What Advanced Practitioners Need to Know About CLL With a Focus on BTK Inhibition

Amber Koehler:
Hello and welcome to JADPRO's Roundtable discussion on CLL, or chronic lymphocytic leukemia, with a specific focus on the current state of BTK inhibition. My name is Amber Koehler. I am a PA at Mayo Clinic in Rochester, Minnesota, and I'm very excited to be here today, joined by my colleagues, Josie and Becca. Thanks so much for joining us. Would you each like to introduce yourselves?

Josie Montegaard:
Hi, my name is Josie Montegaard. I'm a nurse practitioner at Dana-Farber Cancer Institute in Boston, Massachusetts, and I specialize in CLL.

Becca Rezac:
Hi, my name is Becca Rezac, and I am a pharmacist at UC Health University of Colorado in the Blood Disorders Center, so I cover all malignant hematology and bone marrow transplants.

Amber Koehler:
Wonderful. Well, I'm so thankful to each of you for taking time out of your busy days to have this discussion together and definitely value your expertise. For those of you who are watching, if you missed it, there was a fantastic JADPRO CLL Roundtable on BTK inhibition in 2023. That was led by our colleagues, Amy Goodrich, Jill Miller, and Kristen Battiato. These are brilliant CLL clinicians, excellent people, so please make sure you refer to that. Really, what we want to do today is not really belabor or go back over some of the things that they talked about in terms of basics of CLL, the BCR signaling pathway. They covered many, many, many key trials in CLL that have shaped the treatment landscape over the past several years. And so, really for today, what we plan to jump into is a discussion of key FDA approvals in 2023 in CLL.

We'll talk about the most recent updates to the NCCN guidelines from November 2023. From there, in the second portion of our conversation, we'll focus more on adverse event management and drug-drug interactions. And finally, we'll talk about some of the differences between covalent and noncovalent BTKis, as well as different considerations for sequencing BTK inhibitors in the relapsed/refractory setting. In terms of the ABCs of CLL, these are things most of you likely know already, right? So, often incidental diagnosis, whether that's due to abnormal blood work and elevated white blood cell count, or a lymph node that's enlarged and doesn't get smaller or go away, one of the most important things is that patients with CLL really, really need to have prognostic testing done prior to starting therapy.

So, that means FISH testing, IGHV mutation status, and TP53 mutation status at a minimum. You can also consider karyotyping, but in general, we're not always getting karyotyping at baseline or prior to treatment. That guideline is still evolving. The key indications for therapy in CLL would be cytopenias due to CLL infiltration, and not due to nutritional deficiencies or autoimmune cytopenias, certainly large progressive symptomatic adenopathy or splenomegaly. On the screen, you'll see that I've grayed out on purpose, pun intended, that lymphocyte doubling time is more of a gray area in terms of indications for therapy and CLL. It's definitely a different ball game when patients have a white count that goes from 15 to 30,000 in six months, compared to maybe 100 to 200,000. Is that fair and consistent with your practices Josie and Becca?

Josie Montegaard:
Yes, I completely agree.

Becca Rezac:
Definitely.

Amber Koehler:
I think symptomatic extranodal involvement is rare, but it happens, and certainly B symptoms that are not attributed to other things, right? So, fatigue, fevers, drenching night sweats, unintentional weight loss would all be reasons to think about starting treatment.

So with that, let's jump more into the meat of our discussion today. We're going to spend most of our time talking about key FDA approvals in 2023, with a specific focus on the approval of zanubrutinib in January of this past year. That was based on data from the SEQUOIA and ALPINE trials, and then the FDA approval of pirtobrutinib in December 2023 to really bookend the year primarily based on the BRUIN data.

So, to start with looking at the SEQUOIA trial, this looked at zanubrutinib in the frontline setting and they had a bit of a unique design. We've known for many, many years, right, that deletion(17p) patients with this finding really don't do well with chemoimmunotherapy, and that's why they set this up the way that they did. And so, really, patients who did not have deletion(17p) were the only ones who got randomized because the comparator arm to zanubrutinib was the traditional chemoimmunotherapy. These were older patients or those who were deemed not to be fit for the more intensive chemoimmunotherapy of FCR (fludarabine-cyclophosphamide-rituximab). Patients who did have deletion(17p) just automatically got zanubrutinib.

