The Role of BTK Inhibition in the Management of Patients With CLL

Amy Goodrich:

Welcome to this virtual roundtable titled “The Role of BTK Inhibition in the Management of Patients with CLL.” I'm Amy Goodrich. I'm a nurse practitioner at the Johns Hopkins Kimmel Cancer Center in Baltimore, Maryland. Joining me today for this discussion are two of my colleagues, Jill Miller and Kristen Battiato. Now we will turn it over to Kristen to talk about managing adverse events.

Kristen Battiato:

Hello, my name is Kristen Battiato. I'm a nurse practitioner on the leukemia service at Memorial Sloan Kettering Cancer Center in New York City, and we're going to talk about managing adverse events with BTK inhibitors. It's important to counsel patients when starting a BTK inhibitor on the potential of lymphocytosis, which can be quite alarming to patients if they're unaware of this. You can anticipate that your patient may have asymptomatic lymphocytosis after starting therapy with a BTK inhibitor. This can happen one to two months followed by a slow decline. And again, you don't want to mistake this for progressive disease, especially if the lymph nodes are decreasing. It does not require any specific management even when persistent for months. For instance, I had a patient in our clinic who had a white count of 300,000 when we started a BTK inhibitor, and she peaked at 500,000.

Now this was the most severe case of lymphocytosis I've ever seen, but we did not intervene. We monitored her carefully. We noted that her lymph nodes were decreasing in size, and she was responding to drug and we just kept a close eye on her. There’s a subset of patients where lymphocytosis never resolves and this does not affect long-term outcome. For instance, I have patients on BTK inhibitors who have a white count that sits around 15 to 20,000 but with excellent disease control on BTK inhibitors, and that's just what we can expect with this drug class. Amy or Jill, have you seen any severe lymphocytosis like this in your practices?

Amy Goodrich:

I've definitely seen this, and it is something that is so important to talk to patients about and if they really understand that those lymphocytes actually move out of the lymph nodes and into the peripheral blood and understand why that's happening, and as long as they know that if their lymph nodes are decreasing, it's really okay that their white count is heading up, it really is important for them to be ready for that.

Kristen Battiato:

Yes, like you said, I often will counsel patients. Redistribution is the word I use. You're pushing the lymphocytes out of the spleen, out of the bone marrow and out of the lymph nodes into the peripheral blood where your body will eventually just break it down .It takes time, weeks to months, and that's what's happening essentially. It's important that patients can understand this because they can become quite alarmed when they see their white count double. They think they're having rapid disease progression. Jill, have you seen any significant cases like this as well in your practice?

Jill Miller:

Oh absolutely, and I think one other thing that's key is if you're coordinating care with maybe the patient's primary care physician or another provider as they start treatment to make sure that that team is also educated to expect this as well.

Kristen Battiato:

That's a very good point. You might get some panicked phone calls from their outside providers, urgent phone calls, and it's good to educate everybody involved in the patient's care.

Another side effect we see with BTK inhibitors includes hypertension. This is a common side effect and it can occur at any point during treatment. I've seen it actually more of a late onset. Patients will be on BTK inhibitors a year plus and then all of a sudden they'll walk in and they'll be quite hypertensive and we’ll need to address it. It's important to effectively manage medications and lifestyle modifications, and if patients are refractory to interventions, you might want to consider switching to an alternate BTK inhibitor. It's really important to assess and optimize control of blood pressure at baseline, specifically before starting a BTK inhibitor. Regular monitoring throughout treatment by patient and medical team is vital, so every time they come in through your clinic, you want to keep a close eye on that blood pressure and make sure it's not trending up over time.

