Relapsed/Refractory Follicular Lymphoma Part 1 — A Roundtable Discussion on the Selection and Sequencing of Bispecific Antibodies

Welcome to Striving for Consensus, optimizing the selection and sequencing of therapy for patients with relapsed refractory follicular lymphoma. This is medical oncologist, Dr. Neil Love. For this think tank style program, I am joined by Dr. Carla Casullo from the Wilmot Cancer Institute in Rochester, New York. Dr. Laurie Sen from the BC Cancer Center for Lymphoid Cancer in Vancouver, Canada, and Dr. Matthew Matasar from the Rutgers Cancer Institute of New Jersey in New Brunswick, New Jersey.

To begin part one, Dr. Mattisar gives a presentation on bispecific antibodies and follicular lymphoma. I'm Matt Mattisar. I'm the chief of blood disorders at the Rutgers Cancer Institute. And it's my pleasure to be with you today, Neil, and talking about bispecific antibodies in relapsed and refractory follicular lymphoma. So as is... Likely known to your audience, this class of medicine, biospecific antibodies, have been developed not just in folliculone, but a lot of diseases. But perhaps...

in no disease more active than in follicular lymphoma. The way these work is they bind to some protein on the surface of a malignant cell. Here, CD20 on the surface of a follicular lymphoma cell. And on the other end, binding to CD3. on healthy native T cells, creating an immune synapse, allowing T cells to be activated, expand, and T cell-mediated B cell killing doing our job for us.

There's a number of different positive antibodies that have been approved in the treatment of B-cell lymphoma more broadly, and really there's four approved either in America or Europe to date. those being mosonituzumab, epcoritumab, odrinexumab, and clofitumab. For follicular lymphoma in the United States, only mosin and EPCO have been approved in this disease state.

And the first of these that was approved for follicular lymphoma is the medicine Mosonituzumab. was studied in the very elegantly named G029781 trial. This was a multi-arm study looking at single-agent molsanituzumab here in patients with multiple relapsed follicular lymphoma, two or more prior lines of therapy. And the dosing scheme is shown here for those of you that are watching, but it starts with step-up dosing where a tiny dose, one milligram, is given.

day one, the next week, day eight, two milligrams, and then the next week, day 15, a full dose of 60 milligrams, the next week, another 60 milligrams. And that completes the so-called ramp-up dosing, and then it goes to every three-week dosing at 30 milligrams. After eight cycles?

Patients receive PET re-imaging. If they're responding and in a complete response at that point, they're done. If they're benefiting but not getting in a CR, the study had them complete 17 total cycles of treatment. This is fully outpatient therapy. Patients do not need to be... routinely admitted for CRS monitoring or any of that stuff. The patients that were treated on this protocol shown here, this is a pretty real-world heavily pretreated patient population.

as you'd expect with requiring two or more prior lines of therapy. You know, the median here is actually three prior lines of therapy. Some patients had had a prior transplant. The majority of patients refractory to the most recent line of therapy. Half of patients were so-called double refractory patients. This is high-risk disease.

And despite these high-risk features, patients treated with mosin in this trial did very well, with an overall response rate of 78%, a complete response rate of 60%. Responses occurred very quickly. The median time to response was six weeks, the first assessment point. And durability has been very encouraging so far with the median progression-free survival best estimate now.

two years or longer, and even better in patients who achieve a complete response where we have not yet seen the median duration of complete response for such patients. You could ask, are there some patients that do better or worse? And the answer is that it appears to be very active, regardless of your risk category. Number of prior lines, POD24, double refractory, all patients seem to derive benefit.

with mosonituzumab. In terms of toxicity, it's very encouraging that very few patients needed to come off study due to adverse events. Only 4% and 2% patients came off due to mosin-related adverse events. The most common adverse events you see on the slide here are cytokine release syndrome, fatigue, some cytopenias.

