We are going to talk about new therapies. Are the exciting advances you are going to hear about in the next 3 talks and during the next few days at ASH, are they really getting to patients, and if not, why not? And talk a little bit about enrollment in clinical trials.

 

[00:07:22]

 

To ask this question in a more scientific way, we did a discrete choice experiment. We did it in collaboration the FLF with B1. We asked it, not only of patients but of caregivers and physicians. Not surprisingly, everyone wants something that works. Efficacy is an important factor.

 

After that, as physicians, we prioritize safety. If you look at the AE slides, you are going to hear about in the next hour and a half, our eyes always go to grade 3/4. But patients grade 1 and 2, especially if they continue over time, are quite important.

 

Logistics are a key part of what they find. Going 2 hours to a center periodically or having to live at a center for a couple of weeks, as you will hear about, can be a deal breaker for many patients. The varied priorities really highlight the need to have educated patient and time to discuss shared decision-making with them and what is best for them at that time because of all the options that are becoming available.

 

[00:08:36]

 

We also did a global survey. We do these periodically. This is 1 that we just did. It was supported by Genmab, AbbVie and Novartis. We did it in English and in Spanish. We got over 1,000 responses in 3 weeks globally. Most of the patients were US, UK and Spain, but really distributed around the world.

 

The pie chart should show you that there are reasonable distribution of ages where they are in their number of treatments and time since diagnosis.

 

[00:09:14]

 

We got a lot of information from this, but I am highlighting just a few of these things. First of all, most of these patients have never been treated or treated once and some twice. But the number who have been treated 3 and 4 times is relatively small. You will see that later in some of the studies where first-line therapy is fairly effective.

 

Possibly because of this, but also for other reasons, when we think about all these exciting things we are going to talk about, not very many patients actually get them in this day and age. We think they will be moving up closer to earlier lines of therapy. But right now not many patients have had these. These are engaged patients online. You would think they would be aware of these.

 

[00:09:59]

 

The perceived barriers to receiving new therapies for patients are going to a couple of buckets. It is cost, availability. That could mean availability in their country but also availability how close they are to a center to get these therapies. And also quality of life concerns. This reflects that there is knowledge gaps. They do not really understand what some of these new therapies entail in terms of getting them, how they are going to feel, what it is going to impact on their lifestyle.

 

We clearly need to do a better job educating patients and providing that information and making sure that they have time to digest it when they are making decisions.

 

[00:10:38]

 

In terms of clinical trials, I was encouraged that 20% of the people who were second-line or greater had actually been on a clinical trial. Much lower in first-line patients, even though there are so many exciting first-line trials out there. 95% of them said they would or at least consider a clinical trial. Only 5% said, I am not interested in a clinical trial.

 

What was interesting is a quarter of them had never been offered or talked about a clinical trial. We make some assumptions about who is accessible or might go on a trial, or are they are too old or they are too frail, or they do not have the support system. I think we always need to make sure that we are talking to them about trials. If not at your center, then other ones that are available nearby, that might be options.

 

[00:11:36]

 

One thing that comes across in all of our work throughout and is clearly under-assessed, I know as a clinician, yes, patients are anxious about their diagnosis and uncertainty. This was a question, what is the worst ongoing challenge? This was not a multiple choice you could answer, 6 or 8, 1 thing to pick, emotional and mental health in half the patients.

 

We do not think about this all the time. That takes on the fact that we cannot the disease. It could transform tomorrow or never, could progress slowly or faster, the stress of making a decision. How do I choose among all these options? How do I tell my family what do I do with work? All of these things just really great on patients, and we do not do a good job because we do not have time to really discuss that with patients. We do not always have access to resources to refer them to, but we need to build those resources for patients.

 

[00:12:43]

 

This is a slide I started with, and I think the answers are that we need to assess patients continuously at every step in their journey.

 

[00:12:55]

 

Life circumstances change, their health changes where they are and how many treatments, what options, all of these things are changing. We need to provide educational resources for them and emotional and mental health support.

 

Access to new therapies is a very complicated area that I am not going to go into because it has regulatory and all sorts of other things, but it is something we need to think about when we talk about these new treatments and how are we going to get them delivered in the real world.

 

Clinical trial participation is critical, as you will hear in the next 3 talks, to make progress. Patients are open to clinical trials. Please talk to them. Make sure that they are aware and look for trials. Think about ones that might be available even if they are not open to you, open in your area that you can offer them some of these new exciting treatments.

 

[00:13:52]

 

Let us retake our survey. I expect 100% because we were close to that on the first one.

 

[00:14:00]

 

          Posttest 1

 

Which of the following best reflects how healthcare professionals should approach treatment discussions over the course of the patient's FL journey?

 

1. Patient preferences should be documented at diagnosis;
2. Patient preferences should be reassessed regularly as circumstances change;
3. Caregivers perspectives should not influence treatment choices; or
4. Treatment discussions should focus on efficacy outcomes.

 

Yes. The answer is that we were looking for was B. A is certainly correct, but B is more correct because you do not just do it once and have the patient say, “I am not interested in a clinical trial or I do not want this because over time that will change.”

 

Caregivers in our surveys are key. They are the support system. They are the ones that are going to have to drive the patient to their appointments, or maybe stay with them if they have had CAR T. They are really important. Efficacy is important. But with all of these options, there is often no 1 best treatment, and choosing among them really involves thinking about how this is going to impact on their quality of life and their day to day life.

 

Thank you for your attention. With that, I am going to turn it over to Gilles to talk about follicular lymphoma and management.

 

[00:15:49]

 

Dr Gilles Salles (Memorial Sloan Kettering Cancer Center): Good morning. Thank you, Mitch, for this introduction. Thank you for the Follicular Lymphoma Foundation for having organized this event and giving us the opportunity to discuss this field, what is new and what we are aiming for.

 

[00:16:10]

 

You probably are familiar with many of the concepts that I will address during this first talk. Just to remember that we usually consider that follicular lymphoma is an indolent disease that is not a threat for life when it is initially diagnosed. We can debate what means cure and whether we should call it incurable, while many patients will live probably up to 2 decades or more with this disease and eventually succumb from something else.

 

What is important is that it is primarily a nodal disease, so a disease that is diagnosed in lymph nodes. The diagnosis is usually very reproducible. There are discussions about grading. I would not go into that. There are some characteristics of the cells including immunohistochemistry markers, the meshworks of dendritic cells and the genetic abnormalities, that is the (14;18) translocation bringing the BCL2 gene in the vicinity of the immunoglobulin heavy chain locus, which is present in 80% to 90% of the case.

 

Besides this classical conventional follicular lymphoma, there have been variants that have been described, and there is an ongoing work to try to improve our understanding and the classification of these variants. Years ago, we recognized what we call grade 3B called also now in WHO, follicular large cell follicular lymphoma.

 

We have patients that present a very tiny, abnormal piece of the lymph node, which we will call in situ follicular neoplasia, because this patient will probably never, for the vast majority of them, develop lymphoma. But they have cells that resemble those of follicular lymphoma.

 

There are a few cases of follicular lymphoma occurring in other places of the body, some in the childhood and some with different genetic abnormality.

