iwCLL 2023 | Understanding and overcoming resistance mechanisms to novel agents used in CLL
In this interview, Stephan Stilgenbauer, MD, Ulm University, Ulm, Germany, outlines the highly specific resistance mechanisms which arise in response to treatment of chronic lymphocytic leukemia (CLL) using novel agents and which underlie the relapse observed in many patients. Understanding resistance mechanisms to inhibitors targeting BTK and BCL2 allows for rational design of novel agents and doublet or triplet treatment regimens, in the hope of overcoming this resistance. This interview was recorded at the biennial International Workshop on Chronic Lymphocytic Leukemia (iwCLL) 2023 meeting, held in Boston, MA.
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Transcript (edited for clarity)
Yes. Well, with the novel agents targeting BTK and BCL2, we have seen dramatic progress in CLL. However, many of the patients relapse after particular long time on their treatment, and we understand more and more about the resistance mechanisms underlying these relapses. And this allows us for a more rational treatment design in future trials.
So in contrast to chemotherapy, we see very specific resistance mechanisms to BTK inhibitors, mostly mutations in the target molecule BTK itself or in PLC𝛄2, the next downstream signaling molecule...
Yes. Well, with the novel agents targeting BTK and BCL2, we have seen dramatic progress in CLL. However, many of the patients relapse after particular long time on their treatment, and we understand more and more about the resistance mechanisms underlying these relapses. And this allows us for a more rational treatment design in future trials.
So in contrast to chemotherapy, we see very specific resistance mechanisms to BTK inhibitors, mostly mutations in the target molecule BTK itself or in PLC𝛄2, the next downstream signaling molecule. Now with BCL2 inhibitors, namely Venetoclax, we see mutations in BCL2, but also deregulation of other apoptosis relevant genes and a general deregulation of cell metabolism. All these mechanisms are very specific to these targeted agents, and therefore allow for the rational design of other novel agents and sequential approaches targeting these resistance mechanisms so that they can be overcome.
So with the advent of several new agents that allow long-term disease control, the question becomes should we use those sequentially, or should we possibly combine them in combination doublet or even triplet regimens? The evolution of resistance abnormalities in the CLL cells provides a basis for rational design of specific combinations or specific sequences of treatment, and the trials that are currently ongoing using doublets or triplets in comparison to single agent treatment allow for such analyzes.
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