Selecting Treatment for CLL and Managing BTK Inhibitor-Associated Toxicities
Two experts discuss their approach to selecting therapy for patients with CLL and provide insight on managing adverse events when using BTK inhibitors.
Amy Goodrich, RN, MSN, CRNP: We began discussing adverse effects and how we select these drugs. Comorbidities are definitely part of this, and for some patients insurance drives which drugs they go on; some insurance plans will only cover one versus the other. We must do careful messaging to patients. These drugs are all good, they all work well, and for the most part they have manageable toxicities. I try not to hype patients up for one drug versus the other until we understand what their insurance will cover. Now that acalabrutinib is getting rid of this PPI [proton pump inhibitor] contraindication, it’ll be easier to give more acalabrutinib to patients. The data showed the adverse effect profile was more attractive with acalabrutinib. For the dosing, acalabrutunib is twice a day, and ibrutinib is once a day; sometimes that’s a showstopper for patients. I love that with zanubrutnib you have the option to dose daily or twice daily, that’s great flexibility. We must educate patients about the differences from drug to drug, and to look at the family of adverse effects, as they have much more in common than they have unique adverse effects. I try to angle it that way with patients. How about you, Kirollos?
Kirollos S. Hanna, PharmD, BCPS, BCOP: When we’re initiating therapy, like you said, insurance is a huge driver in terms of the space. I haven’t seen too much of an issue at this point. For example, if I’m looking at a patient and I’m trying to go BTK [Bruton tyrosine kinase] with ibrutinib, or venetoclax and obinutuzumab, I haven’t seen a trend in insurance telling me I can’t go one way or another in that specific setting. But for ibrutinib, acalabrutinib, or zanubrutinib, currently in the CLL [chronic lymphocytic leukemia] space, one of the hardest ones to justify is zanubrutinib, until we get an FDA approval. Although we know it’s effective and very well tolerated, many payers will not allow it without that FDA approval. So it’s between acalabrutinib and ibrutinib, and ibrutinib has held the most market share for the longest period. Then again, we are seeing quite a bit of acalabrutinib being prescribed because of the favorable AE [adverse event] profile.
When we’re evaluating our patients, we look at their comorbidities when we’re trying to make that initial treatment decision. If my patient has preexisting cardiac arrhythmias, hypertension, or uncontrolled hypertension to begin with, some of my providers will choose the acalabrutinib route, as the incidences of hypertension and cardiac arrhythmias are slightly higher with ibrutinib versus acalabrutinib. If my patients have a history of headaches or any type of anticoagulation, we have seen studies, in the ELEVATE-RR trial that you had mentioned, acalabrutinib was associated with higher rates of bruising and headaches. Sometimes that makes acalabrutinib challenging. Or if my patient may be nonadherent, I can’t go outside of bid [twice a day] dosing with acalabrutinib, and that’s where that becomes a challenge. We know in CLL, you look at RESONATE, one of the pivotal trials of BTKs, they looked at subgroup analyses, and people who were not adherent to a BTK inhibitor had worse PFS [progression-free survival] than those who were adherent. Those are some challenges that we see that drive our treatment decisions for our patients.
Amy Goodrich, RN, MSN, CRNP: We’re doing a lot of education, and we’ll talk about who’s educating. Kirollos comes from a pharmacy-heavy practice, as do I, and it’s interesting how the physician educates the patient, and then what I focus on, and what the pharmacist focuses on. Those 3 interactions give patients the whole picture, which is wonderful, but not everyone has that. When we’re starting therapy, it’s important that patients understand the highest incidence adverse effects, things like nausea, diarrhea, and bleeding. Almost as the incidences are minor bleeding, they might blow their nose and have a little bleeding, or when they’re brushing and flossing, or some easy bruising, and those are things that we must monitor carefully. Folks must have antiemetic medications. One of the pearls, when I have patients on ibrutinib, if they’re having diarrhea or nausea, I tell them to take it at night when their gut is going to slow down. Often that makes a difference. I also talk to patients about our data on the long-term toxicities and that most of these toxicities peak early and then taper down. It’s important for patients to understand that, that they must get through the first several months and gets this all under control. I tend to see or contact patients every week, because if they’re launched successfully, not only do the adverse effects not get as severe, but patients are more adherent when they don’t have uncontrolled adverse effects on these agents. Kirollos, what is your practice?
