Current management of newly diagnosed follicular lymphoma (FL); choice of observation versus rituximab monotherapy

DR LOVE: Welcome to Oncology Today — Follicular Lymphoma Edition, a special program focused on recently published and emerging research in the management of Follicular Lymphoma, this is medical oncologist Dr Neil Love. For this program, I met jointly with Drs Carla Casulo from the University of Rochester Wilmot Cancer Center in NY and John Leonard from the Weill Medical College of Cornell in NY.

So today we’re going to be focusing on, first, up-front management of FL, then we’ll talk about relapsed/refractory disease and some of the new agents. And then we’re going to focus specifically on PI3 kinase inhibition and where that’s heading. And the first thing we’re going to talk about is the question that often comes up in clinical practice, John, which is the question of observation versus rituximab monotherapy.

John, maybe we can take a step back and talk a little bit about how you think through that question in general.

DR LEONARD: Well, I think the patient who’s newly diagnosed with follicular lymphoma, I tell patients you really have two questions every time you see me: One is, do you need to do any treatment right now? And the second is if you’re going to treatment, what treatment do you do? And so the question of doing therapy really comes down to symptoms, bulk of disease, really issues that would prompt the patient to move forward and need therapy.

So, in talking with patients it really comes down to do they need therapy at all? And there are clearly people that need no therapy at all. There are clearly people that need treatment and for me bendamustine-based therapy is the most common approach. And then there are these patients that fall in between where, maybe, you can observe. Maybe they have low tumor burden and need some treatment and those are the patients where rituximab monotherapy comes into the mix most typically.

DR LOVE: And we’ll get into some of the data behind this. But also curious, Carla, in general, over the years, how people respond when they’re newly diagnosed to the idea of observation? This comes up in CLL and many other situations. And people who are diagnosed with cancer are maybe not used to the idea of not having it treated. How do you deal with that?

DR CASULO: That’s a good question. So, I often talk to patients and tell them that this really, it’s a marathon; it’s not a sprint. This is a 20+ year disease. You want to have a good return on your investment like you would have a good return on your investment of any money that you put into the stock market or something like that.

We know that if you use single-agent rituximab, for example, you’re going to get a response rate that’s anywhere from 50% to 75%. It’ll last from 1 to 2 years. Is that sufficient for someone versus giving someone chemoimmunotherapy? You know that that duration of response is going to be much longer so you’ll have a longer return on your investment. And really, it depends on, again, symptoms. Depends on the age of the person. What’s time to next treatment look like? Is this someone who has some life events coming up where imminent retreatment is really not possible? Or is this someone who, if they recur, the likelihood of them being in the position to get chemotherapy is very unlikely?

So it’s actually a lot of strategic thinking that goes into it.

DR LOVE: I really love that idea of the long-term investment. And I guess there’s another issue that comes out everywhere in oncology, is now starting to factor in COVID and the interest in social distancing, etc. We might get into that as we talk about some of these issues. But, John, why don’t we kind of get into the nitty-gritty of how this plays out in your practice with this 70-year-old man. How did he initially present to you?

DR LEONARD: So this is a patient who presented with lymphadenopathy. Interestingly, his spouse also has follicular lymphoma, which is an interesting scenario and raises all sorts of questions.

It makes you wonder where does that come from? But in any event, the patient was observed for over a year. It took a while to make a diagnosis. The first biopsy was really non-diagnostic. The symptoms were kind of minimal. And then over time the lymphadenopathy progressed in the groin and the patient had some mild leg edema.

So the biopsy showed follicular lymphoma, Grade 1. Really non-bulky disease elsewhere. The patient had one 1.5 cm node in the neck. A few other borderline nodes elsewhere. But the real kind of symptom and the real issue prompting intervention was the fact that the patient had some leg edema in that leg, was a little bit uncomfortable. Was also a little bit anxious, based on the spouse’s experience as well. But really, did not have bulky disease. Was not sick. But really was in a place where it made sense to think about treatment.

And so this is the patient where I was on the fence around observation, but, again, given some symptoms, single-agent rituximab made sense. Didn’t seem to get to a point that warranted chemotherapy, based on the relatively low tumor burden.

DR LOVE: So I’m going to go back and forth and ask each of you to comment on the patients that we’re hearing about today. And I’ curious, Carla, what thoughts you have as you heard this story? Do you think you’d be thinking about rituximab as a single agent? Or what would you be thinking?

DR CASULO: So it sounds like the lymph nodes are small in size, but there is a mild symptom which could potentially get worse. He could develop venostasis. So this person is somewhat borderline for requiring treatment. And if this person were to get treated I agree, I would probably give them single-agent rituximab. We have this study open at the University of Rochester, it’s a study led by Jonathan Friedberg, and that’s the kind of study that I would likely put that patient on study.

Association between vitamin D insufficiency and outcomes for patients with FL

DR CASULO: And I see that you’re putting up slides on the vitamin D and risk of early clinical failure. So that’s something that’s been seen. And we get a lot of questions about vitamins. And vitamin D is one of those things that has been demonstrated as being associated with worse outcomes in patients with follicular lymphoma if they’re insufficient with vitamin D. And this study is looking at vitamin D in combination with rituximab or placebo.

DR LOVE: What’s the thinking in terms of the pathophysiology of how vitamin D has something to do with this, Carla?

DR CASULO: I honestly don’t know the details about why vitamin D — what the mechanisms are. The study is actually looking at polymorphisms to see what are some of the germline — the genetic etiology of why someone might respond to vitamin D or not. But the idea is that there is an association. We don’t know if it’s causality. But those are some of the things that we’re exploring.

We know that hypercalcemia in lymphoma is vitamin D mediated. But I think in terms of the mechanistic process I’m not entirely completely sure.

DR LEONARD: Yeah.

DR LOVE: So John – go ahead.

DR LEONARD: I think that’s the state of the science there. Also, there is some thought that vitamin D may impact ADCC — antibody dependent cellular cytotoxicity. All of this is pretty soft though. But I think the strongest evidence is really what Carla described and what you referenced, these associations which are in other areas as people know well. Even these days COVID’s associated with vitamin D issues. It may just be —

DR LOVE: That’s right.

DR LEONARD: But this is how we need to study this issue, I think, is by a prospective randomized trial.

DR LOVE: I would think that it might be attractive to a patient. How did this man respond?

DR LEONARD: He was very excited about the trial. It’s obviously a relatively benign treatment. The patient was going to get rituximab anyway, really not expecting — I think the biggest reasons why people don’t want to participate is they say, well, why don’t I just take vitamin D? But that being said, I think, given the uncertainties, it’s certainly an attractive trial for people. It’s pretty easy to do. And credit to Jonathan Friedberg for setting it up that way.

DR CASULO: I was going to say, patients can stay on vitamin D of 2000 units, which is the FDA-approved indication. So they’re not really missing out if they want to stay on their own vitamin D. They just get a little extra if they end up on the vitamin D part of the study.

DR LOVE: Interesting. And, John, what’s the status of this patient now?

DR LEONARD: This patient is doing well. He’s about a year, just over a year into it. He had a close to a complete remission I would say. And really, the leg edema got better. Tolerated treatment very well. Really accomplished his goals and that his discomfort is better. Didn’t have much in the way of toxicity. So I think this is a perfect patient where single agent rituximab-based treatment is very appropriate.

DR LOVE: Carla, any comments on subQ rituximab?

DR CASULO: I think it’s great. I think it limits the time in the infusion center for patients that can get it. They can get it if they haven’t had a reaction to the infusional rituximab. And I think it’s really effective for those especially that — even the rapid rituximab is 90 minutes .So I think that giving them subcutaneous rituximab has been a game-changer because it frees up their time and it frees up the infusion center time.

DR LOVE: John, are you generally using subQ rituximab now?

DR LEONARD: We are. We are for patients with their later therapies. Interestingly, in our practice it’s something the nurses often prompt. They basically tell the patient you should get your next infusion subQ. And we generally pursue it. So, yeah.

Efficacy and tolerability of obinutuzumab/bendamustine for patients with newly diagnosed FL

DR LOVE: So let’s hear about another case. Carla, you had this 50-year-old woman with Grade 2 follicular lymphoma. What happened there?

DR CASULO: So a 50-year-old woman, excellent health. Mother of 4 children. Schoolteacher. She developed axillary adenopathy;, just in the shower she noticed it. Had a mammogram that was ordered by her physician that showed some left axillary lymphadenopathy and it showed Grade 2 follicular lymphoma on the biopsy.

So after that, she had a PET scan which showed that she had extensive disease, especially in the retroperitoneal area where she had an 11x4 cm mass, with some hydronephrosis. However, all of the FDG uptake, all the SUV values were fairly dim, in the single digits, ranging from like 5 to 6.

So, based on that, she met indication for treatment because she had bulky disease. She had the possibility of impaired organ damage with hydronephrosis, even though her renal function was intact. So I decided to give her bendamustine-based therapy, which, as John said, is sort of a mainstay, but I chose obinutuzumab for her. I don’t necessarily always use obinutuzumab as my front-line antibody in follicular lymphoma because there’s slightly more toxicity, and particularly that’s the case in older patients. But she’s 50. She’s very healthy. I thought she would be a good person in which to use obinutuzumab/bendamustine. That was based on the GALLIUM study.

So the obinutuzumab is given a little differently, it’s given weekly for the first 3-weeks, cycle 1, and then is given monthly after that with bendamustine. And at the end of her treatment she did great. And I actually also decided to give her obinutuzumab maintenance. Which again, is not something — I think this is really a moving target in follicular lymphoma. If you survey 10 follicular lymphoma doctors you’ll get different responses on whether maintenance is the right thing to do or not. Sort of the way I grew up in lymphoma is that maintenance is not something that I routinely do, but I thought in her, the data for the benefit of obinutuzumab was based on the maintenance use. So I thought that she was as good a candidate as anyone to do that. And she’s someone that really wanted to delay her next treatment as much as possible.

