Introduction: Follicular lymphoma in clinical practice

DR LOVE: Good afternoon everyone. I’m Neil Love from Research To Practice and welcome to Year in Review, as today we talk about new papers and new presentations in follicular lymphoma in 2021, a year I don’t think any of us are going to be forgetting.

We have a great faculty today, Dr John Leonard from the Weill Cornell Medical School and Dr Laurie Sehn from the Division of Medical Oncology at University of British Columbia in Vancouver. If you have any questions or comments you’d like to make to the faculty, just type it into the chat room, if you have any cases you’d like to hear them discuss.

We do also audio programs. A lot of people end up listening to replays of our webinars on our Oncology Today series, including a recent program we did on CLL with Dr Kater. Let me — okay.

We do webinars all the time as we did in 2021. Tomorrow, we’re going to be going at 12:30 Eastern Time with Prof Fizazi in Paris to talk about castration-resistant prostate cancer. Then, on Thursday, we’ll be continuing our Year in Review series. We have a whole bunch of these programs set up for the next few weeks. On Thursday, we’ll be talking about breast cancer with Harold Burstein and Professor Schmid. So many things going on in breast cancer. Next Tuesday, Year in Review continues with non-small cell cancer. We’ll be talking about targeted therapy. So many new targets coming on including KRAS to discuss. Then on Wednesday, we’ll start up our Meet The Professor program for 2022 with Dr Tiffany Traina. We’re going to be talking about HER2-positive breast cancer. The following day, we’ll be back for another Year in Review program, this time on immunotherapy in lung cancer. And then, we’ll be heading out to ASCO, the ASCO GI, the GI Cancer Symposium, I think, in San Francisco. We’ll see what happens. But we have 3 satellites either way that are going to be coming online on these days whether they’re virtual or not. So on Wednesday night, late Wednesday night at this point, we’ll be doing a program on colorectal cancer. The following day, we’ll be doing a program on upper GI cancers. And then on Friday, the 21st, we’ll be talking about HCC.  

But today, we’re here to talk about follicular lymphoma, some really interesting developments and also some things for the immediate future that are going to be really important for people to know about.

Here’s where we’re heading. We’ll just kind of provide a little bit of an overview, but we’re really going to focus our first discussion on first and second line therapy. So we know that BR and R-squared are usually first and second line, but somewhere along the line, whether it’s R upfront, anti-CD20, chemotherapy and IMiDs, specifically lenalidomide. And we’ll talk about some new papers there. And then, we’ll get into beyond second line and third line. And we’ll finish out talking a little bit about CAR T.

Before we kind of get started with the papers, I’m just kind of curious, John, what are some of the questions, in general, you’re getting about follicular lymphoma from docs in practice? When you see second opinions, what are some of the issues that are coming up in follicular lymphoma over the last 6 months or a year?

DR LEONARD: I think the first question that always comes up is, what’s the best upfront therapy? I think people are, for many people, focused on bendamustine with an anti-CD20. I think once patients relapse, it gets much more complicated. We do have a few other options upfront, but in the relapsed setting, particularly when patients have 2 or 3 prior regimens and beyond, we’re going to get into all of the different discussions and options. But knowing that a lot of it is focused on quality of life and that long-term outcomes are good for most patients, not all, with various different options, picking one in particular and deciding which one to choose I think comes up a lot in different scenarios.

DR LOVE: So, Laurie, I just saw a question pop up in the chat room. I want to get the chat room involved here today. We get such great cases and questions. Swati wants to know, do you ever use R-CHOP upfront in follicular lymphoma, Laurie?

DR SEHN: So personally, I never use R-CHOP upfront. We know that R-CHOP is a very effective treatment for follicular lymphoma, but on the other hand, we do have a trial where it was compared head-to-head against bendamustine and rituximab and I think it’s fair to say, at least in the StiL trial, there was a suggestion that the BR had a better progression free survival. I think most importantly, the toxicity of R-CHOP I feel can’t be justified for most patients because we know that it doesn’t offer a curative advantage and I think that my biggest concern is that one of the biggest threats to all of our patients with follicular lymphoma is really the risk of transformation and being able to treat them at the time of transformation. So I wouldn’t want to use up my anthracycline just treating follicular lymphoma if that patient goes on to further develop a transformation. So I guess my answer would be the only time I use it is if I’m suspicious that there might be a transformation at the time of presentation that I want to make sure I’m covering all bases. But otherwise, if it’s just follicular lymphoma, I think it’s hard to justify.

First- and second-line treatment — chemotherapy, anti-CD20 antibodies and IMiDs

DR LOVE: So I want to get your take on, of course, everybody wants to hear about third line and beyond because there’s just so many new agents and options and more coming probably in this next year. But there’s also some new data that came out in the first and second line setting I think is worth considering. And so we’re going to start out talking about the issue of first and second line therapy and some of the papers, one in particular, I’ve always loved the RESORT trial looking at short-term rituximab versus longer-term maintenance. We’re going to get into that in second, but, of course, John, one of the issues that we have now that we didn’t have a couple years ago, obviously, is COVID. There’s been a lot of discussion about COVID and anti-CD20 antibodies. People are generally trying to avoid it. I get the feeling that maybe people are using less anti-CD20 or maybe shorter duration. Any comments about how the issue of COVID, also vaccination, John, how you time that? Any comments about how currently it’s affecting, and of course, it seems like it changes every day with Omicron, et cetera. But in general, John, kind of how are you thinking through this issue of COVID and vaccination in FL patients?