This was a study of 590 patients with a median follow-up of about 26.2 months at the time of this Lancet publication, so pretty short follow-up. Really, the important findings here were that on the left, you'll see a statistically significant improvement in PFS with zanubrutinib compared to BR (bendamustine-rituximab) in this population, but no statistically significant difference in overall survival being reported at the time of the publication.

The most common grade 3 adverse event with zanubrutinib in frontline CLL that was grade 3 or higher was neutropenia. You see pretty similar rates across those two zanubrutinib groups, which are actually quite a bit lower than the bendamustine-rituximab group. But I think importantly, despite those differences in rates of grade 3 neutropenia, you see relatively similar rates of grade 3 or higher infections. And so, certainly something to bear in mind is whether or not neutropenia is associated with infections. Is this similar to what your experience has been with these medications, or with zanubrutinib specifically?

Josie Montegaard:
I think so, and in my clinic, we often find that it responds very well to growth factors, so that's a way to help prevent infection.

Becca Rezac:
Yes, we tend to expect to see more neutropenia than the other agents when we start zanubrutinib.

Amber Koehler:
Yes, compared to the other BTK inhibitors specifically?

Becca Rezac:
Yes.

Amber Koehler:
Yes, I agree. I think that's pretty on par with what we've seen. This table is actually from the supplemental appendix of that Lancet publication, and so if you look at any grade neutropenia and infections, you see a similar pattern where you see lower rates of neutropenia with zanubrutinib compared to BR, but relatively similar rates of infections across those arms. I think you can't talk about BTK inhibitors without talking about things like atrial fibrillation, major bleeding, hypertension, and really, when you look at this data, you don't see a whole lot of differences across the groups with respect to atrial fibrillation or hypertension, but you do see slightly higher rates being reported of major bleeding with zanubrutinib compared to BR, and I would say certainly that is something I've seen within my practice.

How much have you guys seen of increased bruising or bleeding, not only compared to chemoimmunotherapy, but perhaps compared to the other BTK inhibitors with zanubrutinib?

Josie Montegaard:
I would say fairly similar rates of the easy bleeding and bruising compared to the other BTK inhibitors, but definitely more than what I would see with the traditional chemoimmunotherapy.

Becca Rezac:
Yes, I would agree with that.

Amber Koehler:
There was a real quick update too, that they presented at ASH with respect to SEQUOIA, and we won't belabor this, but really, I think the important piece here is that they saw statistically significant improvements in PFS on multiple subgroup analyses, whether that was FISH findings, complex karyotype, IGHV mutation status, that even if you take deletion(17p) out of the picture, you see that statistically significant PFS benefit for zanubrutinib compared to BR in the front-line setting.

The other important trial with respect to zanubrutinib was ALPINE. So, really, this initially was published in the New England Journal of Medicine with a median follow-up of 29.6 months. These are patients who were randomized one-to-one, either zanubrutinib or ibrutinib in the relapsed/refractory setting, a phase 3 head-to-head trial. And this was really the first trial to show a PFS benefit with zanubrutinib compared to ibrutinib. At this time, or at least at time of publication, there's not really been an increased statistically significant increase in overall survival.

Importantly, when you look at the side effects, they're not dissimilar to what was shown in SEQUOIA. You do see about 16% of grade 3 or higher neutropenia as we've discussed. Certainly, with infections, especially COVID-19, there seemed to be a slight increase seen in the patient population that received zanubrutinib compared to ibrutinib, but relatively similar rates of hypertension, slightly lower rates of atrial fibrillation. So, atrial fibrillation is a big one, right? How would you guys say that your experience has been with say, zanubrutinib, acalabrutinib, ibrutinib, in terms of atrial fibrillation?