DR LOVE: And how did she tolerate the therapy?

DR CASULO: Beautifully. Absolutely beautifully. No hair loss. She was active. Still working. I mean did really, really well.

DR LOVE: And what’s her current situation?

DR CASULO: She’s getting maintenance. She’s in complete response still. She’s doing really well.

She told me that some people don’t even know — she never told certain people that she had lymphoma and getting treatment and some people never actually could tell. So that’s not always the case, but she did really well.

DR LOVE: Is she going to be teaching school this year?

DR CASULO: I don’t know. I don’t know. She lives in a part of Western New York where the cases are fairly low. We’ve been really lucky in that sense that we have not had the degree of the surge that we’ve seen in other parts of the State. So she’s not sure what she’s going to do at this point.

DR LOVE: Would you be more concerned about her than somebody else who’d not on —

DR CASULO: Definitely.

DR LOVE: — for example, obinutuzumab maintenance?

DR CASULO: Yeah, definitely. Because the risk of infection with obinutuzumab is a little bit higher. Although, that was seen really in patients who were older. But I think that, because of the uncertainty of COVID, and we know that patients who have malignancies are at higher risk of developing a COVID-related complication. I think it’s certainly a concern. So I’m not certain what she’ll end up doing but I think it’s definitely a concern.

DR LOVE: So, John, a second opinion on this case. There are so many situations in oncology where there are multiple options that people choose. We poll people. We survey people. People give 3 or 4 answers. And this is a good one. So you tell me, in general, John, how would you manage a patient like this? Would you have gone down the same route or maybe a different one?

DR LEONARD: So I think this is a very reasonable approach. Certainly bendamustine-based therapy is what I would do in this patient. I see no reason to give R-CHOP. I don’t think rituximab single agent is going to do enough. Occasionally, we have patients like this that want to try it, just to delay chemo. But in my experience, they don’t get a whole lot of mileage out of it so we tend to discourage people.

The main question that Carla alluded to is really the choice of antibody and the choice of maintenance. And the obinutuzumab data shows an improvement in PFS that’s in the range of about 5% to 10% give or take, compared to rituximab, again in both using maintenance in that arm. But no overall survival benefit; a little more toxicity.

I agree that she’s a younger patient, less likely to have toxicity. I would say probably more often than not, I would give this patient BR without maintenance, but I think you could argue it either way. I certainly would present to the patient do you want to commit to maintenance in this setting, which you may not want to do. And there are pros and cons of that.

So I wouldn’t argue with this. But I think the other option would be rituximab swapped in and perhaps without maintenance.

DR LOVE: Just kind of curious, John, you think about young patients, got little kids, trying to avoid getting chemotherapy, maybe she is the type of patient who’s really, really oriented towards benefit as opposed to toxicity. If she asked you, “Do you think I might get more benefit out of this route, obinutuzumab/benda plus maintenance than BR without maintenance, would you say yes or not really?

DR LEONARD: No, I would say you definitely are going to have a longer remission. I mean maintenance is going to improve her remission duration but without an overall survival benefit. So, some people like the extra 2 years of security blanket coming in once every few months. And other people would say, well, I’ll probably have — I mean even with BR, she’ll probably have a 5+ year remission and then you kind of say, well, when she’s 55, 5 years from now, at the rate we’re getting new drugs for follicular lymphoma who knows what her second-line treatments going to be.

Activity of lenalidomide/rituximab (R²) in patients with FL

DR LOVE: So I’m kind of curious, Carla, did you bring with her, did you consider the possibility of R²?

DR CASULO: It’s not my go-to for front-line follicular lymphoma for a couple of reasons. I think that the treatment is long. The toxicities are not insignificant. And it was not necessarily better than any other of the standard regimens that we use. So, knowing that we have a really very good remission duration with R² in the second-line setting, I tend to use it in the second line. I’ve never used it in the front-line setting.

DR LOVE: And that certainly is a story we’re hearing from a lot of investigators. I have to say, it kind of surprised me when I first saw the data, I was like, oh, everybody is going to start using R². And then I saw that’s not necessarily what’s happening. But we’ll get into that I think more as we take a look at the data. And actually, I think this 76-year-old patient, I think he actually got R². But anyhow, what happened with this patient, Carla?

DR CASULO: So this was a very dear, one of my favorite patients, a 76-year-old man who had a couple of other medical conditions but had a history of pulmonary nodules. Had a surveillance CAT scan for pulmonary nodules and it showed this new adenopathy that was fairly bulky, up to 6 cm and some gastro-hepatic adenopathy as well, causing some mild elevation in his LFTs.

So they thought it was lung cancer. They thought it was metastatic lung cancer. So he had mediastinoscopy but it showed Grade 3A follicular lymphoma, surprisingly. So, PET scan sort of confirmed that there were some slightly higher SUVs there. And I gave him R-CHOP at the time. That was his front-line treatment and he had complete response there.

So then, 4 years later, so he’s now 80, he developed this dyspnea and they thought it was infection. They ruled him out for COVID. He had a large pleural effusion and it showed atypical lymphocytes. I was certainly he had transformed. He was behaving in that way, was becoming really weak and poor performance status. And he ended up having a core biopsy that showed surprisingly, Grade 2 follicular lymphoma. So, based on the AUGMENT data that John is famous for, among other things, we started him on lenalidomide and rituximab. And he’s on that right now currently. He’s doing very well. He did end up getting hospitalized for a fever, but aside from that, he’s doing very well now.

DR LOVE: What happened with the fever? Was he neutropenic?

DR CASULO: No, it was a non-neutropenic fever, but he became — he had a flare of diverticulitis. And he had some diarrhea. I thought it was related to the lenalidomide. But it turned out that he had diverticulitis and a fever with that. So, he was treated with IV antibiotics. Was never neutropenic, at that time anyway, and then recovered from that and did well. So, that was a while ago. And he’s doing well currently.

DR LOVE: So, John, this is typically where see people using R², as Carla was saying, based to a great extent on your data. Any comments on this case?

DR LEONARD: Well, I think this is a very reasonable approach for this patient. The data that we have with R² suggests that his outcomes, the efficacy data are in the range of at least 75% overall response rate. It’s better than rituximab alone. He seems to have a significant amount of disease, summarized here. We know that with R² in particular, from the up-front data, the RELEVANCE data, that even people with bulky disease who need a rapid response can get a good response quickly. And that seems to be confirmed in the AUGMENT data as well.

So I think he’s a good candidate for R² and certainly very reasonable for him.

DR LOVE: So I don’t know if there’s a nickname for lenalidomide/obinutuzumab, but, Carla, what about that regimen, for example, in this situation as opposed to R²?

DR CASULO: I don’t necessarily use obinutuzumab. Unless someone’s rituximab-refractory, I don’t necessarily use obinutuzumab second line. We know that obinutuzumab with lenalidomide is being studied in the front-line setting, Loretta Nastoupil presented that at ASH and that’s very promising. And actually, one of the clinical trials that we have for early recurrent disease is using obinutuzumab-based therapy. We know also that obinutuzumab is one of the few settings where we’ve seen an overall survival benefit in relapsed follicular lymphoma if you use it with bendamustine, based on the GALEN study.

So I think that there is some appeal, and I do use it in certain situations. But I thought that this was reasonable for this person.

Biology of FL; criteria for initiating therapy after diagnosis

DR CASULO: So let’s talk a little bit about the basis of this clinical management paradigm that we’ve just been talking about in terms of first-line therapy. John, any comments on what we know about the biology of follicular lymphoma? Anything that a clinician in practice to could light onto to try to understand?

DR LEONARD: I think that we’ve had a number of different ways of looking at follicular lymphoma. Clearly, part of what’s going on is the expression of Bcl-2, which is very common in follicular lymphoma, an anti-apoptotic protein that people are more and more familiar with. And then genomic instability that’s really leading to this clonal B-cell population.

Clearly, one of the other areas that’s of interest is the interaction with the immune system. And I think that’s something that we’re learning more and more about and certainly has been associated with outcomes, to some degree, and histology. And certainly a number of therapies are immune-based.

But really, at the end of the day, and Carla has done a lot of work on this in prognosis, we don’t have great molecular predictors of outcome. Really, the best predictor of long-term outcome is really progression of disease, which I think we’ll probably talk more about. But biologically, we don’t have a lot that tells us this patient’s going to do better or this patient is going to worse or who should be treated one way or another, based on the biology today.

DR LOVE: Carla, anything you want to add to that? And also, in terms of your vision about transformation and how that affects the biology?

DR CASULO: So I think that one of the things about follicular lymphoma that’s so interesting is that we have a plethora of information about what drives this disease on a molecular level, gene expression profiling. The problem is that we can’t do anything with that information right now. It’s not actionable. Because none of these prognostic markers, like the M7 FLIPI, for example, they’re not things that we can use in daily practice. We can’t take a patient’s biopsy and do that as part of standard of care. And so, we have this robust amount of information that we just can’t really apply in the daily setting.

So our decision-making is based on clinical factors. And then, when someone transforms we also know that there are certain things associated with transformation like p53 mutations and evolution of grade, like if someone starts with a Grade 3 they’re more likely to develop transformation. But at the end of the day, it’s information that is useful for the design of future studies, but we don’t have the ability to act upon that information in daily practice.