Looking more carefully at cytokine release, about half of patients do experience some grade CRS, although this was almost exclusively grade 1 or grade 2 in severity, short-lived and manageable with routine interventions. Importantly, CRS, if it's going to happen, almost exclusively happens during step-up dosing. And after that second 60 milligram dose, cycle two-day one, CRS is basically unheard of.

The second approved agent in this space, relapsed refractory follicular lymphoma, is epcoritimab, and it was approved on the basis of the NHL1 trial. Very similar patient population, two or more prior lines of therapy. And as you see, the schedule is a little bit different, whereas with Mosen, it was, you know, the weekly step up for four and then Q3. With EPCRIDAMAP, it's a little bit more drawn out where it's weekly therapy for the first four cycles. And then every two weeks.

until nine cycles are under your belt, and then it goes to every four-week dosing. Also, in distinction to Mohsen, F-cridumab study in NHL1 is meant to be given continuously until progression or intolerance. So some different design characteristics. The patient characteristics included in the study were quite similar. Again, median prior lines of therapy. Many patients that had four or more prior lines included were high-risk patients, including POD24, double refractory.

and the like. And the activity of Epcot is really quite similar to that of Moson and Tuzumab, as you'll see here, with, again, overall response rate of about 80%, a complete response rate of about 60%. And as you see on the Cobb-Meyer curve, durability seems to be excellent with continuous epcritimab as well. It does seem that there is a little bit of a difference by response.

quality. And this has been a theme across by specific development that patients who achieve a complete response seem to enjoy more durability of response than those who fail to achieve a complete response. Toxicity is, again, quite similar, you know, allowing for cross-trial comparisons. Perhaps cytokine release syndrome is slightly more common, although, again, in follicular lymphoma, almost exclusively restricted to grade 1 or grade 2 in severity.

This study was conducted during peak COVID times, and there were unfortunately COVID-related deaths, particularly during the Omicron surge at that time. But I would say that again, this... safety profile is consistent with mosonituzumab and encouraging for its use in this patient population. The third agent I'll talk about with you guys today briefly is ojonextumab, not approved in the United States, but approved in Europe for patients with relapsed refractory follicular lymphoma.

And its schedule is slightly different yet, where it has this split dose step-up dosing on day one and day two, and then day eight and day nine, and then day 15 and day 16. and then it's weekly cycles 2 through 4, and then it can go to Q2, cycles 5 and beyond, with extending to Q4 if patients achieve a durable CR. Patient characteristics are shown here, and again, a very similar patient population, inclusive of patients with a prior transplant, double refractory, and POD24.

The activity is, I would say, quite similar with an overall response rate of 80%, a CR rate numerically slightly higher at 73%, although I'm not sure that that's clinically different. And again, durability seems to be excellent and driven by the high CR rate. with Odron XTAMAP. Toxicity profile, very similar.

Again, CRS is the major concern here, although, again, largely restricted to grade 1 and grade 2 in severity here, approximately 60% of patients, similar to that which we saw with EpcurativeMap. So trying to summarize the activity of these agents in follicular lymphoma, they're all very highly active and very similarly active with overall response rates of about 4 and 5, complete response rates of between 3 and 4 out of 5.

And CRS happening in usually around half to two-thirds of patients during step-up dosing and manageable with routine medical interventions. Very few patients across any of these trials needed to have treatment discontinuation due to adverse events, and thankfully there were very few fatal outcomes due to adverse events.

So before you go on, I'm just kind of curious if you could talk a little bit about Glofitimab. where you see that heading. And also, you mentioned that odrenuximab is approved in Europe. Is it going to be approved in the United States? And how do you go about selecting among the...

three or four or two available agents, Matt? Great questions, Neil. I'll start with the first. Glofitimab, is it approved by specific, but it's approved in the United States for diffuse large B-cell lymphoma after two or more prior lines of therapy? It's not so clear to me that its development is as clear in follicular lymphoma, particularly given that it's made by the same company that makes mosinutuzumab. And mosin is both very well tolerated as well as active in this disease state.

