Transcript: William G. Wierda, MD, PhD: Let’s talk a little bit about prognostic factors and…so if we’re transitioning into a BTK [Bruton tyrosine kinase]—based frontline treatment scenario, who are you thinking about as high-risk patients now, Susan, compared [with] what we were thinking about in terms of chemoimmunotherapy-based treatments?

Susan M. O’Brien, MD: I guess you could define high-risk for risk of toxicity or high-risk for early progression or not a prolonged response. That’s really hard to say because we know now even in the—I mean, we always would call 17p deletion high-risk historically, or p53 mutation. And certainly, in the phase II trial with ibrutinib, where those patients were previously treated with chemotherapy, that group had the shortest progression-free survival in the relapsed setting of about 26 months.

That being said, the limited data that we have, I would say the biggest data source were frontline 17p with ibrutinib comes from Adrian Wiestner’s [,MD, PhD,] group because they had a trial directed at patients with 17p deletion or p53 mutation, as well as older patients. And so they have the biggest cohort. We have to; you know it’s a difficult cohort to get because on any given trial, they’re very rare, because we know 17p deletion is an uncommon abnormality in a frontline population, rather a much more common abnormality if patients become relapsed and refractory.

So when you look at his data for 17p-deleted patients who are getting ibrutinib up front, before your progression-free survival, [it’s] something like 80%. I mean, it’s really amazing for what we would have considered a really high-risk group before.

So I think it’s becoming hard in the up-front population to define a really high-risk group, and I think that’s partly based on the fact that we have limited ibrutinib frontline follow-up, really limited. So as time goes on, I expect that when we, as the patients continue to relapse slowly off the frontline trials, then when we have a big enough cohort of actually patients relapsing on frontline trials, then we’ll be able to look at that population—who…got maybe 3 years instead of, I don’t know, 7 years or whatever. It’s not totally clear to me what that population is going to look like, but I think it’s hard for me to define a priority of a really high-risk-outcome group with ibrutinib.

Alexey V. Danilov, MD, PhD: So I think the highest group is patients for whom I would never use chemoimmunotherapy, and even though Anthony said he wouldn’t use bendamustine in patients with p53 mutations, deletion 11q, NOTCH1—so any of these high-risk patients. So I think of it now as a high-risk CLL subgroup for whom I would for use a novel agent. But within the novel-agent category, I agree with Susan. And there [are] less data now on what to call this patient.

Matthew S. Davids, MD, MMSc: I think to me, also where the high-risk markers come into play, as we talk about combination approaches with the novel agents, that’s really the group. To get to Anthony’s point from before, those are the patients who may benefit the most from these combinations like ibrutinib, venetoclax, maybe with a CD20 antibody, rather than the sequential monotherapy strategy. We don’t know that for sure, but that’s my suspicion, especially for those young patients who may have high-risk disease, I think moving toward a novel agent combination strategy makes sense.

Transcript Edited for Clarity