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

Amber Koehler:
Welcome back. We're excited to have you for part 2 of our Roundtable discussion on BTK inhibition and CLL. My name is Amber Koehler and I'm excited to be joined again by my colleagues, Josie Montegaard and Becca Rezac. Rebecca and Josie, thank you again for joining us today. Certainly in the first part of our discussion, we had the opportunity to go over some of the key data from the FDA approvals in 2023, as well as current NCCN guidelines. Now we are going to be drawing on Becca's extensive knowledge and expertise as our pharmacist to really look at BTKI adverse events and drug-drug interactions. Thanks, Becca.

Becca Rezac:
Absolutely. So for those of you that tuned in for the first section of our discussion, Amber did a great job highlighting some of the main class effects for our BTK inhibitors, but I will still briefly cover them here for completeness's sake.

One of the main adverse effects that we think about when we think of the BTK inhibitors are cardiac adverse events and so we think of specifically atrial fibrillation, hypertension. I think it’s important just to note that I think patients who have these preexisting conditions wonder maybe whether they're a candidate for treatment with a BTK and for those patients who have atrial fibrillation or hypertension that's well controlled, it's certainly not an absolute contraindication to get started on these agents.

Additionally, maybe some more common side effects that patients may experience include bleeding, bruising, other cytopenias, specifically neutropenia infection, GI upset. And then other notable toxicities that are maybe less common include skin changes, ventricular arrhythmia specifically and then fatigue notably. As far as considering which of our specific BTK inhibitors to select when we're initiating treatment and we've decided that the BTK route is where we're going for a patient, I do think it's important just to kind of note with our individual agents which side effects may be slightly more common among different agents.

So with ibrutinib being our first generation BTK inhibitor, it is our least selective. It has a fair amount more of off-target effects contributing to a slightly different adverse effect profile and risk for some of these different effects. When we think about cardiac adverse effects, we think about ibrutinib typically being associated with the highest risk for those adverse effects.

Just to orient you to the table here, the first chunk of the table that includes ibrutinib, acalabrutinib, and zanubrutinib is the adverse events reporting system through the FDA, the FAERS system, really just to look outside of the initial clinical trial information to see what our real-world adverse events look like just in a broader patient population.

Notably, assuming that maybe some of those lower-grade adverse events may not be reported but hoping that we would capture most higher-grade adverse events through this system. Because pirtobrutinib is a newer agent, it really just doesn't have robust information in the FAERS system. But for completeness sake, I did include just a little segment of it down below that table pulling specifically from the BRUIN trial data, but matching the specific adverse events that were pulled for the other agents.

With regard to other differentiating adverse events for our different agents, acalabrutinib and zanubrutinib really have fairly similar vascular adverse events, specifically highlighting hemorrhage or bleeding. And then when we think about infectious adverse events, specifically pneumonia, zanubrutinib is going to be typically our highest-risk BTK for those specific adverse events.

Additionally, when we're looking at a selection of our BTK inhibitors, I think it's important to also consider a patient's current medication list and also additional medications that we may need to add on in the future and just consider how that may affect our BTK metabolism. So because of this cost of agents as a whole, they all are major CYP3A4 substrates. Really any strong inhibitors or strong inducers of the CYP3A4 metabolic pathway are going to have significant interactions with our BTK agents.

When we think about our strong inhibitors, really some of the more common agents that we might see include our antifungals, diltiazem, clarithromycin, grapefruit juice, notably, and then ritonavir being maybe more significant these days given its inclusion in the Paxlovid drug for use with COVID-19 infection. And we do worry with these strong inhibitors that we would see reduced metabolism of our BTK inhibitors and therefore increased exposure for our patients. I am curious, Josie and Amber, have you noticed with patients who are on a BTK inhibitor who maybe contract COVID-19, is this a conversation as far as starting Paxlovid? Do you have specific practice standards for holding or dose reducing your BTKs associated with use of Paxlovid?

Amber Koehler:
Yes, absolutely. I think certainly this is a rapidly changing field, but right now what I see our infectious diseases colleagues doing is, well A: I think on our end we always counsel people, "Hey, just so you're aware, your BTK inhibitor that you're on, your CLL therapy, whether it's a BTK inhibitor or venetoclax, does interact with Paxlovid." So that's not to say they can't be on it, but we do have kind of a prescribed washout period of stopping it for this long and hold it for this long after taking the Paxlovid.

Generally speaking, I think based on the decreased efficacy that you see with agents like molnupiravir, if we can't hold a BTK inhibitor or they're close, they're in town, they're able to come, I have seen us doing more of the remdesivir and convalescent plasma combination as opposed to Paxlovid. I think multiple reasons for that. We have seen some rebound with the Paxlovid in our patients as well, but I don't know Josie, how does that compare to what you're seeing with your patients?

