Case Study: BTKi Treatments and Side Effect Considerations in Relapsed CLL

Josie Montegaard

In this series of conversations, we've been looking at a case study. Our patient is a 60-year-old male named Jim. He's an accountant and is married with one daughter. After he was diagnosed with CLL, he was on observation for about 5 years, but then progressed and met the criteria for CLL-directed treatment and was treated with a first-line treatment of venetoclax and obinutuzumab. He has been in observation for the 5 years since treatment. Amber, do you want to talk a little bit about what's happened more recently?

Amber Koehler

Yes, absolutely. This patient had a great response to frontline venetoclax plus obinutuzumab. He had those low-risk prognostic markers of that mutated IGHV, really no abnormalities by FISH. At this point, he comes back to clinic and now he's got some recurrent cytopenias, his white blood cell count is up again, and he has these new bulky lymph nodes. And it just feels like he's progressing a little faster than I would've expected, based on what data we've seen from the 5-year follow-up of the CLL14¹ trial, which assessed venetoclax and obinutuzumab in the frontline setting. So, as part of his workup prior to thinking about retreatment and restaging, what we will often do is repeat those prognostic markers that might change.

The IGHV mutational status will not change, but the FISH can change, cytogenetics can change, and TP53 somatic mutational status can change. So as part of repeating that workup, we find that this patient has now developed a new TP53 mutation that was not present prior to initial therapy. We certainly know that with prior standards of care, including things like FCR (fludarabine, cyclophosphamide and rituximab) and BR (bendamustine/rituximab), there is some literature out there to support the incidence of clonal evolution in folks with CLL who did not initially have cytogenetic or abnormalities on FISH, who subsequently develop them later in the course of their disease,² which we don't know as much about in the era of oral targeted therapies. I haven't seen much data on that, have you, Josie?

Josie Montegaard

I have not seen much data. That being said, I think that we can see it in our patients in clinic where they've been back in observation for a while after a frontline treatment and we'll repeat their prognostic testing, and it will reveal something new that they did not have before. And even more rarely, sometimes we see patients who have not even had treatment in the past but have spontaneous clonal evolution. So, I think it's something that we're going to be learning a lot more about, as most patients are now being treated with novel agents in the frontline setting as opposed to chemoimmunotherapy in the frontline setting, which is what the standard was 15 years ago. 

Amber Koehler

Right, I absolutely agree. Particularly for this patient, when you think about retreating him, certainly it wouldn't be off the table to retreat him with a venetoclax-based regimen, but you do see shorter remissions in time-limited regimens, including venetoclax-based regimens, with folks who have things like a TP53 mutation or a del(17p) by FISH. So, I think in his case, I would probably lean toward treating him with indefinite therapy with a BTK inhibitor. What would you do if Jim was in your office? 

Josie Montegaard

I completely agree with you. I think that I would worry about offering him another time-limited therapy, just because he now has that TP53 mutation. Additionally, as we touched on a little bit in the first conversation, now that he has bulky lymph adenopathy, I think a BTK inhibitor would do a great job at really reducing that quickly, as I'm sure when he's here in our office, he's probably pretty uncomfortable from it. 

Amber Koehler

Yes. As we touched on in our first conversation with respect to NCCN guidelines, certainly that changed in the past year or so where ibrutinib is no longer considered a preferred BTK inhibitor. That really leaves acalabrutinib and zanubrutinib, both of which are FDA-approved in CLL, in both the relapsed and frontline setting. What are some of your considerations when choosing between, say, acalabrutinib and zanubrutinib? 

Josie Montegaard

I think that at this point, it really is physician and provider discretion. Recently, acalabrutinib has been formulated to be in tablets as opposed to capsules, and the tablets you can actually take with proton pump inhibitors (PPIs), which in the past you had to avoid while being on acalabrutinib due to a drug-drug interaction. In that case, that would've been a decision-making factor because many of our patients have terrible GERD and it's important for them to stay on their PPI. That being said, now that you can take a PPI with acalabrutinib without issue, it sort of evens the playing field between acalabrutinib and zanubrutinib. I find that most of the side effects are pretty even between the two in my personal clinical practice, but I'm interested to hear about your experience. 

Amber Koehler

I agree with you. It's interesting. I think some people will extrapolate data, so they'll say if you look at ibrutinib and acalabrutinib head-to-head in the relapsed setting, in that ELEVATE-RR trial, there was really no difference seen in PFS, or progression-free survival, but you saw lower rates of hypertension and lower rates of cardiac side effects like atrial fibrillation with acalabrutinib compared to ibrutinib.³ And conversely, if you look at the ALPINE trial, which compared ibrutinib to zanubrutinib, you saw not only lower rates of atrial fibrillation with zanubrutinib, but you also saw superior PFS with zanubrutinib compared to ibrutinib.⁴ So, one could make the argument that if ibrutinib and acalabrutinib have equivalent PFS, and zanubrutinib has improved PFS compared to ibrutinib, that it therefore stands to reason, could zanubrutinib have improved PFS compared to acalabrutinib? 