If needed, it's important to initiate antihypertensive agents, and this is where the collaboration between outside providers will come in particularly with the primary care physician, the cardio oncologist and cardio-oncology as well. Bleeding is also a common side effect in easy bruising of BTK inhibitors that we see. The bruising can be quite benign. I'll often see patients come into clinics with scattered bruises on their forearms from like carrying groceries up and down the stairs or even on their lower extremities from banging into things around the house and they usually are self-limiting and they resolve without any intervention. Big thing we have to look out for is bleeding with BTK inhibitors. If you have bleeding, it's grade one or grade two, you may want to hold the BTK inhibitor and resume at the same dose and monitor closely. Grade three bleeding, these patients are usually hospitalized, and it's really vital to hold that BTK inhibitor until bleeding resolves. You want to consider transfusion platelets if severe enough and you want to resume the BTK inhibitor at a lower dose once the bleeding resolves.

It's really, really vital to educate patients on the importance of holding BTK inhibitors prior to procedures, really vital information you need to provide patients. Minor procedures can include a colonoscopy, a screening colonoscopy with or without a biopsy. You want to hold three days before and three days after with a biopsy. If they don't have the biopsy, they can usually start the day after. Also, teeth extractions, we’ll often hold three days before and three days after. For any major surgeries like an orthopedic surgery, we often recommend they hold seven days before and seven days after. It all depends on the bleeding risk of the procedure. Jill and Amy, is this something that you'll commonly talk about with your patients in clinic as well?

Amy Goodrich:

Yes. I try to remind people this every single time I see them because this is really an easy thing for them to forget about because once they start tolerating their BTK inhibitor and they feel well on it and all the side effects are evened out, they forget about these little details that are so important.

Kristen Battiato:

That's a really good point. Jill, what about you?

Jill Miller:

I would just add that you do have to be very aware of this, particularly with patients who are already on blood thinners for other purposes, and coordinate with whether it's their cardiologist or hematologist who is managing their blood thinners to maybe dose adjust or tweak the regimen as needed based on any bleeding that they may experience.

Kristen Battiato:

Really good point, absolutely. AFib is also a class effect that we see with BTK inhibitors. Risk factors include older age, male sex, history of atrial fibrillation, hypertension, hyperlipidemia, and history of preexisting cardiac disease. We know there's a higher incidence with ibrutinib per the RESONATE-2 trials, including also with the ALPINE and ELEVATE-RR. Time to onset, the median time to onset is usually 2.8 months but can occur at any time, so that's where that physical assessment is really key in getting a really good patient history. Management, you want to definitely involve cardiology consultation if they develop atrial fibrillation. We're going to look at the CHA₂DS₂-VASc score. [CHA₂DS₂-VASc = congestive heart failure, hypertension, age ≥75 (doubled), diabetes, stroke (doubled), vascular disease, age 65 to 74 and sex category (female)]. If the score is between zero and one, you can continue the BTK inhibitor at current dose. If rate or rhythm control is required, beta blockers are preferred. You want to avoid PGP substrates such as digoxin, amiodarone, and CYP3 and CYP4 inhibitors, such as verapamil and diltiazem, so that's where that critical medication reconciliation comes in here.

Also, if the CHA₂DS₂-VASc scores above two, you want to hold the BTK inhibitor until there's atrial fibrillation control. You're going to an anticoagulate that patient. So a DOAC (direct-acting oral anticoagulant) is usually preferred, particularly apixaban if possible, and you often want to avoid low-molecular weight heparin given the CYP3/4 interaction. You want to avoid the use of warfarin due to the increased risk of bleeding with this medication, it's contraindicated. And you also want to consider an alternate therapy if you have poorly controlled atrial fibrillation. Jill and Amy, have you seen a lot of atrial fibrillation in your clinics over the years?

Jill Miller:

It certainly happens. It's something that we have to manage and always ask patients about their experience. Many patients are asymptomatic and so always talking to them about the risk, asking them about any palpitations or their symptoms they may have and really educating them on the risk for this.

Amy Goodrich:

I agree, and even though it's not a high incidence side effect, it is certainly one of the most critical ones that we see. So having patients understand signs and symptoms and us all being aware of it every time is important.

