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Nichole Fisher, RN, BSN:
When patients are referred to our cancer center, it is often based on an incidental finding from lab work with their primary care provider (eg, a drop in the platelet count, an increase in the lymphocyte count, or a decrease in hemoglobin levels). Patients are often asymptomatic at the time of their CLL diagnosis and do not require immediate treatment.
Some of the more common findings we see with symptomatic patients on presentation are fatigue and what we refer to as classic “B symptoms,” which include drenching night sweats, unintentional weight loss, and fever. Those symptoms are what we regularly ask patients about at their first appointment and throughout treatment.
Enlarged lymph nodes also are common in our patient population. Sometimes patients will report having felt a lump or bump in their neck, armpit, or groin for a while, but they may not consider the bump remarkable until it progresses to the point where other people notice it as well. The lumps are often painless lymph nodes. Another common disease-related symptom is pain in the left upper abdominal area, which is due to an enlarged spleen or splenomegaly.
Some patients present to their primary care clinic with recurrent infection, which is a common disease-related symptom of CLL. Perhaps a patient has chronic sinusitis or another chronic infection that clears up with antibiotics but then comes right back. Often, this will cause a healthcare professional to order additional lab work and start looking for a cause for those recurrent infections, which can result in the patient being referred to our facility.
Nicole Lamanna, MD:
Once a patient has been diagnosed with CLL, a decision regarding whether to initiate treatment must be made. When deciding whether to treat a patient with CLL, we use the International Workshop on Chronic Lymphocytic Leukemia criteria to evaluate active disease.1 The workshop’s indications for treatment include progressive marrow failure with worsening anemia and/or thrombocytopenia, massive or progressive symptomatic splenomegaly or lymphadenopathy, and progressive lymphocytosis showing a >50% increase in 2 months or doubling in 6 months. It’s important to remember that cytopenias are relative. A patient with a hemoglobin level of 10 g/dL is anemic, but if the level has been stable and they are otherwise asymptomatic, it could be argued that the patient still can be monitored. However, patients with progressive cytopenias often will become symptomatic. Lymphocytosis also can serve as a guide because we know that a rapid increase in lymphocytosis often can signal the development of cytopenias such as anemia and thrombocytopenia. Absolute lymphocytosis on its own may not require treatment, but progressive lymphocytosis can indicate that a patient should be monitored more closely.
I often perform biopsies to assess for symptomatic or functional extranodal involvement (such as of the skin, kidney, or lung) that may require treatment. Patients who develop progressive disease also may have other symptoms such as fatigue, night sweats, weight loss, and fevers.
Nicole Lamanna, MD:
Let’s shift gears to begin our discussion of managing BTK inhibitor–associated AEs. Two covalent BTK inhibitors—ibrutinib and acalabrutinib—currently are approved by the FDA for treating CLL/small lymphocytic lymphoma (SLL).2,3 Treatment regimens that include BTK inhibitors, along with those that include venetoclax, are now considered standard-of-care treatment options for patients with CLL.4
The covalent inhibitor zanubrutinib is approved for treating specific patients with mantle cell lymphoma, marginal zone lymphoma, and Waldenström macroglobulinemia, and the drug may be approved in the near future for patients with CLL based on phase III data from the SEQUOIA and ALPINE trials.5-7 Noncovalent BTK inhibitors currently are being evaluated in clinical trials, including pirtobrutinib and nemtabrutinib. Pirtobrutinib is the furthest along in development with several ongoing phase III trials.
Nicole Lamanna, MD:
BTK inhibitors, as a class, are commonly associated with atrial fibrillation (AF), hypertension, bleeding issues, infection, arthralgias, and diarrhea.8 In addition, AEs including dermatologic toxicities, fatigue, cytopenias, and ventricular arrhythmias also may be encountered.
Anthony Perissinotti, PharmD, BCOP:
In general, BTK inhibitors are very well tolerated, far more so than chemoimmunotherapy. However, it is important to be aware of the unique toxicities associated with these agents so toxicities can be identified and treated early, with the goal of avoiding premature discontinuation due to AEs if possible.
