Dr Danilov on the Investigation of BTK Degraders in CLL

Alexey Danilov, MD, PhD, hematologist/oncologist, associate director, Toni Stephenson Lymphoma Center Professor, Division of Leukemia, Department of Hematology & Hematopoietic Cell Transplantation, City of Hope, discusses the investigation of BTK degraders in the treatment of chronic lymphocytic leukemia (CLL).

BTK degraders represent a novel treatment approach for patients with CLL and other hematologic malignancies, Danilov begins. The chemistry of these agents has advanced significantly, better enabling these molecules to bind to specific target proteins, Danilov says. BTK degraders are designed to transport the oncogenic protein to the proteasome, ultimately leading to the degradation of protein, thereby disrupting the oncogenic signaling, he explains.

These are small molecules that are easily administered, and many of the BTK degraders currently under investigation are oral, Danilov expands. Since BTK inhibitors are already established in the treatment paradigm for patients with CLL and other malignances, BTK degraders should have a familiar adverse effect profile compared with previous agents designed to target BTK, he says, noting that phase 1 studies will still aim to fully characterize the safety profile of these agents. Overall, the oral availability of BTK degraders, their ability to target BTK mutations, and their acceptable tolerability highlight the potential for these agents in the CLL treatment landscape, Danilov emphasizes.

Within the CLL realm, patients whose disease progresses on or after treatment with BTK inhibitors and BCL-2 inhibitors have a limited number of effective treatment options, Danilov continues. PI3K inhibitors have been tested in this setting; however, their efficacy in this context has been limited, he says. Although there are PI3K inhibitors approved for relapsed/refractory CLL, their use is infrequent due to associated toxicities, Danilov emphasizes. Therefore, BTK degraders represent a promising, emerging class of agents that could overcome resistance to BTK inhibitors, and Danilov concludes that enrolling patients in clinical trials dedicated to this class of drugs is important to expedite their development.