Glow Fidimat may be seen by some... as a little bit more punchy of a bispecific antibody, but does have a slightly higher adverse event rate. It does require pretreatment with obanituzumab to mitigate cytokine release. So it may not be perfectly suited, in my opinion, for follicular lymphoma. But I'd be super interested to hear what Drs. Casullo and Sen think about that as well. What about Odronextamab? Do you expect it to be approved in the United States?

I do. I'll admit that I was a little bit surprised that the FDA took a pass on odronextumab. European health regulatory agencies looked at the same data and decided to give it authorization. I think it certainly is active and safe and an appropriate treatment for patients with follicular lymphoma.

The bigger question in my mind is, what is the value proposition in our current setting where we have access to both Mosa and Nebco? What is Odron Next demand going to do to differentiate itself from its so-called competitors? I think for me, that's a little bit less clear.

Yeah, so we actually got into the same discussion at the St. Antonio Breast Cancer Symposium, where there was a new oral SIRD, selective estrogen receptor degrader that was presented. And people were saying, well, we already have other SIRDs. but then others were saying, well, you know, this gives you some options. Anyhow, Laurie, any thoughts about these questions and how you decide if you have the option between, let's say, these three agents?

Yeah, so I would agree in the comments on glofitimab. I think in general, people perceive it to have a little bit more toxicity and does require the hospitalization. Although some people are trying to get away without the monitoring, we still do it. So I think most of the tuzumab is just more convenient. They're also coming out with a subcutaneous version. So likely it'll be even easier to administer. So I say that.

For me, the choice is likely going to be between Moson and EPCO, and I would agree. I think that I just don't know where Odronextamab would fit in. I think the data looks quite comparable, but I feel like they just, you know. fell a little bit behind and it's going to be hard for them, as stated, to seem like they have something different to offer. And I think people are getting experience with the other two right now.

You know, I see mosinotuzumab and epcoritumab as really interchangeable based on the data that we've seen. I think they look equally efficacious. It's remarkable to me how similar the patient populations were in the two trials. So although we don't want to...

cross-compare across trials, they are very similar populations. But the administration schedule is different. One is finite. One is indefinite. At least one now, right now, you know, Epcurtimab is sub-Q, although that advantage might... disappear soon. But I think, you know, it is nice to have a choice at least between two options because they are somewhat different and patients might prefer one over the other based on administration schedules.

And, Carla, we always have what I call the dervalumab situation from lung cancer where all the PD-1 studies were looking at pembrolizumab, and all of a sudden this study came back in locally advanced disease where pembrolizumab didn't have that great data. Volumab, even though everybody thought they were the same exact drugs, had better data. Now that's the standard of care. So who knows what the next generation is as these agents move up earlier in combinations, et cetera.

Any thoughts, again, about choice between them, at least at the present time, Carla? And also this issue of sub-Q. There have been a number of situations, daratumumab and myeloma is a good one, where you had a lot less toxicity when you went sub-Q. Q. Here, maybe since it's so well tolerated, that's not so much of an issue, but you do have the issue of the inconvenience and curious how much of a factor or benefit you think it is to have sub Q. And again, any thoughts about choosing?

Yeah, I agree with what's been said, but I would add another consideration, and that is that... Some of these drugs are being tested in the first-line setting, and I think that depending upon the success of those strategies, we may see that the treatment options for the relapsed.

patient will be slightly different depending on what they had in the first line. For instance, at our institution, we have some clinical trials that are exploring bispecific antibodies in first line follicular lymphoma. So that could somewhat change the trajectory kind of down into the future. But with regards to selecting amongst the two, I think that patients really help to drive the decision here in a shared decision model with regards to...

Do they want indefinite therapy? Are they really more motivated to be on something for a briefer time point? There can be some cutaneous toxicity with the epcritimab too, and I think any subcutaneous approach has that risk. But I would agree that aside from those considerations, the efficacy and the... The patient population are quite similar between both of them.

