Updates in Targeted Therapies for B-Cell Malignancies - Episode 12

BTK Inhibition's Role in Waldenstrom Macroglobulinemia


Ian W. Flinn, MD, PhD: Matt, some of your colleagues at the Dana-Farber Cancer Institute have done a lot of work with BTK inhibition in Waldenström macroglobulinemia. Let’s start with single-agent ibrutinib.

Matthew S. Davids, MD, MMSc: We have fairly mature data now for single-agent ibrutinib in Waldenström. Studies led by Steve Treon, MD, PhD, and Jorge Castillo, MD, showing high response rates and VGPRs [very good partial responses] observed with ibrutinib as a monotherapy. It has a reasonable durability, and that’s been shown in the relapse setting as well as in the frontline setting. I think that remains a good option for patients with Waldenström. However, there are other options to consider, as well.

Ian W. Flinn, MD, PhD: Do you still think about using chemotherapy in the frontline setting for some patients?

Matthew S. Davids, MD, MMSc: Yes. For some patients, that can be an option. It goes back to the discussion of time-limited versus continuous therapy. You present options to the patients and some patients may elect for a time-limited therapy, even if we might expect more in the way of cytopenias and infections from chemotherapy. But certainly a regimen like BR [bendamustine, rituximab] can be active. There are other Cytoxan-based regimens that are active in Waldenström as well.

Ian W. Flinn, MD, PhD: Brad, there’s a randomized trial that looked at rituximab versus rituximab-ibrutinib. It looked at both frontline patients and relapsed patients. It showed a fairly significant improvement for those patients on the ibrutinib arm. Has this totally changed the way you treat Waldenström?

Brad Kahl, MD: Beating rituximab was not a superhigh bar. It’s almost like trying to beat chlorambucil in CLL [chronic lymphocytic leukemia], so I wasn’t surprised to see that result, although it is nice to see the results quantified. If I remember correctly, the response rates for the combination of ibrutinib and rituximab showed an overall response rate of something around 80%. That’s a very good result, whereas it was only around 25% or 30% for single-agent rituximab. I think a more important question is, does the anti-CD20 added to the ibrutinib enhance the response above and beyond what you would get with ibrutinib alone? I don’t think we know the answer to that question, so there’s an unknown now that’s important to sort out, just as it is in CLL and other settings.

Ibrutinib is clearly a great new option for any BTK inhibitor in Waldenström, as it is in CLL. I will still have a conversation with patients, if it’s a frontline patient, about the option of doing time-limited therapy with bendamustine-rituximab. I hate to sound old-school or old-fashioned about it, but bendamustine-rituximab is effective and it’s pretty well-tolerated for most people. I think it remains a good option and should be in the conversation, along with ibrutinib and some of the newer options we have.

Ian W. Flinn, MD, PhD: Some patients seem to have a more indolent course, and others are moving pretty quickly. Does that change? Do you think the time to response might sway you to use chemoimmunotherapy like BR [bendamustine, rituximab] versus ibrutinib, or ibrutinib in combination?

Brad Kahl, MD: If I need a really quick response, I am more likely to use a chemotherapy-based approach like a bendamustine-based therapy.

Ian W. Flinn, MD, PhD: Yes, it’s a little more assured. The study would have been good if it was—pick your chemotherapy—bendamustine-rituximab versus rituximab and ibrutinib.

Brad Kahl, MD: Yes.

Ian W. Flinn, MD, PhD: John, what do you think? Do you use a combination with rituximab in your patients with Waldenström, or do you use single-agent ibrutinib? Do you not use any BTK inhibition?

John Pagel, MD, PhD: I think these are the patients where I’m going to add a BTK inhibitor if I were to think about single-agent rituximab for a patient. To me, that doesn’t make a lot of sense now with the data that Brad just talked about. The addition of a BTK inhibitor to rituximab certainly seems to be quite good in those patients. We have to realize that we’re palliating these patients, right? The idea of not wanting to have patients on therapy for a long period of time is still in play here. I still like the idea of chemotherapy in the frontline setting for these patients because we’re probably going to visit a BTK inhibitor in combination with rituximab at a relapse, which is hopefully a long way down the road.

We have other agents that are emerging too, right? I’m excited by the idea of improving on what we’ve just been talking about, and hopefully, the newer agents or BTK inhibitors like acalabrutinib and zanubrutinib will do that in Waldenström as well.

Ian W. Flinn, MD, PhD: That’s a perfect time to talk about acalabrutinib in Waldenström. What do you think? What do the data look like?

John Pagel, MD, PhD: There are only phase II data that we have with acalabrutinib. It’s been presented. It’s good data. It looks very consistent with everything we know about acalabrutinib from an efficacy standpoint, as well as from a toxicity standpoint. The improvement over ibrutinib in this setting isn’t clear, and we’ll have to see over time. There’s clearly a role for acalabrutinib in these patients in the future.

Ian W. Flinn, MD, PhD: Matt, the biology is a little different here compared with CLL. In CLL, we know that adding rituximab to a BTK inhibitor—at least to ibrutinib—doesn’t really do much. In Waldenström we don’t really have that data. Do you think you can just apply what we know about CLL to Waldenström?

Matthew S. Davids, MD, MMSc: No. I think the biology of the disease is different. We see nice data from the iNNOVATE study regarding the ibrutinib-rituximab combination. It would have been nice to have an ibrutinib-only arm on there to see that difference. We don’t have that data, but I don’t think we can extrapolate from CLL. Until we have those data, I think it’s a discussion. Using the combination frequently makes sense, because rituximab tends to be more efficacious in Waldenström—at least as a single agent—compared with CLL, where we don’t tend to see much activity of rituximab as a single agent. Using the combination makes sense until we have more definitive data.

Ian W. Flinn, MD, PhD: Are there any other new agents we should talk about in this disease? Zanubrutinib is another BTK inhibitor that has broad activity in all the different malignancies. Is there any reason to believe it’s going to be better or worse in Waldenström than it is in the other diseases?

Brad Kahl, MD: I’m not sure. My understanding is that zanubrutinib may get its first FDA indication in Waldenström. That trial that they’re performing is the most mature, so it’ll be a nice option to have in Waldenström. Whether it offers advantages over ibrutinib or acalabrutinib remains to be seen. There are some theoretical reasons why zanubrutinib might have some advantages in getting into nodal comparts. Again, that’s theoretical and has yet to be proven definitively, but it’ll be a nice option to have.

Ian W. Flinn, MD, PhD: Why would that be? Does it have to do with the PK [pharmacokinetics], or is it the size of the molecule? Why would there be a difference in the compartment effect?

Brad Kahl, MD: I don’t know the answer to that. It may be a real phenomenon, and it may not. I don’t know if you have any insight on that.

Matthew S. Davids, MD, MMSc: Those are the data. With zanubrutinib, they’ve done lymph node biopsies and shown very nice occupancy in the lymph node tissue. Unfortunately, that hasn’t been done as rigorously and in a comparative fashion with the other BTK inhibitors, so we don’t know.

Ian W. Flinn, MD, PhD: Is there a theoretical reason why it would be different?

Matthew S. Davids, MD, MMSc: Not that I know of.

Ian W. Flinn, MD, PhD: Yes. Time will tell.

Transcript Edited for Clarity