William G. Wierda, MD, PhD: Maybe Nicole, can you comment on other chemoimmunotherapy regimens? So, we spent a lot of time on FCR (fludarabine/cyclophosphamide/rituximab). What about BR (bendamustine/rituximab) or chlorambucil or obinutuzumab?

Nicole Lamanna, MD: Yes. The efficacy, I don’t think, is certainly not as good as with FCR. But as we spoke of earlier, clearly those regimens are less myelosuppressive and easier for some of our patients who have other comorbidities to handle more aggressive chemoimmunotherapy approaches. So, bendamustine/rituximab became the most popular regimen over the past couple of years before the TKIs became available, versus FCR for the physicians who weren’t comfortable with the enhanced cytopenias and myelosuppression in FCR. Certainly, I think you can use that as an alternative treatment option.

Now whether or not we’re going to pursue looking at similar approaches with BR and TKIs, probably not. We’ve seen a lot of data in the relapsed/refractory setting where when bendamustine/rituximab and chemoimmunotherapy regimens were so widely used in the relapsed refractory setting, we just started adding ibrutinib, idelalisib, or other TKIs in the relapsed/refractory setting because many patients were getting BR and relapse. I don’t think you see a lot of use of that type of combination any more in the relapsed/refractory despite the HELIOS study and so on and so forth.

Whether or not that people are going to move that upfront, I’m not so sure. I think that it’s important for the trials that we’re all involved with to do similar to what you were doing, or other groups are looking at how to truncate. If we’re going to use some chemoimmunotherapy because we’re looking at MRD and how durable responses will last, and then whether or not you can reinitiate a TKI or a BCL-2 inhibitor upon relapse of the MRD, will that alter their disease or the biology? I think those are important strategies ultimately looking at whether or not you can cure somebody. I think those are important alternative strategies. Right now, I don’t think that’s practical to do in mainstream until we have that data. But certainly, as Steve said, using obinutuzumab and chlorambucil as alternative strategies in older frailer patients who you don’t think can take ibrutinib or a TKI for some reason, I think is OK. But I think we’re going to see movement away from some of the chemoimmunotherapy approaches except in certain circumstances.

Shuo Ma, MD, PhD: I think one important question in this era of the novel therapy is, is there still some role for immunochemotherapy for patients who do not have 17p deletion? I always discuss the options with a patient, so either use ibrutinib as therapy or immunochemotherapy. You never know, some patients may be actually having strong preference for the time-limited therapy. So, the appeal of immunotherapy is that it’s time limited versus an indefinite therapy with TKIs.

Nicole Lamanna, MD: So, if we can enhance that by doing a truncated version, such as what was presented, that would be great.

Matthew S. Davids, MD, MMSc: And I think that may be sufficient for the mutated IGHV patients, like the ones in your study. But in our study, we had unmutated IGHV patients who clearly benefited from the additional 3 cycles of FCR.

Nicole Lamanna, MD: And that might be needed.

Matthew S. Davids, MD, MMSc: Yes, and it might be needed for that group. But I think ultimately, it would be great if we had a chemotherapy-free approach for the unmutated patients that also was time limited. And there are a lot of exciting data I’m sure we’ll get to that look at that of approach as well.

William G. Wierda, MD, PhD: So, maybe Steve, first comment on if there is a role for CD20 monotherapy in CLL and what that might be, briefly. And then, we’ll move into ibrutinib and maybe you can tell us how well does it work, who are the patients at high risk, and what are some of the challenges we have with ibrutinib in the frontline setting.

Steven Coutre, MD: I think, as we all know, there used to be—probably still is—quite a lot of use of single-agent rituximab in elderly patients because it’s not chemotherapy, it’s well tolerated, and it shrinks your lymph nodes and your lymphocyte count goes down. So, for a typical elderly patient who perhaps does not always have comorbidities, it is very, very widely used in the United States. And I think ibrutinib has changed that dynamic and will continue to change it. We perhaps have a better anti-CD20 antibody of obinutuzumab, but I don’t think it’s going to shift from Rituxan to that as monotherapy. I think it’ll go more towards the oral agents. But as I mentioned, you occasionally have a patient where giving obinutuzumab, that’s what I would use, for the typical 6-month course achieves the goal in that patient.

Now with ibrutinib as a single agent for upfront therapy, the longest data we have, of course, is from our very first CLL trial after the first studies were done. And we had long-term follow-up presented at this meeting and other recent meetings. There were 31 patients in that cohort and those, in contrast to virtually any other upfront CLL study that you’ll see, including the combination regimens, were the average CLL patient. You had to be over 65. It was typical criteria for needing treatment. And I think the median age was in the early mid-70s. So that’s what you see in practice.

So, 31 patients. One patient progressed at 8 months. They had some unusual features even at diagnosis. One patient progressed somewhere like 4 to 4.5 years out. Nobody else has progressed. I had several patients on the drug for more than 7 years. It speaks to its efficacy and it speaks to its tolerability in the long term. So, that’s intriguing. And then of course we had the RESONATE-2 trial, which was really the registration trial, and that was randomized to chlorambucil. Of course, we don’t care about that. But that’s how you get it approved at the time.

What’s more interesting from that trial is, how will patients who receive ibrutinib as their initial therapy do long-term? And again, limited to age over 65. And so far, what has been reported—and there’s updates here as well—I believe there have been 4 patients who progressed. There have been other patients who’ve come off for other reasons, but 4 progressions. So, again, very intriguing to me. I think we’re changing the natural history of the disease. I think we’re going to see less 17p in relapse because we’re not using chemoimmunotherapy. And for an average CLL patient, there’s nothing wrong with managing the disease for the rest of their natural lives, even if you don’t eliminate it. After all, that’s what we mostly do with TKIs in CML. So, I think those, to me, are really, really interesting data to follow as it goes out longer.

William G. Wierda, MD, PhD: So, highly effective therapy.

Transcript Edited for Clarity