William G. Wierda, MD, PhD: So, Matt, maybe we can start with you in terms of relapsed disease. What are the things that you use to trigger treatment for relapsed patients, and what factors are you evaluating at the time of relapse, treatment for relapsed disease?

Matthew S. Davids, MD, MMSc: I think a very important consideration is that we sometimes can see early signs of relapse, and this does not necessitate restarting therapy for CLL. We still use the same iwCLL criteria that we use at initial diagnosis to wait, and some patients can be observed sometimes for long periods of time, months or even years, after they’ve shown signs of progression. But once patients do meet either BCL criteria for treatment again, then there’s a number of different considerations. Of course, the usual ones we talked about already. In the frontline setting, age and comorbidities and so forth. And of course, as we’ve discussed, the FISH status can change. So we can’t assume that patients who are 13q prior to their initial therapy still have that marker. We always need to recheck the FISH test in that situation. As I mentioned before, IGHV is a stable test so we don’t typically need to repeat that.

And the other thing that’s important, I think, in terms of determining what the next therapy is, how long did they respond to the prior therapy? Some patients do get very durable response from chemoimmunotherapy, but then relapse 5 or 6 years later. And that is a population where we could consider potentially rechallenging them with chemoimmunotherapy. But I think if we’re going to do that, we have to counsel patients that the likelihood of a durable response, a second time to chemoimmunotherapy, is relatively low. There’s increased risks of myelosuppression and significant infections, and probably an increased risk of myeloid malignancies. So, I think that in general for most patients, we would move to a novel agent-based approach in the relapsed/refractory setting.

William G. Wierda, MD, PhD: So, there are 2 large randomized phase III trials that are being presented at ASH this year. And maybe we can start with Steve. You can comment on the DUO study, which is a randomized trial looking at a novel new PI3-kinase inhibitor, and maybe review that kinase inhibitor for us and what the results were from the DUO study that was presented here.

Steven Coutre, MD: The DUO study uses duvelisib, and duvelisib is a combined delta/gamma inhibitor. So, it was one of the early PI3-kinase delta inhibitors following behind idelalisib. And my read of it is that it’s very similar to idelalisib. In other words, very active drug, as idelalisib is, but I think there are similar toxicities in terms of either the potential for colitis or diarrhea. I think in their study, they mandated certain anti-infectious prophylaxis like pneumocystis, and so that would explain why perhaps they don’t see that as coming out of the idelalisib experience. Remember, the other place we saw very significant idelalisib toxicity was in the upfront setting, the young patients, from Matt’s institution. And those, of course, aren’t the subject of the DUO trial. So, it’s a nice randomized trial. It’ll probably lead to approval of the drug on that basis. But I think you have to really respect the toxicity of this agent to decide where and when you want to use it.

William G. Wierda, MD, PhD: Matt, you and your group have worked on PI3-kinase inhibitors. Idelalisib is a delta inhibitor. There are other inhibitors. Maybe you can comment on the potential difference between the gamma/delta versus delta isoform.

Matthew S. Davids, MD, MMSc: There are actually 4 isoforms of PI3 kinase: Alpha, beta, gamma, and delta. And there’s now a range of different inhibitors. Of course, in solid tumors, folks may be familiar with some of the pan-PI3-kinase inhibitors that have been explored there. But in CLL, we started by looking at delta-specific inhibitors like idelalisib, which subsequently got approved. More recently actually, there is an alpha/delta inhibitor that has been approved, copanlisib, in indolent non-Hodgkin lymphomas. It hasn’t been explored as widely in CLL. It’s also an interesting agent. There’s duvelisib, which we just discussed. And I think another exciting agent is a drug that was just recently named umbralisib, formerly TGR1202.

And at this ASH meeting, I’m presenting a poster on the safety of this drug across different studies in 350 patients. And I would say, based on that dataset, that this drug does seem to have a differentiated safety profile compared to the other PI3-kinase inhibitors. We are seeing fewer of the immune-negated toxicities, like transaminitis and colitis. There’s a reasonable number of patients now out past 1 year on treatment, so I think that that’s a really strong signal. I think that that’s the type of drug that’s being explored also in randomized phase III trials now, and if those also look promising, that can also be headed toward an approval.

Transcript Edited for Clarity