DR LEONARD: Well the first thing is I think you need a score card for all of the names of the drugs. I think the COVID drugs rival the names of the CAR T constructs to try to keep them all straight and pronounce them properly. But I think the — it certainly evolved. We first started with a whole group of patients that were on an anti-CD20 and then vaccines came along and they had the scenario of now they needed to be vaccinated after having had a CD20 directed agent and didn’t, in many cases, respond well to the vaccination afterwards. So we kind of dealt with that way. We still have some patients that have not responded well to a vaccine because of their prior anti-CD20 and/or their disease.

Those are people where I think we need to start thinking about the new prophylactic antibodies that are available. In particular, I believe tixagevimab/cilgavimab is the name of one of those that is recently available. And I think we, once that becomes more widely available, will be covering a number of patients with that agent, particularly in the setting I just described. The scenario where now somebody has gotten vaccinated, needs an anti-CD20 as part of their therapy, you don’t want to compromise curative therapy, so in large cell lymphoma, it hasn’t changed much of anything. I think in follicular lymphoma, we certainly have been much less enthusiastic about maintenance approaches. We’ve been much less enthusiastic about in low tumor burden patients trying to put off therapy more if we can. And then in mantle cell, it kind of fits in the middle because we know that maintenance rituximab in some settings improves overall survival and so we have, in some cases, held doses of anti-CD20 antibodies. But for follicular patients specifically, I think we’ve largely moved against maintenance or minimizing maintenance and minimizing anti-CD20 in patients where it’s a little more elective as an option.

DR LOVE: So, of course, we’ve been hearing these kinds of thoughts since the beginning of the pandemic, but I wanted to — in light of that, I’m going to come to you, Laurie, in a second. But first, I want to take a look at the RESORT data first and then I’m going to get your take on anti-CD20 in general and COVID in particular. But one other sort of practice question I wanted to put out to both of you, again, before we kind of get into the papers, is this question which is, when you use R-squared, and most people are using it second line nowadays — we know from asking people although in many situations, it can and is used in first line. I’ve seen a lot of debate about the optimal duration, Laurie, of the R-squared approach in the first line. In the initial RELEVANCE trial, it was very long. I think it was 2, 2 and a half years. The PI, Dr Fowler, now talks about using it maybe 6 months or a year, particularly somebody who has had a good response. I don’t know if that applies in the second line where people use it and I think people stop, but I’m not sure how long they usually are treated for. So, Laurie, in general, how do you think through how long you’re going to use both the lenalidomide and rituximab and is it different first line and second line?

DR SEHN: Yeah. So it’s interesting because I’d say there’s probably no universal standard that’s used. We’ve got data that’s out there that, as you commented on, has given the R-squared for 6 months versus 12 months versus 18 months in RELEVANCE. And in some scenarios, people have used achieving a CR as an indication to stop. I don’t think there’s a right or wrong answer. In my own practice, I do tend to give it for up to 12 months, but I think that we’re rethinking all of our practices these days in terms of COVID and we are more judiciously giving immunosuppressive therapy. So I’d say that if you think you can get away with a shorter duration of therapy for patients, I think this day and age, it really is becoming an enticing option. I think we also need to keep in mind that these patients can be re-treated with the same option. So these are not curative agents, these are patients that we’re going to be managing over the long-term and I’m not sure that we have any data to suggest that giving a shorter course and then re-treating when necessary isn’t particularly as good of a plan. So I think 12 months is probably most commonly used by people. And whether or not you continue to give the rituximab in a prolonged fashion after that I think is also somewhat optional. And as John stated, I think most of us are rethinking the use of long-term rituximab because of the concern for the need to perhaps get ongoing COVID vaccines as we move forward.

DR LOVE: Quick question from the chat room from Raji, John. I guess theoretically, she’s asking, how long after you give rituximab or obinutuzumab is it “okay to vaccinate?” Theoretically, John, would it matter if you wait a month or 2 or 3, theoretically? Would you get a better response to vaccines?

DR LEONARD: I think the data suggests that the B cell recovery occurs in the range of 6 to 12 months afterward. So in the scenarios, if I’m giving maintenance every 3 months, I might skip a dose and vaccinate a patient a couple weeks before the next maintenance dose would be due. That being said, given as Laurie alluded to, we’re probably going to be using boosters or some re-vaccinations over time. Part of me says, well if I don’t get the greatest response now, I’ll probably be giving it again in another 4 to 6 months and that’ll be another opportunity to do it and to do better at that point. I contrast that with patients with the flu shot where flu season comes around once a year, you either give it or you don’t give it. We don’t wait 4 months to give the flu vaccine if we gave rituximab, we just do our best and give it and know that it won’t work perfectly. And I think with the COVID vaccinations, we’re kind of, you know, we have this option of moving things around a little bit in the course of the timing of rituximab, but at the end of the day, at some level, we’re not going to postpone it indefinitely, so you have to kind of slide it in and if I have the option, I’ll wait 4 to 6 months.

DR LOVE: So, Laurie, another great question from the chat room. And watching football the last couple of weeks and seeing how these teams are depleted of people getting COVID, this is really, I think, a good question. He wants to know, is there any potential interaction between anti-CD20 and the antibodies that are being used for COVID? And it really gets into the issue of, what do you do with somebody who has it, particularly if they’re not that sick? Do you stop the treatment? Do you stop the anti-CD20? Obviously, it’s an individual decision. But any general thoughts about whether there’d be an issue giving the COVID antibody and anti-CD20, Laurie?

DR SEHN: That’s an interesting thought. I’m not aware of any reason why we’d think that they would be contraindicated, for example, or why one would affect the value of the other one. So I’d say that, you know, I don’t see any reason why you couldn’t proceed with an anti-CD20 and use the antibodies for COVID. I’m not aware of any data.