 

[00:18:09]

 

Well, on the left, the first curve is the 5-year relative survival of follicular lymphoma in the United States from 1975 to 2017. As you can see, there have been an improvement in the 5-year overall survival, which in the last outcome was about 89% at 5 years.

 

However, when we look at the cause of death of patients collected both in France and US, you can see that the cumulative incidence of the cause of death remains lymphoma. This remains true for younger and older patients.

 

[00:18:47]

 

If we go a little bit deeper into this notion, we have learned that the cause of death is very often related to an event that occurred during eventually the lifetime, or can occur anytime during the lifetime of patients with follicular lymphoma, which is histologic transformation moving from a classical follicular lymphoma to a more aggressive lymphoma.

 

When we look patients who never transform, the incidence of death or the risk of death is limited, and it is close to all the causes of death. While, unfortunately, patients who have experienced transformation are those patients mostly who might die from the disease, even if these data now are probably 15 years old, and we have made progress also in this area.

 

[00:19:38]

 

Just to complete, I would not go into the depths of the biology of follicular lymphoma. There are many mutations that are present in these tumors. They are present in genes that control what we call the epigenetic, the control of the expression of genes that are encoded by DNA. There are many other genes that are mutated.

 

What I will say is that these mutations that are viable and present in all patients have the particularity to modify the interactions between the tumor cell and the environment, which is composed from different subsets of T cells from lymphoid stroma. In fact, the tumor cell creates a niche which is favorable to its development and its survival. One of the attempts we have right now is to try to modify that and try to restore the immune functions to eliminate these cells.

 

[00:20:41]

 

Which brings me to the management of the patient.

 

[00:20:46]

 

We are close in 2026. Nowadays, what are we aiming and what are we addressing when we see patients with newly diagnosed follicular lymphoma? There are a few patients with truly localized disease, probably a stage I by Ann Arbor, and it considered for a long time that radiation therapy, if singular continuous node can provide cure for a very substantial number of these patients. That is a recommended option.

 

In rare cases, using monotherapy, single-agent with rituximab or watchful waiting will be indicated.

 

Then we distinguish patients with what we call low-tumor burden for those with high-tumor burden. Patients with low-tumor burden are also asymptomatic, and active surveillance or watchful waiting remains a reference because early intervention is not going to change the overall survival of this patient.

 

If these patients are uncomfortable with this management, rituximab single-agent may be appropriate.

 

[00:21:48]

 

For patients with a high-tumor burden, systemic therapy have been developed. This is a representation of a couple of clinical trials that were run in the early 2000, comparing different regimens of chemotherapy. Here is a CVP, CHOP, fludarabine-containing regimen, bendamustine-containing regimen, all in combination with rituximab.

 

What has been shown in the early 2000 is that adding rituximab was dramatically improving the outcome. The differences between the regimen may have been interpreted in different settings, but I will say at this time these 3 regimens: CVP, CHOP and bendamustine are all acceptable, with a tendency to use bendamustine in the vast majority of patients, but not all.

 

[00:22:38]

 

The second information we got is that in patients that received CVP or CHOP using rituximab maintenance. So prolonging therapy after the combination of immunochemotherapy resulted in improved progression-free survival, not overall survival, but avoiding the recurrence of the disease and the new treatment. You can see that the difference at 10 years in the patient who may have a recurrence is significantly important, leading to less patients having to restart therapy despite an equivalent.

 

[00:23:18]

 

I have to say that after bendamustine-rituximab, there have not been a clear demonstration of the same benefit, although it can be used.

 

Based on these findings of GALLIUM study, instead of using rituximab, use another drug which is obinutuzumab, a modified anti-CD20 antibodies and showed again an improvement of progression-free survival with a 7-year progression-free survival of 63.4%, meaning that at 7 years, only 37% of the patients also have experienced a recurrence of disease if obinutuzumab was applied, vs 45% if this was rituximab.

 

Again, there was no difference in overall survival, and this came eventually with some differences in toxicities.

 

[00:24:07]

 

Finally, we also try to avoid chemotherapy in this patient with a high-tumor burden that needed intervention by using the combination of rituximab and lenalidomide, the so-called R² regimen. As you can see—and this were 6 years data and 10 years data will be soon presented - there were no difference between the progression-free survival between this combination and chemotherapy. For complex administrative reasons, this is not a regimen that has been approved by FDA, but it is available by NCCN guidelines in the US.

 

[00:24:44]

 

Again, in summary, rituximab-bendamustine is probably superior to R-CHOP, which is superior to R-CVP for progression-free survival. Overall, there are no difference in overall survival between these 3 chemotherapies. They have different toxicity profiles, and it is possible that certain patients may deserve to have attention from 1 or the other.

 

We learned that rituximab maintenance improved progression-free survival, obinutuzumab improved progression-free survival, and R² is not superior.

 

[00:25:14]

 

A few words regarding the relapsed/refractory setting.

 

[00:25:18]

 

Unfortunately, when patients experience a relapse or treatment becomes less efficient, that is what is described on the right of this slide, the survival of this patient becomes to be dismal.

 

[00:25:32]

 

The patients that deserve the most attention are those patients that experience an early progression, what is called POD 24, progression within 24 months after having initiated therapy. All those patients who are at the end of their first-line therapy, have a positive PET scan. This is well shown in different studies.

 

[00:25:53]

 

There have been many different options that were developed for this patient. We draw this diagram in 2022. As you can see, we have really to individualize the management of this patient.

 

[00:26:10]

 

One of the options that emerged was the combination of rituximab and lenalidomide, which is approved worldwide. This is based on a clinical trial which is called AUGMENT, which compared rituximab vs rituximab-lenalidomide and show a benefit in terms of progression-free survival and a slight benefit in terms of overall survival.

 

[00:26:30]

 

The options have continued to change. Besides this algorithm, which is a little bit complex, recently, the combinations of R² plus tafasitamab or R² plus epcoritamab has become a new tool for this patient.

 

[00:26:46]

 

This is a second-line setting. If we move forward in the third-line setting, there are many options that became available, including bispecific antibody, CAR-T cell therapies, zanubrutinib, obinutuzumab, loncastuximab tesirine, tazemetostat, and my colleagues will document that.

 

[00:27:02]

 

This is a schema that represent a little bit these options. Tazemetostat, an epigenetic modifier; bispecific antibody, tafasitamab; covalent BTK inhibitor, IMiDs and CELMoDs.

 

[00:27:15]

 

There are still questions that are open, including what are the different ways we can individualize patients in the relapsed setting? Those with an early progression at 24 months, those that progressed even early have a positive PET scan. Those are refractory to 2 lines of therapy. Are we able to develop tools that will enable to individualize the treatment based on the biology?

 

There are also questions more general regarding the endpoint, the different sequencing. What has probably changed is that transplants that were used many years ago is probably not used largely in follicular lymphoma. I think this other question we will try to answer also during this meeting. Thank you.

 

I hand over to Dr Martin Peter.

 

[00:28:03]

 

Dr Peter Martin (Perlmutter Cancer Center): Thank you very much. We are going to start with a question. Two of them in fact.

 

[00:28:13]

 

          Patient Case: 72-Yr-Old Woman With Relapsed FL

 

This is a 72-year-old woman with follicular lymphoma who is in need of treatment. She was previously treated for a large B-cell lymphoma 10 years ago. Then 8 years later, is relapsed with follicular lymphoma. Next-generation sequencing is done, and she has an EZH2 wild-type status. Started on rituximab weekly for 4 weeks. Little response, and then is transitioned to R², lenalidomide-rituximab, which she took for 10 months but because of progressive fatigue, she stopped it.

