CME
Physicians: Maximum of 1.00 AMA PRA Category 1 Credit™
Released: April 15, 2025
Expiration: October 14, 2025
ESMO Clinical Practice Guidelines for the Initial Treatment of MCL
The current guidelines for MCL by the European Society for Medical Oncology (ESMO) are from 2017.2 It is expected that new clinical practice guidelines will soon be released by both ESMO and the European Hematology Association. Currently, the guidelines classify MCL treatment according to transplant eligibility. For patients aged 65 years or younger who are transplant eligible, initial treatment with dose-intensified immunochemotherapy including high-dose cytarabine followed by ASCT and rituximab maintenance is recommended as first-line therapy.
MCL is a disease of the elderly. The majority of patients are older than the age of 65 and are ineligible for ASCT. For these patients, initial therapy with conventional immunochemotherapy such as BR, rituximab, cyclophosphamide/doxorubicin/vincristine/prednisone (R-CHOP), bortezomib/rituximab, cyclophosphamide/doxorubicin/prednisone (VR-CAP), or R-BAC (rituximab, bendamustine/cytarabine) followed by rituximab maintenance is recommended as first-line therapy.
Compromised patients include those who are unfit and frail with multiple comorbidities; these patients are unlikely to be able to tolerate standard immunochemotherapy. For this population, the current ESMO guidelines recommend the administration of BR (dose-reduced), rituximab plus chlorambucil, or R-CVP as first-line therapy. It is my hope that these guidelines will change in the near future.
EMA-Approved Covalent BTK Inhibitors in R/R MCL
There are a number of novel agents available for use in MCL in the second- or later-line setting. Among the most important classes of agents are the covalent BTK inhibitors. In this drug class, there are 3 FDA approved agents in the United States: ibrutinib, acalabrutinib, and zanubrutinib.5-7 Until very recently in the European Union (EU), the only covalent BTK inhibitor with EMA approval for use for patients with MCL was ibrutinib.8 On February 27, 2025, the EMA’s Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion, recommending a change to the terms of the marketing authorization for acalabrutinib.9 The CHMP adopted a new indication for acalabrutinib to include the treatment of adult patients with R/R MCL. Therefore, it is possible that acalabrutinib will soon be granted approval for patients with R/R MCL in the EU. The CHMP recommendation is a precursor to the actual EMA approval.
Among patients with R/R MCL after receiving at least 1 previous line of therapy in the pivotal registrational trials of these covalent BTK inhibitors, the ORR was 68% with ibrutinib vs 80% with acalabrutinib.10,11 The complete response (CR) rate with ibrutinib was 21% vs 40% with acalabrutinib. In addition, the median progression-free survival (PFS) seems to be shorter with ibrutinib (13.9 months) vs acalabrutinib (not reached) after a median follow-up of approximately 15.3 months. Of note, however, caution should be exercised with cross-trial comparisons; a randomized trial is needed for accurate comparisons between these agents. Overall, in terms of efficacy, both agents seem to be comparable.
Off-Target Effects of Covalent BTK Inhibitors: Potential AEs
The second-generation BTK inhibitors, acalabrutinib and zanubrutinib, are more selective for BTK than the first-generation BTK inhibitor, ibrutinib. All these agents target BTK, but they also exert off-target effects that explain some of the adverse reactions observed with their use.12 One common adverse event (AE) is rash, and this is an off-target effect on the epidermal growth factor receptor (EGFR), a receptor tyrosine kinase. Another off-target effect on EGFR is diarrhea. Of importance, off-target effects on at least 3 tyrosine kinases (EGFR, ERBB4 and BMX) lead to cardiac toxicity, the most commonly observed being atrial fibrillation. Hypertension and ventricular arrhythmias are other cardiac-related toxicities associated with some BTK inhibitors.
Interleukin-2–inducible T-cell kinase (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 and 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.
Adverse Events of Available Covalent BTK Inhibitors
BTK inhibitors are associated with cytopenias.5-9 However, this may also be a result of the previous treatments received. Neutropenia and/or thrombocytopenia may require dose interruption or treatment discontinuation for some patients. The first to third occurrence of grade 3/4 neutropenia and/or thrombocytopenia may necessitate dose interruptions. For the fourth occurrence of grade 3/4 neutropenia and/or thrombocytopenia, discontinuation of the BTK inhibitor is recommended.
Infection is a known AE associated with the use of BTK inhibitors. Prophylaxis against pneumocystis and herpes infections should be considered for all patients with careful monitoring for signs and symptoms of infection.
Bruising and hemorrhage are very common side effects observed with BTK inhibitors. These AEs usually involve minor skin bleeding like ecchymosis. Some patients may experience severe bleeding events. It is important to monitor patients for signs of bleeding. When needed, the use of oral anticoagulants such as apixaban are recommended. BTK inhibitors should be withheld for 3 to 7 days before and after surgery, depending on the type of surgery and bleeding risk.
A unique phenomenon that may occur with the use of BTK inhibitors is the egress of lymphoma cells from lymph nodes into the blood circulation, causing lymphocytosis. Of importance, lymphocytosis should not be mistaken for disease progression. It is a drug class effect that occurs in most patients when BTK inhibitors are given as monotherapy. Lymphocytosis usually presents during the initial few weeks of therapy and typically resolves within 2 months.
Cardiac Adverse Events of Available Covalent BTK Inhibitors
A more serious AE associated with covalent BTK inhibitors is cardiac toxicity. As previously stated, the most commonly observed cardiac toxicity is atrial fibrillation; it is more frequently seen with ibrutinib, with a reported 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 side effect with ibrutinib; it seems to be less common with acalabrutinib. It is important to monitor patients for BTK inhibitor–emergent hypertension. Patients who develop hypertension may need to be treated with antihypertensive drugs. It is also important to monitor blood pressure in all patients receiving a BTK inhibitor.
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.
Special Considerations for Other Unique BTK Inhibitor–Associated AEs
There are some unique AEs associated with covalent BTK inhibitor use that require special considerations.13-15 For instance, some patients may experience diarrhea whilst receiving a covalent BTK inhibitor. For patients who experience BTK inhibitor–associated diarrhea, antidiarrheals such as loperamide should be administered as needed.
Headache is a common AE that is more often associated with acalabrutinib than 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 to 2 months of therapy. It generally can be managed with acetaminophen and coffee or tea, or with caffeine supplements. The use of NSAIDs should be avoided due to an increased risk of bleeding and platelet dysfunction.
Musculoskeletal pain is another common AE with covalent BTK inhibitors. It can sometimes be treated with acetaminophen. Grade 1 myalgias/arthralgias may not need intervention, and dose reduction/interruption of BTK inhibitors can be considered as needed.
Rash is also 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. In severe cases, oral antihistamines or corticosteroids, together with dose interruption or reduction, may be considered.
Second primary malignancies may occur in patients with MCL. It is not completely clear if this is related to BTK inhibitors or previous treatment. Of note, skin cancer is not uncommon in patients with MCL who are receiving BTK inhibitors.
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