DR LOVE: So, John, can you talk a little bit, maybe review what we know or what we’ve been using as a criteria to start therapy in follicular lymphoma. And I’m curious what you’ve been observing. You see a lot of second opinions, patients coming in from the community, whether you see that there’s been a shift towards rituximab single agent in some of these patients who maybe you or your investigators might be observing. But maybe you can go through the criteria and what you see in practice.

DR LEONARD: So we have really 2 sets of historical criteria, the GELF criteria, which are French, the BLNI criteria, which are British. These are really, to some degree, common sense and I think they’re not absolute criteria. I think they were largely developed for clinical trials to basically say that this was a group of people we’d all agree if they met these criteria were people that needed therapy. So if someone wasn’t doing a trial, getting great results, and a bunch of people that didn’t need treatment, it really comes down to bulk of disease, amount of disease, symptoms, organ compression, laboratory abnormalities, whether it’s anemia, LDH. And I think most of us in practice, when we look at a patient we may not go through this kind of checklist, but we clearly know that this patients’ labs are good or they have more disease/less disease. So there are people that meet these criteria that occasionally I don’t treat and there are people that don’t meet the criteria that I’ll occasionally treat if they have other indications or lack of a need for treatment.

I think the people that fall beneath these criteria are the ones where single-agent rituximab is something that we keep in mind because they would be considered to have less bulky disease and more likely to respond to single-agent rituximab if that’s the route the patient wanted to go.

DR LOVE: Carla, as you see patients like this, where do you factor in the issue of trying to delay chemotherapy? It was one of the findings that we see with rituximab. Let’s say a patient, this 50-year-old woman, how important is it to delay chemo?

DR CASULO: I think one of the things I think about is can this person get chemotherapy? And if so, when? So, for example, if you have someone that has underlying comorbidities, somebody with an autoimmune disorder that’s needing chronic immunosuppression, someone who has some cardiac or renal abnormalities. Someone in whom you really want to delay chemotherapy, I think those are some of the considerations. Someone, for example, this young woman who really the thought of needing to get treated again in 3 to 5 years, when her youngest would be 12, is really not something that she was in the position to entertain. She really wanted to get this done and we’ll make it last for as long as possible.

Those are usually the things I really try to talk to the patient about, their values. Because this is a very, very long committed relationship with your patient with follicular lymphoma. The consults are long. The visits are very thoughtful. And you have to really understand what they value. Because you’re committing them a very long course. So I always say, your opinion is really critical and what you value here and what you want to get out of this really help me make my decision.

DR LOVE: So, John, of course we’re focusing on patients with extensive stage disease. But I wonder if you could comment on your approach to patients with limited stage FL?

DR LEONARD: So, limited stage follicular lymphoma has typically been treated, if it’s truly localized, with radiation. And we know that the majority of patients will have 10- to 15+-year remission with radiation in that setting and excellent long-term overall survival outcomes.

The questions that come up in these patients are do you need to treat them altogether? There are some data from Stanford suggesting that patients monitored with watch and wait actually have similar outcomes and many of them can go 10 years or longer without needing any interventions. The other question comes up, well should you use combined modality therapy? Should we give radiation plus additional treatment? And I think that suggests a benefit in progression-free survival, as you would imagine, but not overall survival.

And then finally, the last thing that’s come up more recently, I would say in my practice, has been the concept of boom-boom radiation or 2 doses of radiation versus a full course of radiation. It’s a little less effective as far as long-term remission, but obviously easier and a little bit less toxic. So that variable has come into that as well.

And so, I think the thing to keep in mind in all of these have great overall survivals. I mean these patients do well, as you would expect, because they have the best prognosis disease. And it really comes down to patient preferences on these issues, with most patients I would say getting treated with radiation alone, but other options are also reasonable here, given the long-term overall survival being similar either way.

DR LOVE: Carla, any comments?

DR CASULO: No, I agree completely. I think that the 2x2 radiation is so appealing for so many, especially your older patients that have their lymphoma in a place where the morbidity is going to be exceedingly small, like axillar or inguinal area. I think that’s very, very appealing.

I think the one thing is that if someone has Grade 3 follicular lymphoma that’s limited stage, I am not sure I would only do radiation; although, it wouldn’t be wrong to do that. But, that would be my only potential pause to say perhaps they need a combined modality approach. But there are many, many options.

DR LOVE: So we were talking about the patient that Carla gave bendamustine/obinutuzumab to, and I want to talk a little bit about the data behind that. And first, John, maybe you can comment a little bit on what we know about the difference between rituximab and obinutuzumab? And what the impact is, not only in FL, but in other diseases, particularly CLL?

DR LEONARD: So, as you can see summarized, rituximab and obinutuzumab have a lot of similarities, they’re anti-CD20, and the key differences are a little bit in what aspects of the mechanism of action have been kind of adjusted. Obinutuzumab has increased direct cell killing, increased ADCC, decreased complement-mediated activity, and these are all relative to rituximab.

So the net of all of this I would say is that it’s modestly better in follicular lymphoma as a single agent, and that’s what the comparative studies suggest, whether it’s alone or in combination. And I think it’s more significantly better in CLL.

And so, from my perspective, there’s relatively little reason to use rituximab in CLL. Really, obinutuzumab is the way to go. I think in follicular lymphoma the benefits are marginal and you can go either way, as we’ve talked about; whereas, in large cell lymphoma there’s no difference. And those are kind of the key ways I would frame it out.

Results of the Phase III GALLIUM study of obinutuzumab or rituximab, each in combination with chemotherapy, followed by maintenance obinutuzumab or rituximab for patients with untreated, advanced FL

DR LOVE: So, Carla, maybe you can walk through the GALLIUM study, what the findings were and what your take was on that?

DR CASULO: Sure. So this was a randomized control study in front-line follicular lymphoma. Patients had to meet GELF criteria, so they had to have reasons for treatment. They could have Grade 1 to 3 follicular lymphoma.

So they were randomized to an obinutuzumab-based arm, or a rituximab-base arm. However, the participating sites could select which chemotherapy the patients would receive. So it’s not completely randomized. And then what they demonstrated was that the obinutuzumab-containing chemotherapy had a better progression-free survival compared to the rituximab-based, but it was very small, so only about 7%, as John was saying, and the overall survival was no different.

When you look at some of the subsets of data that they wanted to tease out, there seemed to be fewer patients receiving obinutuzumab that had early disease progression compared to those receiving rituximab. And there’s some other data that’s probably going to come out soon looking at some other parameters. But the idea being that for certain patients obinutuzumab is more effective than rituximab.

Then this is talking about some of the adverse events. As I was saying earlier, obinutuzumab is associated with a high risk of infection and high risk of infusion related events, as well as a slightly higher risk of thrombocytopenia that I’ve observed in practice and that they also saw here. But I think that the big thing is that for elderly patients, those receiving bendamustine, they had a higher rate of Grade 3 to 5 adverse events and a higher rate of fatalities.

So I think that for patients that are older, who have follicular lymphoma, I probably would not offer them obinutuzumab, And for patients in whom you suspect may have a higher risk of transformation or early progression, you may consider obinutuzumab. Again, though, we don’t have molecular markers — we only have molecular markers really of this. We don’t know for sure at the onset with any certainty who’s going to progress early when you meet them in the office.

DR LOVE: So, John, I kind of have this weird fantasy of suppose they’d done the trastuzumab studies, but they didn’t have HER2 in breast cancer to measure, we never would have seen the benefit. So if you believe, if you think that maybe within the FL patients there’s some subset, for example, these patients who are relapsing early, where the biology is different. Any comment on, if you have that point of view, what this data means and where it might head in the future?

DR LEONARD: Well I think Carla has shown that POD24, which is progression within 24 months or your initial treatment, is associated with a less favorable outcome. And in fact, if you don’t progress in that timeframe, then your overall survival is more or less what it would be even if you didn’t have lymphoma. So, the net is that you would think that an improvement in POD24 would translate into long-term benefit.

The benefit in this study, as far as lower percentage of POD24 patients with obinutuzumab hasn’t yet turned out to show an overall survival benefit. There’s about a 7%, give or take, difference in the 2 arms. Whether or not it’s just a small difference or whether to not it’ll show up in more time remains to be seen. But I think some people have interpreted this as an argument for obinutuzumab.

DR LOVE: So we’ll talk a little bit more about focusing on these patients who progress early, even though maybe we can’t find a marker, as you say clinically, at least we have that.

Phase III RELEVANCE trial evaluating R² versus rituximab/chemotherapy, each followed by maintenance rituximab, as first-line therapy for advanced FL

DR LOVE: Well, let’s just bring out the R² data, the RELEVANCE study, Carla. And maybe we’ll talk a little bit about why it hasn’t affected practice as much as I thought it was going to? Can you just talk about what they looked at and the basic findings?

DR CASULO: Sure. So this is a similar population of patients that were in the GALLIUM study. They were randomized to either lenalidomide with rituximab followed by rituximab maintenance or R-chemo followed by rituximab. And they wanted to see a superiority of the lenalidomide with rituximab. But what they found is that there was the same amount of complete responses, very similar, and the 3-year progression-free survival was very similar. So, really, it didn’t show much in the way of difference. But there were some additional toxicities, as the slide shows here. So, higher rate of diarrhea with the combination. Higher rate of cutaneous infections. There’s a risk of rash. And I find that patients also complain of myalgias when they’re on it.

So I think that, again, this is a long treatment. And because it wasn’t necessarily better, I think that that’s why perhaps you haven’t seen the huge uptick in getting this as a front-line choice. Sometimes there’s an insurance issue as well in terms of coverage.

DR LOVE: Right. And John, this question of how long to use therapy? And there was a very prolonged maintenance in the trial. And yet, I’ve heard other people, Bruce Cheson says he uses it for a year, et cetera. I’m just kind of curious, globally, how you — I assume that you view the benefit about the same, but you prefer BR, for example, because of the tolerability profile?