 

The fatigue improved a little bit, but shortly thereafter she began to progress again. In addition to diffuse adenopathy, she has a slightly elevated LDH, slightly depressed hemoglobin. As you can see, her performance status is getting a little bit worse now with an ECOG performance status of 2. These are real cases. She is also the primary caregiver for her elderly husband, who has Alzheimer's disease and dementia.

 

[00:29:20]

 

          Pretest 2

 

Which of the following is the most accurate statement regarding the patient's specific situation? There may be elements of truth to all of them, but which 1 is the most accurate?

 

1. She is experiencing early progression after R² and her prognosis is poor. So she should receive R-ICE and an autologous stem cell transplant;
2. The rate of grade 2 CRS is low in patients with follicular lymphoma receiving bispecific antibodies, and this may represent a reasonable next option;
3. Bendamustine-rituximab should be administered, and if that does not work, she should get CAR T cells;
4. Since she has EZH2 wild-type, tazemetostat will not work and should not be chosen.

 

We will get more into it a little bit later, but I think everybody is on the right track.

 

[00:30:31]

 

          Pretest 3

 

We have now a follow-up question. You have a clinical trial of a CD19 by CD3 bispecific antibody, surovatamig, which is open for patient enrollment at your center. This gets to a little bit of what Mitch was talking about earlier. Which of the following do you think is a valid reason for not discussing a clinical trial participation with a 67-year-old woman with relapsed/refractory follicular lymphoma?

 

1. She lives in a rural area, and it is hard for her to travel to your center, so you are concerned about her ability to comply with visits;
2. She has a lot of questions about R², so informed consent is going to be too difficult;
3. She has a lot of anxiety about lymphoma, and the possibility of enrolling in a clinical trial will be too stressful for her;
4. Her renal function, history of cardiac dysfunction and concomitant medications do not meet eligibility criteria for clinical trial entry; or
5. She has previously expressed that she did not want to be a guinea pig in a research study.

 

I think we have all heard that.

 

Great. Okay. We will come back to these questions again at the end.

 

[00:32:08]

 

I will talk a little bit about bispecific antibodies and then we will have some time for a discussion. I will invite you, as you are watching this, to start answering questions onto the iPad. We will have about 10 minutes for a panel discussion afterwards. It would be helpful if you ask questions so that I do not have to make them up on my own.

 

[00:32:27]

 

These are the antibodies we will be talking about:

 

• Odronextamab;
• Mosunetuzumab;
• Epcoritamab.

 

We would not be talking about glofitamab because that is applicable to large cell lymphoma. Still an important antibody, but not a topic of discussion for today.

 

[00:32:41]

 

These antibodies are all anti-CD20 anti-CD3 antibodies, but they are all different antibodies. There are important differences including their structure, IgG1 vs IgG4. The way that the 2 heavy chains are conjugated, use different technologies. The Fc regions of these antibodies have been silenced in different ways. This is unique to bispecific antibodies. Remember, with typical monoclonal antibodies, we want a very active Fc engagement in order to induce ADCC.

 

In this case, we want a very little Fc receptor binding due to the risk of increased cytokine release syndrome and drug clearance.

 

[00:33:29]

 

Mosunetuzumab and epcoritamab were both approved a few years ago, specifically in the third-line and beyond setting on the basis of clinical trials. We will discuss briefly.

 

Very recently, November 18th, epcoritamab was also approved in combination with lenalidomide-rituximab in the second-line-plus setting, making it the first antibody with full approval. Mosunetuzumab has accelerated approval.

 

Odronextamab has had effectively a very good drug with very bad luck. They submitted to the FDA twice. The first time the FDA rejected it because they were not making sufficient progress in their randomized phase III trials, the confirmatory trials that was subsequently addressed.

 

Then most recently, it was again went back and rejected due to issues with a third-party manufacturing company. It is an interesting read on Google if you are interested about the issues that manufacturing plant has had. Anyways, so it undoubtedly will be approved someday, just not yet.

 

[00:34:45]

 

This is a slide to show that all 3 antibodies really use a similar step-up dosing schedule. With that step-up dosing, the rates of cytokine release syndrome are relatively manageable.

 

The orange represents grade 1 cytokine release syndrome and the black represents grade 2. You can see the rates of grade 2 cytokine release syndrome are fairly low, and grade 3 cytokine release syndrome is even lower. There are small differences. Mosunetuzumab in this context is given intravenously. It is being studied in a subcutaneous form.

 

Epcoritamab. The step-up dosing of epcoritamab is a little unique in this setting. In follicular lymphoma, there is this Day 15 3-mg dose that is not present in the large cell lymphoma step-up dosing, where there is a little bit more urgency to get up to therapeutic doses. Because of that, in large cell lymphoma, once you step up to the 48-mg dose, there is a little bit more cytokine release syndrome. In follicular lymphoma, this is fairly manageable and can be done as an outpatient.

 

Odronextamab is a little bit complicated. This slide does not show that these doses are all split over 2 days. The first 1 is Day 1; Day 2, 2.5. Then it is 2 mg, 2 mg, 10 mg, 10 mg. So it is a little bit more complicated. But it is a similar strategy to slowly increase the dose and mitigate the risk of cytokine release syndrome.

 

[00:36:24]

 

I have only 1 slide to show the efficacy of these antibodies, but if you were to have 3 slides, they would all be roughly the same. The response rates are all in the 80% range, with complete response rates in the 60% to 70% range. The vast majority of those responses are present at the very first time of imaging. In fact, many patients will tell us, while they are receiving step-up dosing, they are already experiencing some response, even with those tiny initial doses.

 

Most complete responses also are present within the first 3-4 cycles, with small rates of conversion from partial to complete response over the remainder of the treatment.

 

Again, these were all third-line and beyond clinical trials. Median progression-free survival in the context of these trials were typically in the 20 to 24 month range.

 

[00:37:17]

 

When we think about giving bispecific antibodies and we are all doing this pretty routinely now, 1 of the first things that comes up really is how we are going to address and manage cytokine release syndrome or the neurotoxicity ICANS, if it were to exist, which is quite rare.

 

If you are interested in the management of those, then I would refer you to this paper by Crombie et al, which was published in Blood last year. I wanted to show this specifically because of the first part of it, which is around patient education, which I think is probably the most important part of the whole strategy.

 

When we start somebody on R-CHOP, we go over all of the potential risks of R-CHOP dealing with nausea, dealing with neuropathy, getting an echocardiogram, all of that goes into chemotherapy teaching. We do it. We have APPs who do it.

 

The same thing needs to be done around bispecific antibodies. Just the discussion is a little bit different. Patient education is there, telling them to call us. In fact, we are often reaching out to them 24 hours later to make sure that things are going okay. But telling them to call us with any symptoms. Also, at our institution, we send people home with a prescription for dexamethasone with instructions on how to use it, if they do have a fever. There are debates about that, and we can have that discussion a little bit later. That may vary. You may have your own opinions there.

 

I want to say that patient education is a key part around the administration of these antibodies.