Josie Montegaard:
We practice very similarly. I think our go-to for COVID-19 treatment is Paxlovid if we are able to, and we make that decision based on what medications the patients are on that may or may not interact, as well as where a patient is in their BTK inhibitor course. If they recently had progressed disease in their two weeks into their BTK inhibitor, we think a lot harder about whether they can hold their BTK inhibitor for Paxlovid because we worry about disease flare. That being said, there can be benefits to holding your BTK inhibitor. We know it can increase the risk of infection, it can delay clearing a COVID-19 infection. So often even if we weren't holding it for Paxlovid purposes, we also would consider holding it just to allow the patient to hopefully recover a little bit more expeditiously.

Becca Rezac:
Great, thank you both. I will say one thing we've noticed in addition in our clinic is just a patient hesitancy to want to hold their BTK inhibitor even if they've been on it for a while and we think that it might be safe and fine for them to hold it long therapy. We have a lot of patients who say, "My symptoms just aren't that bad. I'll call if they get worse."

So we've had some of that in our clinic too of just hesitancy on the patient's part. I've also listed our strong inducers of CYP3A4, so just notable as a potential risk for decrease in efficacy, decreased exposure to our BTK inhibitors. And then notably too, ibrutinib alone is a minor CYP2D6 substrate. So specifically we'll interact with our serotonergic agents that I think can be fairly commonly used as these are strong inhibitors of CYP2D6, I have those listed there. For patients who are on a BTK inhibitor, the package inserts do have really great standard guidance for adjustments of the dose based on concomitant therapy with moderate inhibitors or inducers and typically they're going to recommend avoidance of those strong inhibitors or inducers if able.

Another notable update has been the acalabrutinib formulation change that took place last year. So our old capsules are gone now. They have been replaced by the new formulation in a tablet. Really, the main benefit to this formulation change is that we no longer have that category X interaction with our anti-acids, so we can administer the new tablets without any regard to dose timing or use alongside even proton pump inhibitors, H2RAs, all of those are just fine to use while on the acalabrutinib tablets.

Additional pearls just to mention before we continue moving along through our discussion, really the last video series I think touched really well upon the risk for transient lymphocytosis with our PTK inhibitors. So just that’s a good reminder to patients on what to expect if they're being managed maybe by a separate local oncologist. I know that's the case for many of our patients here, just looping them in if it's something they're seeing, less common use of BTK inhibitors or maybe they don't see a lot of patients with CLL, just so no one is alarmed if they're seeing that initial lymphocytosis and understanding that that can persist for quite some time, especially as we mentioned with pirtobrutinib.

And then I won't go through all of our adverse events in detail again, but I did highlight what I would consider to be the most common or maybe defining adverse event for each agent that separates it from the others in the class. With ibrutinib, tending to think more about those cardiovascular effects that we discussed with the FAERS data being more common than the other agents, acalabrutinib being pretty notable for the side effect of headache which patients may complain of.

There's some data showing that caffeine might be beneficial for treating this particular headache associated with the drug. And then as we mentioned in the initial video, zanubrutinib being associated with higher risk for neutropenia and infection as well. Ibrutinib we'll see down the road after we have more patients in the real world outside of the trial data in order to better assess what we're seeing on a larger scale for side effects compared to our first- and second-generation covalent binding agents.

And then for completeness' sake, I did also want to include our venetoclax-based therapies. Many similar adverse events listed here as we've already discussed with our BTK inhibitors, but really that notable differentiating side effect being tumor lysis syndrome, so most common to see that risk within about six to eight hours or a day or so after initiation of venetoclax therapy and then after each subsequent dose escalation. So of course, we're doing our dose titrations, which is typically ramped up over four weeks, in the fifth week reaching our final 400 mg daily dose target.

An additional consideration logistically for patients in selecting a venetoclax-based regimen vs a BTK inhibitor would be that potential for an increase in lab draws, clinic visits during that initial dose escalation. I know for some of our higher risk patients, we still do tend to admit them for venetoclax initiation, but for those that are lower risk, we tend to do the entire escalation outpatient. Now is that similar to what you see in your practices, Josie and Amber?

Amber Koehler:
Yes, I think that sounds pretty similar and I think maybe two other thoughts I have thinking about what you've said. So, one is you mentioned the St. John's wort or you didn't mention it necessarily, but-

Becca Rezac:
Oh yes, it's on there.

