Chronic lymphocytic leukemia (CLL) is a chronic incurable mature B-cell neoplasm that often does not require immediate treatment; however, when patients experience symptoms, such as anemia, cytopenias, or bulky lymphadenopathy, therapy is required. During a presentation at the 2022 Oncology Nurse Advisor Summit, Laura J. Zitella, MS, RN, ACNP-BC, AOCN, an associate clinical professor at the UCSF Hematology, Blood and Marrow Transplant, and Cellular Therapy (HBC) Program at the University of California San Francisco, compared approved and emerging BTK inhibitors for CLL and reviewed how to implement evidence-based strategies to manage adverse events.1

“[Bruton tyrosine kinase (BTK) inhibitors] are the most common type of medication to use for CLL at this time, but one of the primary reasons for discontinuation is adverse events. It’s really important that we are aware of the potential adverse events that can happen with these agents, and the best way to manage them,” Zitella said.

When diagnosing CLL, it’s important that molecular testing is performed. “We know that there are several mutations that have an unfavorable prognosis, which are deletion (17p), any TP53 mutation, and an unmutated IGHV deletion (11q),” Zitella explained. “Also, it’s known to be favorable if [a patient] has a deletion (13q) or a mutated IGHV.”

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Molecular testing can help to determine how often patients need to be seen if they are on active surveillance, Zitella stated. Patients who have high-risk disease should be seen more frequently in order to monitor potential progression, while low-risk patients with favorable mutations may need to be seen less frequently.  

Having a patient’s molecular profile also assists clinicians in treatment selection, as patients with deletion (17p), TP35 mutation, and unmutated IGHV do not respond well to chemoimmunotherapy.

The iwCLL Criteria outline when patients with CLL need treatment.2 All patients who are eligible for clinical trials should be encouraged to enroll, Zitella noted, as this will often allow them to receive the most promising therapies. Clinical trial enrollment also assists with data collection and a growth of medical understanding in how best to treat CLL. Other factors that will contribute to treatment initiation for CLL are significant disease-related symptoms, risk of end-organ damage, bulky disease, lymphocyte doubling time, progressive cytopenias, and progressive high-risk disease.

Zitella noted that the biggest change in guidance to treat CLL in recent years is that all of the first-line recommended regimens include targeted agents. The National Comprehensive Cancer Network (NCCN) preferred regimens for first-line treatment of CLL include acalabrutinib with or without obinutuzumab (category 1), ibrutinib (category 1), venetoclax with obinutuzumab (category 1), and zanubrutinib. For patients with relapsed/refractory disease the same agents are recommended, but treatment selection is based on selecting therapies that were not offered in the first-line.

Ibrutinib was the first BTK inhibitor to be approved and for that reason there is the most data and follow up on this drug, Zitella explained. Ibrutinib, however is a nonselective BTK inhibitor, which means that it has more adverse events compared with some of the newer, more selective agents. The second generation BTK inhibitors that are more selective are acalabrutinib and zanubrutinib. Pirtobrutinib is not currently approved, but it is a third generation BTK inhibitor that is unique in that it is noncovalent. Early data suggests pirtobrutinib may be effective in patients who demonstrate resistance to covalent BTK inhibitors.

When it comes to managing patients who are receiving BTK inhibitor therapy, Zitella explained that symptom management is “critical because in real world studies looking at patients taking ibrutinib approximately 40% to 50% discontinued [therapy] because of toxicity.” Because these are daily medications, it is essential to discuss potential side effects with patients and to act quickly when side effects do occur to ensure that patients are able to stay on treatments that offer good survival outcomes.

In a review of the potential adverse effects of therapy, Zitella noted that lymphocytosis is an anticipated effect of therapy with ibrutinib. It typically peaks between 1 and 2 months followed by a slow decline. This adverse effect should not be mistaken for progressive disease if lymph nodes are decreased, and while some patients may develop lymphocytosis that never resolves, it does not affect long-term outcomes.