 

[00:39:04]

 

The other thing that is key is the facility and the training of the personnel who are administering and receiving calls from patients receiving bispecific antibodies. Training of personnel is critical because these side effects are somewhat unique. Whether it is an assistant or a secretary or fellow or resident who is going to be receiving calls, they need to be aware of what they are going to be called about and how to get a hold of us.

 

The facility is an interesting one. I think many of us are in facilities where tocilizumab is available and on hand. That is not practical for every facility in every part, for example, in community offices. Under those circumstances, I would say that this is a great opportunity for academic community partnership. I think patients can be dealt with during this initial step up dosing at academic facilities or larger hospitals and then transferred back to their primary oncologist in the community to continue receiving treatment. So there is a great opportunity with these drugs for partnership.

 

[00:40:21]

 

Infections are common and real. Most people, 50% to 70% of people taking these drugs will get infections. Most of those are grade 1 or 2 infections, sometimes requiring antivirals or oral antibiotics. Grade 3 infections do happen sometimes.

 

Interestingly, the infections that tend to be the most severe tend to happen a little bit early in the first 3, 4 months, for reasons that are unclear to me, but they do continue to slowly escalate over time. So you see an initial rise and then a slower rise over a longer period of time.

 

Neutropenia is a very common side effect. These drugs should be held for grade 4 neutropenia and growth factors should be used liberally. We make it a practice of prescribing PCP prophylaxis as well as HSV prophylaxis to all patients. We are routinely checking immunoglobulins and supplementing with IVIG in cases where that is appropriate.

 

There are some unusual infections that are reported, including CMV, which I have seen. Whether we need to be monitoring for that? I do not know that is necessary. I think in somebody who has had a lot of prior therapy, we should be aware of the potential risk of some uncommon infections.

 

[00:41:45]

 

Once you have got an effective drug that is approved, the next question is, how do you get it to be potentially more effective or used in more people, or move it from third-line to second-line setting? We will go over a few different approaches to that right now.

 

The most obvious approach, Dr Salles Gilles mentioned that R² is used on the basis of the AUGMENT trial in the second-line setting. This would be a very natural partner. Mosunetuzumab and lenalidomide have been combined successfully in a trial here.

 

[00:42:24]

 

That led to the generation of the CELESTIMO trial which is ongoing, a randomized phase III trial comparing mosunetuzumab plus lenalidomide to the R² regimen. This trial is ongoing. We do not have results yet.

 

[00:42:37]

 

A similar approach was taken in EPCORE NHL-2, in both previously treated and untreated arms.

 

[00:42:45]

 

In the previously treated arm, the results you can see here are a complete metabolic response rate of about 80%, with relatively low rates of grade 1 and 2 cytokine release syndrome.

 

[00:43:02]

 

That led to the EPCORE FL-1 trial. This is the trial that led to the approval on November 18th of this regimen. The data will be presented at ASH this year. The most exciting part of this slide is hidden in small print at the very bottom, with a hazard ratio of 0.21. I do not think I have ever seen a hazard ratio in that number, so I would encourage you all to attend that presentation and see what it is about.

 

[00:43:30]

 

The other approach is not necessarily partnering with a drug that is already approved in this setting, but partnering with a drug that you own. That is the approach that Roche Genentech has taken by partnering it with polatuzumab vedotin. I admit. I am guilty of not necessarily understanding the rationale for this combination when it was first rolled out, yet it is remarkably effective and well tolerated, as you can see here, in a small number of patients with a high complete response rate and low rates of cytokine release syndrome.

 

[00:44:01]

 

There are some drawbacks that come with polatuzumab vedotin. This regimen is being studied in follicular lymphoma, large cell lymphoma, and also mantle cell lymphoma.

 

[00:44:14]

 

Surovatamig was something that appeared in 1 of the questions. It is an anti-CD19, anti-CD3 antibody. Similar to the other antibodies, its development involved step-up dosing. Now we are on a double step-up dosing protocol. In fact, they went up to higher doses than this. But the 7.2-mg dose is the recommended phase II dose.

 

[00:44:48]

 

In this initial presentation from last year, you can see that it had a very high complete response rate.

 

[00:44:53]

 

The rates of cytokine release syndrome were very low. In fact, almost all of the cytokine release syndrome was reported as grade 1. This trial is being updated this year again at ASH. A spoiler, the cytokine release syndrome rates have come up a little bit, yet they still remain, interestingly, almost all grade 1, which is fascinating.

 

[00:45:20]

 

 

These are some of the ongoing trials. If you walk around at ASH, you will see that many of these trials are being presented here at ASH this year, including mosunetuzumab-zanubrutinib, mosunetuzumab-lenalidomide augmentation, which is an interesting dose adapted approach.

 

[00:45:41]

 

I will mention briefly the MorningLyte trial, which is a frontline trial comparing mosunetuzumab plus lenalidomide vs R or O chemotherapy.

 

[00:45:57]

 

Then there are key trials also in epcoritamab. I think the most exciting one I have already mentioned, which is the EPCORE FL-1 trial. But there are of course others.

 

[00:46:07]

 

OLYMPIA-1 and OLYMPIA-2: Phase III Trials of Odronextamab ± Chemotherapy for Untreated FL

 

Odronextamab is also in development with the OLYMPIA-1 and OLYMPIA-2 trials comparing odronextamab either in combination with chemotherapy or to chemotherapy.

 

[00:46:21]

 

Also surovatamig is in a randomized trial with the promising data that I showed earlier and a little bit more follow up, which you will see at ASH this year. AstraZeneca has gone all in very quickly, moving right to the upfront setting, comparing surovatamig. Two separate dosing regimens, 1 of which contains a longer maintenance phase to R-chemotherapy. Not O-chemotherapy, interestingly, but R-chemotherapy.

 

[00:46:52]

 

What are the key elements to consider when considering patients in clinical trials? I think increasingly there has been a lot more recognition that patients need a say in this. With most foundations now, patients have a seat on the scientific advisory boards, with observational trials. And now with interventional clinical trials, patients are also being consulted.

 

This is going to become increasingly important because I think we are moving past an era where simply demonstrating a PFS benefit to say that something is better or worse does not cut it. Patients also need a seat at the table to tell us what they actually want, what they would consider significant, and what they are willing to give up or gain in order to get a longer PFS benefit, for example.

 

[00:47:51]

 

Lastly, those of us who are working in the clinical trial sphere do a better job of developing strategies to link patients to clinical trials. Mitch mentioned this a lot. We have seen in the past, clinical trials enroll patients that do not necessarily represent the population that they will be used in. For those who do not think that that is that important, I would say go to the plenary session this year and we will see that there are, in fact, differences in lymphomas amongst different populations of people, a very important finding.

 

We have to consider developing trials that will allow access to all people who will eventually go on to receive these drugs once they are approved. It is important to address common questions and concerns from these patients as they arise.

 

[00:48:53]

 

In summary, bispecific antibodies have significantly impacted clinical practice in a very short period of time, and more changes are expected. In fact, we are in the midst of that right now with a new approval. Many of the initial barriers are practical, but I believe can be fairly easily overcome with a little bit of effort. It will take some time to learn how and when to use bispecific antibodies, and particularly in the context of numerous other effective treatments that we are going to go over, it will be an interesting period of time to think about how we sequence all of these drugs.