Nichole Fisher, RN, BSN:
When a patient is ready to start treatment with a BTK inhibitor, nurses will educate on adverse events to monitor for (as discussed by Dr. Lamanna). We also emphasize compliance to our patients because data show a greater risk of disease reoccurrence if the drug is discontinued longer than a few days, which can lead to tumor flare.
Considering potential AEs with ibrutinib, one of the things I educate patients about initially is how to take the medication. BTK inhibitors can be taken with or without food, but one big caveat is that grapefruit juice will interact with the medication, so patients should be counseled not to drink any sort of grapefruit juice while receiving a BTK inhibitor.
Nichole Fisher, RN, BSN:
Before we continue, let’s discuss a patient case. A 77-year-old man with stage B CLL was started on ibrutinib. At his 3-month follow-up appointment, his adenopathy and splenomegaly had resolved, but he complained of easy bruising and cramps in his feet. His absolute lymphocyte count was 67.3 x 109/L, hemoglobin was 11.2 g/dL, and platelet count was 95 x 109/L.
At the patient’s 6-month follow-up, he complained of intermittent palpitations. At that point, his absolute lymphocyte count was 37.5 x 109/L, hemoglobin was 11.3 g/dL, and platelet count was 98 x 109/L. An ECG showed sinus rhythm, so a Zio patch was placed. The patient showed intermittent AF with a heart rate of 70-128 beats per minute.
Nichole Fisher, RN, BSN:
Looking at this patient’s case, something that stands out is his early complaint of easy bruising and cramps in his feet. Bruising is a common AE of ibrutinib, in addition to bleeding risk. His hemoglobin level and platelet count are both low, and the patient is likely not clotting quite as easily as he should be, which can explain the increased bruising.
His 3-month lymphocyte count is still relatively high. It can take a longer time on ibrutinib therapy to decrease lymphocyte count compared with obinutuzumab. So, to me, that is kind of an expected value.
After 3 more months, the patient is starting to experience palpitations, which also are a known AE with ibrutinib therapy. We would want to continue monitoring those. The ECG showed normal sinus rhythm, but often an ECG will not capture AF unless the patient is actively experiencing it. That can be a downfall of relying on ECG.
The patient’s platelet count did show a slight improvement from 3 months to 6 months. The lymphocyte count dropped by half, which is expected after 6 months of treatment, and lymphocyte count should continue to decline.
These are all expected outcomes for a patient with CLL on ibrutinib. If his disease continues to get worse, then the treating provider would assess whether treatment should be held, dose reduced, switched to acalabrutinib or another agent.
Anthony Perissinotti, PharmD, BCOP:
It is very important to educate a patient like this up front about the likelihood of easy bruising once he starts ibrutinib so that he will not be alarmed by it but will know to call us if those bruises turn into bigger bruises or if it looks like there is fluid under the bruise. In most cases, patients will find that they just bruise more easily if they bump into something, and we educate patients to push through that.
This patient’s intermittent palpitations suggest to me that he probably has AF. I find that most of my patients who have AF don’t even realize it until we spot it on an ECG. This patient does unfortunately have symptoms from his AF, and the ECG shows his heart rate is above normal.
For this patient, we would likely hold his BTK inhibitor and control the AF with a β-blocker. We also would calculate his CHA2DS2-VASc or CHADS2 score to determine if he needs additional stroke prevention with either aspirin or an anticoagulant. Then, we would follow up in 1 week or so to make sure that his symptoms have reduced and that he is not having ongoing palpitations.
Let’s take a closer look at some of these points.
Nicole Lamanna, MD:
Many of the toxicities associated with BTK inhibitors are thought to be due to the off‑target effects of these agents. Different BTK inhibitors have different off‑target effects based on their affinity for TEC, EGFR, and ITK.8 The second-generation BTK inhibitors acalabrutinib and zanubrutinib appear to have a lower incidence of certain AEs when compared with first-generation ibrutinib in randomized trials.7,9
Nichole Fisher, RN, BSN:
The IC50 of a BTK inhibitor for TEC, EGFR, and ITK tells you, in a sense, what AEs might be more prevalent with the medication. With high EGFR inhibition, you likely will see a higher rate of rash and diarrhea; with high ITK inhibition, you can expect more infection and pneumonitis. Ibrutinib has a greater effect on TEC, which is thought to lead to bleeding and cardiotoxicity as common risks.8
Nicole Lamanna, MD:
We are starting to see some of these toxicity differences in the safety outcomes reported from randomized clinical trials of next-generation BTK inhibitors. The ELEVATE-RR study was an phase III noninferiority trial that randomized 533 adults with previously treated relapsed/refractory (R/R) CLL with del(17p) or del(11q) to receive acalabrutinib or ibrutinib. Patients could not have significant cardiovascular disease or prior exposure to BTK inhibitors or the BCL-2 inhibitor venetoclax.9 The primary endpoint was noninferiority of independent review committee–assessed progression-free survival, and secondary endpoints included overall survival, any-grade AF/flutter, and grade ≥3 infection.