Kristen Battiato:

Well, I agree. Patient education is definitely key with these BTK inhibitors. Other AEs that we can see with BTK inhibitors include rash. They usually respond to topical steroids or oral antihistamines. We’ll often collaborate with our colleagues in the dermatology department at some point during their treatments. There's hair and nail changes. I often see, specifically with ibrutinib, some brittle nails and brittle hair, that's a common complaint I hear in clinic. Biotin supplementation and application of nail oil has seemed to provide some relief for patients. Diarrhea can happen in the first couple of weeks of therapy. Once you rule out infectious etiology, you can consider using some loperamide. You want to make sure the patients are staying adequately hydrate. And even consider transitioning to bedtime dosing if daily dosing is being used in order to avoid side effects throughout the day.

Nausea is also something that can happen in the first couple of weeks. Again, moving dosing to bedtime and the use of anti-emetics can be key. One of the main things we see is arthralgias and myalgias, especially in this older patient population. We often encourage them to remain active and exercise. We ask them to avoid frequent NSAIDs due to the increased bleeding risk and then they also can consider alternative supplements and treatments, but I want to caution my patients to always run it by us before starting a supplement to make sure there aren't potential drug-drug interactions.

Also, if the myalgias and arthralgias start to interfere with daily activities, you may want to consider a short drug vacation, a short hold to see if its symptoms improve and then usually when you restart the medication, patients are able to tolerate it a little bit better. If really severe, you can also consider a short course of corticosteroids. Jill and Amy, what has been your approach to treating arthralgias and myalgias? Because I feel like this is the most bothersome to patients when on a BTK inhibitor because this really can interfere with their daily activities.

Amy Goodrich:

It's a tough one. It's so subjective, but it makes such a big impact on patients' quality of life. I agree with everything that you have said. If they do a drug holiday and you restart them and they still have the arthralgias and myalgias, we tend to switch to another drug versus dose reducing, but dose reducing is a reasonable alternative as well. I think that we're more quick to go to a different agent now that we've got first and second generation and there tends not to be a lot of overlap if you switch agents when you have an offending adverse event.

Kristen Battiato:

Agree, we'll try supportive care and try to treat through it, but then eventually if it's severe enough, we'll consider switching as well. Jill, what has been your approach with this issue?

Jill Miller:        

Yes, it's definitely an issue that has led to dose modification and switching therapy, but I agree with both of you and that with all of these toxicities we always try to manage through them and educate patients that these are possibly related to the therapy but also trying to manage through them before making change in their therapies.

Kristen Battiato:

Exactly. I feel like it's a little bit worse in the beginning of therapy in the first couple of months and then at times to settle in, but I often have to just encourage people to hang in there and hopefully this won't be a standard thing while on this therapy. One thing I actually use in clinic, which has been particularly helpful with ibrutinib, I notice a lot of muscle spasms and we've often used magnesium supplements and vitamin B complex supplements as well, which is really provided patients with some nice relief, in addition to encouraging them to remain very well hydrated. Have you guys used those supplements as well in your practices?

Amy Goodrich:

Yes, definitely. Absolutely.

Kristen Battiato:

The secret weapon of mine.

Amy Goodrich:

Yes.

Kristen Battiato:

Jill, what about you?

Jill Miller:

Well, that reminded me of one thing I always talk to my patients about: That is to be cautious when going on the patient blogs and the CLL Facebook discussions because there are a lot of recommendations of different things patients can try and some of it's not so wise. As I think Amy mentioned earlier, if they do pick up on something they want to try, to please run it by us first.

Kristen Battiato:

Absolutely. All right, let's move on a little bit. You can also see headaches when patients take BTK inhibitors. This is more prevalent in acalabrutinib. This usually occurs in the first four to eight weeks while starting therapy. It's usually a frontal headache in the morning and it's self-limiting and it usually abates again after eight weeks. Usually doesn't interfere with activities of daily living but can be just more annoying for the patient. We often encourage them to consume caffeinated beverages or if they're already doing that, drink more caffeine. We use acetaminophen to help control pain. We often, again encourage patients to avoid NSAIDs or aspirin-containing products in order to help mitigate the risk of bleeding. Infection is also something we need to look out for in our CLL patients as we know they are immunocompromised. There're no standard recommendations for routine screening or prophylaxis and practices differ across institutions. You want to monitor patients closely for signs and symptoms of infection and they should be counseled to report any new symptoms.

