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Questions on BTK Inhibitors

Pharmacists Discuss Key HCP Questions on BTK Inhibitors

Released: December 23, 2022

Expiration: December 22, 2023

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Key Takeaways
  • BTK inhibitor choice and adverse event (AE) management strategies are based on AE severity, patient factors, and healthcare professional preferences.
  • Cardiac toxicities and bleeding can occur with BTK inhibitors; appropriate AE management is essential for patient safety and maximizing the efficacy of these agents.
  • Pharmacists should have pivotal roles in treatment decisions, AE management, and other aspects of patient care. 

In this commentary, Karen M. Fancher, PharmD, BCOP, and Anthony Perissinotti, PharmD, BCOP, provide expert pharmacist perspectives on frequently asked questions about the use of Bruton tyrosine kinase (BTK) inhibitors in clinical practice.

How are BTK inhibitors used for CLL and MCL?

Karen M. Fancher, PharmD, BCOP: 
Currently, 3 BTK inhibitors are approved by the FDA: ibrutinib, acalabrutinib, and zanubrutinib.

These 3 BTK inhibitors are indicated for multiple B-cell malignancies. Ibrutinib, a first-generation BTK inhibitor, has indications for treating adults with relapsed/refractory (R/R) mantle cell lymphoma (MCL), chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL), Waldenström macroglobulinemia (WM), and marginal zone lymphoma (MZL). Ibrutinib also has an indication for treating adult and pediatric patients with chronic graft-vs-host disease. Acalabrutinib has indications for treating adults with MCL and CLL, and zanubrutinib has indications for treating MCL, WM, and MZL. We anticipate that the FDA will soon approve zanubrutinib for the treatment of CLL based on the results of the ALPINE trial, which are discussed below. 

All of these BTK inhibitors are selective for BTK. However, each has different off-target binding, which affects toxicity profiles.

What are the common toxicities of BTK inhibitors?

Anthony Perissinotti, PharmD, BCOP: 
Common toxicities associated with BTK inhibitors include dermatologic changes (including rashes), diarrhea, infection, and arthralgia. BTK inhibitors also can be associated with cardiac adverse events (AEs), including atrial fibrillation and, rarely, ventricular arrhythmias. These therapies also can inhibit platelets, resulting in an increased risk of bleeding. Hypertension, an unexpected toxicity, can present in the first few months but can continue to appear after several years of BTK inhibitor therapy.

Is atrial fibrillation an absolute contraindication to the use of a BTK inhibitor?

Anthony Perissinotti, PharmD, BCOP: 
No, atrial fibrillation is not an absolute contraindication to BTK inhibitor therapy. In patients with controlled atrial fibrillation, BTK inhibitors still may be an option. In my practice, I do not immediately eliminate BTK inhibitors as therapy options for these patients if they are the best choice from an efficacy standpoint.

Karen M. Fancher, PharmD, BCOP: 
I agree. I would add that the patient should be an integral part of the treatment decision. They should be made aware of the potential for recurrent atrial fibrillation with a BTK inhibitor and asked about their level of comfort with the risk. 

Anthony Perissinotti, PharmD, BCOP: 
Absolutely. Of course, for highly symptomatic patients with grade 3 or 4 atrial fibrillation, it is necessary to medically manage the atrial fibrillation before initiating the BTK inhibitor. A common topic of discussion is whether such patients can be treated with a BTK inhibitor if their atrial fibrillation is controlled or if they should be treated with another drug class (eg, venetoclax-based therapy). According to the literature, 10% to 20% of patients develop atrial fibrillation with ibrutinib. However, most of these events are of grade 1 or 2 severity and diagnosed incidentally on an EKG, with the patient being asymptomatic. The incidence of grade 3 or 4 atrial fibrillation is approximately 4% to 5%. In patients with higher-grade events, BTK inhibitor therapy typically can be temporarily interrupted while the atrial fibrillation is medically managed. My experience is that with the second-generation BTK inhibitors, zanubrutinib and acalabrutinib, only 1% to 2% of patients need to permanently discontinue BTK inhibitor therapy due to uncontrolled atrial fibrillation. 