Kirollos S. Hanna, PharmD, BCPS, BCOP:I love how you brought up education, because that is key in these patients succeeding while on therapy. We’re very pharmacy driven, and once we or the provider has touched base with that patient, pharmacy will take over. We’ll do an extensive education with that patient, with their caregiver. We give them a handout called oral chemotherapy education sheets, which have been developed by 4 large oncology organizations: NCODA [National Community Oncology Dispensing Association], HOPA [Hematology/Oncology Pharmacy Association], ONS [Oncology Nursing Society], and ACCC [Association of Community Cancer Centers]. We use these education sheets to help solidify the information that we educate the patient about in terms of their medication, regardless of the BTK inhibitor that they’re on.
Our providers work alongside our pharmacists to ensure that a follow-up plan is in place, so our pharmacists will call patients 1 to 2 weeks into therapy to ask, for example, “I want to ensure you’re taking your medication at the right time each day, and you’re taking it how you should. I want to confirm when you started your medication, and are having any adverse events that we didn’t discuss, or have any adverse events pop up?” That allows us to gauge our patient, that they’ve been doing the right thing and doing well, and depending on the type of plan that’s in place for that patient, we will ensure that laboratory tests are set up appropriately. With these medications, we evaluate hypertension during those first couple of cycles, but that’s not to say that hypertension can’t happen a year into therapy. We always have pharmacy on board for follow-up for these patients early on into treatment, during the first 1 to 2 months. It’s following them closely, but going forward, depending on your patient and their ability to maintain the course that they’re on, it dictates how closely we follow them, and how many touch points we have with them.
Amy Goodrich, RN, MSN, CRNP: In terms of shared decision-making, we touched on this a bit with the BTK inhibitors, but the bigger conversation is whether we will use open-ended BTK inhibitors, versus that finite venetoclax with obinutuzumab up front, or with rituximab in the relapsed/refractory setting. That’s where patient preference comes in, whether they want to come in for those infusions and have a finite course of therapy, versus being on an open-ended drug. It’s interesting how patients have opinions about that. Let’s start diving into adverse effects, what do you think Kirollos?
Kirollos S. Hanna, PharmD, BCPS, BCOP: Adverse effects are where it becomes a bit challenging for some of our patients, and we’ve already alluded to some of the most common. Across the board with BTK inhibitors, the most common things are some GI [gastrointestinal] adverse events. Patients will be fatigued, and I don’t think that’s BTK specific for the most part, older age, having a B-cell malignancy, cancer-related things across the board there. GI adverse effects include muscle aches and pains. Then adverse events of interest include hypertension, atrial fibrillation [AF], bleeding, and neutropenias. Those are the adverse events that when we talk about the different BTK inhibitors, if I have a patient with recurrent grade 3 or 4 select adverse events, that’s where I may need to adjust the therapy, switch the therapy, or make a treatment decision in terms of what am I initiating my patient on, which is dependent on their history. A provider will come to me and ask, “What do you think about starting ibrutinib about 280 mg daily, and if they tolerate it go up to 420 mg?” And that’s always a no. I will respond saying that I don’t want this patient to develop a resistance or some type of mutation to where we can’t leverage the BTK inhibitor.
Amy, in your practice and in your approach, when you have patients come to you with some of these adverse events, do you dose reduce automatically? Do you hold? The general recommendation across the board is that we hold for grade 3 or 4 AEs. You let your patient recover, and often you can retry the same dose or reduce it by 1 level. What’s your threshold there? How do you approach these things? Are there certain AEs you don’t reduce for and you do supportive care, versus others where you do reduce?
Amy Goodrich, RN, MSN, CRNP: For things like nausea and diarrhea, typically you can work patients through those. When we only had a ibrutinib, we worked through AF, but now if someone is on ibrutinib, we tend to switch them to acalabrutinib. If someone developed AF on acalabrutinib, that would be a situation where you would then try to get approval for zanubrutinib. We now have more of these drugs, and the slight differences in the profiles make a difference. I have had patients in the older days on ibrutinib who had significant bleeding, and we’ve been able to switch them to acalabrutinib. It depends on what that toxicity is. Neutropenia is common with all of these. We often do a little dose reducing and then support people with growth factors. As we combine these agents, we will be doing more growth factor support versus dose reducing. Here’s a slide with notable AEs with BTK inhibitors. Kirollos, what are you seeing here?