You want to be aware of potential drug-drug interactions when treating an infection, especially with those antifungal agents, that can be particularly problematic. And you may consider holding a BTK inhibitor for severe infections. One thing I also want to highlight is it's really important to try and get these patients vaccinated before starting therapy as they will optimize their vaccine response, because after therapy, their vaccine response tends to be suboptimal. So starting a patient on a BTK inhibitor, it's really crucial to involve the multidisciplinary team. Consistent messaging from across the team is critical to avoid patient confusion. Patient and caregiver counseling reduces confusion and is key to compliance and patient follow up is really, really important. It's important to catch side effects early and it makes managing them more easily. I often will have patients come in about four weeks after starting a BTK inhibitor just to check in on them and see how they're doing and make sure they've been compliant. Amy and Jill, what's usually the first interval follow-up you'll see patients who are newly treated on BTK inhibitors in your clinic?

Jill Miller:

It depends on the patient. Sometimes we'll start out with weekly labs if they have other comorbidities that we're concerned about or if their counts are very abnormal starting out, but certainly at least monthly for the first six months of therapy and then you can space it out if they stabilize and seem to be doing well. But it does vary from one patient to the next.

Kristen Battiato:

Thank you, Jill. I totally agree. Amy, what's your practice been with managing BTK inhibitors?

Amy Goodrich:

Like Jill, I think it's really important to have a plan to watch patients very closely. Initially you talked about a lot of side effects that happen early and if you can make contact, either see patients or do telemedicine, or just making contact with them by phone to make sure that you are handling any side effects that they're having, their adherence is going to be better, they're going to be more successful. So really putting a lot of effort, education, monitoring in upfront, because once they get through those first few months, they do tend to get on autopilot and really tolerate all of these drugs quite well.

Kristen Battiato:

Oh, absolutely. I completely agree. What's your lab monitoring schedule for a patient who's on a new BTK inhibitor? How frequently would you monitor labs?

Amy Goodrich:

It depends on what their initial labs are and most people, their white counts are high and you're looking for that lymphocytosis. And if they have any renal insufficiency or, this is an older crowd, I tend to look at their labs weekly for the first month or so. That's my fallback for monitoring patients.

Kristen Battiato:

Oh, I completely agree. It seems like we all have some consistency among our practices. I think this would be a really good time to talk about a case study to pull everything together. We have a 68-year-old woman diagnosed with CLL presenting to clinic as a new visit. She walks through our doors with a white count of 117,000, hemoglobin 9.8 with a platelet count of 102 with a normal LDH. She's asymptomatic, she's feeling fine. We decided to go ahead and work her up and get some CT imaging which showed enlarged nodes in her chest, abdomen, and pelvis. The largest node was 9.9 cm in her abdomen. We confirmed her diagnosis by flow cytometry. She's got CLL. FISH and array showed a deletion 11q. TP53 was normal or wild type and her IGHV status is unmutated, so somewhat high-risk prognostic profile.

In her EKG, she had normal sinus rhythm and an echocardiogram was without structural abnormalities with a preserved ejection fraction of 60%. We did some counseling with her, and it was decided she's going to begin zanubrutinib. She comes back to clinic in about four weeks. Her white blood cell count is now 180,000, hemoglobin's 10.8, platelets are 120. Her palpable lymphadenopathy is decreasing. Reports bothersome arthralgias in her knees and hips. She's got intermittent diarrhea two to three times weekly and she's quite concerned about her blood work. So, what are the first things that you would tackle with this patient? I'm going to kick this over to Amy. Why don't you start out how you'd manage this patient?

Amy Goodrich:

Got it. I'll start with the lymphadenopathy decreasing and the white count going up. Hopefully we had talked to her previously about that shift in the lymphocyte burden into the peripheral blood. It's a great sign that her lymphadenopathy is decreasing, and it's okay that that white count is heading up. The arthralgias, she's early and you've got to assess how significant it is, how it's impacting her quality of life. Is she going to have adherence issues because of these arthralgias and really encouraging her to take some acetaminophen and potentially use some topical agents and then really making sure that she's hydrated. And well, why don't I leave the diarrhea to Jill?

