Novel targeted agents that inhibit BTK are approved by the US Food and Drug Administration for the treatment of relapsed MCL. There are trials of novel agent combinations for relapsed MCL, and there is significant research interest in the potential use of BTK inhibitors and other novel agents earlier in the MCL treatment paradigm; however, data that might guide such use are not mature.

A number of trials are investigating novel agent combinations (eg, BTK inhibitors combined with anti-CD20 monoclonal antibodies) as initial therapy. We have snippets of data with 40 or 50 patients, for instance. The early results are promising, but we need to know more about the patients enrolled and we need longer-term follow-up. We know that bendamustine plus rituximab generates remission that lasts 4 to 5 years, on average. So, these novel combinations will need to beat that to make an impact.

Some of the investigational work in the front line involves the addition of novel agents up front, as part of a standard chemotherapy regimen. For example, an ongoing, randomized, phase 2 trial sponsored by the ECOG-ACRIN Cancer Research Group (NCT04115631) is comparing the efficacy and safety of 3 different immunochemotherapy regimens in patients with newly diagnosed MCL, with 2 of the arms exploring the addition of acalabrutinib. The 3 arms are as follows: (1) bendamustine and rituximab for 3 cycles followed by cytarabine and rituximab for 3 cycles; (2) acalabrutinib plus bendamustine and rituximab for 3 cycles followed by cytarabine and rituximab for 3 cycles; and (3) acalabrutinib plus bendamustine and rituximab for 6 cycles. The trial is asking the following important questions: Does acalabrutinib add to the efficacy of a high-dose cytarabine-containing regimen, and, if acalabrutinib does add to the efficacy, does one still need the high-dose cytarabine?

Regarding the BTK inhibitors that are currently available, there are some important differences. For instance, although ibrutinib is a fantastic drug for MCL and it was a huge breakthrough, the second-generation BTK inhibitors (ie, acalabrutinib and zanubrutinib) are a bit more selectively targeted than ibrutinib and they seem to have fewer off-target effects, which means fewer side effects and less toxicity. So, we seem to be noticing less atrial fibrillation, less hypertension, and fewer of those nagging side effects. I tend to prefer acalabrutinib or zanubrutinib over ibrutinib for my patients with MCL when I have the choice. I am not certain that they are more efficacious, but they do seem to be better tolerated.