Survival outcomes in MCL have improved in the BTK inhibitor era. Currently, we have the 3 covalent BTK inhibitors for previously treated MCL: ibrutinib, acalabrutinib, and zanubrutinib. Additionally, noncovalent BTK inhibitors are under study, which has been an exciting development.

Regarding the efficacy of BTK inhibitor therapies in MCL, we lack head-to-head data. Most of us in the field are using the second-generation BTK inhibitors acalabrutinib or zanubrutinib because of their more favorable toxicity profiles, and I do not think that there is a strong rationale, from an efficacy perspective, for using one agent over the other. The second-generation BTK inhibitor therapies were designed to be more selective and to reduce the off-target toxicities that are observed with the first-generation BTK inhibitor ibrutinib. 

Although tolerability with these agents has not been directly compared with ibrutinib in MCL, head-to-head data do exist in other B-cell malignancies. For example, the ELEVATE-RR trial (acalabrutinib vs ibrutinib) and the ALPINE trial (zanubrutinib vs ibrutinib) were conducted in chronic lymphocytic leukemia, and the ASPEN study (zanubrutinib vs ibrutinib) was done in Waldenström macroglobulinemia. These large phase 3 studies showed us that second-generation agents appear to have more favorable toxicity profiles, with substantially lower rates of atrial fibrillation and atrial flutter, which are toxicities that can limit the use of covalent BTK inhibitors (especially in older patients with cardiac comorbidities). The rates of diarrhea, peripheral edema, muscle spasms, and bleeding were also lower with second-generation agents than with ibrutinib. We do see more neutropenia with zanubrutinib, and headache occurs more frequently with acalabrutinib, but these side effects are usually not treatment limiting.

Noncovalent BTK inhibitors are now being studied in clinical trials, and this has been an exciting recent development. Pirtobrutinib has shown promising efficacy in patients with MCL who have already received 1 or more covalent BTK inhibitor(s). It seems to be very well tolerated and may overcome BTK inhibitor resistance mechanisms, which is particularly significant because we have few treatment options after BTK inhibitor failure in patients with MCL. Still, we will need to see longer-term data showing the response durability. A large, international, phase 3 study of pirtobrutinib vs investigator-choice, US Food and Drug Administration–approved BTK inhibitor therapies is planned. This will mainly compare the efficacy of pirtobrutinib with that of the covalent agents, but it might also provide another point of reference on comparative tolerability. 

BTK inhibitors are also being studied in frontline regimens. In the phase 3 SHINE study, ibrutinib was combined with bendamustine plus rituximab (BR) and compared with BR, a standard chemoimmunotherapy regimen in older patients with MCL. We anticipate the presentation of these results in the near future, and this study may pave the way for the incorporation of BTK inhibitors into frontline therapy for MCL. Zanubrutinib plus rituximab is also being compared with BR in another study, and, if the results are positive, it could establish a “chemo-free” frontline approach in older patients with MCL. Finally, in high-risk MCL, the BOVen study is evaluating the combination of obinutuzumab, zanubrutinib, and venetoclax in the front line. This regimen is well tolerated and has promising efficacy in TP53-mutant MCL, based on preliminary data.

Right now, the standard of care is single-agent BTK inhibitor therapy for relapsed MCL, but I think that it will be very interesting to see where BTK inhibitors fit in the future therapeutic landscape of MCL.