DR LEONARD: I think that, in my mind, BR, because it’s a shorter course of therapy, typically speaking. If you’re not using maintenance, and as we talked about maintenance is fine, but many of my patients decide not to have it. So you’re done in 6 months as opposed to, say, 2 years. That being said, typically with R² upfront, I would aim at kind of the 2-year timeframe but there are some that have done shorter. And we have some mantle cell patients on our R² up-front trial who’ve been on it, doing pretty well for almost a decade now. So I think it’s still an open question.

DR LOVE: So, Carla, any comments on this trial that was just published? I guess it really didn’t show as much as we’d hoped. It was an ECOG trial comparing BR to BR/bortezomib. Also different maintenance regimens. Any comments on that, Carla?

DR CASULO: I think we’re always looking to move the needle forward in trying to see what you can add to follicular lymphoma therapy. But, ultimately, at the end of the day we don’t see much in the way of difference by adding bortezomib or doing lenalidomide and rituximab maintenance. So, I don’t think that this will necessarily change our practice. But it’s important that we can try to study different combinations to see if we can extend that remission during in follicular lymphoma.

DR LOVE: John, any comments about this study? I know I was optimistic that you see something. Any thoughts?

DR LEONARD: Yeah, it’s hard to say for sure. I think it’s an argument that BR is a very good treatment and very effective. I think we’ve kind of come away from bortezomib a little bit. And I guess the question is really will you see the lenalidomide/rituximab kind of benefit, if there is one, not so much as a maintenance but at the time that the patient relapses? And will that, by giving it later, actually give more of a benefit? Again remembering it’s a time-limited sort of therapy in this study.

DR LOVE: So I wanted to also get your take, John. You had this side in your slide deck I thought it was interesting in terms of following patients in remission. Can you comment on that?

DR LEONARD: Well, I tell patients with follicular lymphoma that if you want to stay in remission longer do fewer scans. So that’s the best and easiest way. If you do a scan in somebody every 6 months or once a year, they’re going to have a shorter PFS than if you don’t do a scan and only do a scan if it’s clinically indicated. And if you give a patient one of these regimens and they have a CR at the end of treatment, they’re probably going to have a 5-year or longer remission.

So the idea that a screening CT scan or a surveillance CT scan or PET scan at 6 months or a year is going to show anything, it’s pretty low. If you do the math, you have to do a lot of scans. And there’s not a lot of evidence that finding these progressions early does a lot of good.

So it’s really focused on symptom -driven and physical finding-driven imaging rather than just kind of ordinarily just sending a patient for a scan. And then, when the patient comes to see you, you’ve they’ve already had the scan and you don’t have to work. It’s easier for the doctor. But for the patient, not so easy.

So I really just see these patients periodically, every 4 to 6 months, spacing it out over time and do relatively few scans unless they have some symptom or finding.

DR LOVE: Any comment, Carla? Of course, these are the kind of people we see getting funneled into telemedicine, the patients are stable, maybe don’t want to come into the hospital. Any comments, Carla?

DR CASULO: This is my approach as well. I try to be really conservative. Because I agree, what I tell my patients is you’ll find your relapse before the scan does and if anything, we can work on it at that point. But there’s more and more research showing that finding follicular lymphoma on an imaging study doesn’t necessarily change anything in the big picture. So I think that it’s better. Again, this is a very long investment and we don’t want to do too much because this is a very long disease.

Selection and sequencing of therapies for relapsed/refractory FL; management of early progression of disease

DR LOVE: So we’re going to talk now about sequencing of therapies in relapsed/refractory disease and particularly some of the new development. I have to learn how to pronounce tazemetostat and mosunetuzumab. But anyhow, let’s get into some cases before we start going into some of these new developments. And John, you have a 65-year-old man. What happened with him?

DR LEONARD: So this is patient who had advanced stage follicular lymphoma and was treated with bendamustine/rituximab. And much to everyone’s chagrin, relapsed 1 year later. So this is a patient who fits Carla’s POD24 definition. He had some mild thrombocytopenia. He had some palpable lymph nodes, not really bulky disease. As we have learned, about half of patients with POD24 seem to have transformation. So we were very concerned that this could represent a transformation even though his SUVs on his PET scan were not particularly high. And so, we biopsied a groin lymph node and it showed follicular lymphoma. He didn’t urgently need treatment, but given that he had progressed within a year, it seemed pretty clear that he was going to need some treatment before long.

He was extremely anxious. And he’s actually a physician who’s a surgeon. Was concerned about vincristine in his therapy. So that figured into his decision making a little bit. And he was a perfect candidate for a SWOG study that Carla is very familiar with that randomizes patients to lenalidomide/obinutuzumab, PI3 kinase inhibitor/obinutuzumab, or CHOP plus obinutuzumab. He was a perfect patient for this trial because we don’t really know among those choices what’s best. But he didn’t want to go on the study, in part because he didn’t want to get randomized to get vincristine. And after a lot of discussion, we decided — and you could imagine — we decided to put him on lenalidomide/obinutuzumab. And he’s been on it for about 4 months now and responding very well. So, it’s, at least so far, been a good choice for him.

DR CASULO: Good.

DR LOVE: That’s funny, because you described that trial, I was thinking I don’t think he wants to go on that. Anyhow, I am curious from a clinical point view, John, would you have considered lenalidomide rituximab, for example, if the relapse was later?

DR LEONARD: Yes, he would have been — so the AUGMENT trial, which we’re basing the data on or I guess the decision on, in part, took patients who were not rituximab-refractory. And so he would not be considered rituximab-refractory by the 6-month definition. That being said, since we had access to obinutuzumab we didn’t think it would be worse than rituximab, in part That’s why that’s on the trial, in that the idea of being that obinutuzumab seems to have some benefit in more refractory patients, not as well established in this particular setting with lenalidomide. But that said, there are published data with lenalidomide/obinutuzumab. We think the safety is good. Whether the efficacy is better remains to be seen. But it seemed like a reasonable way to go. But, yes, you could have given him rituximab as well. It would have been reasonable.

DR LOVE: How did he do with obinutuzumab in terms of infusion reaction?

DR LEONARD: He really has tolerated it very well. He’s very happy with the regimen. We also, with him, had a stem cell transplant consultation as part of all of this. And Carla and others have shown that patients can do well with autotransplant. He was not enthusiastic about that option, but actually we just recently collected his stem cells. We took a pause on the lenalidomide, collected his stem cells in case we need them in the future. Our transplanters were a little worried about keeping him long-term lenalidomide and stem cell effects, although that’s a debatable issue. We decided to collect him now. And he’s going back on the lenalidomide/obinutuzumab. But certainly, you would have to guess that a stem cell transplant might be reasonable in his future, depending on how he does. Obviously, other things are there as well.

DR LOVE: So I was hoping to get the two of you to argue a little bit. I mean it’s such a controversial disease. So, Carla, again, you agree with this management or maybe you would have thought it through a little differently?

DR CASULO: I think it’s very reasonable. It’s interesting that you chose to collect his stem cells now. But I think it’s reasonable. I mean he’s 65, he’s still young. But if he has some toxicity that’s going to limit his ability to collect at a later date. So I think that that’s pretty reasonable. And it’s a shame he didn’t go on the study because we need more patients, but, hey, so be it.

DR LOVE: And I guess the other thing that’s interesting, if you look at this man, the way he presented, John, I guess there’d be no way to predict that he was going to relapse in a year.

DR LEONARD: Exactly. I mean his disease was really, I would say, more favorable than the patient that Carla presented. Maybe I should have done what Carla did with her patient and things would have been different. You never know. But at the end of the day, he’s done well with this regimen, which is interesting. And it’ll be interesting to see in someone who has a 1-year remission to BR, if he continues on the lenalidomide/obinutuzumab, does he have a longer remission with that approach. But these are tough cases because you really run the gamut from being minimalists, to autotransplant would still be a very reasonable thing to do.

DR CASULO: Right.

Biologic predictors of early relapse; role of transplant for patients with FL

DR LOVE: So, Carla, I know you looked at those data every possible way and still no biologic predictor of why people relapse early?

DR CASULO: In terms of biologic predictors, so we know that that higher grade, starting there, higher grade is associated with greater risk of early progression. Male gender is. Elevated LDH. Beta2 microglobulin, although we don’t really routinely get that on lab work. And then patients that have early progression, about half of them have a high-risk M7 FLIPI. Most of them have a high-risk FLIPI. But again, as I was saying, we don’t really do M7 FLIPI routinely; it’s really a research tool.

And at this time, all we know is that if you have some of those things, and we’re looking at that in a larger data set. We looked at that, not just the LymphoCare study, but also in the FLASH data set. All these things seem to keep coming up again. Again, the male gender, elevated LDH, performance status, elevated beta2 microglobulin. They can tell you that this might be more likely to relapse but it doesn’t help you select therapy for them. And it doesn’t tell you with what therapy might they do better. That’s what this study is looking to try to establish.

DR LOVE: So John brought up the issue of transplant. And I’m curious what kind of numbers you would give to a patient like this, Carla, about the potential benefit?

DR CASULO: So when we looked at that in the CIBMTR data set, it looks like if you do the transplant early, so within a year, the 5-year survival is about 70% compared to around 60-ish%. So there’s less than a 10% improvement if you do it early. And again, this is if you look at patients that had their transplant for early disease progression versus just no transplant.