 

[00:49:29]

 

           Patient Case: 72-Yr-Old Woman With Relapsed FL

 

Let us go back to our patient case. Again, this is the 72-year-old woman initially treated with large cell lymphoma, now relapsed with follicular lymphoma. She is the primary caregiver for her elderly husband, but she needs treatment.

 

[00:49:46]

 

          Posttest 2

 

Which of the following is the most accurate regarding this patient's specific situation?

 

1. She is having early progression, and so she should get R-ICE and an autologous stem cell transplant;
2. Grade 2 CRS is low in patients with bispecific antibodies, and this is a reasonable option;
3. Bendamustine-rituximab should be administered. If that does not work, she should get CAR T cells;
4. Since she has an EZH2 wild-type status, she should not get tazemetostat.

 

That is the answer that I would have gone with as well. We all saw that these drugs are effective and well tolerated.

 

[00:50:53]

 

          Posttest 3

 

I guess 1 question about that, though, is the bendamustine. I will maybe turn to you guys. Is there a role for bendamustine in relapsed/refractory follicular lymphoma in the era of the current drugs?

 

Dr Sehn: I would say it all depends on access. We know bendamustine-rituximab is very effective. We still use it as a frontline treatment. We saw some nice curves, how patients get very prolonged benefit from immunochemotherapy upfront. I would never reuse it in the relapsed/refractory setting in the patient had got it initially because I think it is highly immunosuppressive and damaging to bone marrow.

 

In light of all of the less toxic options that are emerging, and particularly the immunotherapy options that are emerging, the last thing we want to do in the relapsed/refractory setting now is lead to lymphoid immunosuppression. Resurrecting chemotherapy in the relapsed/refractory setting probably is less desirable. Using BR puts you at risk of diminishing the benefit of your immune therapy when you bring it in. So I would say no, but curious to hear what others have to say.

 

Dr Martin: I think that was an important part of this question, which is if the bendamustine does not work, then maybe that was the clue that that might not be the right approach, the sequencing of those 2 next to each other.

 

[00:52:29]

 

          Posttest 3

 

Next question. You are considering somebody for a clinical trial. Which of the following are reasons to not discuss a clinical trial?

 

1. She lives in a rural area, and it would be very hard for her to comply with the study visits;
2. She has a lot of questions, and it is going to be too complicated to explain it;
3. She has a lot of anxiety and you are going to make it worse;
4. She is ineligible for the clinical trial; or
5. She does not want to be a guinea pig.

 

I think we did great with this one. Mitch, maybe I will ask you, because you have dug into this a lot. A lot of people answered to the first question early and changed. But it is a significant issue. How do we reach out to people who are living far away and involve them in clinical trials?

 

Dr Smith: Yes, that is a significant problem. That is why I glossed over it, because it is not 1 that we can solve easily. But we should certainly offer these things to patients. They can tell us whether they can arrange it, whether they can get the support. Ultimately, you talked about the complexity of giving a bispecific and the team that it requires. We are going to have to find a way that it can be done locally at a physician's office, which we have done with transplants now become easier.

 

There are ways, as you point out, to overcome it and get them out these drugs out to where the patients really are so that they can have these, especially if the front-line data looks as good as it seems to be.

 

Dr Martin: You guys at Memorial have a very well-established network that I think you can do clinical trials, not just in Manhattan, but also outside of Manhattan, that I think is a big help.

 

Dr Salles: Yes, I think what we have learned is that this family of drugs, which we are discussing today within the follicular lymphoma field, is a biological principle that will expand to all the fields of oncology. Many years ago, I think everybody doing oncology had to learn how to manage febrile neutropenia when you deliver chemo, and I think we will have to spread the word of how to manage cytokine release syndrome when we use bispecific antibodies, as we had to learn how to manage in solid tumors, and more rarely in hematology, the side effect of immune checkpoints.

 

We have new drugs that are efficient, that are useful for our patients. We will continue to do that. I think more and more, we are working on adapting the regimens to avoid any hospitalization for these patients that were initially mandatory. Any prophylactics that might be trials starting with drugs used as prophylaxis, tocilizumab as prophylaxis and things like that. I think it was even recommended for multiple myeloma.

 

We will move forward to improve the management of these drugs and allow, what Mitch said, to clinical practice.

 

Finally, I will say for those who are involved in clinical trial design and generation, it is also simplifying as much as we can the schedule, the inclusion criteria. Our colleagues from Mayo Clinic had done several important work to show what are the barriers, like the initial labs and things like that. If we want to move forward, we should really also break these barriers.

 

Dr Smith: I think also an academic community partnership is something there where maybe the initial step up dosing is done in the center and then the patient is passed off. But it requires a lot of communication and planning.

 

The other thing is, all of that education you had for patients, once they are going to get the drug, it is very helpful to have that early. When they are making a decision, is this something I really want to do? You are going to get this and then they learn all the complexities.

 

[00:57:15]

 

Q&A

 

Dr Martin: Okay. We will move now on to a question and answer session. I have an iPad that has all of your questions, but I do not know how to use an iPad apparently. Do you guys see the questions?

 

Dr Salles: Yes. There are many questions, so we might not be able to answer all of them. One question is, do we understand why there is neutropenia with bispecific antibodies?

 

Like with other immune therapies, we do not necessarily fully understand. I do not think we encounter that many patients with febrile neutropenia. I do not know what is your experience, but I do not. But eventually, because these patients are fragile, because at this time it is third-line setting, patients had received other drugs, being liberal with G-CSF is important.

 

Dr Martin: We do see neutropenia with rituximab and obinutuzumab as well. There might be some link there.

 

Dr Salles: Another question is, do you advise patients to be vaccinated before doing bispecific therapy?

 

Dr Martin: Yes, I am a big advocate for vaccines. I always was, but became a much bigger advocate for them during the COVID pandemic. Many of us did studies looking at serological conversion during and after therapy and saw that it declined, but it did not decline to a rate of zero. It was clear that people could still benefit from vaccines despite having been on therapy or having recently received therapy.

 

My bias is to have people vaccinated in advance. Even if they have started, if they have not been vaccinated, I will still propose that they get vaccinated.

 

Dr Sehn: The 1 thing I would comment is, also patients with follicular lymphoma, you usually have a time window to start treatment. So very often I do talk to patients about vaccines and say, “Well, let us get these done and then plan for treatment in 2 weeks or 4 weeks from now. There usually is not the same pressing urgency, so you have time to have that discussion and time for patients to get missing vaccines in.

 

Dr Salles: There are questions we could take at the end. There is 1 more related to that which is, is IVIG necessary despite low IgG levels? Again, it is per patients decision. The recommendation is less than 400 mg/dL and repeated infections. I have patients with 200 who never have an infection, I do not give them. And I have patients with 500, 600 who probably benefit of them. Is that also your experience?

 

Dr Martin: Yes. In multiple myeloma with the BCMA antibodies now, it is recommended standardly, but those are far more immunosuppressive agents on account of the fact that they are literally clearing the plasma cells, whereas these drugs may be take longer to get there. But I think it has a lot to do with the prior therapies and the degree of immunosuppression that they are coming in with.