Josie Montegaard:
I think we're seeing similar things translate in our clinic from the data that we see here, that there’s less Afib in our patients compared to ibrutinib, and I think acalabrutinib as well.

Becca Rezac:
Yes, I would say with both of the newer agents we've noticed quite a fair decrease in atrial fibrillation. There’re very few patients we're seeing that become an issue after starting treatment.

Amber Koehler:
Yes, absolutely. And I think one of the things about atrial fibrillation that can get a little tricky, and I'm not going to beat myself to the punchline because we'll talk about it later in a case study, but atrial fibrillation in my mind doesn't necessarily mean we need to immediately discontinue a BTK inhibitor regardless of which one they're on, right? Oftentimes, you can dose reduce, you can add in beta blockade anticoagulation if needed. So, I think there are strategies that we can use of patients on BTK inhibition who develop Afib, but more to come on that.

This next slide does show you the updated data presented at ASH in December. So, this was about a three-year follow-up from the ALPINE study, and really, they continue to show a statistically significant improvement in PFS with zanubrutinib compared to ibrutinib in the relapse setting. No major differences in AEs that were updated in the ASH presentation compared to the New England Journal publication. But really, what you see here is, I think most important, you see about a 6.2% rate of Afib or Aflutter being reported with zanubrutinib compared to ibrutinib, which it sounds like is pretty similar with many of our clinical experiences. Any other thoughts on zanubrutinib or things you've noticed in these patients?

Becca Rezac:
I would say the neutropenia, really, we've kind of hit upon. That's usually the thing we think of, setting it apart from the other agents as far as kind of that differentiating side effect. But otherwise, we tend to like it.

Amber Koehler:
Yes. I'm curious, Josie, I think you and I both see a lot of folks who are pretty well-informed, they do a lot of research on their diagnosis. I know this simply because we've had this conversation many times. Do you find that there's concern over COVID-19 with zanubrutinib from the patients?

Josie Montegaard:
I don't think specifically with zanubrutinib. I think there's concern about COVID-19 in general among the CLL patients, whether they're on or off treatment, but I don't think patients are more concerned if they're on zanubrutinib vs. being on ibrutinib or acalabrutinib, and we tend to counsel our patients regardless of which BTK inhibitor they're on, the same with regards to protecting themselves against COVID-19.

Amber Koehler:
Yes, absolutely. So, the last study I want us to talk about in this first chunk of time is the BRUIN study, which led to the approval of pirtobrutinib in December of 2023, and I think this study is important for a couple of reasons. This was a phase 1/2 trial. Pirtobrutinib is the first approved noncovalent BTK inhibitor, which we'll talk more about. The overall response rate was about 73.3%, though that does increase to 82.2% if you include partial response with lymphocytosis. I don't know about you guys, but I've definitely seen more of a prolonged course of that redistribution lymphocytosis with pirtobrutinib than with some of the other BTK inhibitors.

The most common adverse events they saw were things like infections, bleeding, even though they report 42%, only 2.2% of that is being reported as major hemorrhage. Neutropenia being reported in about 1/3 of patients, and of course the cardiovascular AEs, right? So, hypertension at about 14% Afib, or Aflutter at about 3.8%, and a discontinuation rate of 2.8%. A few thoughts that I have about this trial is that their median PFS, it is interesting that it varied by population, so it was shortest in people who had been exposed to both a covalent BTK inhibitor and a BCL-2 inhibitor in the past, something like venetoclax, right?

The infections, 71%, that's pretty high, right, but this is a pretty heavily pretreated patient population. We know that patients with CLL have pretty significant immune dysfunction, and a discontinuation rate of 2.8% is pretty impressive. But also, this is a population of individuals who don't have a whole lot of other pitchers in the bullpen, if you will, at this stage in the game. What's your impression of this data? Do you feel like it represents what you guys have seen when using pirtobrutinib?