The issue is that in the US there’s an under-referral rate for autotransplant. And when I give talks, sometimes I have people coming up to me and saying, how can you do autotransplant in follicular lymphoma? It’s crazy? But it is something that’s been shown to be effective. It is a therapy and about a third of patients can have long-term disease control, possibly cure, after 10 years. So I think it’s a very reasonable think to think about.

And some patients, like the next 2 that I shared with you, they’ve been dealing with follicular lymphoma for decades and I think that they need a break. And maybe transplant can offer them a decent chance of long-term disease control.

DR LOVE: John, any thoughts?

DR LEONARD: I think it’s a good point. And I think it’s a very big challenge for people. The more and more drugs we have, it’s kind of like do you swing for the fences to try to get the homerun, but you might get beaned? Or do you keep trying with the base hits, to kind of, well, let’s use lenalidomide. Well, yeah, let’s use more chemo. Now let’s use tazemetostat. Let’s use a PI3 kinase inhibitor. Maybe CAR-T cells will come along, et cetera, et cetera.

So it’s really I think challenging. And I think as physicians it’s hard because our patients trust us and we can really sway patients one way or another based on our biases. I try to have all these patients at least see the stem cell transplanter at our center. They are doing also the CAR-T, so the patients can hear about both of those. And just like the Stage I follicular lymphoma, I try to always send them to the radiation oncologist, at least for a consultation, to hear their side of it, to try to minimize my biases. I think it’s good for these patients to see a transplanter just to get from the horse’s mouth, a little more bullish perspective I would say.

DR LOVE: So I wonder whether this surgeon tuned into the ASCO virtual meeting to watch the ZUMA-5 presentation, but I wouldn’t be surprised. And speaking of that, Carla, let’s hear about this 61-year-old man.

DR CASULO: So this man, very interesting, very tough case. So, truck driver, excellent health. In 2006 he was seen here for advanced stage follicular lymphoma and was treated with R-CVP. And then had a complete response. Actually lost to follow-up. And I inherited him in 2018. He was actually a consult for abdominal pain, massive ascites. He looked like he had a gravid abdomen. He had significant weight loss, night sweats. He’s now 59 years old.

And he had a PET scan and it showed extensive bulky lymphadenopathy. He had numerous bony lesions, had hepatosplenomegaly. He had extensive ascites.

But his biopsy showed Grade 1 follicular lymphoma, interestingly.

DR LOVE: So, before you go, John, what would you be thinking at this point? I’m just kind of curious with this young patient, presenting with this amount of disease. What would you be thinking?

DR LEONARD: Yeah, I would be worried about transformation. I mean he had a long remission which is good. But really, a lot of disease. That being said, we can see patients with follicular lymphoma present with a lot of disease, particularly 12 years out, my guess is that he, not that Carla would have not done good follow-up, but these are patients that you may not be seeing as often, etc. So they might have a denial when they relapse because it’s been 12 years. So the might kind of neglect things a little bit because they’re thinking they’re done with their lymphoma because it’s been so long. But I’d be worried about transformation here. And the PET scan was very helpful in that regard I would say.

DR LOVE: Plus the biopsy I would guess. So, anyhow, he got R-CHOP. What happened there?

DR CASULO: So I gave him R-CHOP. Bendamustine would have been reasonable, but I was very concerned that this really came out of nowhere and he needed very rapid cytoreduction. Sometimes bendamustine can take a little longer. So that’s the reason I chose R-CHOP. But I think bendamustine would have probably been fine.

So, he had a near CR. He just had Deauville 4 in a couple of small lymph nodes. So we watched him carefully. I didn’t do anything after that. And that FDG uptake, even though the Deauville 4, it’s above the liver, it was very, very dim. So I chose not to do a biopsy at that time. But 6 months later —

DR LOVE: So all the disease went away. His ascites. Everything went away.

DR CASULO: Everything went away.

DR LOVE: Okay.

DR CASULO: He literally became like spaghetti thin. All of this bulk was his lymphoma. It was very, very shocking.

So, unfortunately, 6 months later, he had exactly the same thing, massive ascites. Abdominal girth. He had a paracentesis and it showed atypical lymphocytes. Again, imaging showed exactly the same thing, massive disease everywhere. And he had a laparoscopy. We wanted to make sure we weren’t missing any occult transformation. And again, it showed Grade 2 follicular lymphoma.

So I enrolled him on the ZUMA-5 study, which was open at the institution at the time. It’s now closed for the follicular lymphoma cohort. And his day 30 PET showed he went into CR. And he’s doing great. He’s back at work, driving. He’s completely healthy. And he’s doing very, very well.

Activity and tolerability of CAR (chimeric antigen receptor) T-cell therapies for FL

DR LOVE: How did he do with the CAR-T in terms of cytokine release, neurologic issues, etc?

DR CASULO: He did well. Most patients have some form of cytokine release syndrome. He didn’t require going to the ICU. And what we’ve observed is that in follicular lymphoma the toxicity seems to be a little bit more abated compared to large cell cohorts. And he didn’t have neurotoxicity to any significant extent. So, he di actually quite well.

DR LOVE: John, any comments on CAR-T and ZUMA-5? We’ll take a look at the data later. A lot of times people pick cases of patients do better than average, etc. But what’s your gut instinct right now about what we’re getting out of CAR-T in FL?

DR LEONARD: Well, I think the key thing is it’s still relatively earlier. And I think that really the patient where I’m going to think about CAR-T is the same patient where I’m going to think about autotransplant. I think the populations are pretty similar. The question is, CAR-T is probably less toxic I think we would argue, generally speaking. Although, not a tenth as toxic. It’s not far necessarily from the ballpark, but a little bit different given the rates of severe toxicity. That being said, CAR-T can work in other forms of lymphoma and chemo-resistant disease, where this is a patient where you might not be as excited about giving an autotransplant in that he has some element of chemo-resistance here and then he relapsed within 6 months of R-CHOP.

So I tell patients, if something didn’t work very well you don’t want to do the same thing or a version of the same thing over again. Autotransplant is higher doses of chemotherapy. Yes it’s different but it’s still chemotherapy. So I think the idea of trying immunotherapy here is very, very reasonable and worth thinking about. In my mind, it’s going to be the multiply relapsed patients and it’s going to be a similar group that we would be thinking about autotransplant in where you would think about CAR-T. Maybe not exactly the same but more or less the same.

DR LOVE: Any comments, Carla? Also, again I’m thinking about your surgeon, thinking about his future, sort of when you might lean towards transplant and when you might lean towards CAR-T? I mean theoretically, people could get both. But generally speaking, how do you think it through in terms of what comes first anyhow?

DR CASULO: Well right now CAR-T is only available for follicular lymphoma in the setting of a clinical trial. So I think that if you’re thinking about consolidation and taking that approach, it’s probably going to be in the form of an autotransplant.

The ZUMA-5 study at ASCO was really highly promising. Response rates were over 90%. PFS was over 70%, although, again, follow-up is quite short. So I think that it’ll likely get approved in this space. The question is with so many advances in this disease, who are the adequate candidate, who is the appropriate person in whom to subject to this degree of toxicity? It’s not insignificant. It’s still a hospitalization. It’s less chemotherapy, it’s biologic therapy so it has a lot of appeal. But it’s not without risk. So I think that that’s really the question who is the right patient to think about this in?

Response to the PI3 kinase inhibitor umbralisib in combination with obinutuzumab for relapsed FL

DR LOVE: So you have another case that I think is really great that I want to get into because I think it helps us understand a bunch of important issues, this 54-year-old lady. What happened there, Carla?

DR CASULO: So she’s another one of my dear patients. So she is 54. She has a history of asthma and obesity, but aside from that she’s healthy. And she was diagnosed with high tumor burden follicular lymphoma both low grade and that was about 2017. She had bendamustine and rituximab. She went into remission. But then June of 2018, so a little over a year later, she had this rapidly growing left chest wall mass. And I remember she called my clinic and said I need to be seen right away, something’s coming out of my chest. You could literally palpate that mass over her chest wall. So, I was again very concerned for transformation.

She had widespread disease everywhere, all the lymph node stations. And she had an excisional biopsy of her left axillary lymph node and it showed Grade 1 follicular lymphoma.

DR LOVE: These were lymph nodes that was the chest mass? What was it?

DR CASULO: It was a mass of axillary lymph node mass actually eroding into her chest wall.

DR LOVE: Wow. So it was actually — have you seen that before? Eroding into the chest wall.

DR CASULO: Yeah, bony involvement.

DR LOVE: Have you ever seen that, John?

DR LEONARD: Not so much with follicular lymphoma. That’s the unusual thing here.

DR CASULO: Yeah.

DR LOVE: Maybe you can talk about this trial. She was qualified for it? She went into the trial.

DR CASULO: She went into the trial and I felt that it was — knowing that there’s no perfect answer for this population of early progressing patients, I felt comfortable putting on it, particularly given that the area that was the most rapidly progressing was biopsied and I felt comfortable that we weren’t missing occult transformation.

So the study is SWOG study, a cooperative group study, and patients are eligible if they disease recurrent within 2 years of if they were primary or refractory to their initial line of therapy. And so, if someone had CHOP before or bendamustine, they’re eligible. But what they get subsequently is obinutuzumab. So obinutuzumab with either a PI3 kinase inhibitor, obinutuzumab with lenalidomide, or obinutuzumab with CHOP or bendamustine, whatever they didn’t get previously. And the primary objective is complete response after 6 cycles. But patients are eligible to go onto transplant if they so choose as a consolidation strategy. And so far the study is enrolling, somewhat slowly, but it’s still open and enrolling nationwide.

So she ended up getting the umbralisib/obinutuzumab arm.

DR LOVE: And what happened?

