Dr Danilov on Considerations in Frontline Treatment Selection for CLL

"For the previously untreated CLL, we currently have two big choices. One is continuous therapy with BTK inhibitors, and the second is time-limited therapy with venetoclax-based tablets."

Alexey Danilov, MD, PhD, the Marianne and Gerhard Pinkus Professor of Early Clinical Therapeutics, medical director of the Early Phase Therapeutics Program for the Systems Clinical Trials Office, co-director of the Toni Stephenson Lymphoma Center, and a professor in the Division of Lymphoma in the Department of Hematology & Hematopoietic Cell Transplantation at City of Hope, discussed how recent trial data have influenced frontline treatment selection for patients with chronic lymphocytic leukemia (CLL) in 2025.

At the 9th Annual Live Medical Crossfire: Hematologic Malignancies meeting, Danilov explained how within the current treatment paradigm, most patients with previously untreated CLL are offered one of two general approaches: continuous therapy with a BTK inhibitor or time-limited therapy with venetoclax (Venclexta)–based regimens. BTK inhibitor–based strategies typically involve acalabrutinib (Calquence) or zanubrutinib (Brukinsa), both of which have largely supplanted ibrutinib (Imbruvica) in clinical practice due to a more favorable safety profile.

For time-limited approaches, venetoclax combined with obinutuzumab (Gazyva) remains a preferred option based on findings from the phase 3 CLL14 study (NCT02242942), Danilov said. However, emerging data from the phase 3 AMPLIFY study (NCT03836261) have expanded this section of the treatment paradigm by evaluating the combination of acalabrutinib plus venetoclax with or without obinutuzumab. These combinations generated improved progression-free survival compared with chemoimmunotherapy, further supporting the move away from cytotoxic regimens.

With these developments, oncologists now have 3 evidence-based strategies for first-line therapy in CLL: continuous BTK inhibition with acalabrutinib or zanubrutinib; fixed-duration venetoclax plus obinutuzumab; and triplet therapy incorporating BTK inhibitors, venetoclax, and anti-CD20 monoclonal antibodies. Danilov noted that although ibrutinib is still available, it is less frequently used due to concerns over toxicity and other off-target effects.