Another frequent discussion topic has to do with dose reductions in patients with BTK inhibitor‒related atrial fibrillation. It is not known whether atrial fibrillation is a dose-dependent AE. My strategy generally is to follow the prescribing information in terms of dose reductions.

For patients who just started taking a BTK inhibitor, how often should I tell them to monitor their blood pressure?  

Karen M. Fancher, PharmD, BCOP: 
I work in a community-based practice, and we do not have an in-house cardio-oncology consult or anyone similar, so we are highly dependent on the patient’s primary care provider (PCP). We defer to the patient’s PCP for decisions on choice of drug, lifestyle recommendations, and other aspects of the patient’s care.

Anthony Perissinotti, PharmD, BCOP: 
That is a great approach, as the patient’s PCP will be the expert in their care. In our clinics, we generally tell our patients to check their blood pressure once monthly, stay in touch with their PCP, and alert us if they start to notice trends toward larger increases of 10-20 mm Hg. We also remind them that there may be several years of BTK inhibitor therapy before hypertension presents.  

Because 40% of patients receiving ibrutinib require antihypertensive medication, the issue arises as to whether preemptive hypertensive medication should be prescribed. I do not think preemptive antihypertensive medication is warranted when starting a BTK inhibitor because, although 40% of patients eventually will need an antihypertensive medication, that means 60% will not. In addition, the incidence of hypertension was shown to be lower with acalabrutinib in the ELEVATE-RR trial of acalabrutinib vs ibrutinib for previously treated CLL. We haven't seen the same comparative reduction in hypertension with zanubrutinib yet, but it's possible that we need a longer follow-up period to compare the incidence with ibrutinib.

Karen M. Fancher, PharmD, BCOP: 
I agree. As you pointed out, it can take years for a patient to develop hypertension. In this case, if the patient was proactively treated with an antihypertensive medication, they may be taking an unnecessary medication for a long time.  

My patient had a nosebleed and went to the ER. Do I need to hold their BTK inhibitor for that mild bleeding event?  

Anthony Perissinotti, PharmD, BCOP: 
In these cases, I take the same approach as I do with apixaban or rivaroxaban. That is, if the patient’s nosebleed was controlled in a reasonable time or if they are not having multiple nosebleed recurrences, then the BTK inhibitor can be continued without interruption. However, if the patient experiences multiple nosebleeds, then I will have them temporarily interrupt the BTK inhibitor while they consult with an ENT or PCP to ensure that there is no underlying cause. Once the issue is resolved, I will have the patient continue on their BTK inhibitor regimen. Dr Fancher, do you have a different approach?

Karen M. Fancher, PharmD, BCOP: 
No. I agree with you 100%.

Anthony Perissinotti, PharmD, BCOP: 
Let me throw a curveball question at you about patients who are at high risk for bleeding. Let’s use the example of a patient who is receiving clopidogrel with aspirin and apixaban. Would you be wary of prescribing any BTK inhibitor for this patient and recommend a different class of therapeutic agent, or would you consider a BTK inhibitor? If so, would you prefer a second-generation agent over a first-generation agent such as ibrutinib? In this instance, I would switch the patient to a completely different, non‒BTK inhibitor therapy. 

Karen M. Fancher, PharmD, BCOP: 
I would definitely be wary of ibrutinib in this case, and I might be wary of zanubrutinib based on data with myelosuppression, even though these data are not specific for platelets. This leaves the options of acalabrutinib or another therapy, such as venetoclax. Of these 2 options, I am not sure I have a preference. 

Anthony Perissinotti, PharmD, BCOP: 
The patients you describe are the populations we worry about in the real world. Moreover, in patients with MCL, we do not have better options than BTK inhibitors. Venetoclax is potentially an option for patients with CLL, but eventually these patients will need a BTK inhibitor. The lack of alternatives means that, ultimately, we need to talk with the patient about the risks vs benefits of BTK inhibitor therapy. It also is essential to educate patients about the signs and symptoms of bleeding, reporting bleeding to us should it occur, and when they should go to the ER. It should be noted that all of the approved BTK inhibitors are associated with some degree of bleeding risk. Between acalabrutinib and zanubrutinib (the second-generation BTK inhibitors), the most robust data are available for acalabrutinib. 