DR CASULO: I would say she did fair. She had some unusual toxicity. So the LFT abnormalities are not that unusual for PI3 kinase inhibitors. She had very mild LFT abnormalities. But what she developed was massive headache. Lots of headache which isn’t really a known toxicity of either of these 2 drugs. It’s not a prominent toxicity. But she had really debilitating headaches and that made her treatment very morbid because she was suffering from a lot of headaches.

After 6 cycles, she had a partial response. And then we continued on for 12 cycles. She had a complete response after that. But then shortly thereafter, that same chest wall mass started growing again. Biopsied again and it was follicular lymphoma again.

So this time I gave her R-CHOP for 6 cycles and then she had a complete response to that. And then she actually went to autotransplant.

DR LOVE: So, before we go on, can you just talk a little bit about umbralisib and how it’s different from the 3 approved PI3 kinase inhibitors, if at all?

DR CASULO: So the 3 PI3 kinase inhibitors are idelalisib, copanlisib and duvelisib. Two of them are oral, one of them is IV. Umbralisib is also oral. And I think it’s fairly similar, but there’s a slightly lower risk of some of the toxicities, like less GI toxicity, less LFT abnormalities, less risk of infection. The PI3 kinase inhibitors as a group have very, very similar response rates. They’re all on the order of like 30, 50%. The complete response rates are very low. And the toxicity I would say moderate.

So I’m not certain what the kind of global usage of these drugs is, given that we have others that are available. That being said, they’re there. They’re effective. And I’d be interested to hear what John thinks. I don’t know what your utilization of PI3 kinase inhibitors is in follicular lymphoma. But I find that they’re not always the easiest drugs to give.

DR LOVE: And John, in addition to that, I’d like to know what you think about this case in general. We talked about bad biology, but I guess the question is how do you reverse it?

DR LEONARD: So, first, as far as this case, I mean I think that it’s not acting like a follicular lymphoma that’s behaving itself for long remission. So I think trying something different makes a lot of sense and I think the PI3 kinase inhibitor is certainly different than chemotherapy. And that worked for a while, as we heard. And then I think moving on, I mean this is a patient who’s young, who’s got decades to live hopefully, and she’s cycling through therapies pretty quickly. So I think this is clearly somebody who I would be aiming toward an autotransplant or something more intensive in the absence of other options or contraindications.

I’ve tended to use PI3 kinase inhibitors in patients, particularly older patients, who have been through a couple of previous therapies. I mean those are patients that you may not want to give R-CHOP to. They’re not going to be transplant candidates. They’re not going to be perhaps CAR-T cell candidates perhaps. And so, when you’re getting the third-line therapy in an older patient with follicular lymphoma who needs treatment, you maybe have cycled through bendamustine, rituximab, obinutuzumab, maybe lenalidomide. And then you’re really talking about more intensive chemo or a PI3 kinase inhibitor as an alternative.

So that’s my, these days, my typical patient who might be on a PI3 kinase inhibitor.

Outcomes for patients with early relapse of FL in the National LymphoCare Study

DR LOVE: So, Carla, let’s go through some of the data; we’ve already been talking about it a little bit about this subset within follicular lymphoma. You and John Friedberg have really brought out to everyone’s attention, beginning with the LymphoCare study.

DR CASULO: So this a study that we did now 5 years ago, looking at the National LymphoCare study which is a prospective observational study that was conducted over several years in the United States. It enrolled patients from community sites and academic sites, thought to be representative of the US approach to follicular lymphoma. And we looked at patients that were treated with R-CHOP. We chose R-CHOP because it was one of the most common chemotherapies used in LymphoCare. And we had a little over 500 patients. And we wanted to see whether or not patients treated with R-CHOP who relapsed early had any difference in outcome. Because the observation, if you look at some of the Kaplan-Meier curves on chemotherapies used for follicular lymphoma, a very similar proportion of them will have recurrent disease within that time frame of about 2 years, about 20% will have recurrence within 2 years. Pretty much across the board.

So the question was does that matter? Does it matter that these patients all consistently relapse within that period of time? And so, what we found is that patients that relapse within 2 years had inferior survival, 50% at 5 years. And that, compared to patients who never progressed within the 2 year period, they had a survival of 90% at 5 years. So 50% overall survival at 5 years compared to 90% overall survival at 5 years.

Then we looked at patients treated with R-CVP, R-fludarabine. And the same thing — nothing changed. It was the same effect. And this has been validated multiple times by many other groups and it’s very consistent and reproducible.

DR LOVE: What about the impact of targeted therapy, Carla, in terms of these patients?

DR CASULO: So what we know is that, aside from S1608, which is the study I just referred to, all of the subset analyses looking at efficacy and early progression have been kind of post hoc analyses in subsets of patients, at least the ones that are demonstrated here. And it seems that they do about the same. So when you look at lenalidomide with either obinutuzumab or rituximab, the PFS, it’s a little higher with obinutuzumab but it’s, generally speaking, at 1 year it’s in the range of 50 to 75%. When you look at the PI3 kinase inhibitors, again, about a year or so progression-free survival, which is the same as what you observe in the noninferiority population. So it appears that the majority of patients will respond similarly and probably have the same duration of response for their disease.

So I’m not sure that we have a winner yet with regards to targeted therapies.

DR LOVE: So I want to get into the issue of transformation as an issue. And John, maybe you can go through what we know about the incidence of transformation in FL, the diagnosis and management?

DR LEONARD: Well, the data that we have, and obviously transformation is an important event for patients with follicular lymphoma. It seems to happen somewhere around 30% of people over the course of 15 to 20 years. Obviously, you have to biopsy the patient to find transformation. The patient also has to live long enough to have transformation, so all of these things influence the relative incidences of what you see.

Historically, patients have not done well with transformation, with poor median survivals. That said, if a patient has never had therapy or had minimal therapy, they tend to do pretty well, even if they’ve transformed; whereas, if a patient has had multiple chemotherapy regimens over time that’s associated with more resistant disease and an even less favorable prognosis.

So there’s been some controversy in the literature about PET scans and I would say we tend to do PET scans in relapsed follicular lymphoma patients when we’re concerned about transformation or when the patient has a relapse. We think that a higher SUV tends to go along with histologic transformation. There have been some different analyses of this in the literature. And I would say that in the GALLIUM study there has been less convincing data. But there are other data suggesting that a high SUV goes for transformation. If I’m worried about transformation biopsy the patient — I would generally try to biopsy the patient with the highest SUV. And if I saw high SUVs be particularly concerned for transformed disease.

DR LOVE: Carla, any comments on transformation?

DR CASULO: I agree. I think it’s hard to know because the GALLIUM study didn’t demonstrate that PET helped to identify these patients. But I think routinely, most of us will try to biopsy an area that is more hot on PET. Sometimes though, a patient will come in with their biopsy and have their PET afterwards, so it’s not always possible to get that information at the time of the visit. And insurance companies are not always approving repeat PETs just so you can check and see if there’s areas that are more hypermetabolic. So sometimes it’s a challenge.

That being said, it is what it is. So I think that, when possible, try to biopsy the areas that are hotter, but if you can’t then you have to go with the information you have.

DR LOVE: So I want to go through a couple of data sets related to kind of what we available now and really spend the rest of our time talking about what might be coming up in the future. John, we’ve talked about the AUGMENT study. Anything you want to say about that?

DR LEONARD: Well, this was a study looking at patients with relapsed/refractory follicular and marginal zone lymphoma. Most of the patients had follicular lymphoma. It basically asked the question, does lenalidomide improve the efficacy of rituximab? And if so, what’s the added toxicity, which obviously occurs. You see the primary endpoint here was progression-free survival. And you can see that patients were in remission significantly longer using R² or lenalidomide/rituximab versus rituximab alone.

So, for many people, you see that the response rates were also better, 78% versus 53%. So the efficacy is clearly better when you add lenalidomide/rituximab. Interestingly, in the follicular subset we saw an overall survival benefit as well. And so, that even suggests a more dramatic effect. And obviously, there’s going to be more toxicity. There were more cytopenias, more infections, more GI toxicity. I would say this is typically manageable, but something that obviously has to figure into the equation as you present this to patients and make your choices.

DR LOVE: So, Carla, any comments about R² as a regimen for relapsed disease?

DR CASULO: I really like it. I think it’s a very well-tolerated regimen. It’s limited duration. I think that those are the 2 things that I like about it — it’s effective, it’s limited duration. I think the patients really like it. It’s very easy to give. And it’s really something that we use all the time.

Integration of the PI3 kinase inhibitors idelalisib, copanlisib and duvelisib into the management of FL

DR CASULO: So I want to also bring in the issue of PI3 kinase inhibitors. We already talked about it a little bit, particularly as it relates to the trial. But I’d like to get a little more granularity about how you’re using these agents. And John, let’s hear about your 85-year-old lady.

DR LEONARD: So this is a very fit 85-year-old woman who lives with family, but actually had a family business — has a family business. And has been going to the office 1 or 2 days a week to participate in that. She developed follicular lymphoma, diffuse cervical adenopathy and anemia. Was becoming symptomatic. Had some voice, respiratory symptoms. Was anemic and hemoglobin in the 10 range and so felt like she could benefit from some treatment. Wasn’t enthusiastic about chemotherapy. I wasn’t excited about giving it to her. We gave her single-agent rituximab. She responded for 10 months and then had progression of disease.

So this is somebody that we moved to bendamustine/obinutuzumab, recognizing the issues with older patients, maybe some people might have argued giving this patient CVP with obinutuzumab. Would have been another alternative and I have some colleagues that specifically avoid bendamustine specifically in these older patients. But I was okay with it. We had some dose modifications in her, reduce the dose of bendamustine. She tolerated it pretty well. Had a 14-month response, and then progression of disease.

