Dr Danilov on How to Approach Second-Line Treatment Selection for CLL

“There is now emerging data for noncovalent BTK inhibitors which are now approved in the second-line [for patietns with CLL]”

Alexey Danilov, MD, PhD, associate director for Clinical Services, 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 at City of Hope, discussed how to navigate treatment selection for patients with chronic lymphocytic leukemia (CLL) who have received time-limited, venetoclax (Venclexta)-based regimens in the frontline setting. Danilov also touched on emerging therapies in the CLL field that might become viable options and affect treatment sequencing for this patient population in the future.

Danilov kicked off the conversation by highlighting that the expanded FDA indication for the noncovalent BTK inhibitor pirtobrutinib (Jaypirca) now includes patients who have have previously received a covalent BTK inhibitor, making this a potential option for patients who received a regimen such as acalabrutinib (Calquence) plus venetoclax as first-line therapy. Although time-limited venetoclax-based regimens can lead to long-term remissions for patients with CLL, Danilov explained that for patients who experience relapse on venetoclax-based regimens, class switching is a potential option.

Danilov then noted that it is becoming increasingly important for clinicians to emphasize personalized treatment regimens based on the genetic characteristics of patients with CLL. For example, although patients harboring BTK C481mutations may experience added benefit with pirtobrutinib, other BTK mutations such as C474I and L528W can drive resistance to pirtobrutinib and other noncovalent BTK inhibitors, he added. Danilov mentioned that knowing the genetic characteristics of patients in addition to how certain characteristics interact with treatments is crucial to second-line treatment selection.

Ultimately, Danilov concluded by looking to emerging treatments that may become second-line options for patients with CLL in the future like BTK degraders, bispecific antibodies, and next-generation BCL2 inhibitors. As data continue to emerge for these novel classes of agents, additional treatment sequencing considerations will be needed.