Dr. Danilov on the Rationale to Target MCL1 and BCLX in CLL

Alexey V. Danilov, MD, PhD, associate director, Toni Stephenson Lymphoma Center, professor, Division of Lymphoma, Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, discusses the rationale to target MCL1 and BCLX in chronic lymphocytic leukemia (CLL).

MCL1 and BCLX are pro-survival family members of BCL-2, which can currently be targeted with venetoclax (Venclexta), Danilov says. When BCL-2 is inhibited for a period, it may develop dependence on these alternative family members, providing clinical rationale to evaluate targeted therapies against MCL1 and BCLX. Several direct inhibitors of MCL1 are under investigation in early phase clinical trials to establish their feasibility and understand their toxicity, Danilov adds.

Preclinical data suggest that targeting alternative BCL-2 family members, such as MCL1 and BCLX, may disrupt mitochondrial function, reprogram cell metabolism, affect oxidative phosphorylation, and sensitize lymphoid cells to venetoclax and other agents, Danilov concludes.