The Evolving Role of BTK Inhibitors in Treating Chronic Lymphocytic Leukemia - Episode 11

The Future of CLL Management

April 16, 2020

Ian Flinn, MD: We just have a few minutes left, so I wanted to touch on some of the new combinations or new regimens that are coming out. Some of this we already talked about. We talked about ibrutinib and venetoclax, and personally I think these are very exciting data. There are different studies ongoing at different centers. Let me ask you the same question about how deep a remission you can get, whether you need to keep people on a maintenance-type approach, randomizing patients. There are some trials, such as the CAPTIVATE trial, where patients are randomized after a year or so of therapy. If they’re MRD [minimal residual disease] negative or not, whether they need to stay on therapy or not. These are really important questions.

There are also other much more smaller studies looking at 3-drug regimens such as ibrutinib with obinutuzumab and venetoclax or acalabrutinib with venetoclax and obinutuzumab. Personally, my take on this is that they show great efficacy, but it’s way too early to know whether 1 of these is better than the next and frankly way too early to know whether you need all 3 drugs or not. I mean, I look at some of these data. You compare them with the phase I studies that were done with obinutuzumab with venetoclax. The MRD negativity rate with 3 drugs versus 2, comparing the same study done in the same population, doesn’t look that radically different to me. I personally think we still have to wait and see where that plays out, whether it’s really worth doing all that or whether it should be a sequential rather than a concurrent approach and that’s going to go on.

There are data now with a new PI3 kinase inhibitor, umbralisib in combination with a CD20, ublituximab, and venetoclax in a refractory-patient population. Very high efficacy. I know they’re interested in trying to develop this in the frontline setting as well. These are exciting, important data, much better tolerated PI3 kinase inhibitors than what we’ve seen in the past. But there are really going to be many more patients that need to be studied before we’re going to know how to use that. Jan, I went through that pretty quickly because of limited time. But do you have any different take on those studies that I just mentioned?

Jan A. Burger, MD, PhD: Maybe just a brief discussion about the PI3 kinase inhibitors because we just didn’t discuss them much. At least for CLL [chronic lymphocytic leukemia], 2 of them are approved. If we imagine we wouldn’t have BTK [Bruton tyrosine kinase] inhibitors or venetoclax, then we would have probably talked a lot about the PI3 kinase inhibitors. They are effective, and they’ve been around for a few years, and their use has just been discouraged by adverse effects that are, in comparison with the other agents, more concerning. Autoimmune complications and infectious complications make them more difficult to give. And their efficacy seems to be somewhat lower when compared with BTK inhibitors and venetoclax.

But they are still a good alternative in select patients. If they’re intolerant, for example, to the BTK inhibitors, then I still sometimes use the PI3 kinase inhibitors. I’m very happy to hear that other PI3 kinase inhibitors are being developed, because we are sometimes struggling with adverse effects and intolerance to the BTK inhibitors and resistance to venetoclax. So there’s still a need to keep the PI3 kinase inhibitors in the field. They’re currently not much used, but it’s good to have that option. And if there’s a better PI3 kinase inhibitor—like the ones which you talked about, umbralisib—then that would be helpful to the field, I think, for select patients.

Maybe 1 last discussion since you brought up these combination trials. I think the role of minimal residual disease is very controversial because many of these combination trials aim for getting many patients in to MRD-negative remissions. But what we’ve also learned is that ibrutinib really gets patients into very long remissions, and patients have very good survival and best survival with the BTK inhibitors, which are agents that don’t get patients into MRD-negative remission. What we are traditionally coming from is this belief that only MRD-negative remissions are good remissions, and only patients who have very deep remissions are doing very well. The BTK inhibitors taught us a different story, and therefore I think the role of MRD testing and the necessity to get patients in to MRD-negative remission is right now quite controversial.

Ian Flinn, MD: Well, I appreciate that. I want to close by just mentioning 2 other therapies that are out there. Zanubrutinib of course is approved for mantle cell lymphoma but not yet approved for CLL. It has some of the same properties we talked about with acalabrutinib, perhaps a cleaner adverse-event profile. But we’ll need to see some comparative data. There is a randomized trial going against ibrutinib, and that will be important to know.

And finally, CAR [chimeric antigen receptor] T cells. We saw this year in mantle cell lymphoma—not CLL, but in mantle cell lymphoma—really encouraging data. For CAR T cells, the earliest publications were in CLL, and then it was lost for a number of years. Mostly because with these other therapies, it’s hard to know whom you would want to put at risk. I think, though, there are also other problems about the fitness of T cells in patients with CLL. What’s the right patient population, not too early, not too late. But you have more to come in CAR T cells in CLL. Certainly there are trials out there now ongoing, trying to investigate this again after a long hiatus.

Jan A. Burger, MD, PhD: Yeah, agree. I think with the CAR T cells, we have to stay tuned as these treatments are being improved, as safety is increased. The Seattle, [Washington], group just recently published a small series from the Fred Hutchinson Cancer Research Center, in patients who are ibrutinib resistant. They combined CAR T-cell therapy still with ibrutinib, even though patients didn’t respond that well to ibrutinib anymore. But it had a beneficial effect on the adverse effects, on the cytokine release syndrome. I think many groups are still investing into CAR T-cell therapy to improve it, to make it safer, to reduce cytokine release syndrome, and hopefully also to achieve more durable remission with the CAR T-cell products. Right now it’s something that’s still experimental, but I think we’re going to hear more about that.

Ian Flinn, MD: This has been extremely informative. Thank you, Dr Burger, for this insightful discussion. And thank you to our audience for watching this Targeted Oncology™ presentation on precision medicine. We hope you found this discussion to be useful and informative.

Transcript edited for clarity.