So, the issue here is she needed treatment. She’d been through bendamustine/obinutuzumab. She’d been through rituximab. I guess I could have given her CVP, but I didn’t think that it was going to be that much different than bendamustine as far as efficacy, probably worse. And so, idelalisib is something that we just started on just in the last month or so. She’s tolerating it well. She does have some fatigue, but hard to know if that’s her disease that just hasn’t yet responded or related to the drug.

But I think this is somebody where a PI3 kinase inhibitor is a very reasonable approach and something that I’ve had several elderly patients in variations of this scenario that have responded well to this type of treatment.

DR LOVE: Before I ask Carla for her response about this trial, John, I’m kind of curious, do you use radioimmune therapy much?

DR LEONARD: I have not used radioimmunotherapy in a good long while. We’re very involved in a number of the early studies with I-131 tocilizumab in particular, but also ibritumomab tiuxetan. This is somebody who, because of her counts and presumed bone marrow involvement, probably wouldn’t be a candidate for that. But certainly it’s something that we should use more. I think all these other options we have now, if you had pushed radioimmunotherapy down on the list even farther. Having done a couple of studies with RIT as part of initial therapy and having a few of those patients develop MDS has really also changed my thinking about using that in the early treatment of the disease. But that being said, the SWOG data, in particular, show that these patients can do well long-term.

DR LOVE: I think 10, 15 years ago, I was thinking it was going to be used a lot more. I guess it just never really happened. Anyhow, Carla, any thoughts about this case? And also radioimmune therapy if you have any thoughts?

DR CASULO: I think radioimmunotherapy is very effective. I agree, I don’t use it. I don’t think I’ve ever used actually. But it’s effective. And I think idelalisib makes sense. Just out of curiosity, since she never had lenalidomide did you —

DR LOVE: Right, I noticed...

DR CASULO: — why lenalidomide was not something you thought about or you wanted to —

DR LEONARD: Yeah, it was there. It’s a good point. I thought that the PI3 kinase would be a little bit easier for her. Good point. She could have also had lenalidomide-based therapy as well. She was a little bit cytopenic, so I was a little less enthusiastic for that reason. But that being said, another good choice and probably something I’ll keep in mind in the future.

DR LOVE: What about choice between the 3 PI3 kinase inhibitors, John? Why did you choose idelalisib for her?

DR LEONARD: The 3 choices that we have are idelalisib/duvelisib, which are oral, and then copanlisib which is IV. The toxicity profiles are a little bit different. I thought for her, I mean it’s a production getting her into clinic because of family getting her here and issues and she’s not tremendously mobile. So I thought one of the oral drugs would be a better choice for her.

And she has a supportive family, so I know she’s taking the drug where compliance is more of an issue, the IV copanlisib I think is more clear there. I would say that I’ve not been convinced that idelalisib and duvelisib are particularly different. The efficacy is similar. Safety profile. It’s hard to know if they’re meaningfully different. And having participated in some of the idelalisib studies, I do have a handful of patients who’ve been on it for years doing well. And so, that’s just something I started with. But duvelisib would have been a fine choice as well if someone preferred that.

DR LOVE: Any other comments, Carla, about this? Kind of I’ve been hearing some people prefer IVs, maybe not so much anymore. Is that the way you think it through, IV versus oral? Or any specific issues you consider in terms of choice of agent?

DR CASULO: Ideally, when you can give something oral I think that that’s preferred. We serve a very big catchment area here, too, with a lot of rural patients, where sometimes they travel 3 hours on dirt roads to get here and sometimes IV is not really a choice that’s easy to make. So, I think that whenever possible doing the oral chemo’s are better.

DR LOVE: So, Carla, you have this slide. Usually when I see these slides I hope other people understand it. But anyhow, maybe they do. Maybe you can explain it.

We were talking about PI3 kinases also, obviously, in breast cancer. I know it’s different, but I guess it’s the same pathway. Anyhow, Carla, what’s your vision on how these work?

DR CASULO: Really the point of this is to demonstrate that PI3 kinase is a downstream target from the B-cell receptor pathway. And it’s a very, very old genetically conserved, universally expressed family of enzymes. And there in numerous different subtypes and subclasses. And it has different isoforms. And we target various of these isoforms in PI3 therapeutically. And it is just to demonstrate that all the different PI3 kinase inhibitors shown here, they target 1 or more of these isoforms. So copanlisib is a pan Class I PI3 kinase, idelalisib is a delta. Just to give you a sense of the landscape of where these different drugs act.

DR LOVE: So, John, it seems like trying to look at early progression, at least there’s some marker that you can look it. And I am curious, in your slide deck you had a couple of slides about PI3 kinases in early progressors. I hadn’t seen these data. Can you comment on it, John?

DR LEONARD: So the concept I think goes back to some of the other scenarios, the idea being that these early progressor patients have a less favorable outcome. Admittedly, they largely don’t have transformation in these studies, and these are more less post hoc analyses. But I think people have argued that if a drug works in early progressor for follicular lymphoma that that’s a nice attribute and probably means that it has some useful activity that one could say is an advantage.

And these are the data with idelalisib, a retrospective analysis of 31 patients. And you can see that the efficacy is about the same as in the total population, just over half of people responding. They’re mostly PRs, as it is with all of these agents. But there are similar data with the other PI3 kinase inhibitors as well. And the duration of response is in the range of about a year or so, give or take.

DR LOVE: And this is pretty impressive waterfall plot, Carla. Any comment about this? I’ve have kind of had the feeling that people don’t maybe value the type of benefit that you get. But at least from the trials it looks like it’s substantial.

DR CASULO: It’s a great drug. I think that the issue that the side effect profile is just a little different with copanlisib. So, again, it’s promising in the early progressing cohort, possibly a little bit more responses in this subset. But, overall, I think is very similar. A little over 50% of the early progressors respond and the responses last about a year. With copanlisib you see some hypertension, you see some hyperglycemia. So I think it’s just a little bit different. And again, its IV. So it’s not something that we’ve used as much in my practice but it’s certainly an effective drug.

Mechanism of action, efficacy and tolerability of the recently approved EZH2 inhibitor tazemetostat for relapsed/refractory FL

DR LOVE: So, I actually want to move on now, so let’s talk a little bit about some of the new things. And this sort of sneaked up on my, John, EZH2, epigenetic regulator of gene expression now an approved drug. Can you comment on it, John?

DR LEONARD: Sure. So EZH2 really is involved in normal B-cell biology germinal center formation and it’s most applicable I would say, it seems, in germinal center B-cell lymphomas. So follicular lymphoma and a subset of diffuse large B-cell lymphoma. There are patients who have mutations of EZH2, about 20% of patients with follicular lymphoma. A relatively small fraction of DLBCL patients also have EZH2 mutations.

So this is an oral agent. And it’s pretty well tolerated. There’s a little bit of GI side effects. A little bit of cytopenias. But pretty well tolerated. And the bottom line of the Phase II trial is that about 75% of people in follicular lymphoma, 75% of the mutant EZH2 patients — and now there’s an assay you can get commercially on paraffin — that about 75% of those patients will respond to tazemetostat, the EZH2 inhibitor. But interestingly, the wild-type patients, the patients without the mutation, about a third of patients will respond to it. And so it still can work in that patient population, although it works better in the mutant subset of patients.

Interestingly, EZH2 inhibition may actually improve T-cell function. It may be a way of improving anti-tumor immunity. And so there are a lot of other directions where we and others are interested in exploring this drug. And now it’s approved for patients particularly with the mutation, but also in the wild-type patients who don’t have other options, at the discretion of the physician, can go on and receive this drug. And it’s, again, oral, twice a day, continuous therapy.

DR LOVE: So have you used it, John?

DR LEONARD: So we have treated a few patients. Most of the clinical trials were done in Europe for this drug, Morschhauser in France, so a number of the patients, many of the patients were European where this was approved. But it’s a well-tolerated drug. And something that I think will in some ways be considered in the same group of patients where PI3 kinase inhibitors might be thought of as well. And one has to think that we’ll be starting to be testing for EZH2 mutations more in our workup and if you knew the patient had an EZH2 mutation with a 75% response rate there, you may go to it a little bit sooner.

DR LOVE: Imagine being a general medical oncologist nowadays and this thing floats across your screen and there’s like 800 other things like that that are coming out.

So, Carla, like where would you be thinking about this? You think you would use it before PI3 kinase? And again, any — I don’t know if you’ve used it at all, any sort of ballpark intuition in terms of tolerability and clinical effectiveness?

DR CASULO: Yes, I have used it. And in fact, one of the first patients I used it was one of the patients I presented — that I referred to transplant. So, unfortunately, after her transplant she had progression of disease again. And it was follicular lymphoma

DR LOVE: Wow.

DR CASULO: Yeah. So she’s on tazemetostat right now. And she’s doing great, actually. She’s had a response — clinically she’s had a response. We haven’t staged her again yet, but clinically her lymph nodes are shrinking. And it’s very well tolerated. So she’s my first patient so far that I’ve used it on. It just happened to coincided with the approval so it was fortuitous that we were able to get it.

But what I like about this drug, it’s one of the first times in follicular lymphoma that we have some biology to act upon. It’s a predictive biomarker. And it’s a prognostic biomarker in the sense that patients with EZH2 mutations do better, but it’s also a predictive biomarker of response because if you have the mutation you’ll also be more likely to respond to the drug.

So I think that that’s one of the first times we’ve seen that in follicular lymphoma. And it would certainly be appealing to seek these mutations out in your multiply relapsed patients because they’ll more likely respond.

DR LOVE: So we’re looking for FGR in bladder cancer nowadays, so cool for follicular lymphoma as well.