And Matt, how hard and fast do you stick to the indefinite versus finite? If you have a patient who's in a CR on EBCO, will you consider stopping it? Yeah, I mean... Generally speaking, I'm trying to make that choice up front. So if I have a patient who prefers time-limited therapy, that's for me a motivation to pursue mosonituzumab as the choice.

Yeah, if you're treating somebody with apricritumab, the intention is supposed to be until progression or intolerance. Intolerance can take a lot of different shapes and sizes, and schedule intolerance is still intolerance. So for a patient who's in a deep CR who wants to stop treatment, understanding that it's a decision that we don't have a ton of data behind. We don't yet know a lot about the efficacy of retreatment by specifics for patients who come often.

A complete remission, but subsequently relapse. But for patients that are comfortable making that choice, I'm certainly comfortable making it with them.

So another issue, and we'll get into this with CAR-T as well, Laurie, is the interface between the general medical oncologist and community-based practice and the doctor investigators at tertiary centers. At least in this particular... arena of bispecifics with the agents that we have for licular lymphoma. What do you see as that interaction? From your point of view, is it okay for a doc to start this in community? In the past, they would start out.

in a tertiary center and then go back to the dock in the community. Obviously, you don't see that much high-grade CRS. Any thoughts, and how does it work in Canada? Well, I think particularly in follicular lymphoma, these are easy to roll out in the community. So neither of these agents requires patients to be hospitalized for the ramp-up period.

As you've seen from the data, the risk of high-grade CRS, which is what we're most worried about, is very low. And I would also state that the risk of ICAN, so neurological complications, is... minimal with these agents. And I personally don't even think it's the same scenario as CAR T cell therapy in terms of neurological complications. So I think CRS is the main... issue that needs to be managed. And I think that given the fact that high-grade CRS is very low and we're all starting to get

used to managing CRS to a certain degree. I think all community doctors will probably have to have a mechanism to initiate these drugs. And people I know are rolling out some standard operating procedures. But I think it's very... administered role in the community. But what you do need to have is...

knowledge in how to manage CRS. You need to have a mechanism that your patient is alerted to know what to look out for. And then the patient has to have a plan. You know, who are they calling when symptoms develop? Maybe that you are going to need to rely on your local emergency room, in which case there also is a learning process and a relationship that needs to be developed probably with a local emergency room. So I've heard all kinds of... you know, scenarios

And I know that many academic centers are happy to see patients and to get them onboarded through the ramp-up process, and then they can easily go back into their community. And I think that was happening a lot more initially, but I think... You know, as these are becoming bread and butter treatments for lymphoma, I think most community doctors are creating mechanisms and safe management practices to be able to deliver this within their own practice.

It's really amazing. I think being a general medical oncologist last night. We did a webinar on biliary tract cancer, an entire hour just on that. And there's this new bispecific anti-HER2 antibody which was just approved in November. Nobody's used it. Nobody knows anything about it. Fortunately, the faculty...

had done the research and could talk about it, but it's really amazing. It seems like every day they wake up to a new agent available. Carla, can you provide a little more granularity of the issue of infections?

Also, vaccinations in patients on bispecifics. You know, those are things that we recommend routinely to our patients. Vaccinations, again, SARS-V, influenza, and COVID. along with all their other routine vaccinations like pneumococcal pneumonia and varicella and things like that. So we would still consider that to be important. And a lot of these bispecific antibodies also have a requirement for pneumocystis prophylaxis.

and viral prophylaxis too. So I think that that helps to mitigate the risks to an extent. So we routinely recommend all the standard of care vaccinations and prophylaxis as mandated by each treatment. And I was just going to add another consideration, sorry, to what was mentioned earlier with regards to use in the community.

I also, in our community, we serve a large area of rural patients where the community oncologist will refer them for the ramp up. But what we've also started seeing is that if a patient lives within a certain radius to their community center, they feel more comfortable. with administering the ramp up with us kind of on standby should the patient have any complication.