 

Dr Salles: Maybe just 1 comment, because it is again, only on bispecific. There is a question regarding PJP prophylaxis, pneumocystis [inaudible]. I think it depends a little bit on the kind of patient we are treating. I do not routinely use it in the first-line setting or in second-line setting.

 

At the beginning these drugs came in patients who failed therapy after transplant after CAR-T. We use it widely, but I will say this is very rare in my experience. The question is, should we prolong? I will say the patient had experienced significant T-cell depleting therapy. Yes, but I do not think I prolong it for 6 months in most of the patients. I do not know, Laurie?

 

Dr Sehn: Yes, I would agree.

 

Dr Martin: I guess I do not have a hard and fast rule for it. I will say with the subcutaneous administration, we get a lot of rash, not just at the site of administration, but sometimes a little bit more globally. For that reason, I will often hold off on starting Bactrim. But I do often start it afterwards.

 

I think only that iPad has the questions on it, so you might want to bring that one.

 

[01:02:18]

 

Dr Salles: Okay. We are going back to the podium for discussing the use of CAR T-cell therapy in the setting of a patient with follicular lymphoma.

 

[01:02:24]

 

I will briefly review 3 clinical trials that led to the approval of 3 different products in the setting of relapsed/refractory follicular lymphoma.

 

The first trial to be performed was the use of axicabtagene ciloleucel. It is a trial that recruited patients with both follicular and marginal zone lymphoma. It is a very classical trial design, with patients receiving lymphodepletion with fludarabine cyclophosphamide, then received the CAR T-cell. The primary endpoint was response rate.

 

[01:02:59]

 

You can see on this graph, and I think this was, we should say, a surprise for all of us. The response rate in this population of highly refractory patients, patients who have experienced failure to many therapies, was extremely high. As you can see, there was a 94% overall response rate with a 79% complete response rate for this patient with follicular lymphoma.

 

The second information is described on the right, which is the duration of response for patients with follicular lymphoma. At this time, the median lymphoma specific progression-free survival. That means the patients who have not experienced a relapse, but they could have experienced another event, remains extremely high at 5 years. Its median is not reached, and 64% of these patients have not experienced a relapse.

 

What is meaningful is that, if you look at the number of patients at risk between 3 and 5 years, there is a stable number of patients and very few events suggesting a very prolonged benefit.

 

[01:04:08]

 

This is outlined also on these 2 curves, which is the duration of response and the time to next treatment, showing that there is at least a group of patients that may benefit on the long-term from this kind of therapy.

 

[01:04:24]

 

Moving on to the second trial. This was the another drug, tisagenlecleucel in relapsed/refractory follicular lymphoma, an international trial. Again, a phase II trial. Complete response rate was the primary endpoint, very similar design. Again, with CAR T cells, you have to harvest the T-cell to manufacture the T-cell. It takes 3-4 weeks. You have to do the lymphodepletion and then infuse the cells.

 

[01:04:55]

 

This is now the four-year update of this trial, and 5-year update will be presented during ASH. As you can see, again, for those patients who achieved a complete response, and this was a majority of the patients if I recall well, 78 or complete response, the curve looks to be stable and very high. At four years, 66% of these patients remain free of progression.

 

[01:05:25]

 

This data suggest also that even in patients that have experienced early progression after first-line therapy, POD 24, there is a benefit, maybe a little bit less marked than for those patients with a high FLIPI score, double refractory and bulky disease. Different categories of patients more difficult to treat had a benefit, even if it may have been not as patent for favorable groups.

 

[01:05:55]

 

Finally, the TRANSCEND study with lisocabtagene maraleucel is the last one to be presented and published. Again, exactly the same design, exactly the same clinical trial way.

 

[01:06:10]

 

This is a follow-up with a little bit shorter at this time around 2 years, but showing that both in third-line follicular lymphoma patients, but also in some patients that were treated in second-line, the progression-free survival appears favorable.

 

[01:06:29]

 

This is well depicted on these 2 next slides. The first one is the overall response rate and CR rate across different groups. Again, these are unprecedented results. We are talking here about complete response rate of 93% in different group of patients, depending on the line of treatment. The only thing that appeared to eventually affect the high CR rate was a recent use of bendamustine, which is a T-cell depleting agent.

 

[01:07:03]

 

If we look at the result now, again, about 70% to 80% of the patients that were in this trial were responding remains free of recurrence at 2 years. During this meeting, we will hear the 3 years data being presented. Again, the group that may not benefit are patients recently exposed to bendamustine, which comes back to the discussion we had with the previous clinical case.

 

[01:07:32]

 

Real-world data are not yet available for all of these drugs, but colleagues from France have a registry called DESCAR-T, where they collected prospectively all patients receiving CAR T in the country. It is quite an exhaustive registry that presented data with patients receiving tiso-cel and axi-cel. Liso-cel has not been available. Basically the result from the clinical trials were reproduced in terms of CR rate, in terms of 1 year duration of response and survival, so confirming that the data from the clinical trial were available.

 

[01:08:11]

 

Just to summarize what we have learned from these 3 trials in the relapsed/refractory setting for patients with follicular lymphoma, extremely high overall response rate in a population of patients, which had usually about half of the patients having experienced POD 24, or two thirds or more, the patients that were refractory to their last line of therapy.

 

Depending on the trial design, some patients had to receive bridging therapy or not. I will say that in my experience, we can often avoid bridging therapy in patients with follicular lymphoma. Again, CR rates that were extremely high and probably unprecedented.

 

There is some toxicity like we encountered with all CAR T-cells. We will discuss that in a few seconds. But as you can see, eventually toxicity varies among different products. I will say that CRS, cytokine release syndrome, which occurs 3-5 days after the infusion of CAR T-cells is frequent with axicabtagene, less frequent with tiso-cel and liso-cel, and it is essentially low grade with these 2 later products.

 

[01:09:23]

 

Finally, the ICANS, which is a neurological side effect is also rarely present.

 

Finally, the median PFS shows that at 5 years, the majority of responders are still in response.

 

[01:09:39]

 

The management of toxicity at this time requires still accredited centers. There is guidelines which are byproduct but usually adopted by each institution. Again, the rate of side effect varies among product. We need to screen the patient, but I will say it is rare and it becomes rare to have a contraindication to CAR T-cell with a new product which has a diminished rate of toxicity. Obviously, like any therapy, we have to adapt.

 

The CRS management is usually having the patient well hydrated. Tocilizumab for grade 2 CRS is a consensus, sometimes used a little bit earlier. Steroids can be used also quite liberally. There is a question whether tocilizumab repeated dose may have a detrimental effect or not, which is questionable, and brings the question of neurotoxicity for which the treatment is essentially high dose steroids.

 

As I mentioned earlier, we are dealing here with neurotoxicity in the less than 10%, mostly 5% rate and 1% to 2% grade 3/4 neurotoxicity, something very rare.

 

[01:11:00]

 

There are, however, some long-term toxicity we should be aware. This long-term toxicity, 1 is the side effect of CAR T cells. They target not only malignant B cells but normal B cells. There is a B-cell aplasia and hyperglobulinemia. This occurs in about 30% of patients who is having received CAR T-cell. I follow patients who have received CAR T-cell 5 or 8 years ago who do not have B cells and eventually receive IVIG.

