BTK Inhibition in Relapsed/Refractory CLL

John M. Pagel, MD, PhD:I also want to briefly refer to the relapsed/refractory setting and make sure everybody understands that BTK [Bruton tyrosine kinase] inhibitors are appropriate not only for the frontline setting but also for patients in the relapsed setting. We do know that patients who get chemoimmunotherapy in the frontline setting will do very well with ibrutinib or acalabrutinib in the relapsed setting.

In fact, a recent trial known as the ASCEND trial led to the approval of acalabrutinib in the relapsed setting. This was a trial that compared acalabrutinib versus another novel agent, idelalisib, and rituximab, a PI3 kinase inhibitor. There were also some patients who got bendamustine and rituximab. That ASCEND trial in relapsed/refractory CLL [chronic lymphocytic leukemia] patients showed a significant progression-free survival advantage for those patients who got single-agent acalabrutinib over the idelalisib or bendamustine and rituximab arms. That was the first trial that compared 2 novel different drugs in a randomized setting. The most important part about the ASCEND trial in the relapsed setting, however, is the tolerability of acalabrutinib. It appears to be an extremely well-tolerated therapy.

As we move through 2020 and beyond, clearly we have made major advances, but we’re just getting started. I think 1 of the things we’re going to learn very quickly in the upcoming many months is more on the idea of stopping treatment and who that’s appropriate for and who it’s not appropriate for. If you’re in the community and you’re treating CLL patients right now, if you’re on a single-agent BTK inhibitor, patients should be treated indefinitely until progression or intolerance.

Alternatively, a very appealing regimen is the venetoclax-obinutuzumab regimen that gives time-limited therapy. It’s given for a year in the frontline, or patients are treated with 2 years of venetoclax and rituximab in the relapsed setting. It’s important to remember that with venetoclax there’s a high risk of tumor lysis, so you have to be very diligent. Follow the ramp-up schedule, and pay attention to the patient and those laboratory parameters.

The evolution is now, though, in combinations of treatment. The combinations will drive us to time-limited therapy, undetectable minimal residual disease, and sequencing of agents. Hopefully what this is going to do is really work toward something we never talked about in CLL before, and that’s curing these patients with standard treatments.

Transcript edited for clarity.