Anti-CD20 Antibodies for Advanced Hematologic Malignancies

Transcript:Ian W. Flinn, MD: And there are some antibody drug conjugates that are being developed in the B-cell lymphomas. Polatuzumab is one that’s in the forefront of that, which is a CD20 antibody. There was also a CD22 antibody that was being developed, and, frankly, you couldn’t even tell. I think the manufacturer was in a pretty good position that they couldn’t tell which one was going to be better, because they were both really excellent. There are some associated toxicities with that, and I’d love to hear your thoughts on this, Andre. When you’re repeatedly dosing patients, especially the low-grade lymphomas, with these things that can cause neuropathies, that’s something to take into account when picking therapies.

Andre Goy, MD, MS: Absolutely. We know from the data on brentuximab, which is an anti-CD30 with MMAE (monomethyl auristatin E), it has neurotoxicity. The mechanism of neurotoxicity is not totally understood. It doesn’t seem to be just leakage, but clearly some patients develop really severe neuropathy and durable neuropathy. That’s why, in the context of R-CHOP, vincristine can be dropped so as not add to the neuropathy. And this is something—that when we pick the treatment, particularly sometimes a commitment for a quite durable treatment—that’s tricky. So, I see them [antibodies] playing a role more than just as a single agent for long duration in a combination setting, as we are starting to do in Hodgkin lymphoma, but also in CD30-positive T-cell or large-cell lymphoma; for example, for anti-CD30. There are numerous other antibodies, including actually a big effort for decades of coupling them as a loading agent with a radioisotope. There was a lot of hope that radioisotopes would actually have great activity, because lymphomas are very radiation-sensitive. And the activity has been somewhat disappointing.

Ian W. Flinn, MD: Yes, that has been a disappointment. Very early, in some of those projects, we saw great responses—but not necessarily the most durable remissions. There were also tremendous logistical issues in terms of delivering the therapy that made a lot of that go out of favor, and that’s too bad. But, the antibody drug conjugates, I think there’s a lot working. I mentioned polatuzumab was a CD20. It’s actually a CD79b target, but that’s another antigen that’s being targeted instead of CD20. We talked earlier a little bit about the T-cell re-directing therapies that are being developed and the bi-phenotypics that are being developed. So, there’s a lot of excitement. There are other ways to engage the immune system other than the direct targeting of the tumors.

Andre Goy, MD, MS: Correct. And then we always talk about lymphoma. There’s now really an opening of a new chapter in myeloma, where the monoclonal antibodies, anti-CD38 particularly and other targets, seem to have activity. There were some data presented at ASCO on a combination with small molecules, where this is going to be very helpful in a disease that is a perfect model for immunotherapy being an essentially bone marrow disease.

Ian W. Flinn, MD: How do you pick which antibody to use in which disease? Is it solely based on everyone with a B-cell malignancy gets a CD20 antibody? But there are different CD20 antibodies out there. There’s obinutuzumab, there’s ofatumumab, there’s rituximab.

Andre Goy, MD, MS: So, obinutuzumab is not approved in a lot of indications and ofatumumab is approved in CLL in patients who have failed multiple indication agents. Alemtuzumab, at the time, was used in refractory CLL and ofatumumab supposedly has more CDC (complement-dependent cytotoxicity) activity. The responses, that we know from the data from the large randomized trial with ibrutinib, are really not that impressive with ofatumumab. It’s not something that we use routinely. Obinutuzumab is also something that has a lot of infusion reactions and much more—and I would have expected, to be honest—but it’s manageable. It’s definitely more of an antibody. In somebody who is outside of a protocol, in someone who has extensive disease, CLL particularly, and has failed prior therapy, obinutuzumab is something that we do. But as you mentioned, once we see more data maturing in the lymphoma area with obinutuzumab versus rituximab, maybe there will be a shift, as well, this way.

Frederick L. Locke, MD: One setting where we’ve utilized ofatumumab therapy is in combination with rituximab as a bridge to allogeneic transplant for CLL patients with really refractory disease. In that setting, it seems to at least hold patients, or get them enough of a response, to get the allograft in. And patients with CLL can have significant responses after the allogeneic transplant. Patients who actually have disease going in can shrink down and go away in a year’s time, or some cases even longer. So, monoclonal antibodies might be used as a bridge to transplant in some cases.

Krishna V. Komanduri, MD: I think the natural areas for synergy would be to take two antibodies with different targets, whether it’s CD79b, CD40, CD22, or CD20. I think these are combinations that will make sense.

Andre Goy, MD, MS: There are data. We’re part of this one study. There are data with anti-CD79.

Transcript Edited for Clarity