DR LOVE: So okay, John, real quick case from the chat room. Sorry. I can’t resist it when somebody puts in a cool case. So Venu has a 62-year-old man with a pancreatic mass in the head of the pancreas and mesenteric lymphadenopathy, multiple nodes 4 cm in size. Biopsy of pancreatic mass, Grade 2 follicular lymphoma. Patient is asymptomatic. This was found on a screening CT. Liver function normal. And the question from Venu is, given the COVID pandemic, what would you do?

DR LEONARD: Yeah. I think it’s a question of the patient’s asymptomatic, they don’t quite have bulky disease, but you’re getting a sense that there’s a possibility of obstruction in the future. This may be somebody I watch. I don’t do a lot of CTs in follicular lymphoma or PET scans, but this might be somebody where I try to hold off a little bit and maybe repeat the imaging in another 3 months or so and see if it’s getting bigger. Obviously, you don’t want to run into trouble, but this mass might have been there at the same size for the last 3 years and might sit there at the same size for another few years. So this is someone I’d probably reimage with a short interval and see if there’s any change and then make my decision at that point.

DR LOVE: All right. Well let’s talk about some of the papers. And as I said, I always thought it was — I always loved that RESORT trial. I remember when Brad Kahl and Mike Williams presented it. It seemed like 100 years ago, but it was a cool study. And, Laurie, you talked about it. I should mention that I met with both John and Laurie last week. I think it was last — I’m losing track of time now. But in the last couple weeks. But anyhow. We — both of them recorded a presentation that goes through in detail these papers we’re going to talk about. So ideally, if you want to get into more depth, please consult the presentations when they’re posted in a couple weeks. But, Laurie, you went through the RESORT trial. Can you just refresh our memory about what that trial looked at? And then they just presented follow-up data at ASH that I thought was pretty interesting. But can you just remind us what the trial looked at?

DR SEHN: Sure. So this was a trial that explored 2 different treatment strategies in what we’d call the low tumor burden patient with follicular lymphoma, so those patients who we frequently would term watch and wait patients. And still to this day, watch and wait is a perfectly acceptable approach. But this trial compared 2 options. One was to give a course of monotherapy with rituximab, so 4 doses weekly over a month and then observe. And at the time when patients needed additional treatment to keep going with additional courses of monotherapy as necessary versus more of a prolonged rituximab where they got their initial monotherapy and then got 1 dose every 3 months virtually indefinitely. And so this was previously presented and essentially what we learned is that there wasn’t a lot of practical value for the use of ongoing rituximab maintenance.

So in the end, I think what we learned is that patients really got to the same place, but using a lot more rituximab in the maintenance arm. I think if you got back a slide to the other one that you just showed, this was interesting actually. So this was the long-term overall survival data of these 2 arms. And I think it really serves to make 2 points in my mind and that is that the overall survival at 10 years is about 84% in these patients. Many of them are elderly, they’re dying from other problems. So this is a really good risk patient group. And I think the most important thing is to remember that we don’t want to cause harm in these patients. The fact that the overall survival between the 2 arms is not any different I think is also intriguing. Many of us have worried about if you keep exposing a patient to rituximab, are you inevitably inducing resistance to rituximab and somehow patients will have poor outcomes down the road? I sort of thought this was somewhat reassuring that the rituximab didn’t seem harmful, but at the same token, didn’t really offer any long-term benefit.

When I actually saw this presentation at ASH and I saw Brad Kahl, the author, field questions, I thought he made a very important point. In this asymptomatic low tumor burden follicular lymphoma patient, right now, most of us have reverted back to a watch and wait approach because of what we discussed that weighing in the pros and cons of using a monoclonal antibody such as rituximab in this scenario versus watch and wait would probably be in the favor of watch and wait given the concerns for COVID and the lack of antibody response. So I used to use rituximab monotherapy in my own population for this scenario based on the RESORT data in part, but currently, we’ve gone back to just observation alone.

DR LOVE: So I want to get, John, I want to get your take on it. I kind of think, when I saw this, I actually was all excited. If it weren’t for COVID, it might have a different meaning. But, John, one thing that was presented and Laurie, when she went through this, brought up issues about how the data was collected and et cetera. But it did show that the patients who got maintenance therapy had a longer time before they had to get chemotherapy. And anyhow, COVID is another issue. But any thoughts about why this played out this way, John? Do you think it’s for real or maybe an artifact of how the study was done?

DR LEONARD: I think it’s interesting. This view also got my attention as well, not necessarily enough to change my practice, but I thought that this was really the first or really only way efficacy-wise that it showed a benefit to maintenance rituximab. So I thought that was an intriguing finding. I think time to first therapy or time to a specific type of therapy is always a little bit of a challenging endpoint because it’s very subjective. But I did at least take note of both that and the issue around transformation. But at the end of the last as Laurie mentioned, the fact is that overall survival was quite good with both directions and really no different. So I think that, to me, remains the overall guiding piece of information from this study.

DR LOVE: So, Laurie, I can’t resist these cases coming into the chat room. I’ve got to throw a couple more of them out to you. Hassan has a 50-year-old man, liver mass resected, 6 cm liver mass, found to have MALToma type NHL. No other sites of disease. Any comments on therapy?

DR SEHN: It’s interesting actually. So I’m assuming that this patient had an isolated MALT lymphoma involving the liver which is unusual. If it was resected in its entirety and the patient didn’t have active disease elsewhere, this would be a patient that I would probably simply observe at this point. We know that if a patient has Stage I MALT, we often manage them with local radiation, but if it’s been removed and based on concern for radiating the liver, I think needlessly, I would just be observing this patient. They would likely have a very good outcome regardless.

DR LOVE: Okay. John, here’s a case from Stuart. Otherwise fit and healthy 85-year-old man. I always like it when it starts out that way. History of localized FL in 2004 treated with radiation therapy. Then, aggressive B-cell lymphoma in 2012 treated with R-CHOP and radiation. Did very well. Now has localized FL on the arm. All imaging outside the arm negative. Any thoughts?

