Sequencing Therapies for Relapsed/Refractory CLL

Transcript:Krishna V. Komanduri, MD: John, we see these remarkable new targeted therapies come in along with, again, the role of modified antibodies like obinutuzumab. And now we have to think, as with the discussion with low-grade lymphomas, about what we do at the time of relapse and how do we sequence when we have actually so many options on the table. You want to start talking about, first, what are the risk factors for relapse and then how would we look at, for example, the role of ibrutinib or other therapies in the relapse setting?

John Byrd, MD: The risk factors at the time of relapse are pretty much the same as at diagnosis—so, the IgVH unmutated patients, the 11qs, the 17ps, the complex karyotype, and the time of remission. Those are going to be risk factors that we factor in, but generally, the same principles hold for the most part, particularly with ibrutinib. If they have low-risk feature in the setting of relapse, as long as they tolerate ibrutinib, it’s extremely unlikely that they’re going to progress on ibrutinib. If they have a 17p or complex karyotype—and Susan O’Brien will be presenting updated data from the initial phase II study—only about 30% or less of those patients at 5 years are still in remission and on therapy. There’s a subset that have gone off for alternative reasons, but a good number of those patients progress.

There are registry data. I don’t like registry data, but they get down to the granularity of real patients and what’s done in the community. And Dr. Mato from PennMedicine looked at patients receiving different targeted therapies and who did best. I’ll be interested on Michael’s take. It confirms, I think, clinically that there’s not a randomized study comparing ibrutinib to venetoclax versus idelalisib in the relapsed patient population. And I have my own bias, having done a lot of work with ibrutinib, but when you compare across the studies, all 3 work very well in the relapsed setting in all genetic groups. But the durability with ibrutinib appears better, again comparing across phase II studies with all caveats of that and personal biases. And say Dr. Mato’s study was interesting and it reproduced that in the real world, showing that people tend to stay on that longer, we’ve treated a lot of patients at OSU with ibrutinib, myself, in particular. I’d be interested in Michael’s opinion of how he sequences. Because, in general, for the relapsed patients, my first choice—if there’s not a contraindication to ibrutinib—is to use ibrutinib.

Michael J. Keating, MB, BS: I agree totally with that. I think the early phases of treatment, the results, are so good and the patients feel so well that everyone is happy. The question that has not been raised is, do you need to continue it all the time? And the other question that we’re trying to address is, do you need the full dose all the time? Because when you give ibrutinib, the covalent binding of ibrutinib with the BTK (Bruton's tyrosine kinase) is so tight and most of the BTK will be in the CLL cells. But if the CLL tumor burden goes down, do you need the same amount? And if you’re giving them the same amount, do you get to the point where there’s a free drug floating around? We know that certainly there are off-target effects on different enzymes that were presented again this morning. Acalabrutinib is under investigation and, fortunately, a chlorambucil arm is in a 3-way randomized trial at the present time.

John Byrd, MD: I think it’s chlorambucil/obinutuzumab.

Michael J. Keating, MB, BS: Yes, chlorambucil is still there.

John Byrd, MD: That’s better than a chlorambucil arm.

Michael J. Keating, MB, BS: It refuses to die. Anyway, I think the situation is that we fell in love with these drugs so much that we stopped investigating them. I think that one of the very good presentations so far in the meeting was talking about the long-term outcomes, how many progress, how many don’t. And those who do progress, how many of them have mutations in the BTK, what are the consequences, and what is the change in the biology that gets induced by prolonged exposure? The resistance cells with mutations behave differently, and John and his group have done a spectacular job in documenting the long-term sequential impact of the drug in their patients.

Transcript Edited for Clarity