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Managing BTK Inhibitor Toxicities

CE / CME

Optimizing the Use of BTK Inhibitors in B-Cell Malignancies: Addressing BTK Inhibitor Toxicities

Pharmacists: 1.00 contact hour (0.1 CEUs)

Physicians: Maximum of 1.00 AMA PRA Category 1 Credit™

Nurses: 1.00 Nursing contact hour

Released: September 29, 2021

Expiration: September 28, 2022

Christopher R. Flowers
Christopher R. Flowers, MD, MS
CME/CE Information

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BTK Inhibitor AE Management: Bleeding and Infections

Turning now to management of these AEs, we will first discuss hemorrhage and bleeding with BTK inhibitors. These events can be mild. Some increased risk of bleeding is associated with the BTK inhibitors, but the risk is much greater when patients are receiving concomitant anticoagulation or antiplatelet therapy.20

When the sole risk factor is the BTK inhibitor, bleeding and hemorrhaging generally can be managed by supportive care measures alone for events such as nosebleeds. More significant bleeding or bleeding risk can be managed by holding the BTK inhibitor, which we will discuss later in more detail. In rare instances, platelet transfusions may be needed to resolve bleeds.16

When a minor or major surgical intervention is being planned, the BTK inhibitor should be held 3-7 days before and about 3-7 days after the surgery, depending upon the intensiveness of the surgical procedure.21

Pharmacists and nurses play a key role in educating patients about the ongoing risks of hemorrhage and bleeding with BTK inhibitor therapy. For example, patients starting therapy should be counseled to avoid NSAIDs for headache, myalgias, or other events because of the higher risk of bleeding.22,23 Patients also should be educated on the importance of monitoring for symptoms of bleeding, such as easy bruising, and to report these symptoms to their care team. As mentioned above, anticoagulant and antiplatelet therapy can increase the risk of bleeding with BTK inhibitors. Pharmacists and nurses are vital to screening for these and other drug–drug interactions, which we will review later in more detail.

As discussed earlier, infections also can occur with BTK inhibitor therapy. It is important to monitor and evaluate patients for fever and infection, and treat them appropriately. Infection always should be considered when a patient on BTK inhibitor therapy develops a fever.16,24 These can even be unusual infections, such as progressive multifocal leukoencephalopathy and pneumocystis pneumonia. Herpes simplex virus and hepatitis B reactivations have occurred in some patients receiving BTK inhibitors.24

It is important to discuss infection risk with patients and to make sure that appropriate prophylaxis is taken, particularly for patients at high risk for herpes simplex virus reactivation or Pneumocystis jirovecii pneumonia. Infections are especially a problem for patients who are immunocompromised and/or on long-term corticosteroids in addition to their BTK inhibitor.16,24 The need for prophylaxis is greatest for these patients. The American Society of Clinical Oncology and Infectious Diseases Society of America have developed guidelines for management of fever and neutropenia that can help with support for prophylaxis procedures.25

Patients with hematologic malignancies are at a higher risk for developing severe disease and dying from COVID-19, so they should be vaccinated to decrease their risk of infection as much as possible.26,27 At this time, patients should be performing universal masking precautions whenever they are in public spaces with more than 1 other person and performing good handwashing and hand hygiene.

BTK Inhibitor AE Management: Lymphocytosis, Headache, Rash, and Second Primary Malignancies

Lymphocytosis typically occurs within weeks of beginning BTK inhibitor therapy and can be managed with monitoring.21 When this phenomenon was observed in the very first patients receiving BTK inhibitors, it was viewed as a potential sign of disease progression—leading healthcare professionals to discontinue the BTK inhibitor. We now know that this is a transient phenomenon and that we should not discontinue BTK inhibitor therapy. Lymphocytosis generally resolves spontaneously within 2 months and is not associated with any clinically significant AEs.17