Results of the Phase II ZUMA-5 study of axicabtagene ciloleucel for patients with relapsed/refractory indolent non-Hodgkin lymphoma

DR LOVE: John, what about the ZUMA-5 study? We’ve talked about it a little bit. Axi-Cel in FL. Can you talk about the data that was presented and what you think it means?

DR LEONARD: Sure. So this is Axi-Cel, axicabtagene ciloleucel, CAR-T product being used in patients with relapsed/refractory indolent lymphoma, predominantly follicular lymphoma had been analyzed. And interestingly, the marginal zone group, which was a much smaller number of patients, didn’t seem to do as well. It’s hard to know if that’s inherent to marginal zone or to just a small number of patients. But this trial looked at patients with 2 or more prior therapies. The majority had 3 or more prior therapies. They tended, as you might expect, to have more refractory disease. About a third of them had prior PI3 kinase inhibitors. About half of them had POD24 s part of their history.

And so the net is, that this had a very high response rate, over 90%. A high CR rate, in the 80% range. And the median progression-free survival was 2 years. So the net of this is that clearly this is very active. And to some degree, it’s better durability than we’ve seen in DLBCL. That being said, these were not as refractory as we’ve seen in the DLBCL studies. And one might argue a 2-year remission median for follicular lymphoma, while it’s better than many of the other things, it’s not knock your socks off. I think the question is really going to be how many of these people are still in remission 5 years later, etc, etc. But that said, I think for a patient who you would be thinking of an autotransplant, for example, who’s been through a number of different treatments, this may be something that would be an alternative to think about.

DR LOVE: Carla, any comments? And also, we were talking before in terms of tolerability issues, particularly cytokine release.

DR CASULO: So I think our experience at the University of Rochester, we enrolled several patients on this study and one of the patients that I told you about earlier. I find that the cytokine release syndrome is lower, it’s less than 10% in the follicular lymphoma population. It’s higher than that in the DLBCL population. And you’re right, the durability is longer than you see in large cell lymphoma. But at the same time, these are your really refractory patients.

So, where this will evolve in the sequence of treatments for follicular lymphoma, I think, to me, is still to be determined. Because we have a lot of things available, the cost is going to be a big issue. And we may need to look at maybe a randomized study of auto versus CAR-T in follicular lymphoma possibly at some future date. But I think that that’s really the biggest question, who is the patient in which to offer this therapy?

DR LOVE: And I think that trial is going on right now in diffuse large B-cell, a trial like that. John, any comments?

DR LEONARD: There are a lot of similarities here, if you think about it, to radioimmunotherapy. That was a short-term treatment or it is a short-term treatment, that you have to refer to another doctor too. That has durable remissions but is complicated. And it makes you wonder, we use radioimmunotherapy for other things so maybe people will be in the habit of doing it. But to be quite honest, the radioimmunotherapy curves are not all that different. People don’t refer for radioimmunotherapy, will they refer their follicular lymphoma patients, particularly when they can just continue to try things in their office. I think will be interesting to see if this is more widely available.

DR LOVE: Carla, any thoughts?

DR CASULO: No, I agree. I think there may be a resurgence of radioimmunotherapy in the setting of this CAR-T cell therapy.

DR LOVE: Interesting.

Biologic rationale for the use of the novel bispecific antibody mosunetuzumab for relapsed/refractory FL

DR LOVE: So, John, we’ve heard about bispecific agents in various situations in oncology. And now we have mosunetuzumab. Can you explain what that is?

DR LEONARD: So I think the bispecifics are kind of a mini-CAR-T cell approach is kind of how I think about it. The idea is that in CAR-T cells, you’re collecting the T-cells, you’re taking them to the lab. The company is engineering them to be more potent. And then giving them back. Here all of that is happening in the patient where basically you’re treating the patient with an antibody that with 1 arm binds the target, in this case, CD20 on the tumor cell, and in the other side engages here CD3, engages the T-cell. And so the idea is that you’re conducting that activation in the patient.

And the net of this is that it works a little less well than CAR-T cells I would say, but it’s also easier and a bit less toxic than CAR-T cells. So some of the same toxicity issues come up, such as cytokine release, but not to the extent that they do with CAR-T cells. And it’s also something that is an off-the-shelf therapy, so that you could treat the patient. And many of these trials include hospitalization at the beginning, so it’s entirely an outpatient treatment, although on these trials the later infusions can be as an outpatient. You still need to watch the patient for these adverse events. But that said, the efficacy is in the ballpark or getting closer to what we see with CAR-T cells without some of the same toxicities, not as much long-term follow-up as well for efficacy.

DR LOVE: I mean the one that people have heard about is blinatumomab. Is this similar conceptually to that, John, in terms of how it works?

DR LEONARD: I would say there’s some similarities. Blinatumomab is a continuous infusion administered a little bit different. And there’s lots of engineering technical differences, but these are closer to kind of standard antibodies, at least in their structure. But that said, it’s an infusion. They’re typically given on a weekly basis for a period of time, although there’s some variation and nuances to the initial dosing. Because you do have to watch for cytokine release and some of those toxicities in the early parts of the treatment course.

DR LOVE: Have you actually treated a patient, John?

DR LEONARD: We have treated patients, actually not with this agent, mosunetuzumab. Another bispecific. And I would say that they are similar in what we’ve seen so far. Obviously, hard to compare across studies, particularly in Phase I. But also has had interesting activity. And I’ve seen responses in patients with a refractory follicular lymphoma that have been quite impressive. So, I think these really do have a future as well as a class.

DR LOVE: So again, Carla, have you used this agent or any similar agents? Any thoughts about where it might be heading?

DR CASULO: Again, such as John, not this one in particular, but others in the same category. And I think this is a really interesting drug. I believe that for follicular lymphoma it’s also given in the outpatient setting. But it was for the large cell lymphoma patients. And if you remember, that this was also presented at the Plenary at ASH last year and for the patients that had indolent lymphoma, some of them also were patients that had prior CAR-T therapy. So you’re talking about really, really high risk patients. And I think that this has some appeal for use in the future. Again, though, the question is, in what sequence and at what point? Really, that’s the golden question, right, when do you use these and for what patient? But they all seen really, really promising.

The side effect profile is more aggressive. The cytokine release syndrome and the neurotoxicity, if they occur and they’re serious enough, require hospitalization. So that could be potentially serious. So those are things to take into consideration.

Novel agents and approaches under investigation for patients with FL

DR LOVE: So I want to close by asking both of you for your thoughts about where we’re heading in this disease? What are some trial concepts out there that you’re excited about that we might be seeing some results on in the next couple of years? I’ll start with you John.

DR LEONARD: Well, I think that the idea that we have new drugs available, and we’ve talked about a number of them. Things that are relatively newer like the PI3 kinase inhibitors, lenalidomide/obinutuzumab, but now bispecific antibodies. Tazemetostat, EHZ2 inhibitor. CAR-T cells. All of these suggest to me that the progress is going to continue. The outcomes of patients with follicular lymphoma are going to continue to improve over time as we have these new agents and work.

The challenge is really how do we choose between them? And the more drugs we have the better it is for patients, but we’re kind of imposing our clinical impressions on what we think is best for the as best as we can explain it to them and discuss it with them. But we don’t have biomarkers, other than, as Carla mentioned, the EZH2 mutational status to guide therapy. And that’s really the challenge. And you would think that either a biological marker or some sort of quality-of-life profile where we could say well you’re a patient that would do better with this or with that, a short therapy, a chronic therapy, we don’t have good options to make those choices other than our clinical judgment. And I think that’s the biggest challenge.

DR LOVE: Carla?

DR CASULO: I agree. I think that it’s been a great year for lymphoma in terms of therapeutic options. And more will likely come. We had CAR-T cell therapy approved for mantle cell. We have tazemetostat. We have tafasitamab for large cell lymphoma. So I think that we’re really in this very accelerated era of drug development. My personal question and idea is, what is the right patient in which to use these drugs? Who is appropriate in terms of prognostic markers? As you said, patient reported outcomes are important. And I think that what is see patients saying to me is that they are seeking the perfect combination of efficacy, limited duration, quality of life. Those are the things that I think will move the field forward. People don’t want to be on treatment for years and years and years. It really starts to wear on them. and I think that I’m looking forward to studies that use drugs that are of limited duration and that are efficacious and that have some sign of signal — some type of signals that we can evaluate who’s more likely to respond.

DR LOVE: And of course, that’s one of the attractions for CAR-T, the idea that maybe they can be off therapy for a while.

John, what do we know about the immune profile for follicular lymphoma and how amenable it might be to immune manipulation?

DR LEONARD: I think we’re still learning about this area. Certainly, the immune checkpoint inhibitors have not been particularly successful so far. But that being said, CAR-T cells are working. Lenalidomide, in part, works for the immune system. We see that manipulating the antibodies with bispecifics and with newer anti-CD20s makes a difference.

So I think we will hopefully be at a point before too long where we can profile patients and be able to choose therapy based on whether it’s the tumor immune profile or the host immune profile in a more specific way.

DR LOVE: Carla, any thoughts?

DR CASULO: Yes. I think that follicular lymphoma is really the prototypical disease in which to study the microenvironment. There’s a very rich and robust cellular milieu that interacts with the neoplastic cell. And unfortunately, the deliverable has been very modest I would say, with the checkpoint inhibitors. It’s really not what you would have hoped. That being said, I think that the more we understand about how to target the microenvironment uniquely, like with lenalidomide and these other drugs, I think that that’s going to get us farther ahead. But there’s a lot to be learned about that interaction. And there’s a lot of prognostic markers that we know about, how the follicular lymphoma microenvironment affects prognosis.