And there were recent guidelines that were updated in blood by Jennifer Crombie looking at how to manage cytokine release syndrome and toxicity of bispecifics that are very accessible. Very easy to follow. And these were sort of consensus guidelines that I think can really help community practices navigate this area a little more easily. I was just going to ask, response to vaccinations is the same in patients on bispecifics?

I can't say I know the data behind that, to be honest. I don't know if others on the call do. I think anytime you're suppressing B cell function, you're going to have some limitation in vaccine function. But I can't say that I. know exactly what the case is with these drugs. Yeah, I would agree. I think there's a lot of data. We all know that anti-CD20 monoclonal antibodies really...

lower the ability to respond to vaccines. I suspect it's the same with bispecifics. There's not a whole lot of data out there yet, but we have to assume that these patients are highly... immunosuppressed. And not to mention the fact that most of the patients are receiving these agents on the...

backbone of already having received anti-CD20s previously and other immunosuppressive drugs. So I think, you know, we have to recognize that patients come into these treatments often very immunosuppressed, and then we deepen that further. Yeah, I totally agree. We routinely recommend revaccination.

And we counsel patients not to have any confidence that the vaccines are going to provide total coverage. We also routinely check quantitative immunoglobulins on patients receiving such treatment and have a very low threshold. for instituting intravenous immunoglobulin therapy to further reduce the risk of infection.

So Matt, one of my favorite things at meetings are the trials in progress posters that so many meetings are doing now. Maybe you can go through some of the trials that are going on right now with these agents. Yeah, we could have had a half-hour talk just about the clinical trial landscape with five specific antibodies, but I think that would probably bore your audience. So I tried to pull out just a few of what I think are some of the interesting studies being conducted in this space.

And Dr. Cozillo-Carla mentioned that there's a number of first-line studies that are ongoing looking at mozonituzumab. And we have such studies going, too. I think everybody does because it's so promising. But I think that it's nice to look at those studies and divide them into people with high burden of disease who would meet indication for current therapy. And many of those are either using Mohsin as monotherapy or combined with an immunomodulatory drug like lenalidomide.

Ours uses mosin monotherapy and then adds lenalidomide if they are slow responders. There's a very important cooperative group study being conducted looking at Mohsen monotherapy versus rituximab monotherapy for patients with low burden of disease. Then in the second line setting, there's all sorts of combinations being looked at.

you know, pick your partner, polituzumab and tazimetastat being two interesting ones being paired with mosin. With Epcor, Bernstein studies ongoing, usually leveraging lenalidomide as a partner. that those data have been reported out, at least in preliminary fashion, and are showing it to be very active and adequately tolerated. And again, in the second-line setting, we're often seeing lenalidomide-based combinations across the spectrum.

Odro's doing first-line work. They have a randomized phase 3 trial being conducted globally, comparing Odro monotherapy to chemoimmunotherapy. And then again, we see Odro plus Len in the second line as their relapsed strategy. I hate to ask this, but it's just such an interesting idea. What do you think they're going to see comparing ODRA to chemoimmunotherapy? It seems like a real big difference to the patient in terms of quality of life, I would think.

It's going to have very different patient-reported outcomes in both of those arms. I think we could all say that with confidence. You know, it seems to us like the durability of response with specific antibodies is comparable to that which we see with chemoimmunotherapy. The study is being conducted as a superiority study, not as a non-inferiority study. So it'll be interesting to see how those data mature. So here's my bottom line.

We're at a point now that biocytic antibodies really are a critically important addition to our armamentarium in the treatment of relapsed follicular lymphoma, and that's really because of this pairing of high activity and acceptable safety. We have two drugs approved in the U.S. We have Odro in Europe. More to come, and there's a lot of very exciting work being done to further identify how best we can leverage this class in service of our patients.

