Relapsed/Refractory CLL: Practical Advice and Future Directions in Care

Transcript:

Andrew H. Lipsky, MD: So I think when you have a relapsed refractory patient in front of you, it’s really important to look at them again, almost as if with fresh eyes. You want to take a thorough history. And given how long patients with CLL [chronic lymphocytic leukemia] have been on their frontline therapy, it may be that several years have gone by. So checking in with their primary care doctor, trying to think about where their comorbidities are, and taking a fresh look is really important.

When it comes to selecting therapy, the most important factor is the prior therapy that they’ve received. Did they get chemoimmunotherapy in the front line? Did they get a BTK [Bruton tyrosine kinase] inhibitor? Did they get venetoclax? If they got time-limited therapy, how long was that response? Is it where you would expect it to be, is it shorter? How did they tolerate that therapy? That’s, for example, when thinking about [INAUDIBLE] starting venetoclax. If they are a good candidate for a BTK inhibitor, looking at their comorbidities and selecting which therapy you want to choose can be informed by these head-to-head trials. The 2 trials that I previously mentioned, BTK inhibitors of the second generation compared to the first generation, I think that we are fortunate to have that data, and we really should be preferring these second-generation agents when it comes to treating patients in the relapsed/refractory setting.

In the relapsed/refractory setting, I think the greatest unmet need currently is for patients who are double refractory. So that’s patients who have seen a BTK inhibitor and venetoclax-based therapy. For those patients, we do have therapeutic options on the horizon. The advent of a noncovalent BTK inhibitor promises to be a helpful treatment option. In this patient population, the drug pirtobrutinib has been approved in the setting of mantle cell lymphoma, and we have data from the BRUIN CLL study [NCT05023980] utilizing that drug in CLL.

I think that there’s an increasing body of evidence that we are learning more about the mechanisms of resistance to BTK inhibitors and how those mutations work. That landscape is looking more complex and may inform how we do sequencing in terms of how to utilize a noncovalent BTK inhibitor. I think it’s also really important to think about comorbidities when selecting agents. It’s nice to know that some of these agents do not have toxicity profiles that would appear to substantially limit patients who need that drug from getting it. And, of course, another unmet need in all CLL patients is Richter syndrome, which can happen even in patients who are relapsed/refractory. That transformation is a devastating complication for CLL and always in need of new clinical trials and new therapies.

Another thing to think about in the relapsed/refractory setting for patients who are double refractory is potentially novel mechanisms of targeting BTK. There are several new classes of medicine under investigation. One particular class is the BTK degraders. Those agents, which are currently under active clinical investigation, have exciting promise of being able to overcome some of the known mechanisms of resistance to BTK inhibition. I really look forward to additional data with these agents.

Transcript edited for clarity.