Anthony Perissinotti, PharmD, BCOP:
In this trial, the second-generation BTK inhibitor seemed slightly better tolerated than ibrutinib (AEs leading to treatment discontinuation: acalabrutinib, 14.7%; ibrutinib, 21.3%). Incidence of any-grade AF, hypertension, arthralgia, diarrhea, and contusion were significantly lower with acalabrutinib compared with ibrutinib, as were grade ≥3 hypertension and diarrhea. Overall, bleeding events occurred in 51% of patients who received ibrutinib and 38% of patients who received acalabrutinib.
Nicole Lamanna, MD:
The phase III ALPINE study randomized 652 patients with previously treated R/R CLL/SLL to receive either zanubrutinib or ibrutinib. The primary endpoint was investigator-assessed overall response rate.7
Anthony Perissinotti, PharmD, BCOP:
Similar to ELEVATE-RR, the ALPINE interim analysis of 415 patients showed a significant reduction in any-grade AF with zanubrutinib compared with ibrutinib (2.5% vs 10.1%). Results of this study still are too early to be able to fully evaluate other AEs. We are eagerly waiting longer-term follow-up of these studies to determine how second-generation BTK inhibitors compare with first-generation inhibitors in terms of efficacy and safety.
Nicole Lamanna, MD:
BRUIN was a phase I/II, first-in-human study of pirtobrutinib—one of the next-generation, noncovalent BTK inhibitors—in patients with CLL/SLL or B-cell non-Hodgkin lymphoma.10,11 This dose-escalation/expansion trial enrolled patients who previously were treated, including those with intolerance to a first-line BTK inhibitor. The safety analysis included 323 patients receiving pirtobrutinib.
Nichole Fisher, RN, BSN:
Fatigue of any grade was the most common AE reported, occurring in 20% of patients. Diarrhea and bruising also were seen and were most often of grade 1 severity. I have worked with patients on clinical trials with this medication, and so far it has been very well tolerated.
Anthony Perissinotti, PharmD, BCOP:
Pirtobrutinib has a greater selectivity for BTK than ibrutinib and appears to be a promising agent for patients who have progressed on a BTK inhibitor. It is important to remember that a patient who progresses on ibrutinib can’t receive zanubrutinib or acalabrutinib and vice versa—progression on any of the covalent, irreversible BTK inhibitors means you cannot switch to 1 of the others. The second-generation BTK inhibitors were not developed for improved efficacy and don’t overcome specific resistance of ibrutinib; they were specifically designed to improve tolerability by being more selective for BTK.
Pirtobrutinib does have activity in patients who progress on ibrutinib, zanubrutinib, or acalabrutinib, and in addition to overcoming some of the resistance with these agents, pirtobrutinib also seems to be well tolerated without many of the traditional BTK inhibitor–associated toxicities. We will continue to monitor how well tolerated this agent is as we start to see phase III comparative data.
Nicole Lamanna, MD:
AF is perhaps the most well-known of the cardiac AEs that can be associated with BTK inhibitors. It occurs most frequently with ibrutinib and is observed in 5% to 15% of patients, most often within the first year and especially within the first 3 months of treatment initiation.12 Age can be an important risk factor for AF; many of our patients with CLL are older, and there is a higher incidence of AF in our older patient population.
When considering treating a patient with a BTK inhibitor, it is useful to obtain a baseline clinical risk assessment of their cardiovascular risk factors before initiating therapy. There are multiple scoring systems available, including the CHA2DS2-VASc assessment, which offers an interdisciplinary risk–benefit assessment.
