MRD and 11q Deletions in CLL

Alan Skarbnik, MD: I have the same concern about patients with 17p deletion. If by any chance patients end up being on venetoclax because of intolerability or concerns for tolerability with a BTK [Bruton tyrosine kinase] inhibitor, I tend to continue the treatment beyond the 1-year mark. The data have shown that they actually drop off pretty interestingly after the venetoclax is completed. Now, of course for the time-limited therapy, there’s the question of depth of response. If you look at the CLL14 data [phase 3 CLL14 trial] for discontinuation of treatment, it seems that the patients who had detectable MRD [minimal residual disease] tend to relapse much more often than patients who had undetectable MRD and get completion of therapy.

So, is this something that you’re generally doing for patients who are planning on stopping treatment? I’ve been trying to do a peripheral blood MRD in the patients who had venetoclax at the end of the 1-year mark to see if I would continue the treatment or not at that point.

And a second question would be what we do for the patients with 11q deletion. As we see with BTK inhibitors, these patients have tremendous responses. There are no head-to-head comparison data, but if you look at the curves, it seems that the patients who have an 11q deletion and take a BTK inhibitor tend to do even better than patients who don’t have an 11q deletion in the trials. So, what are your thoughts about that?

Jennifer R. Brown, MD, PhD: Regarding the MRD issue, I think it’s absolutely critical, in terms of evaluating response to venetoclax/obinutuzumab. What we don’t know is whether continuing really improves their outcome, right? What we actually need for that is serial MRD data showing whether patients continue to improve. If a patient is continuing to improve as they get to their 1-year mark, I’d definitely be inclined to continue and see if they continue to improve and get to undetectable MRD. But if patients sort of stabilize and are not improving, the question is, does continuing really make a difference? We see this a little in the MURANO trial, in the relapsed venetoclax/rituximab study, where many of the patients who had high MRD who relapsed very quickly after stopping at 2 years demonstrated a rise in MRD at the end of their time on venetoclax. So, there’s still a lot we need to learn about that. But in general, I certainly do favor a MRD-guided strategy. The 1-year mark was basically chosen as a convenient duration of therapy, and I think there are probably patients who need therapy for longer than that to get to undetectable MRD.

I agree with you. Even independent of MRD, I worry about patients with 17p deletion on venetoclax. I would probably be inclined to continue them on therapy, even in the frontline setting. In a relapsed setting, I definitely continue them, especially if they’ve had prior BTK and progressed. Those are patients who I don’t think you’re likely to want to stop therapy. Most of them don’t get to undetectable MRD. Most of them don’t get to a CR [complete response]. The CR rate was only 9% in the study of venetoclax post BTK. So, they need to continue.

Now, regarding the patients with 11q deletion, that’s an interesting question. I have to say that I’m not sure I completely believe the data that reflect that they do better on ibrutinib. I definitely believe that they don’t do worse, but I feel like the curves may be converging as we get to longer times. It’s interesting. I wish we had data—I’m not aware of any—breaking out the outcomes of patients with 11q deletion treated with venetoclax. I feel that venetoclax has some similarities to chemoimmunotherapy. It achieves deep responses rapidly, and it’s time limited. Hence, we see patients with 17p deletion who do better initially. They get a deeper response, but then they relapse. So I wonder if we’re going to see the same thing with patients with an 11q deletion that we saw with FCR [fludarabine/cyclophosphamide/rituximab]. They get a better response than patients with 17p deletion initially, but they relapse earlier. I wonder if that will happen with venetoclax/obinutuzumab, which is another factor to consider in addition to the fact that maybe sometimes they do better on ibrutinib. I haven’t seen a good biological rationale for why they would do better than other patients.

Alan Skarbnik, MD: Yeah, me neither.

Jennifer R. Brown, MD, PhD: Maybe there are more unmutated. It may be the case that they have just higher levels of signaling if they’re on it.

Alan Skarbnik, MD: That’s a possibility.

Transcript edited for clarity.