I'm not sure and we don't have the data to say this. In general, what I have seen is really what's been borne out in the literature. To date, I have seen the lowest rates of atrial fibrillation with zanubrutinib, but we'll see how that bears out over time. I have seen more bruising and bleeding with zanubrutinib compared to acalabrutinib in my practice. With acalabrutinib I tend to see those headaches upfront as people get started on treatment, but again it's usually pretty manageable to get them through. What are your thoughts? 

Josie Montegaard

I completely agree. The headaches upfront are sort of a unique side effect of acalabrutinib that I don't typically see in other BTK inhibitors, including zanubrutinib, but they are actually pretty manageable with caffeine. Often the headaches occur in the morning and so no one is too mad about being prescribed a cup of coffee in the morning to ameliorate the headaches. I think they're pretty manageable and usually self-resolve over time. Usually, after a week or two of being on acalabrutinib, they're really a non-issue at that point. What has been your experience with hypertension and both acalabrutinib and zanubrutinib?

Amber Koehler

That's a good question. I don't know that I've seen much of a difference. Have you? 

Josie Montegaard

I don't think so. And that being said, as we see hypertension occur later in therapy on ibrutinib and acalabrutinib, a lot of my patients on zanubrutinib have not reached the 3 or 4+ year mark in their treatment. So, it'll be interesting to see, at that time, if we're seeing similar rates of hypertension as we do with the older BTK inhibitors. 

Amber Koehler

Absolutely. I think the other things I think about in terms of considerations here would be the higher rates of neutropenia with zanubrutinib. Now to be fair, zanubrutinib was being studied and this data was coming out as we entered the COVID-19 pandemic, so infection is certainly going to be a big player and likely a confounding variable there. But I think one of the other benefits of zanubrutinib compared to acalabrutinib, as we weigh these pros and cons, is the dosing. 

Certainly, the dosing with zanubrutinib has more flexibility. We can feel more comfortable dose reducing the zanubrutinib without being worried about potentially driving resistance based on half-life of these medications. Looking at the pharmacokinetics compared to the acalabrutinib, where if you're needing to dose reduce, really you're going down to just once a day. There's no option to go to from, say, 100 mg twice a day to 50 mg twice a day. 

Josie Montegaard

Yes. I think that brings up an excellent point because with BTK inhibitors, you want these patients to be on them long term, so the name of the game is figuring out how to make these drugs tolerable so the patients derive that long-term benefit. So rather than throw in the towel on this type of drug when a bad side effect comes up, you really want to get creative with your dose reductions while making sure that you're not fostering possible BTK resistance. 

Amber Koehler

Absolutely. And I think this certainly applies to Jim in this case, where we're deciding between acalabrutinib and zanubrutinib. Even if we have people in our practice who are on ibrutinib for relapsed CLL and they've been on it for some time, I do think there's also a lot of room for dose reduction with ibrutinib in order to keep people on treatment. 

Josie Montegaard

Yes, I completely agree. Thinking about once Jim does go on a BTK inhibitor, we've touched a little bit upon counseling on the cardiac side effects, the bleeding side effects, the gastrointestinal side effects. Another point that I always talk to my patients about, piggybacking on the risk of bleeding, is to make us aware of any procedures that they have coming up. Most of these patients are older and they're getting knees replaced, hips replaced, or having cataract surgery. And any CLL patient is at risk for secondary cancers, but particularly skin cancers, so they're always having Mohs procedures as well. It may be new for them to have to hold medications surrounding these procedures, so it is important to explicitly talk about how  important holding BTKis is in preventing post-procedural bleeding. Is that something that your clinics counsels on as well?

Amber Koehler

Yes, it is. We spend a lot of time making sure people remember that. It's tough. People have a lot of things to remember. They have a lot of appointments. But I think it's really important for patient safety. 

Josie Montegaard

And I make it part of the visit. Just as I ask, "How many doses of each medication have you missed?" Rather than wait for them to offer that information, I ask, "Do you have any procedures coming up?" Many times they'll say, "Oh, I didn't realize a tooth pull counted," or something like that. It's better to jog their memory than ask for them to offer up that information.

Amber Koehler

Absolutely. And I think one thing that's really helped in our practice is we have created SOPs or standard operating procedures to empower our nurses who are fielding a lot of these phone calls and patient portal messages. So, it’s great when a patient writes in and says, "Hey, Josie, I'm going to have my knee replaced in two weeks. What do I need to do? I remember you said something about needing to hold my medication." That way, the nurses can field that and then that helps decrease the inbasket burden on the providers as well. 

So Josie, the million-dollar question, which BTK inhibitor are you going to start Jim on?

Josie Montegaard

I think based on our conversation, he could go on either, but I do have high hopes that zanubrutinib will offer less cardiovascular toxicity than the older generation BTK inhibitors. And given that he already has a history of hypertension, why not try him on that? Then we have the option of a dose reduction, should he run into cardiovascular complications down the road.

Amber Koehler

I think that's reasonable. I look forward to picking up this case study in our next conversation.