The use of BTK inhibitors has been an exciting advance in the treatment of relapsed/refractory MCL. The first reports of BTK inhibition in this setting were with ibrutinib, which was associated with significant activity (ie, an overall response rate of 67%). In terms of the depth of response, however, only a relatively small proportion of patients (ie, 23%) achieved a complete response. And the durability of the remission was brief, with a median duration of response of 17.5 months. It was also appreciated that ibrutinib is somewhat nonselective in its inhibition and may inhibit other kinases in the TEC family, such as ITK/EGFR, to drive some of the off-target toxicity associated with its use. With BTK inhibitors, we have seen cytopenias, arthralgias, and myalgias; increased risks of infection, bleeding, and atrial fibrillation; and interactions with other medications. The rationale for the development of the second generation of BTK inhibitors was to see whether we could improve upon the efficacy and toxicity profile of ibrutinib with more selective BTK inhibitors. Acalabrutinib and zanubrutinib have thus emerged as more selective second-generation BTK inhibitors with potentially more favorable toxicity profiles.

As practitioners deciding among these different drugs, we are challenged because they have not been compared in head-to-head trials. Concerns regarding toxicities and preexisting comorbidities may drive treatment decision making when considering the use of any particular BTK inhibitor. These agents are widely used for other B-cell malignancies, such that the extrapolation of data from experiences with the use of second-generation BTK inhibitors compared with first-generation BTK inhibitors in patients with other B-cell malignancies (eg, chronic lymphocytic leukemia, Waldenström macroglobulinemia) alerts us to some unique considerations when it comes to treatment-related toxicities. In a patient with MCL and atrial fibrillation or a prior history of bleeding, I would likely choose acalabrutinib or zanubrutinib over ibrutinib therapy. Now, even with the second generation, there may be interactions. For instance, acalabrutinib cannot be coadministered with proton pump inhibitors, so you might switch to an H2 blocker in that case, if feasible. Further, all BTK inhibitors have important drug-drug interactions with CYP3A inhibitors. CYP3A inhibitors, including some antihypertensive and antifungal drugs, can significantly increase the concentration of BTK inhibitors. The bottom line is that I usually recommend a second-generation BTK inhibitor if I am concerned about a preexisting comorbidity or a particular adverse effect. If there is no compelling reason to use a second-generation BTK inhibitor, I often use ibrutinib because longer-term follow-up data are available.