Anthony Perissinotti, PharmD, BCOP:
I often recommend stratifying a patient’s risk of AF using a scoring tool created by Shanafelt and colleagues13 that uses clinical characteristics that include age, sex, and the presence of hypertension to estimate the likelihood of a patient developing AF.13 If the patient has a high score with this tool, we generally will lean toward using a second-generation BTK inhibitor to help reduce the risk of AF.
Nicole Lamanna, MD:
When a patient develops AF, many healthcare professionals will hold the drug temporarily until the condition is controlled and then discuss with the patient whether they would like to go back on a BTK inhibitor.2,3 An option for those who wish to continue with a BTK inhibitor might be to choose an alternative second-generation agent if the patient was receiving ibrutinib.
Anthony Perissinotti, PharmD, BCOP:
In general, the management of AF in patients receiving a BTK inhibitor is no different than management in the general population. The first goal is to get the patient either rate controlled or rhythm controlled. If we’re doing rhythm control, we’ll consult with our cardiologists and electrophysiologists for help. Most of the time, though, in our clinics, we focus on rate control, generally with β-blockers. If we do use calcium channel blockers, we have to be aware that both verapamil and diltiazem can interact with BTK inhibitors and increase their concentrations, which could end up leading to more toxicity. We always have to be cautious of drug interactions.
The next consideration is whether the patient needs anticoagulation to decrease their risk of a stroke. A CHADS2 score >1 indicates that the patient should receive anticoagulation. We generally try to avoid warfarin; warfarin is not commonly used even in the general population anymore, and in early BTK inhibitor trials, it was associated with additional bleeding. Instead, we use newer oral anticoagulants such as apixaban or rivaroxaban. These drugs appear to be safer, but it’s still important to educate patients about bleeding risk. The anticoagulant slightly increases the risk of bleeding, and the BTK inhibitor can inhibit platelets and cause increased bleeding risk. Where possible, we want to avoid combination with a vitamin K antagonist.
Nichole Fisher, RN, BSN:
When a patient is receiving warfarin or another anticoagulant, we often work with our pharmacists to make sure that the patient maintains a therapeutic prothrombin time/international normalized ratio range. Patients are often started on a β-blocker, and they also can have antiarrhythmic drugs such as sotalol or dofetilide if they have other cardiac conditions such as congestive heart failure.
Nicole Lamanna, MD:
Hypertension is a notable potential AE with this class.8,14 For a patient who has hypertension before beginning BTK inhibitor therapy, it is a good idea to work with their internist or cardiologist to optimize management. A patient may require dose adjustments of current medications while receiving the BTK inhibitor.
Nichole Fisher, RN, BSN:
Hypertension also increases over time, so we monitor it closely for any patient receiving a BTK inhibitor.
Anthony Perissinotti, PharmD, BCOP:
Controlling hypertension in patients with CLL who will receive a BTK inhibitor is very important to reduce their risk of cardiovascular events, including myocardial infarction and stroke. Anywhere from 20% to 40% of patients receiving ibrutinib may end up requiring an antihypertensive agent; some patients require 2 antihypertensives. It is important to monitor the patient, and we initially have our patients monitor their blood pressure at home. Hypertension often occurs in the first 3-6 months of treatment, but I’ve had patients develop it even years later. We manage hypertension in patients receiving BTK inhibitors just like the general population. No specific antihypertensive works best; typically I recommend an ACE inhibitor for hypertension.
Nicole Lamanna, MD:
Bleeding is another AE that can be encountered with BTK inhibitors.8 Most often it is minor bleeding, petechiae, and ecchymoses, which do not necessitate stopping the therapy. However, patients should be told about this risk so they don’t panic if they experience some form of bleeding. Major bleeding is relatively rare, but if a patient is going to have a surgical procedure, you want to counsel them about when to hold their BTK inhibitor.2,3
The mechanism underlying the increased risk of bleeding is thought to involve inhibition of BTK and TEC family kinases, which play an important role in platelet aggregation mediated through the collagen receptor glycoprotein VI.