All right, so let's hear about your cases, beginning with this 68-year-old man. And, Laurie, maybe you can respond to this case. So I picked three cases in the interest of fairness. I picked one of... one patient from my clinic treated with each of the three specifics that I focused on. So here's our first. So this was a 68-year-old man. He'd been previously well. He developed bulky adenopathy, non-bulky adenopathy on peripheral examination. He went to have imaging done.

That revealed, unfortunately, bulky intra-abdominal disease. This was subsequently biopsied and was shown to be typical low-grade follicular lymphoma. PET staging revealed stage three disease at the time with everything low avidity on PET scan. His labs were pretty normal at the time.

He received BR as his first-line therapy at that time, but unfortunately and unexpectedly progressed through treatment, developing both progressive adenopathy and a nupral fusion. We tapped that, and it showed follicular lymphoma cells in the... pleural fluid. There were no large cells seen in the pleura. We repeated a PET scan and everything was still dimly avid. LDH was only mildly elevated.

He was given a cycle of rice chemotherapy at the time with an intention of pursuing an auto transplant, but he did not respond to rice. At that point, he was offered clinical trials. with Mosin, with a clinical trial-based CAR or a targeted therapy, and he preferred to go on the Mosin clinical trial at that time. He was one of the first patients treated at my center with the drug at that time. He achieved a very rapid, complete response after four cycles.

came off of treatment after eight cycles as per protocol. And we went on to offer and deliver a consolidative reduced-intensity allotransplant in an intention of curing the disease. And what's his current status? He's about five years post-transplant now. He had very mild GVH and is doing fine now. No chronic GVH and no evidence of disease.

So, Laurie, very curious about your thoughts about this case, about the aloe and whether that might happen with your care. Also, any thoughts about patients who progressed during chemoimmunotherapy? That seems very unusual. Do we know anything different about those patients? Yeah, so progressing through BR is not very common. We know that the overwhelming majority of patients, over 90% will respond to BR, but occasionally we do see patients that seem to be quite...

chemoimmunotherapy refractory. And of course, this patient's particularly concerning because he was exposed to two types of chemoimmunotherapy and didn't respond to either of them. So I would... fully agree that this is the kind of patient that needs to move on to something different. And what we've really seen over the last several years is how effective some of the immunotherapies can be in the setting of patients who

have varied chemoimmunotherapy refractory disease. So this patient was lucky. It sounds like he came along at a time when most of the tuzumab was just becoming available or being tested. I think all of those options were on the table. I think CAR T-cell therapy would have been an attractive option as well, but he selected mosinetuzumab.

It sounds like probably it was done at a time when probably nobody understood what the durability might have been from most of the twosmab alone, and he moved on to an aloe. I have to say that right now... I can't even remember the last person I'd recommended an aloe to. I mean, we all see these bad actors, but I'm hopeful that many of them do go on to benefit from other modalities, namely...

immunotherapy and between bispecific antibodies and CAR T cell therapy. I think that many of these patients are going on to get very durable benefits. And the comment was made before about the reuse of bispecific antibodies. We don't have a lot of data on that, but...

But I personally have patients who have now gone on to second rounds of bispecific antibodies and are benefiting and under control. So I think that the trigger to jump to aloe is no longer there because we do have... have options that offer even these high-risk patients some durable control. So, Carla, any comments? And also the question of, is there a plateau? Do we have enough follow-up to see whether some of these patients actually might be cured with bispecifics?

I think it's hard to know about cure because this is a disease where people will live decades and decades. And most people are older when they're diagnosed. It sounds like this person was very high risk and it sounds like this was. you know, the appropriate thing to do for them. I think that we need longer follow up to really get a sense of whether these remissions are durable. And that's probably what the first line trials are going to show us.

But with regards to a plateau, as Dr. Matazar showed, it sounds like... those patients that are in a complete response are the ones that will have a plateau, whereas patients that have a partial response may not enjoy the same benefit of durability. So as in most cases, if you have a complete response, you'll likely do better. So before we go into our next case, just kind of curious, Matt, anything used in terms of MRD assays in follicular lymphoma?