Amber Koehler:
I think that we live in a world where a lot of people, they're searching for some way to control or help themselves and so there's a lot of allure with different supplements and there's great marketing and branding and certainly people, it's not that they can't get benefit from certain supplements, but I think the struggle becomes that we don't always know which ones will or won't interact with a BTK inhibitor or with venetoclax and so that is something that I always try and clarify.

I have had people who have experienced side effects associated with their BTK inhibitor, but when you get to the core of it you find out, "Oh, they've started a new supplement," and so if you stop the supplement, the side effects resolve. And so again, it's not that there isn't a space for them, but I think we have to be really cautious in patients on these different medications in CLL.

And the other thing I think about is, you brought up a really good point about acalabrutinib with the headaches and one of the things that I always try and counsel patients on is that the headaches tend to be upfront and they tend to respond to Tylenol. We try and avoid ibuprofen because of the impact on platelets, but they tend to respond to hydration, caffeine, Tylenol, and they do tend to go away or at least get significantly better after the first few weeks. Personally, I've not had anybody who I've had to discontinue acalabrutinib for headaches, but I'm not sure. What has your experience been, Josie?

Josie Montegaard:
I agree. I think caffeine is our best friend in those first couple weeks with patients on acalabrutinib reporting headaches. I really find that that works far better than any oral pain medication I could offer the patient. And as you said, usually they start out mild and fizzle out over time, so it's really not a longstanding issue for these patients. Very manageable and treatable.

Becca Rezac:
Great, thank you both. Okay, so that brings us to our case study and our patient is Joan. She's a 71-year-old female, diagnosed with CLL in 2018. Initially she was monitored but presents today with complaints of night sweats for the past six weeks, enlarging lymphadenopathy, and the decision has been made to initiate her on treatment. Her past medical history is significant for type 2 diabetes and frequent headaches. She does report that she'd like to avoid receiving infusions if possible, but is open to those if that's her only option for treatment. So just based on those first initial points about Joan's history and her desires for treatment, what options do we feel might be good options to initiate her for her first therapy?

Amber Koehler:
I think I'll take the first question. If you look at the NCCN guidelines that we covered in the first section of our discussion, you would be looking at acalabrutinib plus or minus obinutuzumab. So certainly, if she's looking to avoid infusions, you could do acalabrutinib monotherapy. Venetoclax and obinutuzumab would be another preferred category one recommendation. That one of course would be logistically challenging with the infusions if she's already not wanting them.

And then finally zanubrutinib monotherapy would be the menu I would be thinking about for her. So really I would be thinking about either acalabrutinib or zanubrutinib. You've conveniently included that she has frequent headaches in her past medical history, so that may lean you toward zanubrutinib over acalabrutinib as someone who already has that history that may be exacerbated, but those are some of the conversations that I would have with her in terms of the kind of menu I would offer.

Josie Montegaard:
I totally agree with everything Amber said as well.

Becca Rezac:
Josie, do you want to address how your treatment selection might change if Joan had a history of uncontrolled heart failure or atrial fibrillation?

Josie Montegaard:
Yes, so I think this is when that treatment choice may change. While often I will still consider a BTK inhibitor for someone that has controlled Afib or really well-controlled other cardiovascular issues, if she truly has uncontrolled heart failure Afib, I'd really want to steer clear of a BTK inhibitor if I have access to a venetoclax-based regimen. She reports that she doesn't want to receive infusions. And so that's where the conversation starts with, "Why is that? Is there a transportation issue? Is there a fear of infusion?" See if we can pull our resources together to get around that concern about infusion.

I also at this point may loop in our onco-cardiology department to determine is there a way that we can control her cardiovascular issues so that a BTK inhibitor would still be safe for her. I think this is where you sort of get the troops together to really figure out what would be a safe option for her while still meeting her requests and what's meaningful in treatment for her.

Becca Rezac:
Great. I loved those additions of pooling in our other resources, definitely. Trust but verify. Are we sure this can't be controlled if that's really the option we're leaning toward? Okay. So Joan is initiated on zanubrutinib and during the first six weeks of therapy she reports her lymphadenopathy is improving, but she has noticed maybe an increase in fatigue that she feels is inhibiting her ability to do the things she likes to do, including walking her dog and being out in her garden. And so she's curious whether you have any recommendations on changes to her current regimen?

Amber Koehler:
Yes, fatigue is tricky. Fatigue is a common thing that we hear from patients with CLL and sometimes it's really challenging to tease out how much of it is the disease, how much of it is the medication, how much of it may be other things like untreated sleep apnea or depression, how much of it may be other things that we just aren't looking at, thyroid and all of that. The fact that her fatigue seems to be worsening over the past six weeks with starting treatment to me would be more suggestive of a potential relationship to therapy.

