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Tx Selection and Optimization in MCL

CME

Optimizing Mantle Cell Lymphoma Care: Case-Based Guidance From EU Experts

Physicians: Maximum of 1.00 AMA PRA Category 1 Credit™

Released: May 29, 2026

Expiration: November 28, 2026

Mats Jerkeman
Mats Jerkeman, MD, PhD
CME/CE Information

Activity

Progress
1 2 3
Course Completed

Off-Target Effects of Covalent BTK Inhibitors: Potential Adverse Events

Although ibrutinib, acalabrutinib, and zanubrutinib selectively target BTK, they also exert off-target effects that explain some of the adverse events (AEs) observed with their use.15 One common AE is rash, and this is an off-target effect on the EGFR, a receptor tyrosine kinase. Another off-target effect on EGFR is diarrhea. Of importance, off-target effects on ≥3 tyrosine kinases (EGFR, ERBB4, and BMX) lead to cardiac toxicity, with the most commonly observed being atrial fibrillation. Hypertension and ventricular arrhythmias are other cardiac-related AEs associated with some BTK inhibitors.

ITK is a T-cell–specific tyrosine protein kinase that is important for mediating intracellular signaling in normal T-cells, neoplastic T-cells, and natural killer cells. An off-target effect on ITK may antagonize the effect of CD20 antibodies like rituximab and obinutuzumab. Targeting BTK may also lead to the inhibition of the enzyme TEC, which is involved in platelet activation. This explains the platelet dysfunction, ecchymosis, and the risk of bleeding seen with BTK inhibitors. Inhibiting BTK may also lead to the inhibition of JAK3, which can cause a negative effect on T-cell function.

A serious AE associated with covalent BTK inhibitors is cardiac toxicity.16-18 The most commonly observed cardiac toxicity is atrial fibrillation; it is more frequently reported with ibrutinib, with an incidence of 3.7% to approximately 12% compared with acalabrutinib (1.1%) or zanubrutinib (1.9%). It is important that patients receiving a covalent BTK inhibitor are monitored for atrial fibrillation during treatment. An electrocardiogram should be performed at baseline before starting treatment and then regularly during treatment. When atrial fibrillation is diagnosed, patients should not receive warfarin as it is contraindicated for use with any BTK inhibitor; a direct oral anticoagulant such as apixaban can be given. If atrial fibrillation is not medically controllable, the BTK inhibitor should be discontinued.

Hypertension is also a common cardiac-related AE with ibrutinib, but it seems to be less common with acalabrutinib. It is important to monitor patients for BTK inhibitor–emergent hypertension that may require treatment with antihypertensive drugs.

Cardiac failure is a rare event with all 3 covalent BTK inhibitors. Another rare but serious cardiac-related AE associated with covalent BTK inhibitors is ventricular arrhythmias, a rare cause of sudden death.

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Special Considerations for BTK Inhibitor AE Management

There are some unique AEs associated with covalent BTK inhibitor use that require special considerations.19-21 For instance, some patients may experience lymphocytosis, an elevation in lymphocyte count, which usually occurs early on after treatment ensues but typically resolves within 2 months.

Headache is another AE associated with covalent BTK inhibitors, and it is more often associated with acalabrutinib compared with the other covalent BTK inhibitors. It is typically low grade, has an early onset—usually within the first few weeks of treatment—and resolves within 1-2 months of therapy. It generally can be managed with acetaminophen and coffee, tea, or caffeine supplements. The use of nonsteroidal anti-inflammatory drugs should be avoided because of an increased risk of bleeding and platelet dysfunction.

As previously stated, rash is associated with covalent BTK inhibitor use. It may be asymptomatic petechial, or palpable, eruptive pruritic rash with pustules. Eruptive rash can be managed with topical antihistamines or corticosteroids together with dose interruption or reduction.

Second primary malignancies may occur in patients with MCL. It is not clear if this is related to covalent BTK inhibitor use or previous treatment. Skin cancer is not uncommon in patients with MCL who are receiving BTK inhibitors. Patients receiving treatment with a covalent BTK inhibitor should be advised to use protection against sun exposure and should be encouraged to undergo regular cancer screening.

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Case Study Continued: Individualized Upfront Treatment of 70-Year-Old Patient With MCL Requiring Frontline Therapy

Back to the case of the 70-year-old unfit patient with newly diagnosed classical MCL. My treatment choice is BR in combination with acalabrutinib based on the results of the TRIANGLE, ECHO, and ENRICH trials.3,7,8 The patient is older than 65 years of age and is unfit with multiple comorbidities. He is unlikely to be able to tolerate anthracyclines, making regimens such as VR-CAP, R-CHOP, or R-CHOP alternating with R-DHAP too aggressive to tolerate. The only chemotherapy backbone that I would consider for this patient with newly diagnosed MCL is BR. However, evidence demonstrates that the addition of a covalent BTK inhibitor to BR will significantly improve treatment outcomes.3,7,8

Because the patient has preexisting hypertension and atrial fibrillation, the choice of covalent BTK inhibitor is of particular importance. My covalent BTK inhibitor preference for this patient is acalabrutinib. In my clinical experience, acalabrutinib has a more favorable safety profile when used in combination with BR for patients who are unfit and have cardiac-related comorbidities. As of May 2026, zanubrutinib is not approved by the EMA for use in MCL in the European Union. Since the EMA recently approved the ECHO regimen of acalabrutinib in combination with BR for adults with previously untreated MCL, acalabrutinib plus BR is my preferred treatment option for this patient.22

Careful consideration should be given to the presence or absence of biological risk factors, and the presence of more risk factors warrants a stronger consideration for the addition of a covalent BTK inhibitor to CIT.

Next, I review the available evidence guiding the personalized treatment of patients with R/R MCL in the European Union.

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