DR LEONARD: Well this is clearly a follicular lymphoma recurrence so we know that there’s occult systemic disease. I think that certainly this is somebody who if this wasn’t bothering him, you could leave him alone. I certainly wouldn’t be in any rush to give him systemic therapy. There is the boom-boom or 2 doses of radiation that is a very good palliative approach, not quite as good as a full course of radiation in the curative localized disease setting. But if his arm was bothering him, that might be something that could control his disease for a period of time and spare him the need for any systemic treatment. But he may need no therapy at all, but if he needed something, I’d probably give him a little bit of radiation.

DR LOVE: So I’ve got a question that just popped into my mind. I haven’t thought about it at all, Laurie, which is how are you treating transformed FL nowadays? In light of your POLARIX study with polatuzumab, would you, if you could, would you do that?

DR SEHN: That’s a really good question. I’d say that we don’t know the answer to that from POLARIX since that would have excluded patients with transformed disease. So it really was untreated DLBCL although most of what we do for transformed lymphoma has been extrapolated from optimizing management for DLBCL. So I think it’ll be interesting. In clinical practice, it may be that it does get extrapolated over and people will use it. So we still don’t have access to it yet in my own clinic, but I think it wouldn’t be unreasonable to consider that since in the end what we’ve learned is that trying to optimize the treatment for the DLBCL actually can have very good outcomes in patients with transformed disease. But we don’t — we won’t learn that from POLARIX for sure.

DR LOVE: So I can’t resist asking John. Is it your take that pola/CVP is — or COP is standard of care based on the POLARIX study? Is that what you’re hearing from your colleagues, John? Is that what you want to do?

DR LEONARD: Well I think there’s a lot of chatter about the fact that there was more or less a 7% PFS benefit without an overall survival benefit. But I, from my perspective, if I had access to the drug, I would certainly use it. If it’s going to reduce my chance or recurrence by 7% with a very similar toxicity profile, why wouldn’t you do it? The main reason not to would be toxicity which seems to be quite comparable and cost. So, again, the societal question is a different one and I’m sure Laurie in her role in her province will be tackling that. But to me, it seems like if you have it available for a patient in front of you who met the study criteria, who wouldn’t want a lower chance of relapse and presumably a higher chance of cure and a slightly higher chance of not needing more therapy in the long run?

DR LOVE: And, Laurie, it’s all well and good to say 7%, but you could also look at the hazard rate. And it was a pretty decent hazard rate for a lethal disease. What was it, around 0.7, I think? I don’t remember exactly.

DR SEHN: Yea. Exactly. If you look at it proportionally, 1 out of every 4 people that would relapse didn’t relapse on the pola arm. So I think there was a substantial proportion of patients that were saved needing to go on to next line therapy. And we know that relapsing with DLBCL is always a bad thing. It’s hard to cure many patients with relapsed disease.

DR LOVE: Of course, we could get into that too because, of course, at ASH, we saw the CAR T versus transplant, but we’ll talk about that another day. Just to finish out on the first and second line therapy, Laurie, you presented in your talk, first of all, follow-up from the RELEVANCE study looking at first line. I don’t know if there’s anything you want to say about that. It looks like the same thing that we saw in the beginning. Very similar outcomes with both R-squared and BR.

DR SEHN: Yeah. I think it’s fantastic to see this longer-term data emerge. It just is really reassuring that both of these approaches are probably very reasonable for the upfront treatment of follicular lymphoma. We know that the RELEVANCE trial was a negative trial and, therefore, it didn’t earn an indication for the R-squared approach in the upfront setting, but if it can be accessed, it’d probably be very reasonable for some patients. And I think this is where the art of treating follicular lymphoma comes in. We want to match the toxicities and the tolerance of a given treatment with a given patient. But I think it’s very reassuring to see these curves really super imposable after more than 6 years of follow-up.

DR LOVE: And, John, we were talking before that right now for a lot of reasons I think the common pattern is to use BR upfront and R-squared second line based on the AUGMENT study, but we saw also at ASH some follow-up data from the MAGNIFY study that, to me, looks a lot like AUGMENT in terms of using R-squared, but in the relapsed setting. There, they’re doing a randomization that they haven’t reported yet in terms of maintenance. Any comments about the use of lenalidomide or R-squared specifically in relapsed disease, John? We were talking about duration of therapy. And in what situations do you use it first line?

DR LEONARD: So I would say that it’s pretty uncommon for me to use it first line. I think it’s not problematic. If a patient and a doctor chose it, I would be fine with it, but I’m not sure that there’s a clear advantage or big advantage to using it versus something like BR upfront. But I use it a lot as a second line therapy in the relapsed group of patients. Typically, I follow the AUGMENT regimen which is basically a year of therapy. And the MAGNIFY study is in some ways confirmatory, at least what we know about it right now, but is also going to ask the question a little bit about the duration of therapy and the benefit of longer therapy or potential benefit of longer therapy. We need more follow-up to really answer that question. But most of the time, I’ll use it for a year of therapy as in the AUGMENT approach although, you know, patients who are tolerating it well and doing well and have had relapsed disease often have different perceptions and are less enthusiastic about stopping treatment. But putting COVID aside, I think once somebody has had a relapse, in some cases they do like to stay on therapy a little bit longer in some cases.