Anthony Perissinotti, PharmD, BCOP:
Although ibrutinib was associated with a numerically higher bleeding risk than acalabrutinib in ELEVATE-RR, bleeding risk is difficult to study in clinical trials. You need a very large patient population and long follow-up, neither of which we have in ELEVATE-RR or ALPINE.7,9
Nichole Fisher, RN, BSN:
Bleeding often can be mitigated by a temporary hold on the medication. We also have patients hold a BTK inhibitor around surgical procedures, usually 3 days for a minor procedure and 7 days for a major procedure. We educate patients to watch for signs and symptoms of bleeding, such as a cut that won’t stop bleeding after 5 minutes or bleeding of the gums. We educate patients to call the clinic if they see any of these common signs so that we can assess their symptoms.2,3
Nicole Lamanna, MD:
If patients have severe bleeds, they may need transfusion of platelets to overcome their clinical bleeding, regardless of their platelet count. And, again, it is important to take a good over-the-counter supplement history from your patients to determine if they are taking any other supplements, such as vitamin E or fish oil, that may exacerbate bleeding risk.
Anthony Perissinotti, PharmD, BCOP:
To reduce our patients’ bleeding risk, we scan their full medication list, including those over-the-counter medications, and try to eliminate any they do not need that may increase bleeding risk. Prior to any procedure, we also ask our patients to tell their healthcare professionals they are taking a BTK inhibitor that has antiplatelet effects.
Nicole Lamanna, MD:
Infections are common in patients with CLL and occur in about 50% of patients receiving BTK inhibitors.8 Pneumonia and sinusitis are the most common infections we observe in our CLL patient population, but you also should have a higher index of suspicion for opportunistic infections, such as aspergillus and pneumocystis, which have been reported in patients receiving BTK inhibitors. It is important to counsel your patients to call you about any signs or symptoms of infection and work with other members of their care team who may be less familiar with BTK inhibitors—such as a pulmonologist, internist, or infectious disease specialist—to help monitor for and manage infections.
In the case of a severe infection, particularly if you think a patient may need a bronchoscopy, biopsy, or other procedure, you may want to hold the BTK inhibitor until you make a definitive diagnosis and then restart after clinical improvement. For minor infections that don’t require procedures or antibiotics, you generally can continue the BTK inhibitor without interruption.
Clinically indicated vaccinations are recommended for patients prior to starting BTK inhibitor therapy, as appropriate. For heavily pretreated patients, you might want to consider PJP or zoster prophylaxis, depending on the patient’s prior therapies, how heavily they were pretreated, and their history of infections.
Nichole Fisher, RN, BSN:
Diarrhea is the most common nonhematologic AE observed in patients receiving BTK inhibitors and often occurs early in the treatment course. Diarrhea is typically self‑limiting. We often recommend antimotility agents; patients are given loperamide, and if that is not sufficient, they may be prescribed diphenoxylate/atropine. We also can switch from tablets to capsules to help reduce gastrointestinal distress and continue therapy. Typically, we do not have to reduce the BTK inhibitor dose due to diarrhea, but if the diarrhea continues or worsens to grade 3, the medication is often held until that is resolved.
Nicole Lamanna, MD:
Other AEs that can occur with BTK inhibitors include fatigue, arthralgias, and myalgias.8 Fatigue is commonly reported in our patients with CLL, and it can be difficult to distinguish whether this is related to the drug or to the disease itself. Especially early in the treatment course, we encourage patients to continue taking the drug if possible, and we also look for other possible causes of fatigue. If the fatigue is debilitating despite a negative workup, you may want to hold the drug to see if it is related to therapy. I have seen cases in my practice when it was related.
Arthralgias and myalgias can be difficult to manage. When low-grade events occur early in treatment, they usually can be managed with supportive care and often resolve with time. Higher-grade events or those that develop later can be more difficult to manage. You can try to reduce the dose or hold the therapy until symptoms resolve and then restart at a lower dose.
Most evidence for treatment is anecdotal. Some people have tried magnesium or quinine, a short course of anti‑inflammatory agents if the patient is able to tolerate them, or short courses of steroids. Early on, arthralgias and myalgias tend to improve. In some cases, however, they may keep recurring. At that point, patients may need to move from ibrutinib to acalabrutinib or zanubrutinib or even switch to a different class of therapy, such as a BCL-2 inhibitor.
