Exploring Why Venetoclax and Ibrutinib Have Synergy in the CLL Population

William G. Wierda, MD, PhD, D. B. Lane Cancer Research Distinguished Professor, section chief of Chronic Lymphocytic Leukemia, and center medical director in the Department of Leukemia, Division of Cancer Medicine, and executive medical director of The University of Texas MD Anderson Cancer Center, discusses the synergy between ibrutinib (Imbruvica) and venetoclax (Venclexta) in patients with chronic lymphocytic leukemia (CLL).

Ibrutinib, a Bruton’s Kinase inhibitor (BTK), inhibits a molecule that is downstream of the B-cell receptor–signaling pathway, BTK. It was approved for use in patients with relapsed disease first and then as frontline treatment in CLL. Wierda says it is very effective and active, including in patients who have been considered high-risk; these patients are defined as those who harbor 17p deletions or TP53 mutations.

Venetoclax is also a small molecule inhibitor that inhibits BCL-2. When patients’ CLL cells are exposed to venetoclax and BCL-2 is inhibited with this agent, it pushes the cells into apoptosis and causes cell death of the CLL.

Ibrutinib is very effective at managing this disease, according to Wierda. Clinically, it works well in shrinking lymph node size in these patients. Many of those who respond achieve a partial response. This means there is still some measurable disease, usually in the bone marrow or blood. Wierda says venetoclax is highly effective at killing CLL cells and is very potent at killing cells in the blood and bone marrow. However, it’s less active when it comes to shrinking nodal disease.