Sequencing Therapy in CLL: BTK and BCL2 Inhibitors

Transcript:

Tara Graff, DO, MS: One of the questions that comes up at a lot of our national meetings—especially since ASH [the American Society of Hematology Annual Meeting & Exposition] with all the hype around acalabrutinib and venetoclax and obinutuzumab, and all the different studies—is which drug do you use first? Does the order matter? At this point, we don’t know. I do think we’re going to find this out over the next couple of years. We know that there are some preliminary data that suggest that acalabrutinib actually primes the cells for venetoclax, making it more effective. When you think about the immune system, when you’re changing the niche or the microenvironment, you are basically setting it up for the next treatment to come and are hopefully making that treatment work even better. So sequencing is important, but we just don’t have the answer today.

We’re looking at pairing acalabrutinib with venetoclax and obinutuzumab. The preliminary data look good. We know that when ibrutinib was combined with venetoclax and obinutuzumab, there was increase in neutropenia and infusion reactions. Unfortunately, the adverse-effect profile sort of squashed that.

But I’m hoping that maybe by next ASH meeting we’ll see if we have a new triplet regimen. Right now, I think you need to look at your patient population. Again, does using a BTK [Bruton tyrosine kinase] inhibitor mean you can’t use venetoclax-obinutuzumab later? No. I look at my patient. Right now, I tend to use a BTK inhibitor first. I think patients tolerate it no matter what age they are. You do have to take note of any comorbidities, obviously. If you have a much older patient who has atrial fibrillation and is on warfarin, for whom which you can’t treat with a BTK inhibitor—specifically, acalabrutinib—then I think venetoclax and obinutuzumab makes more sense.

One of the questions, or the main questions that we’re asked as oncologists when we’re with our patients and we’re picking different treatments is, “How long do I have to be on this therapy?”

When you’re specifically talking about ibrutinib or acalabrutinib, there really is no fixed duration of treatment. You’re on the BTK for as long as you’re tolerating it, or as long as you’re responding, which is great because you can view it as a maintenance drug, kind of like you view a blood pressure medicine. But for some people, that’s not good enough. They want to know, “OK, in 12 months I’m going to be done.” And if you have a patient like that, that’s someone for whom you might want to look at giving them venetoclax and obinutuzumab. Then you do have a fixed duration.

You can also look at things like MRD [minimal residual disease] status, and that drives how long you’re on therapy. There is speculation, though, that if a patient is responding well and they’re MRD negative, a lot of physicians would keep them on the venetoclax. There goes your fixed duration. But just looking at a BTK inhibitor versus venetoclax and obinutuzumab, if you have a patient who is older, for whom you’re worried about atrial fibrillation—I don’t worry about it so much in acalabrutinib, but if they have significant risks for bleeding or are on warfarin, which is a contraindication to acalabrutinib, and they can’t be switched to a different anticoagulant, for that specific patient I would probably use venetoclax and obinutuzumab.

For the scientific people, which I am, MRD is pretty fascinating. We’re not doing MRD testing prime time yet in the BTK inhibitor monotherapies. We are doing it more with the venetoclax and obinutuzumab group. For some people, that is very important in making decisions on treatment duration. I think we’re going to get there, but if that’s important, then in that situation venetoclax-obinutuzumab can go first.

Transcript Edited for Clarity