Nicole Lamanna, MD: In the relapsed setting, what do we do with our patients? This is a little trickier because it depends on what they might have received in frontline therapy. Have their disease characteristics changed? Of course, our patient population certainly will be older by the time they hit relapse. Are there different comorbidities that we’re facing? One needs to take into account all these factors, just as you do in the front line, but certainly you have to consider what they’ve gotten and how their disease might have changed with regard to their frontline therapy. I think that’s very important.

Clearly, we have data, and some of it may not be data-driven either. We have more data for our patients who got BTK [Bruton tyrosine kinase] inhibitors in the front line, that certainly patients can then be salvaged by venetoclax-based combinations such as venetoclax-rituximab in the relapsed setting. We have a lot more data on that. Because many patients have received venetoclax-obinutuzumab frontline, we’re accruing data and getting more data about salvaging those individuals with a BTK inhibitor. One option, obviously, when we talk about the relapse data, is looking at venetoclax-rituximab or the MURANO study. Those individuals who received venetoclax-rituximab for 2 years were able to discontinue therapy and be monitored. If their disease came back, a small number of patients were rechallenged with venetoclax-based therapy, and some of them went back into remission. Can you rechallenge your patients with venetoclax-based therapy as well? Certainly, we’re waiting to accrue more data to show how you can salvage or sequence if you started with a BTK or BCL2 inhibitor up front and then in the relapsed setting. Many of us feel comfortable doing those alternatives because we know that. You’re going to have to consider what that patient has been through, has their disease changed, and what you might do depending on what has occurred prior. It’s a little trickier for sure.

We don’t see necessarily that the chemoimmunotherapy use has increased because of that in the relapsed setting. If a patient has gotten a BTK or a venetoclax-based frontline therapy, do we see then a lot more chemoimmunotherapy? I don’t necessarily see that in practice from referrals. Most people are just alternating 1 versus the other if they’ve gotten that in frontline.

Let’s talk a little about PI3 kinase inhibitors. There have been many data. Remember, ibrutinib was first to market, but the second was idelalisib-rituximab. Those were the first approvals of B-cell receptor agents in our CLL [chronic lymphocytic leukemia] patient population before venetoclax became available. Certainly, there was a lot of transitioning. If somebody had an adverse effect on ibrutinib, they would go to a PI3 kinase inhibitor, and idelalisib was used more frequently in that setting. Now there’s no PI3 kinase inhibitor that’s been approved in frontline. You have idelalisib that’s been approved with rituximab in relapse, and you also have duvelisib. That’s also been approved in relapsed CLL patients. Recent data that were presented looked at acalabrutinib versus idelalisib and rituximab versus bendamustine and rituximab in relapsed/refractory CLL patients, and the data favored acalabrutinib over idelalisib-rituximab or bendamustine-rituximab. Many of us tend to use a BTK before we use a PI3 kinase inhibitor.

What can you glean about what happens if your patient got ibrutinib or acalabrutinib in frontline therapy and then they relapse? Many of us would probably go to a venetoclax-based regimen. What about PI3 kinases? Can you use that then? There were data—most of this is retrospective data that came out, and some of that from the real-world data setting that many of my colleagues published—in multiple publications looking at that initial ibrutinib data, what happens to patients if they discontinued for adverse events versus whether they had progressive disease.

There’s no doubt that there are data for if you have a patient who is intolerant to a BTK inhibitor. Could you then salvage them with a PI3 kinase inhibitor? I think that’s absolutely correct. If you have a patient who is intolerant, whether it’s to ibrutinib, acalabrutinib, or other BTKs, can you then use idelalisib in the relapsed setting or duvelisib in the relapsed setting to salvage that individual? Yes, I think you can. Certainly, there are other adverse effects of those agents that you have to take into consideration if your patient is appropriate for them as well, but that’s certainly an option, using a PI3 kinase inhibitor.

What about patients, though, who had ibrutinib or acalabrutinib or a BTK inhibitor front line and then failed that agent? Can you use a PI3 kinase inhibitor in that situation? That’s trickier. The data from the retrospective and pooled data from real world suggests that obviously those individuals don’t do as well. Intolerance is 1 issue, where a PI3 kinase can be attractive. If they’re really refractory to a BTK inhibitor, then they won’t get much mileage out of a PI3 kinase inhibitor. A venetoclax-based combination would have more appeal.

Unfortunately, because of the plethora of agents that have now become available, the usage of PI3 kinase inhibitors has declined in CLL given the ibrutinib and now the second-generation BTK inhibitors, such as acalabrutinib or zanubrutinib. There are data even for patients who are intolerant to ibrutinib. they could possibly be tolerant to acalabrutinib. There are data showing that in a cohort of patients, not all of them had those adverse events occur again. You have multiple options about your patients who may have an adverse effect. Can you transition to another BTK inhibitor? We have covalent and noncovalent BTK inhibitors. There are more clinical trials running on different BTK inhibitors and whether there are patients you might be salvaging with other BTK inhibitors.

The role of PI3 kinase inhibitors has decreased, but there’s certainly still a role for them. We know that depending on the age of our patient and how long they’re living with CLL, some of these patients go from 1 regimen to another over a period of time, and you do need alternative strategies for those individuals. I think PI3 kinase inhibitors are still an important modality, but you need to self-select who those patients are depending on if they had intolerance versus real resistant disease.

Transcript Edited for Clarity