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ASH 2025 | MCL1 copy number gain is a recurrent mark of venetoclax resistance in patients with CLL
Romain Guieze, MD, PhD, CHU Clermont Ferrand, Clermont Ferrand, France, discusses work that investigated the incidence of MCL1 copy number gain in patients with chronic lymphocytic leukemia (CLL) treated with venetoclax, identifying it as a marker of resistance to this agent. While BCL2 mutation is a known mechanism of resistance to venetoclax, MCL1 overexpression due to 1q locus amplification is another significant mechanism that compensates for BCL2 inhibition, with Dr Guieze suggesting the need to test for 1q amplification in clinical trials and potentially in routine practice. This interview took place at the 67th ASH Annual Meeting and Exposition, held in Orlando, FL.
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Transcript
So we know that venetoclax resistance is associated with mutation of BCL2, that is a target of venetoclax. So that we know and it is tested in the setting of clinical trials and also sometimes in the routine practice, notably when we want to restart venetoclax in certain patients, we want to re-challenge with venetoclax, we need to have this characterization. But something that has been underestimated is that we have seen in one of our previous works that some patients relapsing on venetoclax have an amplification of the 1q locus that is associated with an MCL1 overexpression, and this MCL1 overexpression actually compensates for the BCL2 inhibition and it’s another mechanism of resistance...
So we know that venetoclax resistance is associated with mutation of BCL2, that is a target of venetoclax. So that we know and it is tested in the setting of clinical trials and also sometimes in the routine practice, notably when we want to restart venetoclax in certain patients, we want to re-challenge with venetoclax, we need to have this characterization. But something that has been underestimated is that we have seen in one of our previous works that some patients relapsing on venetoclax have an amplification of the 1q locus that is associated with an MCL1 overexpression, and this MCL1 overexpression actually compensates for the BCL2 inhibition and it’s another mechanism of resistance. But to date, it was found in three, four, five patient series. So it was very rarely verified and checked across multiple series.
So we have conducted a retrospective series, including more than 70 patients relapsing on or after venetoclax. And we actually have seen, of course, the BCL2 mutation in almost a quarter of the patients. But we also saw in 29% of patients this amplification of 1q. So by now, given that we also have data showing that this amplification of 1q provides resistance in vitro, we do think that we need to check this 1q amplification using FISH assays in the clinical trials and maybe in the near future in the routine practice.
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