Dr. Danilov on the Need to Identify Novel Pathways in CLL

Alexey V. Danilov, MD, PhD, associate director, Toni Stephenson Lymphoma Center and professor, Division of Lymphoma, Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, discusses the need to identify novel pathways for targeted therapy in chronic lymphocytic leukemia (CLL).

The treatment landscape has shifted dramatically in CLL to phase out chemoimmunotherapy and integrate targeted therapy for most patients, Danilov says. Although targeted therapies, such as BTK inhibitors and BCL2 inhibitors, have improved patient outcomes, they present unique challenges.

Most notably, patients receiving targeted therapy often develop resistance to these novel options, Danilov explains. The resistance may be mediated by mutations in BTK, which prevents targeting with ibrutinib (Imbruvica) or acalabrutinib (Calquence), or in BCL2, which prevents targeting with venetoclax (Venclexta).

However, several therapies are being developing that could potentially overcome this resistance. For example, noncovalent BTK inhibitors that bind to BTK C481S mutations could overcome BTK inhibitor resistance. Agents targeted toward MCL1 and BCLX could have utility as well because these alternative prosurvival family members of BCL2 could be activated and account for resistance to venetoclax, Danilov concludes.