted therapies, she explains.

Although modern therapies have improved outcomes for high-risk patients, along with the CLL population as a whole, optimal treatment selection remains a topic of ongoing discussion in the high-risk population, Coombs continues. Coombs explains that while venetoclax (Venclexta)-based regimens, such as venetoclax plus obinutuzumab (Gazyva), provide durable remissions, patients with high-risk features tend experienced disease relapse more quickly than those without high-risk markers. Among experts, continuous BTK inhibitor therapy is widely considered the preferred approach for patients with del(17p) or TP53 mutations, given the ability to provide sustained disease control with continuous therapy. However, venetoclax-based therapy remains an acceptable option for patients who strongly prefer a time-limited approach, with the recognition that remission durations may be shorter.

The implications of high-risk classification also extend to patient monitoring. Coombs notes that patients identified as high risk require closer follow-up to detect disease progression, potentially warranting more frequent visits compared with lower-risk counterparts. She emphasizes that these patients are also ideal candidates for clinical trials evaluating novel treatment strategies.