Nicole Lamanna, MD:
Cytopenias also can occur with BTK inhibitors and often can be managed with supportive care—such as growth factors—or dose reduction.8 Treatment-emergent flares of autoimmune cytopenias can be managed with a short course of corticosteroids or sometimes a CD20 monoclonal antibody treatment that can be added to the BTK inhibitor.
BTK inhibitor–related skin manifestations are often responsive to corticosteroids, but it may depend on the degree of the skin AE. For something small, a topical treatment is usually effective; for a more profound condition, you may need to consider holding the BTK inhibitor and giving a short course of oral corticosteroids, as needed. Patients can experience textural changes in their hair or nails, which can be treated with biotin supplementation and the application of nail oils, although we have seen variable results with those products.
Headaches can be seen after initiation of acalabrutinib, but headaches usually resolve with extended treatment and are often responsive to caffeine. I have never had to take a patient off therapy due to headaches.
Nichole Fisher, RN, BSN:
Headaches are the most unique side effect of acalabrutinib. They typically occur early in treatment and don’t recur once they subside. These headaches often can be addressed with hydration or caffeine, and it is uncommon for them to be severe.
Nicole Lamanna, MD:
When ibrutinib was approved, most of the data available were from studies that enrolled heavily pretreated patients with R/R disease.2 In that population, holding a dose due to an AE frequently led to disease progression.8,15 As the BTK inhibitors have been studied in less heavily pretreated patients, additional data suggest that dose reductions or temporary cessations of therapy do not compromise long‑term clinical outcomes in these populations.16 So, although I think that dose modification or interruption of BTK inhibitor therapy is a concern in refractory and heavily pretreated patients, it is less of a worry in the frontline setting. Fortunately, clinically indicated dose reductions—if a grade ≥3 AE doesn’t respond to management, for example—are unlikely to lead to the development of drug-resistant clones. Overall, though, we want to manage BTK inhibitor AEs in our patients to allow them to extend their usage of this class, given its efficacy in CLL. A patient receiving ibrutinib can try a second-generation BTK inhibitor. A patient receiving a second-generation agent may need to think about switching therapeutic classes.
Nichole Fisher, RN, BSN:
To summarize, the primary safety considerations with ibrutinib are AF, increasing risk of hypertension over time, and bleeding risk, which often can be mitigated by a temporary hold of the medication. Diarrhea, although common, is typically self‑limiting with the use of antimotility agents and rarely requires dose reduction.
With acalabrutinib, AF is of a potentially lower concern than with ibrutinib, but it remains important to monitor for this AE. Diarrhea is generally the most common nonhematologic AE with acalabrutinib, and patients may require antimotility agents for management. Headaches are the most unique AE with acalabrutinib, often occurring early in treatment, and typically can be treated with caffeine and hydration.
A history of AF, gastrointestinal issues, chronic kidney disease, or congestive heart failure all can play a role in the therapy decision between the doctor and the patient. Regarding concurrent medications, we work with our pharmacist to check for any interactions or exclusions, such as any type of proton pump inhibitor with acalabrutinib, that might necessitate a medication change.
Nicole Lamanna, MD:
It is very important to take a complete clinical history—including patient‑specific comorbidities—when considering therapy for your patient with CLL. For a patient with arrhythmias or poorly controlled hypertension, you may want to consider another treatment option instead of a BTK inhibitor. As data continue to emerge on the use of BTK inhibitors in combination with other therapeutic agents, such as venetoclax, we hope to reach a point where most frontline treatment will be of a fixed duration rather than indefinite, which may reduce the challenge of longer‑term toxicities observed with extended BTK inhibitor–based therapy. Longer follow-up with randomized clinical trials comparing ibrutinib with newer BTK inhibitors will provide clearer differences in the toxicity profiles of the different BTK inhibitors. Given the impressive efficacy of BTK inhibitors in the treatment of CLL, appropriate management of BTK‑emergent toxicities is of critical importance. We can expect that this class of inhibitors will remain a mainstay of CLL therapy for quite some time.
Let’s now return to the question from earlier in the activity.
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