Yeah, response assessment of follicular lymphoma has lagged behind some of our other diseases. In regards to tools like MRD, it's explored in every trial that we run now. We put on some MRD exploratory endpoint, but I would say that it's not borne out in a way that we can use in routine clinical practice at this time.

All right, how about this 58-year-old woman? All right, so behind door number two, this is my second patient I'll present, 58-year-old woman. She'd been previously well. She presented with constitutional symptoms and dyspnea. She was found to be cytopenic, and she had diffuse non-bulky adenopathy. A biopsy showed low-grade. AFL. There was no transmission on the biopsy. Her PET scan was a little bit more concerning with some of her abdominal disease having more highly FDG avid.

findings on PET scan. Her LDH was more markedly elevated. So she was treated for a concern for de novo transformation with ARCHOP chemoimmunotherapy. She tolerated a fine, achieved a CR. We did not go on to administer maintenance rituximab. Twelve months later, she developed recurring adenopathy and constitutional symptoms. She was again pet avid. A biopsy again showed FL without evidence of transformation microscopically. Her LDH was normal at this time.

She received R-squared, rituximab and lenalidomide, but after six months on this treatment, began to progress radiographically and symptomatically. So she received third-line epcoritimab and monotherapy. tolerated treatment well with only grade 1 CRS during ramp-up, and achieved a complete response both on functional imaging as well as repeat bone marrow biopsy.

She's chosen to stay on Epcor and is getting Q4-week therapy. She's been on treatment about two years now and is doing fine and feeling great. So, Carla, any thoughts about this case? Also, the scenario, we get so many questions from docs about this, of patients where there's a consideration for potential transformation. Would that affect your choice of agent? for example, in this situation, if you could, and any other thoughts about this case?

Yes, I think, I don't know that I would use Glofitimab in this situation on the basis of suspected transformation, but in practice, this is what we all do. Whether there's concern for a higher SUV, you worry that perhaps there's... missed transformed disease, recognizing follicular lymphoma is a very heterogeneous disease. And RCHOP is great therapy for follicular lymphoma as well as for large cell lymphoma.

So I think that that makes a lot of sense, even though some studies have not borne out the concepts that high SUV max. really predicts for transformation. But I think clinically, we all still have that concern. So I probably would do the same thing. And if there's other trials available where someone could get a different first-line therapy incorporating another bispecific, that would have some appeal.

as well to see if that could bypass some of these high-risk features. Laurie, any thoughts? Yeah, no, I agree. I mean, I have to say, though, I'm glad to see that biopsies were... And I think that reassures me that this patient just has stubborn follicular lymphoma. But in a patient where that... question about whether or not they're still harboring a cult transformation exists. I wonder whether or not CAR T-cell therapy might have been more desirable at this point.

rather than a bispecific as the next line of therapy. And certainly that would have entered the discussion in my clinic. And truthfully, we did discuss both options with her. And the choice of epcoritimab was just, as you're saying, Neil, wanting to go for perhaps a little bit more active, biospecific. It is approved in large cell as well.

So perhaps it's a little bit more active and gives her a little bit more of an advantage in this specific context. At least that was my thinking at the time. You don't lose the opportunity to use CAR T-cell later on.

I always love cases that start at 88-year-old man. What happened with him? So this is a patient I'm still seeing in my clinic. He's an older man, although looks great. probably more active than I am right now. He had a long-standing history of FL before I met him. He'd received multiple prior lines of therapy, both for low-grade follicular lymphoma as well as prior histologically confirmed transformed disease.

When I met him, he was again presenting with progressing adenopathy and some constitutional symptoms, including pruritus. He had a pet that revealed dimly avid adenopathy. We performed a biopsy to see whether we had low or high-grade disease and found only low-grade disease.