Cytopenias can also occur, typically within the first few months of therapy. These are usually mild and occur more frequently in patients who receive ibrutinib compared with patients who receive acalabrutinib or zanubrutinib.

Infections are a major consideration for patients with CLL. There is no standard for routine screening or prophylaxis but when treating patients with CLL, be aware that serious bacterial, viral, and fungal infections can occur. Opportunistic infections are also common, such as hepatitis B, pneumocystis jirovecii pneumonia, and herpes simplex virus, and these should be addressed with prophylaxis. Fungal pneumonia is also a possibility, however prophylaxis is not recommended because there are drug-drug interactions with azoles. Vaccinations are recommended, including influenza, pneumococcal, and COVID vaccination.

Bleeding and bruising is a very common adverse event. Zitella noted that educating patients to anticipate easy bruising is important; although it is not serious and not associated with increased bleeding risk. However, patients must avoid over-the-counter medications that can increase bleeding risk such as aspirin, NSAIDs, fish oil, and vitamin E. For patients who require surgery, BTK inhibitors should be held for 3 days before and after a minor surgery and for 7 days before and after a major surgery. If major bleeding occurs, BTK inhibitor therapy should be stopped and the patient should receive a platelet transfusion.

Diarrhea is common, with approximately 50% of patients who received BTK inhibitors experiencing this side effect. Assessment is key to rule out infectious causes. If there is no reason to suspect infection, diarrhea can be managed with hydration, dietary modifications, antimotility agents, bile acid sequestrant, and bedtime BTK inhibitor dosing.

The occurrence of hypertension in patients who receive BTK inhibitors increases over time, it tends to occur after years of therapy. For this reason, it’s important that patients monitor their blood pressure at home as long as they are on therapy. Clinicians should initiate an antihypertensive if a patient’s blood pressure is higher than 130 mm Hg and it should be noted that CYP3A inhibitors should be avoided as they increase ibrutinib concentrations.

Atrial fibrillation is an adverse event that is most commonly seen in older male patients with a history of atrial fibrillation, hypertension, hyperlipidemia, and pre-existing cardiac disease. Zitella noted that patients are typically managed with a cardiology consultation and their ability to continue therapy will depend on severity.

Arthralgia and myalgias can have a major impact on patient adherence. Supportive care treatments include topical creams, acetaminophen, short-course steroids, NSAIDs (which are controversial because of the increase in risk of bleeding), or a magnesium supplement. Zitella also noted that she has experienced good outcomes when making minor dose reductions to address these symptoms.

Hair and nail changes may also occur and can increase over time. Pruritic maculopapular rash can be treated with topical steroids and oral antihistamines.

Adherence is a key factor when patients are on oral medications. Patients should be educated about the importance of not missing doses and taking their medications at approximately the same time each day, Zitella said. Patients who miss doses have been found to have inferior outcomes. Patients should also be encouraged to report their side effects so they can be effectively managed. It’s also important to discuss financial support with patients and make them aware of assistance programs as the expense of these drugs is a frequent concern given the costs and the length of time that patients remain on therapy.

“The BTK inhibitors have really changed the landscape of CLL, with a median progression-free survival of more than 7 years,” Zitella concluded. “Toxicity is really the primary reason for discontinuation of these highly effective medications, making optimal management of side effects critical to help patients stay on therapy. Importantly, blood pressure control is important and reduces the risk of cardiovascular events.”


1. Zitella L. Clinical Advantages: Targeting BTK in CLL. Oral presentation at: 2022 Oncology Nurse Advisor Summit; March 25-27, 2022. 2. Hallek M, Cheson BD, Catovsky D, et al. iwCLL guidelines for diagnosis, indications for treatment, response assessment, and supportive management of CLL. Blood. 2018;131(25):2745-2760. doi:10.1182/blood-2017-09-806398

This article originally appeared on Oncology Nurse Advisor