Oftentimes I'll consider things like drug holds in these patients and say, "Listen, does it get better when you hold the medication vs when you're on the medication?" However, she's only been on it six weeks, so I would be real cautious. I wouldn't be very excited about doing a drug hold six weeks into treatment.

Truthfully, I would probably ask her if she was amenable to giving it a little bit more time and do a very short follow-up, whether it was a phone visit in two weeks, return to the clinic in a month, just try to give her some guidance and supportive care to help with the fatigue to see if it's something that abates. But certainly, we would have to start thinking about whether or not dose reduction was warranted.

And I think the other piece to consider is that she's on 320 mg daily, so would you go to 160 mg daily? Would you consider going to twice daily dosing, either at 160 mg twice daily or 80 mg twice daily? I wonder if there wouldn't be ways to either move the timing of the dose to see if maybe say taking it in the evenings helps and the fatigue maybe abates some by the time she wakes up in the morning vs thinking about dose reductions. What do you think, Josie? How would you handle that?

Josie Montegaard:
I agree. I think that I would probably see if she's willing to ride it out for a bit. If she started out with any cytopenias at the start of treatment as well, sometimes those can get a little worse before they get better until the CLL is better treated, so that certainly could contribute to some fatigue as well. I'm a fan of letting people ride it out, seeing what we can do to address other sources of fatigue before altering our treatment plan.

Becca Rezac:
Yes, I would say we manage side effects like fatigue very similarly. Trying to not necessarily tell the patient to power through, but see if they're willing to give it a longer shot during especially that initial six weeks, the first couple of months of treatment. I guess, one additional thing we might discuss is also sleep hygiene. Is she waking up frequently in the night? Are there things that we can do to make sure she's having really restful sleep? Is she able to still try and keep her regular activity by doing two or three shorter walks? How can she build up that stamina?

Especially as Josie mentioned, she may still be having count recovery from disease and how can we in the interim allow her to still enjoy those things that she likes to do? So she is willing to tough through this fatigue in the hopes that it'll continue to get better and knowing that the therapy does appear to be working, she's also willing to implement some sleep hygiene suggestions. However, several months down the road, unfortunately, Joan is noticing some cardiac palpitations and after she's received evaluation for this, she is found to have new Afib and her cardiologist is requiring management with beta blocker and an anticoagulation regimen. So with that in mind, I'm curious how each of you in your practice may move forward with treatment of her CLL while also keeping in mind these new therapies and management of her atrial fibrillation.

Amber Koehler:
Sure. I think, broad strokes when I think about Afib in a patient with CLL on BTK inhibition, regardless of which BTK inhibitor, they're on beta blockade, anticoagulation, and usually dose reduction. So the ibrutinib package insert has actually fabulous dose reduction strategies. And how many times does it recur before you stop? In a patient who was on a full-dose ibrutinib, I would probably drop the dose to 280 mg, have them on the beta blockade, and be on anticoagulation, not warfarin.

That's a big thing, right? Do not put your patients on BTK inhibitors on warfarin, they should be on DOACs (direct oral anticoagulants). You can also consider a dose reduction of the DOAC. We usually will use apixaban, 2.5 mg twice a day. I would think about that similarly with acalabrutinib. Acalabrutinib I would drop to 100 mg a day. The zanubrutinib, again, she's on 360 mg, or excuse me, the 320 mg once a day. So, I would drop her either to 260 mg daily or to 80 mg BID. When it starts to become recurrent, or if it was severe like a ventricular arrhythmia, that's when I would be much less keen to try and manage it with supportive cares.

Josie Montegaard:
I agree, and in our practice, we tend to treat through Afib so long as it can be adequately controlled and the patient is tolerating anticoagulation in the setting of a BTK inhibitor okay without significant bleeding events. We often, if it's just one episode of atrial fibrillation, we'll keep patients at full-dose BTK inhibitor. That being said, if they're having recurrent episodes, at that point we could consider a dose reduction, or really at that point we may even consider switching to alternative treatment.

Becca Rezac:
Great. I would say yes, we have very similar practice here. Maybe the one caveat being if it's a patient who's still on ibrutinib as their initial therapy, I would say we may have a bit of a lower threshold to switch therapies for some of those patients even before the atrial fibrillation becomes a recurrent event, but I would think that that's potentially more related to our provider preference here.

That does conclude the second portion of our discussion here. So thank you everyone for tuning in. Please join us for our next segment, which Josie will be leading on sequencing BTK inhibitors in the relapsed/refractory setting.