Updates in Targeted Therapies for B-Cell Malignancies - Episode 13

Waldenstrom Macroglobulinemia: Non-BTK Novel Strategies


Ian W. Flinn, MD, PhD: Let’s get away from BTK inhibitors in Waldenström macroglobulinemia. They’re clearly a really important addition to our armamentarium for this disease. What else excites you? John, is there anything else that’s coming up that you think is going to make its way into Waldenström?

John Pagel, MD, PhD: I think venetoclax has a role in Waldenström, as well. Matt and I were on the very first phase I trial, and there were some patients who had Waldenström in that trial who are still on the venetoclax. It’s been about 5 years since starting treatment and they have ongoing and even complete remissions with single-agent venetoclax.

Unfortunately, we don’t have much data on it yet. We need to do another, bigger study, but I think venetoclax will definitely be an agent that we’d want to turn to in patients who have failed BTK inhibition, or at least that might be the sequence we’re thinking about. Maybe it would be chemotherapy up front, and they get a long time. Then it’s BTK inhibition with rituximab, and maybe it’s venetoclax as an agent down the road.

Matthew S. Davids, MD, MMSc: If I could just add—

Ian W. Flinn, MD, PhD: Please.

Matthew S. Davids, MD, MMSc: I fully agree. At our institution Dana-Farber Cancer Institute, Jorge Castillo, MD, has been leading a study of venetoclax monotherapy. It’s a phase II study that’s still early. He’s presented some interim data, but it seems to be holding up that experience we saw from the phase I. We’re seeing very nice response rates in the phase II setting with venetoclax as a monotherapy. Based on that, they’re developing a combination approach of venetoclax with ibrutinib for Waldenström patients. That’s a very exciting approach for these patients.

Ian W. Flinn, MD, PhD: The CONTRALTO study is not the same disease, but there wasn’t a lot of additional activity when venetoclax was added to rituximab or to chemoimmunotherapy, although it was not in Waldenström. I don’t know if we can apply that same data. Here, you’re taking about another small molecule.

Matthew S. Davids, MD, MMSc: I think it’s really hard to know. I probably wouldn’t extrapolate from these other diseases. I think there’s a distinct biology here with Waldenström.

Ian W. Flinn, MD, PhD: I’m hearing that there’s ultimately some promise to the combination of venetoclax and BTK inhibition. Brad, are there any other combinations that you could think of that are around the corner?

Brad Kahl, MD: Proteasome inhibition is fairly useful in Waldenström. Bortezomib has a response rate, and it’s used in several different combination regimens. I haven’t seen much data yet, but it’ll be interesting to see how the newer proteasome inhibitors like carfilzomib and ixazomib may pan out in Waldenström. I’d like to see those agents brought forward and developed.

Ian W. Flinn, MD, PhD: Hopefully, carfilzomib is a little less toxic. One of the issues for many patients with Waldenström is that bortezomib has been associated with some of the neuropathy issues that they’re already prone to.

Brad Kahl, MD: Right. They’re limiting in that disease, for those reasons.

Ian W. Flinn, MD, PhD: This has been an extremely informative discussion. Before we end the discussion, I’d like to go through final thoughts from each of our panelists. Matt?

Matthew S. Davids, MD, MMSc: I think this is a very exciting time in B-cell malignancies. We have a lot of new tools available to us. Most of these agents were developed as single agents, but as we’ve discussed, the combinations are particularly exciting and potentially allow for time-limited therapy. I’m certainly very optimistic for the future.

Ian W. Flinn, MD, PhD: Brad?

Brad Kahl, MD: I am very eager to see the next generation of trials that will use these targeted agents in combination with the goal of time-limited therapies. I think that’s what the next 3 to 5 years is going to look like.

Ian W. Flinn, MD, PhD: John?

John Pagel, MD, PhD: I think there are 2 major trials that we’re going to learn about very soon that are going to be helpful, and they’re around the acalabrutinib, including the up-front ELEVATE-TN trial to see the combination of acalabrutinib with obinutuzumab, or the use of acalabrutinib in frontline CLL [chronic lymphocytic leukemia] patients. Then there’s the head-to-head randomized trial of acalabrutinib versus ibrutinib, which will help us understand if acalabrutinib is truly a better-tolerated agent, and that may change the landscape in CLL. We’ll see what that does to mantle cell and even Waldenström down the road.

Ian W. Flinn, MD, PhD: OK. Thank you all for your contributions to this discussion. On behalf of our panel, we thank you for joining us and we hope you found this Peer Exchange discussion to be useful and informative.

Transcript Edited for Clarity