Kirollos S. Hanna, PharmD, BCPS, BCOP: In terms of atrial fibrillation, hemorrhage, and those kinds of things, many people come to us with questions. I had a patient who had preexisting atrial fibrillation and it was well controlled, he was seen by cardiology, had been diagnosed with CLL for 7-plus years, and he was one of those patients who falls into the bucket of watch and wait. He was asymptomatic, he had some type of lymphocytosis, it lingered for years, until he started becoming symptomatic. The provider felt strongly about starting ibrutinib because this patient’s atrial fibrillation was very well managed. It’s important to know that having some type of AF, atrial flutter, is not a contraindication to any BTK inhibitors, and it can happen. As long as these patients are well managed, it generally stays under control for the most part. Things like hemorrhage, bleeding, and other areas where we tend to intervene are, is this patient undergoing a surgical procedure or a dental extraction? Do we need to hold therapy? Often that’s because these BTK inhibitors hit a kinase called ITK. ITK has a lot to do with how platelets aggregate and bind to one another to form clots. With BTK inhibitors, we just need to hold therapy 3 to 7 days prior.
We have many patients where we use growth factor support for their infections, and we haven’t had to dose reduce them; there are many interventions. One other thing is hypertension, which has led to discontinuation. There have been real-world data published with ibrutinib where hypertension was an issue, so we ensure that patients know how to check their blood pressure appropriately. They take averages, so that they weren’t just running a marathon or having a large cup of coffee, which falsely elevates their blood pressure. Many of our patients who visit us in the clinic are nervous, their blood pressure is falsely elevated, but at home it’s normal. These are things that we try to incorporate into clinical practice to help support patients throughout their treatment course. Patients with CLL tend to be older and frailer, so how are you incorporating their caregivers? Do you see many caregivers supporting these patients, or are therapies generally easy for patients to adhere to and stay on?
Amy Goodrich, RN, MSN, CRNP: It’s preferable for folks to have a caregiver with them. Back in the COVID-19 days, when we were not allowing people in, I called in or used FaceTime with the patient support system. We know that every person in the room will retain about 10%, so it’s better if you have more people, we’re allowing 1 visitor at this point, but it’s better than just the patient alone because they’re very overwhelmed. If the caregiver can’t be there, we message through our Epic system, answering everyone who has questions. I tell patients and caregivers to get a composition book or notebook, and come in with questions. I worry when people don’t come with questions, that they don’t understand what’s going on. Not only should they take notes during our appointment, but write their questions down. When I see these patients in follow-up, I ask them how many doses they have missed, because that opens the door for them to be honest. They’ll say “I went away for the weekend and I forgot it, I left it home, or I missed 1 dose when I went to the movies,” or whatever it is. It’s not judgmental, I just want to know how many doses they’re missing. I don’t judge people.
Often you can get co-pays down, you can have this be affordable for patients. For the ones who are a little more challenging, we’ve got social work and other layers of folks in our pharmacy who help get patients plugged in with resources. It’s important that patients understand that your goal is for them to be successful on this therapy and get the best remission possible. Also letting them know they will come in a lot in the beginning, and we will tweak these adverse effects. Fortunately, with these patients with CLL, we often have a long-term relationship with them, which is a real advantage because we have an idea of who will struggle with things, and who will be compliant and let us know if they’re having issues. That’s the other thing that patients need to know: who to call, where to call, when, and why.
Kirollos S. Hanna, PharmD, BCPS, BCOP: To many of our attendees tonight, the entire landscape of CLL has been extremely exciting. For the longest time, BTK inhibitors have completely moved chemoimmunotherapy out, it’s no longer the preferred treatment approach. With the caveat of IGHV mutation status, chemoimmunotherapy plays a small factor there. Although BTK inhibitor monotherapy is potentially one of the most utilized standards of care, based on what we learned from ASH [American Society of Hematology annual meeting], the landscape will continue to drastically evolve. I believe we’ll get to a point in CLL treatments where we’re only treating patients for a finite period, getting them to MRD negativity, or undetectable minimal residual disease, and getting them off the therapy, and letting them return to a normal life, and potentially not having to treat these patients who will live another 10, 15 years. Amy, what about you?
Amy Goodrich, RN, MSN, CRNP: I agree completely. It’s an exciting time to be involved with these patients, long gone are the days of mass FCR [fludarabine, cyclophosphamide, rituximab], Campath, and those agents. It is an exciting time, and I love that each BTK inhibitor that has come to market has been a little smarter, safer, and less toxic. It’s an exciting class of drugs.
This transcript has been edited for clarity.
