Evolving CLL Treatment in 2025: Optimal Strategies Explained

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, outlines the growing availability of targeted therapies, including BTK inhibitors, BCL-2 inhibitors, and anti-CD20 therapies, both individually and in combination during an interview at The 2nd Annual HemOnc Pulse Live! held in Asutin,  Texas.

The AMPLIFY trial is highlighted as a key study supporting the use of acalabrutinib and venetoclax, with or without obinutuzumab, in first-line treatment.

There is ongoing debate about indefinite treatment versus fixed-duration, or “time-defined,” therapies. For high-risk patients, such as those with a chromosome 17p deletion, indefinite BTK inhibitor therapy continues to show the longest progression-free survival. However, time-defined regimens may offer advantages in minimizing resistance, as patients often remain sensitive to retreatment if progression occurs during a treatment holiday.

Resistance mutations to both covalent and non-covalent BTK inhibitors are addressed, with mention of pertobrutinib and emerging BTK degraders as promising options for patients with double-refractory disease. Dr. Jacobs also covers the role of prognostic markers such as IGHV mutation status, which may influence treatment decisions.

Medical comorbidities, including cardiovascular disease and renal dysfunction, are described as important factors in therapy selection. Dr. Jacobs notes that patient preference plays a significant role in treatment planning, especially as more oral-only regimens become available.

Dr. Jacobs goes on to discuss therapies for difficult-to-treat CLL cases. CAR T-cell therapy and combinations such as a BTK inhibitor with CAR T during the apheresis process are discussed. Additionally, epcoritamab shows promise in the EPCOR CLL trial for heavily pretreated patients. Overall, the landscape of CLL treatment is rapidly advancing, with multiple novel strategies under investigation to improve outcomes.