Sequencing third line and beyond — bispecific antibodies, PI3K inhibitors, tazemetostat

DR LOVE: So let’s jump into the real controversy which is third line and beyond. And we’ve had PI3 kinases out there. We had tazemetostat come in fairly recently. But also now, we’re looking at the potential for bispecific antibodies, CAR T therapy that we’ll also talk about in a second. So here are some of the things we’re going to go through in terms of bispecifics, particularly in terms of mosunetuzumab which sounds like it’s going to be the closest to coming into practice and I’m really curious about how that’s going to fit in. We’ll talk a little bit about some of the newer data, particularly at ASH, with PI3 kinase inhibitors and bring back the issue of tazemetostat although I don’t know that there’s anything spectacularly new.

I’m just kind of curious from the audience, have you used a PI3 kinase inhibitor in a patient with FL? We talk about it a lot. I don’t think we’ve ever asked anybody how many times you’ve actually used it. So, audience, have you used a PI3 kinase inhibitor in a patient with FL? And in how many patients have you used it? And also, Laurie, the issue comes up, and we’ll get into this in a second, of choice of PI3 kinase inhibitor because now we have 3 oral and 1 IV. Interestingly, only 28% of the audience has used a PI3 kinase inhibitor. Oncologists, Laurie, are always in the position of using a drug they haven’t used before. I feel like it’s almost every day this happens with new approvals, et cetera. How do you go about, first of all, selecting a PI3 kinase inhibitor, Laurie? We’ll get into the sequence, but which one do you tend to use?

DR SEHN: It’s funny. I’d say that I still use idelalisib quite frequently if I were to use a PI3 kinase inhibitor mainly because it’s the one I’ve become most familiar with. I think there is a learning curve to PI3 kinases. These are drugs that patients take indefinitely and they need to be monitored for the risk of cumulative toxicities that can happen over time. And I’d say it’s interesting. We don’t have any comparison trials between the PI3 kinase inhibitors, so we’re really looking at independent Phase II studies. And I think it’s hard to be convinced that one is better than the other in terms of efficacy and I think it’s also hard to be convinced that the toxicity profiles are very different. So I would suggest that if people do use PI3 kinase inhibitors, it’s probably good to develop experience with one and get to know what to look out for for patients. So I think there is a bit of habit that comes into play. But I don’t have a strong preference for one over the other. I think copanlisib being an IV drug is very difficult in terms of its schedule and I wouldn’t probably favor that because the big value of the PI3 kinase inhibitors is that they are oral drugs that are easy to administer to patients.

DR LOVE: Not to mention that people are still trying to avoid coming into clinics in general. So what about tazemetostat? I feel like we talk about that all the time. EZH2 assays. I’ll ask John in a second how he approaches it. But, audience, I’m curious whether you’ve used this drug. Have you used tazemetostat to treat a patient with FL even on a trial? Have you used it? I’m just curious. We know our audience is general medical oncologists. They’re taking care of everything. There are so many new approved drugs. Wow. Here we go. 10% of the audience has used tazemetostat. But like you’ve got to be ready to use it. You’ve got to know about it. John, where does tazemetostat fit in? And I’ve heard a lot of debate about whether even to get an EZH2 assay. Can you comment on that issue also?

DR LEONARD: So the data with tazemetostat are that patients with an EZH2 mutation have about a 70% response rate whereas patients with wild type EZH2 have about a 35% response rate, give or take. So it’s a significantly higher, but not 0 difference from the standpoint of there is still some value in using it in patients that are wild type. So that raises the question, do you need to check it or not and so on? And so I think it really depends on the patient’s situation a little bit. Certainly, if I knew a patient had an EZH2 mutation, it would move it up higher in my list, but on the other hand, the advantage of this drug, the durability is median of about a year in both groups and the advantage is it seems to be better tolerated. The main side effects are some generally mild GI toxicity, occasional cytopenias. But I would say if you look at side by side the toxicity of this drug versus the toxicity of any of the PI3 kinase inhibitors, in separate studies, this looks a little bit easier to tolerate. And, you know, a 35% response rate versus a 45% response rate is not a huge difference. And so I think this is a perfectly reasonable thing to consider and in some FL patients would be something that I would use before PI3 kinase inhibitor.

DR LOVE: So what I want to know is the answer to this question which is, are things about to change big time? Because we’ve debated this issue, Laurie, many times this whole issue of PI3 kinase. Radioimmune therapy comes up sometimes. But when you look at the bispecific stuff, you’ve got to wonder how people are going to be answering this question if and when, I expect it is going to happen, it’s going to be approved. And my question is, is this going to become third line therapy? And we can talk about whether it matters what the age of the patient is, tolerability, we’ll go through that. But let’s talk a little bit about bispecifics. We’re hearing about that in so many different diseases, myeloma, for example. And we know that there is a bispecific that has an FDA breakthrough designation, mosunetuzumab, and John went through the data. So just to start out with this, John. I don’t know that PI3 kinase inhibitors have this kind of a waterfall plot, but can you talk a little bit, John, about what mosunetuzumab is and globally, you don’t have to go through all of the details because you went through that in the talk, but what we know about efficacy and tolerability, particularly as it compares to these other options?

DR LEONARD: So I think I would argue that these are pretty clearly, as well as you can compare across studies with different populations, pretty clearly very active and probably more active agents in this setting. You saw that the response rates were in the up to 80% range. The CR rates were clearly higher than we see with the other agents that we’ve talked about. These are agents that target typically CD20 and CD3, so it’s kind of an in vivo CAR T-cell sort of program. And I think the biggest thing is that, in my mind for follicular lymphoma, it certainly pushes CAR T-cells down lower on the list. We have an approval of CAR T-cells for FL and I’m not sure that many patients would go to CAR T-cell for follicular lymphoma versus trying a bispecific first given that these are easier to handle and mostly outpatient in regard to how they’re used. I think there is a learning curve with a bispecific antibody.

