Updates in the Management of Follicular Lymphoma - Episode 12
Ian W. Flinn, MD, PhD: Let’s tackle the question of new agents in follicular lymphoma. There are a variety of new agents that are being studied. One of them is polatuzumab vedotin, the anti-CD79b antibody-drug conjugate. There are data in single agent; there are data in combination. Matt, what do you think about that?
Matthew Lunning, DO: As a person who’s never given polatuzumab, I have tried to follow along the story. Because I think the story has been very interesting across non-Hodgkin lymphoma, right? You have a POLA/BR [polatuzumab/bendamustine-rituximab] versus BR [bendamustine-rituximab] in relapsed-refractory large-cell lymphoma shows an overall survival advantage. When have we ever shown in a randomized study in relapsed-refractory DLBCL [diffuse large B-cell lymphoma] an overall survival advantage? Personally, I can’t remember 1. But then you flip over to follicular lymphoma when there wasn’t, and it was like BR [bendamustine-rituximab] and what was POLA [polatuzumab] adding.
This study is very interesting because it’s going at POLA, polatuzumab plus obinutuzumab, plus lenalidomide. So it’s kind of getting into that building-block approach. I know it was a phase I kind of study in which they were dose escalating the polatuzumab as well to lenalidomide. I believe lenalidomide started at 10 mg and POLA [polatuzumab] was at 1.4 mg. And when they figured out the recommended phase II dose, it had a pretty good overall response rate as well as I think about a 50% complete remission [CR] rate.
Sometimes you can curse a study by saying, “interesting data,” or “hopeful or promising data,” but I think that data are going to move forward and be informative.
Pier Luigi Zinzani, MD, PhD: I remember the historical data of polatuzumab versus pinatuzumab at least 7 years ago in combination with rituximab. This kind of drug was active not only in diffuse B-cell lymphoma but also in follicular lymphoma. And then for at least 3 or 4 years, the company decided to put on the corner that now there are several interesting data concerning polatuzumab with BR [bendamustine-rituximab] in diffuse but also in follicular lymphoma. Because as a single agent, it’s quite active also in the setting of patients.
Ian W. Flinn, MD, PhD: Yeah, I was an investigator in that study, and I was impressed by the data. I think 1 of the take-home messages, though, was to be very careful about the peripheral neuropathy. The limit, the dose was a little less than given in large-cell lymphoma, and to limit the number of cycles of therapy and to start, and to stop very quickly when you got into things.
I like the combination. It seems exciting to me. I also sort of wonder how that’s ultimately going to be the developmental pathway of that combination to get it approved. We now have R2 [lenalidomide-rituximab] rather than obinutuzumab-lenalidomide as a proved second-line regimen. Does it really matter whether it’s obinutuzumab or rituximab in this combination? There are a lot of questions to be answered.
John M. Pagel, MD, PhD: Maybe it depends on whom it matters to. It might matter more to the FDA than it does to us, I suppose. But you know, I do think the important thing is that polatuzumab has a role. It’s certainly going to have a role in large cell lymphoma. But again, it comes with a cost, right? And that neuropathy is about 50%, if I’m not mistaken, in the large-cell study. And most of those were grade 1s, but you know there are those rare patients who are really severely impacted from a neuropathy standpoint. And we have to understand how to use the drug, as you said.
Matthew Lunning, DO: I think we use it right. I think for those of us who have used brentuximab vedotin, it’s the same warhead; MMAE [monomethyl auristatin E], some of us have given it up front; PTCL [peripheral T-cell lymphoma], up front; Hodgkin, we’ve given it in relapsed and maintenance settings. You have to ask the right questions. You have to know when it’s time to hold and then dose reduce, because 1 dose too many, you know, it’s different.
Ian W. Flinn, MD, PhD: Right.
Pier Luigi Zinzani, MD, PhD: Also, because in particular the neurological toxicity is more evident in older patients, most follicular lymphoma is in older patients.
John M. Pagel, MD, PhD: I think in follicular lymphoma, given that these neuropathies are usually cumulative, it kind of builds. If we’re not curing these people, being willing to stop treatment or take a holiday or something, is the mind-set I think you should go into probably with most follicular lymphoma patients.
Matthew Lunning, DO: And educating the patients that that’s OK.
John M. Pagel, MD, PhD: Absolutely.
Matthew Lunning, DO: Sometimes there are drugs that you need only a squirt or 2 to get some durability, not that you have to be giving it every single time.
Ian W. Flinn, MD, PhD: Well, in that combination you mentioned, it is a lower dose, it’s 1.4 mg, which I think is the dose they’re trying to do in follicular lymphoma. And maybe with the combination, you’re going to get on and get off. You’re not going to have the cumulative toxicities.
Matthew Lunning, DO: We have active agents on the other side, right?
Ian W. Flinn, MD, PhD: I was really impressed by that data. I wasn’t part of the study, but I was impressed with it. So let’s talk about some other new agents, or maybe not new agents. Immunotherapy and checkpoint inhibitors seem to have a role in pretty much every solid tumor I can think of. But maybe not so much in a lot of lymphomas. We know that maybe, with the mediastinal B-cell lymphomas maybe being the exception in Hodgkin disease. But there are some data with the combinations in follicular lymphoma. What do you think, Pier Luigi?
Pier Luigi Zinzani, MD, PhD: If you change the data using nivolumab-pembrolizumab as a single agent, it’s most likely. But there was a phase II study from The University of Texas MD Anderson Cancer Center presented by Loretta Nastoupil 2 years ago at ASCO [American Society of Clinical Oncology Annual Meeting], ASH [American Society of Hematology Annual Meeting and Exposition], and AHA [American Heart Association’s Scientific Sessions] concerning the combination of pembrolizumab plus rituximab. And the CR rate was 50% in relapsed and refractory patients with follicular lymphoma. The overall response rate was 65%. They were quite interesting, this data. Because in this case it is a chemotherapy-free regimen.
Ian W. Flinn, MD, PhD: Yeah, though I worry that there are also 3-drug regimens in combination. I worry; these are available agents. I do worry a little that someone is going to start combining all these things before we really have definitive proof of the efficacy and toxicity. There have certainly been other examples in this field in which we’ve combined drugs that seemed like they should be combinable, but they’re not.
John M. Pagel, MD, PhD: Well, your point is excellent because even though we love this idea of immunotherapy and PD [programmed death] inhibitors are very, very attractive, they can be extremely toxic. And if we don’t really understand how to use them in follicular lymphoma, we have to be very cautious.
Matthew Lunning, DO: You don’t want to set back the field. I mean, PI3 kinase inhibitors have a story in which they’ve been combined with things that were rational that ended up having toxicity and probably slowed down the development.
Transcript Edited for Clarity