William G. Wierda, MD, PhD: Maybe Dr. Ma, you can comment on this. Who are the patients who may be a little bit higher risk or may be a higher risk category among patients who are receiving ibrutinib monotherapy? Are there data that indicates a particular patient population that we need to monitor more closely?

Shuo Ma, MD, PhD: Right. I think probably the most information I got was from the relapsed ibrutinib trial that analyzed relapsed/refractory patients who were treated with ibrutinib alone. That’s from the RESONATE study. So, based on subgroup analysis, the progression-free survival overall was 52 months, median progression-free survival for all patients. But if you look at some 17p deletion patients, the median progression-free survival was only 26 months. So, that’s one high-risk category. The other high-risk category is the patients with complex karyotype. For those patients, the median PFS was 33 months. So, those were significantly lowered compared to the rest of the patients. The rest of the patients, actually, the median progression-free survival for the low-risk patients have not yet been yet reached. So, there’s definitely a difference.

Matthew S. Davids, MD, MMSc: I think one important point is that in the data that Steve was quoting in the frontline setting, we’ve seen very few patients with 17p treated. In the original study, I believe there was 1 patient. In the RESONATE 2 study, that actually excluded patients with deletion 17p. So, we don’t know as much. We have 1 study from the NIH that looked at the upfront setting for 17p patients with ibrutinib, which looked promising, but I think that’s an area where we need more data.

Steven Coutre, MD: Yes, it’s interesting. Some of our colleagues are already advocating, for those patients right off the bat, combination therapy. Of course, we can’t do that from a practical standpoint, but I think that’s an area that definitely needs to be looked at.

William G. Wierda, MD, PhD: Nicole, can you comment on how you manage atrial fibrillation and…

Nicole Lamanna, MD: No, I want to talk more about 17p. I’m kidding. I think the one point to make is that even though it has been a game changer, everybody needs to take that as if you have a 17p-deleted patient, you need to start them on a novel therapy. So, yes, I think that’s one thing that we can all agree with and that we should promote. But those curves, absolutely. The PFS for those patients are shorter. So, we have to think that just because you’re starting them, let’s say, on ibrutinib, that’s not the end, particularly if they’re younger. You actually have to plan ahead and think, “OK this is great for now, but what about transplant, venetoclax, CAR?” There are so many other things, because they will relapse. It’s just better than chemoimmunotherapy when median life expectancy of patients was 9 to 12 months. So, it’s just very different, but it’s by no means a matter of we are done with our 17p-deleted patients.

William G. Wierda, MD, PhD: Just briefly, atrial fibrillation and management of anticoagulation and…

Nicole Lamanna, MD: Yes, I think this is probably the question we all get asked the most. Do you stop a patient if they develop atrial fibrillation on ibrutinib? And I think it does vary and it varies by patient, too, and patient preference. I think if somebody is asymptomatic, develops atrial fibrillation, that’s something that’s still potentially manageable. Then you don’t need to necessarily stop the ibrutinib. However, there are some of our patients who develop profound symptoms like congestive heart failure, poor rejection fractions, and those need to be managed. I usually hold the ibrutinib and manage their cardiac issues and get them through that.

It also depends on which line of therapy we’re also talking about, right? So, for patients who are multiply relapsed, and ibrutinib was a great drug, they will stay on therapy because they realize that their potential options of, depending upon what they may or may not have received, are more limited. And so, you’re comanaging their side effects with concomitant therapy with ibrutinib. I have patients who have AFib who are still on ibrutinib and doing well. And then I have other patients where it was their first-line therapy and they were like, “Absolutely not. I don’t want to have to be on anticoagulation and cardiac medicines for the rest of my life. Please choose an alternative agent.” So, I think that it depends on the option and how symptomatic the patient may be. And so, your discussions may be different depending upon the patient.

William G. Wierda, MD, PhD: So, it’s a great option for sick patients with 17p deletion. Maybe briefly you can comment, Matt, on how we used to think of 11q’s as a high-risk group. Do we still? Do we need to check for 11q? Is it something we should pay attention to?

Matthew S. Davids, MD, MMSc: Yes, the data are a bit mixed now so I think it has gotten more confusing, if anything. So, we originally thought 11q was a marker of good response to FCR so we were arguing that those patients should get FCR. Then we saw the data from the 1102 study with ibrutinib monotherapies suggesting those patients had an inferior progression-free survival on ibrutinib. But now we’ve seen some larger pooled data sets suggesting that actually perhaps patients are doing slightly better with deletion 11q on ibrutinib. So, it’s a little bit all over the place. I think it is important to check still, but I think it’s become more of a research question now.

William G. Wierda, MD, PhD: Mutation status in ibrutinib therapy?

Matthew S. Davids, MD, MMSc: I think this is a really important point. So, we’ve had so many different chemoimmunotherapy-based regimens over the years. Every single one has showed an inferior progression-free and overall survival based on IGHV mutation status. And the ibrutinib data at 5 years suggest that there’s an equivalent progression-free survival based on mutated versus nonmutated IGHV. That’s the first time we’ve seen that with a therapy in CLL. There are some earlier data with idelalisib suggesting the same thing, and with venetoclax as well. So, it does seem like the novel agents are potentially able to overcome the negative prognostic factor.

William G. Wierda, MD, PhD: And Shuo, maybe you can comment on metaphase karyotype. It’s not a test that we’ve done routinely in CLL. Historically it’s useful in other leukemias. Is there utility for metaphase karyotyping? And is it a special test that we might be able to do in CLL?

Shuo Ma, MD, PhD: So, recently introduced was the concept of complex cytogenetics or complex karyotyping. That’s really referring to a patient who has 3 or more unrelated chromosome abnormalities using stimulated karyotyping technology. And what I’ve seen is those are very high-risk patients who seem to have overall survival, but also it is a very important prognostic factor when you look at different treatments. So far, I think across all different types of treatments, the patients with the complex karyotyping seemed to have poorer prognosis or response, or duration of response, compared to other patients. So, I think that’s probably going to become one of the things we should do more as a standard of care. It’s not widely available yet.

Steven Coutre, MD: I think it’s hard to recommend that as a routine test to do. If you’re going to get the information, of course you want to do it from the blood, and getting metaphase karyotype from the blood is difficult, so we do just stimulate the culture. Readily available to a lot of people. But I think that as we start looking at, say, our younger patients, even patients who are on novel agents, you’re looking at the broad picture. How are we going to manage them for many, many, many years? That might be where you want to get that information. So, for example, they can decide at some point whether to take the risk of a more significant therapy: transplant, CAR T-cell therapy. If you have somebody with 17p and a complex karyotype, as good as our novel agents are, it’s not going to be good enough. And that’s somebody that might be enough to say, “OK, let’s enter this clinical trial for CAR T cells or something.”

Transcript Edited for Clarity