William Wierda, MD, PhD: Well, this has been a great discussion. We’ve covered a lot of topics, and I think what I’d like to do is conclude by asking my colleagues what they’re most excited about in CLL [chronic lymphocytic leukemia], what they’re most excited about in terms of what we’ve seen at ASH [the American Society of Hematology annual meeting] 2019, and also what they think might be practice-changing that was presented at this meeting. This meeting is where most of the new data get presented, and occasionally they are practice-changing. We’ll start with you, Carolyn, in terms of what you’re most excited about that was presented here and what you think might be practice-changing.

Carolyn Owen, MD: I think I’m most excited by the longer follow-up for the MURANO study. In Alberta, we already thought that a finite duration of therapy would be good. Again, I’ve mentioned we’re in a setting of a publicly funded healthcare system, so we tend to use a lot of chemoimmunotherapy frontline, which I still think is a good option for many patients. But there was a lack of certainty as to how long those remissions would remain. We have much longer data with ibrutinib. The data with ibrutinib still look excellent in terms of the longer follow-up, which is always shown at the meetings. But I do think that the MURANO, that PFS [progression-free survival] curve, more than 50% of patients still without progression at the 4-year mark, is very impressive. I think that that’s what I’m most excited about.

From a practice-change perspective, acalabrutinib is going to become available, and I’d really like to see with the ongoing data, I’d like personal experience as well. I’ve treated only a few patients with the drug, and if it proves to be more tolerable, then it would be excellent to have another good option for patients. Because BTK [Bruton tyrosine kinase] inhibition is such an important part of the management of CLL, it’s nice to get more options and hopefully more tolerable options.

William Wierda, MD, PhD: That’s great. Dr Ma.

Shuo Ma, MD, PhD: I think the most exciting things to me are: 1) is the next-generation BTK inhibitor that can potentially overcome the known resistance mechanism, the next-generation PI3 kinase inhibitor that has a better toxicity profile, and then the CAR [chimeric antigen receptor] T-cell therapy that can overcome potential novel agent resistance. And then in terms of practice-changing, I think the novel/novel combination is still a little bit early, but the data look so great, for example, the ibrutinib plus venetoclax combination.

That question is being tested in several ongoing large clinical trials. For example, in the United States, the ECOG study for younger patients, the Alliance study for older patients, having similar designs combining ibrutinib plus obinutuzumab with or without venetoclax, so looking at triple combination versus a double combination, whether there’s any clinical benefit.

I think I like the German study design better, the CLL17 study, which is comparing what we’re using as the standard of care targeted therapy design nowadays. One arm is ibrutinib alone, the second arm is venetoclax plus obinutuzumab, and then a third arm is ibrutinib plus venetoclax. That’s really going to tell us whether the double targeted therapy combination, how does it compare to the known standard of care therapy.

William Wierda, MD, PhD: Great. Stephen.

Stephen Opat, MBBS: I think the ASCEND study, with the addition of obinutuzumab to acalabrutinib, it challenges the paradigm that adding an antibody to a BTK doesn’t add anything. I think that while it might be ready for clinical application, it’s actually a change in the way we think about combining agents. I think now we have many different strategies. I like the CLL17 comparing them up front. We still have to work out whether it’s best to give all these drugs sequentially or concurrently, and from some of our colleagues treating for myeloma, they tend to suggest giving all your active agents together may be the way to go.

I’m impressed by MURANO and for many patients, I think the point is that most patients with CLL will respond to whatever therapy and they will have a durable disease control with good disease tolerability. There’s only a small number of patients, perhaps those with deletion 17p, who we select for in the trials that really are the problematic cases. I think the overall story is good, and it’s going to be getting harder and harder to show improvements for this smaller number of patients who have difficult disease.

William Wierda, MD, PhD: I would agree with everything that’s been said. I’m most excited about the combinations, the prospect of getting most of our patients into good, deep MRD [minimal residual disease]-negative remission and a treatment-free interval, and we’re seeing that now with the newer combinations. I was happy to see the longer-term follow-up with venetoclax-based therapy. I think that makes people think more about the fixed-duration concept and will bring that concept forward. I liked to see the MURANO update and the CLL14 update.

I would agree with Carolyn in terms of acalabrutinib and also with zanubrutinib, the emerging irreversible inhibitors, next-generation irreversible inhibitors coming in to the forefront. I think probably that will be potentially practice-changing. We will have the option of acalabrutinib, zanubrutinib, and we’ll need to figure out how we’re going to make that decision and select treatment. The thing that I’m thinking about a lot now is unmet needs for our patients. They still have risk for infection, they still get second malignancies, and we’ve seen that even in patients who are getting very deep remissions. So, I think that’s an area, having an understanding of immune function and the immune system in patients with CLL is a big knowledge gap right now, and how we can fix that because our patients are living longer.

We don’t want them getting infections, we don’t want them dying of infections or dying of second cancers. And we still see a small population of patients getting Richter transformation. I think that still is an unmet need, studying and understanding and knowing how to better treat Richter transformation. But it’s been a great meeting. It’s been a great year for CLL I think, and we’ve made a lot of progress. So, thank you. Thank you all. Thank you on behalf of our panel. We hope that you found this Peer Exchange a useful and informative activity.

Transcript Edited for Clarity