Update on the role of venetoclax and rituximab in the treatment of relapsed or refractory CLL

Abstract

For the treatment of mature B cell malignancies including chronic lymphocytic leukemia (CLL), the last 5 years has brought major advances in the application of targeted therapies. Whilst monoclonal anti-CD20 agents such as rituximab have a central role in combination with traditional cytotoxic therapy, their combination with novel agents that target the B cell receptor signaling pathway and other intracellular mechanisms of B cell proliferation is a new approach to treatment. Venetoclax is a highly specific novel agent inhibiting the bcl-2 anti-apoptotic pathway and has potent activity in CLL. Its combination with rituximab results in deeper and more durable responses and this regimen is a valuable option in the treatment of relapsed or refractory CLL including adverse prognostic variants such as cases that are fludarabine refractory or harbor the 17p chromosomal deletion. This review centers on the use of venetoclax and rituximab in relapsed or refractory CLL.

Discovery of Small Molecule Bak Activator for Lung Cancer Therapy

“…Synergistic drug combinations can be rationalized using knowledge of single-drug action mechanisms. Venetoclax (ABT-199) is an FDA-approved selective Bcl-2 inhibitor for the treatment of CLL and AML 11 , 12 , 63 , 64 . However, venetoclax has limited potency in the treatment of lung cancer.…”

“…Indeed, the BH3-mimetic specific Bcl2 inhibitor venetoclax (ABT-199), designed to selectively bind and inhibit Bcl-2 protein, has been approved by the FDA for the treatment of patients who have relapsed or refractory chronic lymphocytic leukemia (CLL) with a genetic abnormality known as 17p deletion. However, there remains a small proportion of patients, in the range of 15-25%, who develop venetoclax failure with either venetoclax monotherapy or the venetoclax/rituximab combination 11 , 12 . In addition to CLL, clinical trials have demonstrated the clinical benefit of venetoclax-based therapies in newly diagnosed acute myeloid leukemia (AML), leading to the recent FDA approval of venetoclax in combination with hypomethylating agents or low-dose cytarabine for older adults with newly diagnosed AML 13 .…”