Resistance to Venetoclax in CLL

Transcript:William G. Wierda, MD, PhD: Let’s move on to venetoclax resistance. Matt, I think you were at the late-breaking session. There was a discussion about venetoclax resistance and the mechanism of resistance for venetoclax. We know a little bit about ibrutinib. We’ll talk about that next, but you can touch on the venetoclax resistance mechanisms that have been discussed and the data that were presented here?

Matthew S. Davids, MD, MMSc: This was a very exciting presentation from the Australian group where they were able to examine 15 samples from patients who had pretreatment samples and then a sample at the time of disease resistance. And these were all patients progressing with CLL [chronic lymphocytic leukemia], not with Richter syndrome. They were able to identify a mutation in BCL2, a G101V mutation, which is actually around the site where venetoclax binds. And so, in 4 patients they identified this at a fairly high fraction of the cells and were able to then go back into the laboratory and do a bunch of functional studies to show that cells that have this mutation are quite resistant to venetoclax.

And so, it does seem to have functional significance, and once they knew about this, they were able to use even more sensitive sequencing techniques to detect the mutation in 4 other patients in that same 15-patient cohort. So 8 of the 15 had this mutation at least at some level. They were actually able to detect it, in many cases, several months before there were even signs of MRD [minimal residual disease] detectability and eventual clinical progression.

I think that this is going to be part of the story for venetoclax resistance. It certainly has important implications in terms of how we tackle treating these patients because there are other resistance mechanisms that we’ve clearly thought about. And these include other pro-survival proteins like MCL1, a protein that’s now being drugged, and there are several different drugs in development. So, if you had a patient with a BCL2 mutation on venetoclax and that was the cause of resistance, and you added an MCL1 inhibitor, it’s probably not going to do very much. Whereas, other patients, like the other 7 patients, don’t have this mutation. Maybe they’re more reliant on MCL1, and those are the patients who might benefit from an MCL1-directed therapy. So these are very early data. The numbers are small, and I think this needs to be validated in other independent data sets. But, certainly, if this holds up, it’s going to have major implications for how we approach venetoclax resistance clinically in the future.

Susan M. O’Brien, MD: Although it’s interesting and this has come up before with ibrutinib in terms of, as you and I were discussing, if you have to do deep sequencing to detect the clone and the patient is already resistant to venetoclax, you have to think that there’s more to the story, right?

Matthew S. Davids, MD, MMSc: Absolutely.

Susan M. O’Brien, MD: Because if it’s such a small clone, how can it be contributing to florid clinical resistance?

Matthew S. Davids, MD, MMSc: And they’re not mutually exclusive either, so patients can have multiple resistance mechanisms in the same cell.

Alexey V. Danilov, MD, PhD.: Well, it’s interesting. Although the published data so far does not point to a single mechanism of resistance, there are data that the BRAF pathway is mutated, a CDKN2A. You mentioned upregulation of MCL1. In mantle cell lymphoma, there is clear contribution of the PI3K signaling pathway. It seems to me there is not a single pathway that seems to be implicated in venetoclax resistance so far. It may be more of a mosaic. I agree with your point, Susan. The allele burden is also a very interesting point. In the ibrutinib setting, Steve Treon, MD, PhD’s, group published a paper where they looked at how the BTK [Bruton tyrosine kinase]-mutant CLL cells, or Waldenstrom cells, might make other bystander cells resistant to ibrutinib. I wonder if the same will be happening with this venetoclax clone.

Matthew S. Davids, MD, MMSc: It’s possible. And the Australian group did show a different kinetics of growth for these clones with the mutation. They were growing much faster, so they do surmise that even though they are low allele fraction initially, that might be growing over time and at later time points may be clinically significant.

Transcript edited for clarity.