They do have some of the side effects of CAR T-cells including cytokine release, but these are at lower rates and they are largely treated, used as outpatients. But there is some supportive care and some preparation needed. There’s been a lot of tweaking going on in the step up of the dosing and the combinations to try to reduce the toxicities and I think they are much improved. And we will have to see how they’re used and how practical they are in practice. I do think it’s interesting that many people have not even used the oral agents. So I wonder is it that these patients are just less common in practice? And are you going to want to, in practice, kind of figure out the routine of giving one of these agents in your practice if it’s something you don’t do very often? So I think that’ll be an interesting thing in how it plays out. But clearly, these are more effective agents. And I think it’s going to come down to the risk/benefit of the patients wanting to deal with a little more involved therapy versus one of the oral drugs, but clearly a more active option.

DR LOVE: I just decided I’m going to wait about a year and then ask that question again about mosunetuzumab. Have you used mosunetuzumab a year from now? I don’t think it’s going to be 10%, but we’ll see. Laurie, actually I had the pleasure earlier today working with Dr Jesus Berdeja from Sarah Cannon. We were talking about bispecifics in myeloma, tremendous excitement there. But the issue of cytokine release and toxicity, of course, comes up. This is something we don’t usually think about in an outpatient oncology setting. Here’s one of the things that were presented at ASH in terms of tolerability. But pretty much CRS is definitely an issue. How do you see this playing out in an oncology setting, Laurie? Do you think this could be done in a general medical oncology type setting?

DR SEHN: Yeah.

DR LOVE: Or are they going to need to be admitted? What do you think?

DR SEHN: I think I echo a lot of what John said and that is that there will be a learning curve. I think it’ll be very similar to the learning curve that people had to go through when we started to introduce venetoclax into our practices, you know? There was — keep in mind that the toxicity that’s seen with the bispecifics is really only in the first cycle. So there will be strategies developed, I’m sure, to make sure that it’s administered safely so that patients are managed for their CRS in an effective and efficient way. But I think these are off-the-shelf products. I think that even in the context of the Phase I trials that we’ve seen evolving over time, the administration schedule has evolved to make sure that they’re given in such a way that the risk is relatively low. It’s generally low-grade CRS. And I can easily see these being incorporated into standard of care practice. And, as I said, it really is cycle 1, so it may also involve a shared relationship where patients might get started in a sort of larger center and then roll over into community practice because beyond that first cycle, these are remarkably well tolerated drugs. I’ve had many patients tell me that they can’t believe they’re actually getting treatment. There’s really relatively few side effects with them.

DR LOVE: When you were talking about people getting used to new agents and strategies, for some reason I flashed on a meeting we did about 3 years ago with general medical oncology Florida Cancer Specialists and we were bringing up azacitidine and venetoclax for AML. And we were like you’re going to have to give it because there are too many old people with AML and everybody in the room’s eyes were like wide and I’m like, look you give FOLFIRINOX, you can do that. Of course, now they use it like water. So we’ll see how it plays out, but really exciting. John, the other issue that you got into in terms of the future of this strategy I was very interested and surprised by is the combination strategies. So here’s mosunetuzumab and polatuzumab. And I don’t know if you have any thoughts about sort of the future, and this is with lenalidomide, of combinations with bispecifics, John.

DR LEONARD: Well it’s not surprising that immunotherapy like mosunetuzumab would be combined with other immunotherapies or at least partially immune mechanism drugs like lenalidomide. I am less sure, I don’t know if Laurie has any insight, as to the mechanism of why polatuzumab would be potentially synergistic with a bispecific antibody. But I think there have been some interesting data, small numbers of patients and this is going to be looked at in more detail, I think, in future studies both dissecting out the 1 versus 2-drug. But it’s, again, not surprising that you would combine a bispecific. I think we do have to keep in mind, no doubt, we’ll see more toxicity and these drugs are immunosuppressive like CAR T-cells and in the COVID era, but hopefully that will be transient, but time will tell. But there will be some longer-term immunosuppression issues as well that we’ll have to keep in mind with patients treated with bispecifics and one might argue that may be worse in some ways in the combinations. But some of the early data, I think, are very intriguing and we’ll have to see how they all play out with more follow-up.

DR LOVE: Interesting that you mentioned COVID though because you kind of wonder how does CAR T affect? I haven’t really heard anything about CAR T in COVID, bispecifics, et cetera. Laurie, another bispecific —

DR LEONARD: CAR T are really, it’s a risk factor. These patients, sorry to interrupt you, but these patients —

DR LOVE: No. Go ahead. No. I didn’t know that.

DR LEONARD: They do have prolonged B-cell depletion because of the CD19 target. They do get immunoglobulin depletion as well as we’ve seen with anti-CD20-directed therapies. And the current guidance, much like transplant patients, they do get kind of a whole new cycle of booster vaccines after CAR T. And so that is one group that has been identified at particularly high risk of COVID complications and lack of response to vaccines. So if you do have those patients in your practice, be aware of those. I think most of the transplant community who are treating these patients know that pretty well, but do recognize that these patients can be profoundly immunosuppressed for a significant period of time.

DR LOVE: Interesting. So, Laurie, there’s another bispecific that sounds really exciting. I’m not sure it’s quite as close to coming into practice, but this is glofitamab that John, again, talked about in his talk. And it seems like it has a lot of activity in diffuse large B-cell or aggressive lymphomas. I don’t know if that’s kind of where it’s going to start. But any thoughts about this agent, Laurie? It looks like it’s very effective, again, being combined with other agents. Here, it’s obinutuzumab. Any thoughts, Laurie, about glofitamab?