Kristen Battiato:

Yeah, I'm sorry you got the dirty portion of this. Can you tell us how you'd manage her diarrhea?

Jill Miller:

Absolutely. I would start off by emphasizing the positive, which is the favorable response in her lymph nodes, the expected increase in her white count and to reinforce that this is all very positive and an expected response to therapy. And then as far as her diarrhea is concerned, I would of course want to find out more about it and make sure it's not something infectious, but if it's mild, if it's loose and not watery and if it's not too many episodes per day, I would try to manage through it and talk to her about diet and fluids and also using over-the-counter remedies. When it comes to the bowels, I always encourage patients to try very gradual changes and not swing from one extreme to the other. I might recommend trying a single dose of Imodium after one episode of a loose bowel movement and see how she responds. But really try and educate her, reassure her, and encourage her that hopefully this will improve with time as her body adjusts to being on the treatment and hopefully remain at the same dose.

Kristen Battiato:

Completely agree with both of you. And I just want to highlight that I feel like the first couple of weeks, the months of patients being on a BTK inhibitor is like you're coaching the patient through this. They're a little bit more fatigued, they have a little bit more AE side effects, just coaching them and supporting them through and encouraging compliance are really key things. Thank you both for weighing in on this.

So now it's been 12 months, she's been on zanubrutinib. She returns to clinic with a white blood cell count of five, hemoglobin's 13, platelets are 200,000, but she's got a blood pressure of 180 over 89. She's asymptomatic and reports that she's going for a right knee replacement within the month. On exam, she has resolution of palpable lymphadenopathy, arthralgias are improving and diarrhea has resolved. Jill, what would you tackle first with this patient? I'll have you tackle the blood pressure. How about that? How would you address that?

Jill Miller:

Well, that is obviously a concern. This is a possible side effect. It may also just be incidental to being on therapy, but regardless of the cause, the hypertension that needs to be addressed. I would want to first find out if this is an isolated episode and encourage her to keep a log. Let's see what it's normally running. And if it's consistently high, then she certainly needs to be either started on an anti-hypertensive or if she's already on one, have that regimen adjusted. And this is when you can really benefit from the cooperation of onco-cardiologists to advise on the optimal management of the blood pressure. And again, reassuring her this is something that is expected, and it can be managed through, and again, trying to manage through this issue rather than stop therapy or reduce her dose so she is responding so well.

Kristen Battiato:

Completely agree. We often have to collaborate with multidisciplinary teams with these patients. I also encourage my patients to buy a home blood pressure cuff because a lot of them come in with white coat syndrome, I feel like. They're very anxious when they come in. They're afraid we're going to tell them, "Oh, something's not working, your disease is progressing." They're riddled with anxiety a lot of times. I often encourage them to get a home blood pressure cuff and check it around the same time every day, keep a log like you said, and then present that to their cardiologist or primary care physician for a more accurate picture of what's going on. Amy, how would you advise her on this knee replacement?

Amy Goodrich:

Yes, so that's a big one, a knee replacement. She should hold seven days before and seven days after. I also make sure patients understand that when they hold that drug for two weeks, we may see a blip up in their white blood cell count because these drugs, although they're very effective and they can induce prolonged remissions, most patients are not in a complete remission. There's disease just under the surface and when they hold that drug, we can see increases in that white blood cell count and it's okay. And those tend to just go right back down. But that's an important teaching point as well.

Kristen Battiato:

I think you hit on all the really great points and I agree with you completely. All right, that concludes this section of the BTK AE management. I'm going to hand it back over to Amy. Thank you for your time and attention.

Amy Goodrich:

Yes, thank you. Thanks so much, Kristen, and thank you, Jill. So this brings us to the end of the discussion. Please see our other segments for further discussion on chronic lymphocytic leukemia or visit JADPRO.com. Thank you so much for joining us today.