BTK inhibitor therapy—particularly with acalabrutinib—also can be associated with headaches, which are typically low grade and observed early in therapy.9-11,24 The headaches usually resolve within 1-2 months and can be managed with analgesics and caffeine supplements. Because bleeding risk also is associated with BTK inhibitor therapy, NSAIDs should be not be used for headaches.22,23 Given the higher incidence of headache with acalabrutinib, this agent should be avoided in patients with a history of headaches and/or migraine.28

Rash is another complication that can occur with BTK inhibitors.9-11 It is usually low grade and associated with petechiae.16,24 Occasionally, palpable or eruptive rashes can occur with pustules, but when an eruptive rash occurs, it can be managed with topical antihistamines or corticosteroids. Very rarely, severe cases of rash may require oral antihistamines or steroids and may necessitate dose interruption and potentially dose reduction, which we will discuss later.

Second primary malignancies also can occur following prolonged use of BTK inhibitors, potentially due to disruption of BTK-mediated signaling leading to a dysfunctional immune response.9-11,29 In clinical trials, skin cancers and other solid tumors were observed in 10% of patients receiving ibrutinib, 12% receiving acalabrutinib, and 9% receiving zanubrutinib. The most common are skin cancers. It is important to advise patients on BTK inhibitors to protect themselves from sun exposure and to use sunscreen. Patients also should be regularly screened for skin malignancies.

Risk Factors for Developing Atrial Fibrillation

Turning now to cardiovascular events, important steps can be taken to mitigate the risk of atrial fibrillation with BTK inhibitor therapy. First, healthcare professionals should take a careful history to identify the patient’s risk factors. Key risk factors for developing atrial fibrillation include:

  • Hypertension
  • Congestive heart failure
  • Diabetes mellitus
  • Older age
  • Obesity
  • Excessive alcohol consumption
  • Valvular heart disease or an observable murmur
  • Chronic obstructive pulmonary disease
  • Hyperthyroidism
  • Obstructive sleep apnea
  • Chronic kidney disease
  • Acute infections30,31

It is important to optimize the modifiable factors and to reassess these risk factors on a regular basis, because patients continue receiving BTK inhibitors for a prolonged course. It also is important to educate patients and their caregivers regarding monitoring and management strategies.

BTK Inhibitor AE Management: Cardiovascular

Management of atrial fibrillation and flutter relies on regularly monitoring for cardiac arrhythmias and, if symptoms develop (eg, palpitations, lightheadedness, syncope, chest pain), testing with electrocardiography.9-11 This typically also would involve recommendations for a cardiology consult and comanagement with specialists. Atrial fibrillation is neither an absolute contraindication for giving a BTK inhibitor nor an indication for discontinuing the BTK inhibitor, but the use of BTK inhibitors should be considered carefully when atrial fibrillation does occur.

It is important to use anticoagulants with caution, given the risk of bleeding associated with BTK inhibitors and the additional risk associated with the anticoagulation use for atrial fibrillation. It also is important to manage cardiac arrhythmias appropriately and to consider dose modification of the BTK inhibitor or discontinuation for persistent atrial fibrillation.

Hypertension also has been associated with BTK inhibitors. Healthcare professionals should document baseline blood pressure before starting a BTK inhibitor to be able to monitor patients over time and to initiate antihypertensive medications as needed.32

BTK Inhibitor AE Management: Musculoskeletal

The most common musculoskeletal AEs with BTK inhibitors are arthralgias and myalgias, which typically occur early in the treatment course.9-11 The most common approaches for managing these events are monitoring and using over-the-counter medications such as acetaminophen.16,32 Occasionally, a short course of prednisone is necessary. As noted previously, NSAIDs should be avoided to minimize risk of bleeding. Transitioning to a more selective BTK inhibitor sometimes may be needed to reduce or resolve some of these symptoms.

Other musculoskeletal AEs that have been reported with BTK inhibitor therapy include pain and muscle spasms, which should be managed similarly to arthralgias and myalgias.

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