So he was enrolled on a clinical trial of ojonextumab in combination with a second novel bispecific antibody, this being a co-stimulatory bispecific that targets both CD22 and CD28, trying to recapitulate that signal 2 that we got from CAR T-cell therapy. He tolerated his ramp-up of both of those agents without cytokine release, went into a rapid PET-CR, stays on study drugs. He's been on treatment about a year now, as per protocol, and feels great in an ongoing CR.

So can you educate me a little bit about this co-stimulatory bispecific antibody? I would say that the theory behind this effort is that right now what we do with specific antibodies is we simply are creating a single immune synapse between the T cell and the B cell. And many of us... are worried that T-cell fatigue or exhaustion can result from constantly stimulating T-cells with these immune synapses.

and trying to reinforce the... the activated T cell phenotype and allowing them to continue at their work rather than become exhausted through this second signal process may offer more durability. than using these drugs without that second signal alongside it. So, Laurie, any comments about this case? Also, the issue of older patients, patients with comorbidities.

poor performance status. I mean, it kind of, the way you describe the side effects profile of these agents, it really doesn't seem to stand out very much, but I am curious whether any particular comorbidities or situations that concern you.

We were doing a program yesterday on myeloma. I never even thought about this. I asked the doc anything that you think people aren't aware of. This is actually in CAR-T, but I think it might apply for bispecific. She brought up something I never even thought about. I guess, I never even thought about this, was can you use these therapies in people with serious renal issues, including dialysis? Can you? Yeah, so for bispecifics specifically, you know,

Unfortunately, those patients would have been excluded from clinical trials. So there's probably no data to really point to. But, you know, it's in the real world, I'd say. shouldn't be a contraindication. We have treated some patients really with minimal, I haven't yet treated a person on dialysis, but we've treated patients with minimal renal function. And, you know, to my knowledge, there really shouldn't.

be a contraindication to considering these agents in that scenario. I think then the lovely thing about this case is that when I look at the array of

therapies this patient had about three or four years ago, I would say that, you know, you've really been through all the available effective therapies. And now, just in three or four years, we've seen this flourish of, you know, new... treatments that have come out that really can get disease under control and and the important thing in this 88 year old patient that is not a limitation to receiving

We know that there's similar to CAR T-cell therapy. There's no age limit on bispecifics, but, you know, we know bispecifics are really... Quite well tolerated across the board. After the ramp-up period that we talked about, which needs to be carefully monitored because of CRS. These are remarkably well-tolerated, and they do cause some cytopenias, and we always have to watch our patients for infection, but clinically, patients feel very, very well on these agents.

Also a great endorsement for participation in clinical trials nowadays. One of my favorite cases to present, I actually did a video of this patient. was a patient who I did a video on who was on teclistamab, the bispecific myeloma, and that he'd been on it for a year and a half, no toxicity, doing great, just like some of these patients you're talking about here. But the thing that was so great was the day that I interviewed him was the day it got approved.

So he'd already been on it for a year and a half and doing great. And I was like, yeah, that's the way it goes with clinical trials. But any other thoughts about this case? And also the issue of the transformation. Carla, like once you see it, do you assume even if you biopsy again, it's still there? No, not necessarily. You can have, again, as I mentioned, follicular lymphoma being so heterogeneous, you can have the large cell component.

be addressed and then you still have those smoldering as Dr. Sunsets those kind of the indolent cells that just don't respond to much else, and so they'll still linger behind. So you can definitely have recurrence of both follicular and large cell over the patient's lifetime, but a higher likelihood that you'll see follicular recurrence over the long term.

I also love seeing this 88-year-old man that appears younger than seated age. That's always great and so validating that we can treat patients with as much of a curative intent as possible despite their age. And it just kind of highlights the importance of... kind of physiologic age, not just chronologic age when we're approaching each individual person.

This concludes our program, and be on the lookout for the other two parts of this program. Special thanks to the faculty, and thank you for listening. This is Dr. Neil Love for Striving for Consensus, current and future management of relapse refractory follicular lymphoma.