Managing Venetoclax Resistance in CLL

Matthew S. Davids, MD, MMSc, Dana-Farber Cancer Institute, Boston, Massachusetts, discusses venetoclax resistance in CLL and how to manage patients who become resistant to the drug.

Transcript

I'm Dr. Matthew Davids. I'm the Associate Director for the Center for Chronic Lymphocytic Leukemia at the Dana-Farber Cancer Institute and an assistant professor of medicine at Harvard Medical School, both in Boston.

I'm here at the 2019 Lymphoma & Myeloma meeting in New York City. Today I was tasked with the job of talking about resistance to the BCL2 inhibitor drug venetoclax and also how to manage patients who become resistant to venetoclax.

This is an area that we haven't known much about until recently, but over the last year, there's been a new mutation identified in BCL2 that actually makes the patients resistant to the drug. This was found in patients who had been on long-term venetoclax monotherapy but has actually not yet been discovered in patients who have been on combination time-limited venetoclax approaches.

We also think there's other mechanisms that may contribute to venetoclax resistance, in particular functional issues with other anti-apoptotic proteins, such as MCL1, which has recently been shown to be overexpressed in venetoclax progressors, as well as amplification of AMP-1, which can affect the OXPHOS pathway in mitochondria.

In the second part of my talk, I went into possible ways to overcome these deficiencies and resistance patterns. I focused on the development of novel BH3 mimetic drugs that target other anti-apoptotic proteins. These include Bcl-xL and MCL1 inhibitors as well as indirect ways to modulate MCL1, such as oral CDK9 therapies.

We're optimistic that we can use some of the novel tools from the lab, including a technique called BH3 profiling to help identify specific anti-apoptotic proteins that patients depend on for their survival. If we can target those more effectively with these newer drugs, we can actually potentially overcome venetoclax resistance. This is something we'll hopefully be able to explore in prospective clinical trials moving forward.