DR SEHN: Yeah, you know, it’s interesting. So one of your earlier slides was really a table of the bispecifics in development and we have at least 5 of them right now that are out there being developed targeting CD3 and CD20 as their primary targets. And if you look at the different agents, there are some differences in the construction. Glofitamab is quite unique in that it has 2 CD20 sort of targets for 1 CD3 and there’s some suggestion that this may augment its effectiveness. But I think it’s really hard to compare across these trials, but I’d say that the — certainly, glofitamab is looking like a very effective agent for aggressive B-cell lymphomas and the way it gets given, it is combined with obinutuzumab as a way of trying to ameliorate the CRS upfront, so it is a combination treatment. But whether or not one of these will prove to be better in aggressive versus indolent lymphomas, I think, is really hard to say from the data. But, you know, it’s unquestionable, I think, that bispecifics will become very important drugs, both for indolent and aggressive lymphoma. And as we see more data emerge, what becomes the preferred drug might be first to market or one with the least toxicity, the one easiest to deliver in a community setting. I think there will be a lot of reasons why one drug might emerge as preferential over the other. But really hard to compare cross-trial.

DR LOVE: And in John’s talk, he also talks about another agent, epcoritamab. As Laurie said, there are a number of these agents out there. John, what about the issue of PI3 kinase inhibitors? We saw some data, I think this is from ASH, looking at copanlisib with rituximab versus rituximab alone. Also, umbralisib, we talked about that before. We talked about choice of PI3 kinase inhibitors. John, any comments on some of these more recent data with PI3 kinase inhibitors and whether you use it alone or with anti-CD20?

DR LEONARD: Well the copanlisib data is kind of very similar to the AUGMENT study. It was a randomized trial on relapsed follicular lymphoma that looked at relapsed patients and essentially randomized them to rituximab/placebo versus copanlisib/rituximab and showed a pretty clear benefit in PFS and response rate, if I recall. There is, obviously, more toxicity and more complexity there. But it certainly suggests if you’re going to use copanlisib in somebody whose rituximab relapsed that adding rituximab seems to have some benefit there. The umbralisib data, I think, are pretty well in line with the other oral agents. There are some differences in properties of this agent. But at a high level from the clinical perspective, they’re more similar than different, I would say.

DR LOVE: Laurie, any comments on umbralisib? We have the U2 regimen in CLL, but what about this agent in FL? And particularly, toxicity profile? We talked about the 3 oral agents. Any way to distinguish them? Here’s some data from the JCO. It’s a dual PI3 kinase inhibitor also. Any comments on this agent?

DR SEHN: Yeah. I would echo what John said that I don’t think that any of these agents stand out as being much more effective or much less toxic to declare one the winner. So I would say that people who use these drugs should probably get familiar with one drug and get to know the toxicities and how to manage patients on them. But I think the data with umbralisib looks similar to what we’ve seen with other ones. It’s hard to compare across trials because the patient entry criteria were a little bit different and the umbralisib trial had a very highly pretreated patient population. So modest activity but, again, those patients had had at least 3 lines of therapy in most cases.

DR LOVE: So a question from the chat room, John. Maintenance rituximab in upfront therapy with BR, before COVID and now?

DR LEONARD: Well it’s an interesting question. I think that some have argued that the bendamustine is more immunosuppressive and by adding rituximab maintenance that that could add to infectious complications. There was some evidence from the GALLIUM study both with BR and BO of a little bit more infectious complications and some won’t even use those combinations in older patients. I’ve come across an occasional colleague or two that is very worried about that. I would say that the data are probably less compelling to use maintenance after BR or BO, but certainly that’s within the realm of practice and the data from the GALLIUM study at least, if not particularly looking at that issue, included that. So we do have significant data on that. But at the end of the day with COVID concerns, as we’ve talked about, I think the issue of maintenance is less compelling for patients with follicular lymphoma after upfront chemoimmunotherapy.

DR LOVE: So, Laurie, I think this question is for you theoretically which is, in terms of the use of — let me see if we’ve got it here. We have this patient who is a 90-year-old patient who has gotten rituximab times 4 for low-burden symptomatic follicular lymphoma, now has disease progression. What are you usually thinking about in a scenario like that, Laurie?

DR SEHN: So when I treat patients with single agent rituximab, which I do less often now for the watch and wait group because of COVID, but when I had, at the time when they do have recurrent disease and require treatment, I sort of think of them similar to what I would think for an untreated patient and go back to square 1 and say, what’s my preferential treatment plan now that this patient is unexposed to chemoimmunotherapy and requires treatment? So this is a patient in my own practice I would most typically give BR. But this is an elderly patient and it’s fair to look at, what is the extent of the disease? What are the indications for treatment? Can you get away with another round of rituximab monotherapy? Is that better for this older patient given all competing risks? So I don’t think it’s a straight answer. I would probably need to find out more about the burden of disease and the need to get a quick response. But if this is somebody who I thought needed to go on to chemoimmunotherapy, BR is still my standard of care and I would be looking at this as an untreated patient.

DR LOVE: So, John, a case from Adley and this is something we’ve heard — I hear a lot of cases like this. Well not starting out 90-year-old necessarily. But 90-year-old, in this case, good performance status who has large cell in the node biopsy, but follicular in the bone marrow.

DR LEONARD: So this would be a patient who has a kind of a de novo transformation. Basically, that sounds like having occult follicular lymphoma that was undiagnosed, only found when the bone marrow was assessed and then presented with a node that showed a large cell lymphoma. This is somebody that I would treat as a de novo large cell lymphoma. If they were young and fit, typically, R-CHOP would be the standard. We could argue from the POLARIX study if that would change even though the patient, and it goes back to the issue we talked about earlier. But in an elderly — this patient was, did I hear correctly in their 80s or 90s?

DR LOVE: 90. 90. 90.