Did data from ALPINE presented at ASH 2022 affect how you will approach treatment for patients with CLL?

Anthony Perissinotti, PharmD, BCOP: 
The final analysis of ALPINE was presented at ASH 2022; interim results from this trial were presented at EHA 2021. In ALPINE, 652 patients with R/R CLL/SLL who had received ≥1 prior systemic treatment (but no prior BTK inhibitors) were randomized to receive zanubrutinib or ibrutinib. The primary endpoint was noninferiority and superiority of investigator-assessed overall response rate (ORR), and secondary endpoints included progression-free survival (PFS) and incidence of atrial fibrillation/flutter. 

In this study, zanubrutinib significantly improved PFS vs ibrutinib (HR: 0.65; 95% CI: 0.49-0.86; P = .002; median follow-up: 29.6 months). ORR also was significantly improved with zanubrutinib vs ibrutinib (86% vs 76%; P = .007). AEs leading to treatment discontinuation occurred numerically more frequently with ibrutinib (22%) vs zanubrutinib (15%), and the incidence of atrial fibrillation/flutter was significantly decreased (zanubrutinib 5.2%; ibrutinib 13.3%; P = .0004).

Based on these results and results from the SEQUIOA trial, zanubrutinib will likely receive FDA approval for CLL in the near future. The ALPINE trial adds to findings from the ELEVATE-RR trial of acalabrutinib vs ibrutinib; per national guidelines, the second-generation BTK inhibitors are now preferred therapies for CLL. While it is tempting to cross-trial compare the ELEVATE-RR and ALPINE studies and conclude that acalabrutinib is the safest BTK inhibitor and zanubrutinib is the most effective BTK inhibitor, this cannot be concluded with certainty in the absence of a trial directly comparing these second-generation BTK inhibitors. Both acalabrutinib and zanubrutinib are excellent options for our patients with CLL and MCL.

How should BTK inhibitor dose modifications be approached for nonhematologic AEs?

Anthony Perissinotti, PharmD, BCOP: 
Following the recommendations in the prescribing information for each BTK inhibitor is a good strategy for dose modifications with nonhematologic AEs. I like the strategy in the ibrutinib prescribing information, which advocates dose reductions for the first 2 occurrences of grade 3/4 AEs and discontinuation at the third recurrence. This strategy was updated during the last label update in August 2022. Previously, the ibrutinib prescribing information advocated a strategy that mimicked that for acalabrutinib, which recommends dose reductions at the third occurrence of grade 3 or 4 nonhematologic AEs. In some situations—for example, if I am concerned about a patient with their first grade 4 nonhematologic AE—I will initiate an early dose reduction with acalabrutinib, and I definitely will initiate a dose reduction at the second occurrence. 

What is the pharmacist’s role in optimizing therapy?

Anthony Perissinotti, PharmD, BCOP:
I think it is essential that pharmacists have integral roles in therapy decisions. Most treatment decisions in CLL and MCL are based heavily on patient comorbidities and drug toxicity profiles—both of which are pharmacists’ fields of expertise. In addition, pharmacists can provide insight into potential drug interactions.

Pharmacists also should be included in AE management. Data show that AE management is enhanced when pharmacists contribute, and patients who were treated by a pharmacist had better PFS than those who were not under a pharmacist’s care. This survival benefit may be attributed to patients receiving better AE management when a pharmacist is part of the care team, resulting in fewer grade 3 or 4 AEs. Consequently, patients tolerated therapy better and stayed on it longer.

Pharmacists also have pivotal roles in adherence. Patients who are nonadherent—meaning patients who miss their dose ≥20% of the time—experience lower overall survival and PFS. Missing a dose ≥20% of the time is essentially equivalent to missing >1 day of the week. Hence, therapy adherence is essential for maximal therapeutic efficacy. Pharmacists have expertise in ensuring patient adherence through counseling and can help patients tolerate their therapies, thereby making it less likely that the patient will miss doses.

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