 

This is something to consider when we discuss the risk benefit, particularly in young patients of using CAR T-cell. There is a cytopenia because of the lymphodepleting therapy and because of some immune side effect. It can be prolonged in a small number of patients, 20% to 30%. Usually everything resolves by 3 months, and there are scores that can be applied to identify those patients at risk.

 

Obviously, this is a risk of infections and appropriate monitoring of patients should be done.

 

[01:12:04]

 

CAR T cells were developed for patients with large cell lymphoma, which had no other options and have cured a significant number of these patients. This was a major progress. The situation is a little bit different in follicular lymphoma, where despite the very encouraging results that I have shown with the 5-year follow-up, we do not know whether this product will lead us to achieve cure of patients with follicular lymphoma.

 

I have tried to summarize here the pros and cons of using CAR T cells in follicular lymphoma. The pros is that it is a simple treatment. You have to do leukapheresis. You have to inject the cells, but it is done. It is once and done with a single infusion of the product. With new products, the toxicities are manageable. They are predictable. I will say we treat patients in the ambulatory setting.

 

During the first 7-10 days, they came daily to the hospital for monitoring. After that 2, 3 times a week, now the regulations have changed and they have to be in the proximity of the hospital for 2 weeks.

 

Because follicular lymphoma, as outlined by Laurie Sehn early on, it is not necessarily an urgent treatment. We do not have many patients with very bulky disease. Bridging is not always necessary. The response rates are high. We have encouraging results, and I think we will see if the future tell us that this is a treatment that change the natural history of this disease.

 

Obviously, the obstacles are many, including the logistics. You have to do an apheresis. You have to collect the T cell. You have to wait for the manufacturing. This is only available in specialized centers. I think in the United States, about 200 or 250 centers.

 

You need to be in the close proximity, 1 hour from the CAR T center just after the infusion. If a side effect is encountered, such as CRS or ICANS, you need to be hospitalized. The patient needs to be hospitalized for a few days, and we need to manage this side effect. There could be a long-term IG supplementation needed in a small percentage, but in some patients.

 

Obviously, this is a genetic therapy. I remind you that CAR T cells are cells that are genetically modified, and they persist in the body of the patient for years. Whether there are risks associated with this product, whether there are risks that are associated with the whole procedure, the combination of fludarabine cyclophosphamide, remains to be determined, and we need to continue to follow our patient with that.

 

[01:14:49]

 

With that on, we will go to the question and answer regarding the CAR T-cell part. There are a few questions here that are coming. Once we got the tumor volumes that affect the outcome, and I showed data suggesting this is true, at least for some products. One question maybe for my colleagues is, probably the burning 1 we have those days. What is the role of CAR T-cell vs bispecific? What is the order of sequence?

 

Maybe the 3 of you may have different opinions. Let us start with Lauri.

 

Dr Sehn: It will probably be individualized on a patient by patient basis. If I had to make a blanket statement, I would probably say that, for follicular lymphoma, I still think of bispecifics ahead of CAR T just because of what I think as a more intensive therapy, maybe a little bit more serious risks with CAR T, although, as you mentioned, it may occur in a minority of patients only and the logistical aspects and the cost.

 

That the efficacy, toxicity profile is probably in favor of bispecifics for follicular lymphoma. Many of us are intrigued by that plateauing of the curve for CAR T, which I certainly like to see longer term data. I would also point out that that plateau still seems to be there for bispecifics as well. Maybe in the end, with longer term data, many of us may shift where we prioritize it. But right now, for me it is bispecifics and then CAR T.

 

Dr Martin: Yes. Mitch and I were talking earlier about the emotional impact of being on something and having no evidence of disease, and potentially believing that you may be cured. The more exposure I get to the CAR T cells in follicular lymphoma, the more I wonder about that.

 

I agree with Lauri that, in general, my impression is that the bispecific antibodies are more practical. Most people with follicular lymphoma do not want to be in the hospital for a couple of weeks, although I think maybe with liso-cell, it is not always necessary.

 

I do wonder maybe I need to reconsider this a little bit. As researchers, we have a hard time understanding from the data that we generate how to compare something that you are receiving continuously, potentially until progression vs 1 and done and the impact of that on somebody's life. I do not feel like I have the data to be able to really advise people. So it is a long discussion.

 

My experience has been that most people are choosing bispecific antibodies when I present both, but it may be the way I present it. I am not sure.

 

Dr Smith: I agree. I mean, that is the natural progression. But it is going to change anyway because with all the data coming out bispecifics, either with rituximab, with lenalidomide, something will be first line. And I do not think CAR T is ever going to be first-line. Then that will go away if bispecifics are done first-line.

 

From a patient standpoint, they want to know more about what is the risk of prolonged hypogammaglobulinemia[?]. Do I need to be on that? Because if I am cured, but I am on monthly IVIG for 5 years. There is lots of information that we really need to continue to gather. Is there a sequence? Now you have got the CD19 bispecific, is that going to affect? You get CD19 CAR T after that.

 

Lots of questions that we just need to answer. But right now I would agree with you guys.

 

Dr Salles: I think most of us at this time in the third-line setting in general, where these 2 tools are approved with the recent approval of EPCORE with R² changing the game. But most of us will offer in general bispecific before CAR T. Although, I am thinking about some patients recently which were patients that had received rituximab single-agent. Then because of very aggressive presentation received R-CHOP, started obinutuzumab maintenance and relapsed during obinutuzumab maintenance. She received CAR T.

 

I have another patient that had received chemotherapy 5 years ago, relapsed, received R², is progressing during R². I am thinking that maybe CAR T is the best option, while patients that relapse with 5 years interval obviously bispecific is preferred.

 

My presentation regarding the options was a little bit quick. But there are so many options that, again, we should individualize decision and it should be a shared decision process with our patient.

 

There is 1 question quite specific with CAR T, which is, autologous stem cell transplantation of CAR T. I think in places where CAR T are available, I do not think there is a role for autologous stem cell transplant in follicular lymphoma anymore. The efficacy and toxicity is clearly superior, and I do not think I have recommended autologous stem cell transplant in the last 5 years for follicular lymphoma patients, although 15 years ago this was a common indication in my previous team.

 

Regarding CAR T POD 24. Again, this is more individualized decision.

 

Maybe a question for you, Peter, who have probably more access to the different CAR T product. Do you think there are differences and do you think there are different products that should be chosen for different patients? Or do you have a preferred option for your patients with follicular lymphoma? I know it is a difficult question, but I will let you try it.

 

Dr Martin: Well, at the 2 centers where I have worked, we have been fortunate to have a cell therapy team. For the most part, I will defer to them. Although I often have my own biases, I admit.

 

As I mentioned, I think that many people with follicular lymphoma are biased towards more outpatient management and less time in the hospital. As Laurie mentioned in particular, there is a bias towards lower rates of toxicity. I think that it is probably true that liso-cel and tisagenlecleucel have slightly lower rates of those. Whether there is an efficacy difference that I do not know without a randomized trial, but just in terms of tolerability.

 

And that might be different, for example, for mantle cell lymphoma, where there is often much more urgency to get something into somebody as quickly as possible, where axi-cel is often maybe more appropriate in follicular lymphoma. As Laurie mentioned, there is maybe a little bit less urgency. My thinking has been more along those lines.

