Unpacking Controversies in CLL Treatment

At The HemOnc Pulse Live! held in Austin, TX in May 2025, Ryan W. Jacobs, MD, clinical director of the Lymphoma Division and an associate professor of medicine at Atrium Health Levine Cancer, Wake Forest University School of Medicine, delivered an in-depth presentation on the evolving treatment landscape for chronic lymphocytic leukemia (CLL). Drawing on the latest findings presented at the American Society of Hematology (ASH) Annual Meeting, Dr. Jacobs highlighted key advances, clinical trial updates, and ongoing debates in frontline and relapsed settings.

The presentation opened with a review of CLL treatment history, moving from traditional chemoimmunotherapy to the groundbreaking introduction of BTK inhibitors as indefinite therapy, which remains a dominant approach. Dr. Jacobs contrasted this with the underutilized yet highly effective venetoclax-based regimens, particularly in combination with obinutuzumab, which offer fixed-duration therapy and long treatment-free intervals. He explained how oral doublet and triplet regimens that combine BTK and BCL-2 inhibition are poised to provide patients with more convenient and durable alternatives.

Using compelling analogies, Dr. Jacobs compared indefinite therapy to running a marathon, long and taxing, versus fixed-duration treatment as a sprint, offering patients powerful outcomes and meaningful time off therapy. He emphasized that beyond efficacy, time-limited regimens may reduce toxicity, improve quality of life, and even alleviate financial burdens.

A major focus was the AMPLIFY trial, evaluating acalabrutinib with or without obinutuzumab compared to chemoimmunotherapy. Results demonstrated a clear progression-free survival benefit with acalabrutinib, with the greatest advantage seen in patients with unmutated disease, while also highlighting the potential role of triplet therapy in deepening remissions.

Dr. Jacobs concluded by stressing the importance of tailoring therapy based on patient characteristics, disease biology, and long-term outcomes. With ongoing studies of doublets and triplets, the future of CLL care is shifting toward more personalized, effective, and patient-friendly treatment strategies.