DR LEONARD: Right. So this is somebody that I would probably typically would think about a mini-R-CHOP which is a dose reduced R-CHOP regimen. And most commonly, that’s probably what I would use. But I tell my elderly patients with large cell lymphoma what we start with often is not what we end with and we kind of take it one cycle at a time. But if this patient was a fit 90-year-old, I’d probably start with some version of mini-R-CHOP which is a dose reduced R-CHOP.

DR LOVE: So, Laurie, is there such a thing as mini-POLARIX?

DR SEHN: Not officially, but there are trials going on that are testing mini-POLARIX. So I think it’s fair to say that we’ll probably extrapolate with what we do right now for R-CHOP, but in general for older patients, we do dose reduce initial cycles and then titrate to tolerance. I personally don’t use R-mini-CHOP, per se, but we do sort of titrate lower doses and then titrate up based on tolerance. I guess why I’ve never used R-mini-CHOP is that as designed, the doses stay the same throughout and there’s no suggestion to increase them. But I think that it really is something that needs to be adjusted on a patient-by-patient basis because in every patient, we want to try and maximize the therapy and minimize the toxicity.

DR LOVE: Any reason to think that older people have more problems with peripheral neuropathy with polatuzumab, Laurie?

DR SEHN: I’d say that I haven’t seen it reported out of POLARIX, but we do know that many older patients come in with some baseline peripheral neuropathy. So the neuropathy with polatuzumab in the POLARIX trial was actually relatively minimal because it is given for only 6 cycles. And we do know with agents like polatuzumab just like rituximab, it’s a cumulative problem. So if you go beyond 6 cycles, it certainly would set in more. So I guess my expectation would be that it would probably be more of a concern in an older patient, but we would generally manage these patients and watch for concern for toxicity that might warrant lowering the dose or eliminating the drug. And it certainly within POLARIX was not a major concern even for older patients.

CAR T-cell therapy

DR LOVE: So I want to finish out with some thoughts about CAR T in follicular lymphoma, now approved. We brought up the question of whether or not the bispecific is going to sort of push these back or even away maybe. Who knows? But I just want to start out with a question to you, John, which we ask a lot and is the question of eligibility for CAR T based on age. So my question to you, John, is assuming you have, I mentioned before, a 90-year-old who has no comorbidities. I’ve heard — we’ve had cases presented of 95-year-olds who weren’t on any medications which is hard to believe. But you have a very healthy patient. Is there an age in a healthy, I’m sure there is, John, but what is the age where just based on age alone, you’re not going to go to CAR T? And how does that number compare to the number you would give for autologous transplant?

DR LEONARD: Well I think there is a — there is a Venn diagram of patients that are eligible for CAR T and eligible for autotransplant. The circle is bigger and stretches into an upper age range and a less robust fitness a little bit more with the CAR T-cell. So I would say that there are patients well in their 80s that have had CAR T-cells. I’m not sure that I can cite a 90-year-old who has received CAR T-cells, but I think for — the main message is that the population that can get CAR T-cells is certainly not narrow and can include the elderly including patients into their 80s. I do think in follicular lymphoma though, our bar to use CAR T-cells is going to be a little different than it is in large cell lymphoma, mostly because of the fact that we will have the bispecifics, presumably, that are close and easier.

DR LOVE: I certainly can understand that with these options available, Laurie, but it kind of looks like CAR T is pretty effective though in FL if you are going to use that. Any comments on what we’ve seen with FL? It kind of, like I said, you can comment here. We can put the slides up in terms of the ZUMA-5 study, but any thoughts about efficacy with FL?

DR SEHN: Yeah. I think what we’re seeing is that the response rates are very high. You can see the overall response, almost 95% and CR rate, 80%. And the data is still, in my mind, relatively early for a long disease like follicular lymphoma, but many patients do seem to have durable benefit. But those curves are not flat, they do come down. And I think I’m most interested in seeing whether or not there might be an emerging plateau over time. And that would make this a much more attractive option if we actually had something that can cure a currently incurable disease, but we’re not really seeing a plateau yet with the amount of follow-up that we see. So CAR T is still a big gun treatment. It’s an expensive therapy. It has substantial resource implications. And there are toxicities that come with it, both acutely and delayed with prolonged cytopenias for many patients. So I think that it’s all going to come down to, what are your other options for the patient, what’s their disease behavior? But I think we’ll learn more over time about where CAR T fits in as we see longer follow-up on that data.

DR LOVE: John, any comments about CAR T? Have you had patients with FL go to CAR T?

DR LEONARD: Well I think what I’m seeing is that patients are starting as they get to be third line where they’ll have a cell therapy consult. They’ll learn about CAR T, they’ll learn about autotransplant, they might learn about allo which is going to be even less common. But I think the other options are going to be higher on the list. I agree with Laurie, we need more follow-up. And just a reminder, almost every study in recurrent follicular lymphoma has 20% long-term patients in remission. If you go back to radio meta therapy, if you look at even the PI3 kinase inhibitors, the chemotherapy studies, you do see that there are patients that have longer-term remissions even in the relapsed setting in a minority setting. So I think we do really need to have more follow-up before we can say that we’re really curing patients with recurrent FL with CAR T.

DR LOVE: So it wasn’t that long ago that it was kind of boring to talk about FL and those days are gone. There’s a lot of cool stuff going on with this disease. I want to thank Laurie and John for joining us today. Audience, thank you for tuning in. Come on back tomorrow. We’re going to go 12:30 Eastern Time with Dr Fizazi and talking about new agents. Can’t wait to hear what he says about lutetium. Going to change prostate cancer forever. Thank you so much. Be safe, stay well and have a great night. Thanks, John. Thanks, Laurie.

DR LEONARD: Thank you.

DR SEHN: Great. Thank you. Have a great day.