An exciting development in the treatment of MCL is the advent of a number of newer agents targeting this disease, including BTK inhibitors. The use of BTK inhibitors results in high response rates and long progression-free survival in patients with MCL, although these drugs may cause toxicities that are distinct from the side effects of immunochemotherapy. Ibrutinib was the first BTK inhibitor to be approved by the US Food and Drug Administration for MCL, followed by acalabrutinib and then zanubrutinib. There are some side effects that are relatively common across the class. The greatest experience has been with ibrutinib and thus the risks of adverse effects are best characterized for this agent.

Side effects of BTK inhibitors range from bothersome rash and diarrhea, where treatment may have to be temporarily discontinued, to more serious complications such as atrial fibrillation, where treatment may have to be stopped if that is a continued side effect. Rash can occur relatively commonly. It is usually mild and typically develops during the first few weeks of BTK inhibitor treatment. Most cases of rash are low grade and can be managed with topical therapy, but some cases may require the temporary discontinuation of treatment. When diarrhea occurs, it is usually a grade 1 diarrhea that appears soon after treatment initiation and lasts approximately 2 to 3 weeks. Diarrhea can be managed by stopping the drug for a period of time, and it usually does not recur when treatment is restarted. Atrial fibrillation and the requirement for anticoagulation can be a significant concern, particularly in those treated with ibrutinib, due to the risk of serious and central nervous system bleeding that has specifically been observed with warfarin but may also occur in settings with other forms of anticoagulation. Acalabrutinib is a more targeted BTK inhibitor, and we see a greater affinity for and targeting of the BTK receptor with this drug. Acalabrutinib may have fewer off-target effects and perhaps less bleeding and fewer incidents of atrial fibrillation than ibrutinib, but this drug was only recently approved, and more clinical experience is needed before we can verify whether the bleeding risk is lower. BTK inhibitor therapy may have to be discontinued if the patient is experiencing atrial fibrillation as a continued side effect.

Immunosuppression and cytopenias are being increasingly recognized with BTK inhibitor use, and these effects can put patients at an increased risk of infection. We have not really seen dramatic increases in the risk of bacterial or viral infections, but there may be a heightened risk of fungal infections, particularly with later lines of therapy. Antifungal prophylaxis should be considered in those who may have prolonged lymphopenia or are cytopenic from previous lines of therapy. BTK inhibitors are typically used in later lines of therapy, so you have to worry about immunosuppression from previous lines of therapy, particularly in patients who have relapsed early and are receiving BTK inhibitors relatively soon after relapse.