Josie Montegaard:
I think it does, and while you may look at the PFS being a little shorter than what we would traditionally want to see for CLL patients, as you know, these are pretty heavily pre-treated patients. Often, they have complex cytogenetics, so kicking the can to needing additional treatment down the line almost two years could make the difference of new FDA approvals and clinical trials available. So, I think this holds a really important space in the field right now.

Amber Koehler:
Yes, absolutely. Becca, are you guys using much pirtobrutinib yet?

Becca Rezac:
We've only used it a handful of times, so I will say I haven't really noticed any of the increased infection risk that the trial seems to hint at. So, I know that's something that is a point of interest for us to see if that ends out panning out in our patients or if it's not something we seem to notice as we continue using it more.

Amber Koehler:
Yes, absolutely. And they did present some updated data at ASH with respect to the BRUIN trial. They did present 30-month follow-up data, which continues to show efficacy in this population. I think the most important thing you see is there is, again, that kind of dropping off of that PFS curve more quickly in patients who have been previously treated with a BCL-2 inhibitor. Certainly, there are trials that are ongoing looking at the potential role of pirtobrutinib earlier in those lines of therapy, but I think we just don't know yet where it will end up fitting in the treatment paradigm. So, more to come.

I think the last thing we just want to touch on briefly is based on these FDA approvals, where do these things fit, right? So, how do you fit the puzzle pieces in to find the right treatment for the right patient? The NCCN guidelines were most recently updated in November of 2023, and regardless of whether these patients have deletion(17p), TP53 mutation or not, these guidelines actually look pretty similar. When you think about BTK inhibition and CLL, either in the frontline or the relapse setting, your preferred category 1 recommendation BTK inhibitors are going to be acalabrutinib and zanubrutinib. If you look at patients without deletion(17p) or TP53 mutation, you will see that the recommendation says acalabrutinib plus or minus obinutuzumab. That would be based on the ELEVATE TN trial. They also list venetoclax and obinutuzumab as category 1 preferred regimen based on the CLL 14 trial. And then of course, zanubrutinib, which we've talked about based on the SEQUOIA trial.

Pirtobrutinib doesn't really start to come into the picture until that second- or third-line therapy. If you look at the NCCN guidelines, in the second- or third-line therapy, they'll call it out as being potentially useful under certain circumstances, but certainly they call it out as a good option for patients who have relapsed after both covalent BTK inhibition and venetoclax-based regimens. That's very, very similar for their recommendations both in the frontline and relapse setting for patients with deletion(17p) or TP53. What I'm hearing from you both is that these kinds of second- or third-generation BTK inhibitors like acalabrutinib or zanubrutinib are kind of your go-to agents in CLL compared to ibrutinib. Is that a fair summary of what I'm hearing?

Becca Rezac:
Definitely, yes.

Amber Koehler:
Okay. We've talked about where the NCCN guidelines put pirtobrutinib, but where would you guys put that in your treatment paradigm?

Josie Montegaard:
I think for us, it all depends on sequencing and sort of the patient variables, which we'll talk a little bit about later in this presentation. But I do think we are reserving it for those double relapsed/refractory patients. We're certainly using our second-generation BTK inhibitor in a venetoclax-based regimen before we're moving toward pirtobrutinib, typically.

Becca Rezac:
Yes, nothing different here. We're tending to kind of take one from each area, one second-generation BTK first. And I guess, sequentially maybe, it depends if they start on a venetoclax-based regimen, but seeing both of those before we're moving on to pirtobrutinib.

Amber Koehler:
Fantastic. Yes, I think we're pretty much on par. So, to conclude our first chunk of our discussion, really, the most important thing, I think in 2023, from an FDA approval and CLL standpoint, would be the approvals of zanubrutinib and pirtobrutinib, and just recognizing that the preferred BTK inhibitors in CLL at this time are acalabrutinib and zanubrutinib.

Thank you so much for joining us. I hope you'll join us for our next video where we'll be diving more into BTKi adverse events and drug-drug interactions. If you have questions or for more information, you can definitely go to JADPRO online at JADPRO.com. Thank you so much for joining us, and I hope you'll be there for the next video.