 

But if there were an efficacy difference, maybe that would influence things? I do not know.

 

Dr Salles: Yes. Well, I use CAR T and prescribe my CAR Ts, and I do not think I have used axi-cel in patients with follicular lymphoma in the last 2 years. Clearly, it is completely ambulatory. I mean, we try to process this patient ambulatory. That does not mean that the patient will not spend 3 days in the hospital because of a CRS. But that is not the plan.

 

About 40% to 50% of the patients do not present the CRS of an infection, so remains in the ambulatory setting.

 

There is just maybe 1 question, which is with bispecifics, with CAR T, with what we discussed regarding bendamustine, should bendamustine be avoided in the first-line setting?

 

My answer is that there are very few patients that relapse early. This is not to disqualify this drug in the first-line setting. But, Laurie, I saw you were smiling.

 

Dr Sehn: No, I think it is becoming a very topical question now. I mean, bendamustine-rituximab is actually the standard frontline therapy in my center. The question might be taken away from us. As is mentioned, we suspect that with all the treatments that are being investigated in the frontline setting now, that highly likelihood that we might have an immunotherapy approach upfront in the future with bispecifics combined with lenalidomide possibly. So it may be pushed out by the clinical trials.

 

Right now I would agree that it is hard to deny how effective it is frontline. And many patients will have prolonged benefits. They are going 7, 9, 10 years sometimes. By then I would presume that most of the immune effects have already resolved. I am not changing my frontline yet, but it is also a matter of access. I do suspect that over time frontline therapy will evolve, and probably that is for the better.

 

I will continue to hand you over the podium by handing you over the podium for the next presentation regarding new therapies in this area.

 

[01:25:11]

 

Dr Sehn: Great. I am going to remind people that there is still other therapies out there beyond bispecifics and CAR T, although they certainly have been very, very topical as all of that data has been emerging.

 

I am going to focus now a little bit on other targeted therapies and monoclonal antibodies that are also important considerations for patient treatment.

 

[01:25:45]

 

First, we will start by considering a patient case.

 

[01:25:49]

 

          Patient Case: 75-Yr-Old Woman with FL  

 

This patient is a 75-year-old woman with follicular lymphoma. She was diagnosed initially with stage III but low burden disease, grade 1/2 in December of 2020. She has retired, lives alone, lives approximately 3 hours away from the hospital. Does have some prior comorbidities. Initially was observed, still watch and wait. Still commonly used at the time of diagnosis for patients.

 

Then in June of 2023, her scans revealed that she had evidence of progression. She also started to have symptoms that included B symptoms and fatigue related to anemia, but she was re-biopsied prior to starting her consideration of treatment and confirmed that we are still dealing with follicular lymphoma, not areas of transformation.

 

She went on to receive what many people use frontline still, and that was bendamustine and rituximab, which she got for up to 6 cycles. She actually had a really good response and end of treatment response. Ultimately, in March of 2025, she experienced progressive disease. She is now symptomatic again, requiring treatment but still with follicular lymphoma.

 

[01:27:13]

 

          Pretest 4

 

The question I would throw out is, which of the following is the most accurate statement regarding this patient's specific case?

 

1. The patient is experiencing early progression on immunochemotherapy; hence she is a candidate for immediate allogeneic stem cell transplantation;
2. Based on the results of the AUGMENT trial, lenalidomide and rituximab is the best option as second-line treatment after immunochemotherapy;
3. Combining R² with tafasitamab is preferable because this combination has shown higher response rates and improved progression-free survival over R²; and
4. Given the patient's age and disease history, she is an ideal candidate to receive CAR T-cell therapy at this point.

 

If you could please answer.

 

Okay, a bit of a variety, but let us go through some of the data.

 

[01:28:35]

 

Gilles has already shown a slide before that looked at the huge array of treatment options that we now have for our patients with follicular lymphoma. This is another summary. We often think of it as buckets. What is the patient after getting chemoimmunotherapy, which is often the frontline therapy patients receive. What do we consider second-line options? What do we do for third-line options?

 

In the second-line as well as the third-line, we can always reconsider chemoimmunotherapy. I have to say that with all of the options, I would prefer myself not to go back to chemoimmunotherapy, but to move on to some of the more novel options, many of which relate to immunotherapy, as we have heard.

 

Lenalidomide-rituximab has become a preferred option in the second-line setting based on the AUGMENT trial, and we will see some data now combining tafasitamab with that. Perhaps omitted from this has been the recent approval of epcoritamab with lenalidomide and rituximab also now in the second-line setting.

 

We know that for some patients, rituximab monotherapy might continue to be an option, particularly for some frailer patients. We also have tazemetostat. Transplant has gone by the wayside, as we have heard. Then we spent some time already talking about bispecific antibodies and CAR T-cell therapy.

 

Also now in the third-line setting, we have got the emergence of BTK inhibitors.

 

[01:30:11]

 

When you think about all of those options, what are some of the key determinants that might lead us to select 1 option over the other? Always when you have got the patient in front of us, you do need to think, does that patient actually need treatment? So we do not rush into treatment at the first sign of progression.

 

I mentioned that watch-and-wait is still acceptable up front. It is also acceptable in the relapsed/refractory setting. Usually there needs to be a trigger for the patient to require a treatment to go on to something next. It is perfectly acceptable and standard to actually monitor patients until they need treatment.

 

At the time that you need to make that treatment decision, not all patients have the same biology. You might be influenced by kinetics of disease. Many patients can have slow evidence of progression, yet others can come with very fulminant disease, rapidly evolving symptoms. Always need to think about the possibility of transformation. What is the bulk? Are we trying to get something that is going to come in and reduce things down quickly? Do we have time to have an impact?

 

What about prior therapy? In the relapsed/refractory setting, it is relevant to understand what the patient received previously, how they tolerated it and the duration of benefit. Because you might get some clues as to what agent you might want to avoid next, or what you might need to want to move to an alternate type of mechanism of action.

 

We have talked quite a bit about patient preferences and circumstances, and how the different options we have do have different modes of delivery and different logistical implications. More and more with all of these options, that is really coming to the forefront of discussion with many of my patients.

 

Then, of course, all of our patients are not equal, and they do have other medical problems. Many of these patients are elderly. Sometimes, very importantly, we need to consider the context of their medical issues in determining what might be the safest option for them next. There are a lot of factors that will go into the decision making.

 

[01:32:29]

 

Let us think about some of the alternate options. EZH2 inhibitors are an option for patients with relapsed/refractory follicular lymphoma. EZH2 is actually an epigenetic regulator of gene expression, and it actually regulates the germinal center formation.

 

It is important in the pathogenesis of follicular lymphoma cells. We know that about 15% to 20% it can actually harbor an EZH2 mutation. But regardless of whether or not mutations are present, it is a key element in the pathogenesis of follicular lymphoma.

 

[01:33:20]

 

You can test your patient for EZH2 mutations. We know that tazemetostat, based on some data that I will show you, has been approved for patients with relapsed/refractory follicular lymphoma after at least 2 prior lines of therapy in patients who are positive for an EZH2 mutation. But it is also approved for adult patients with relapsed/refractory follicular lymphoma, where it is thought that there is no other satisfactory alternative treatment option, regardless of EZH2 mutations.

 

There is an FDA-approved companion diagnostic that was labeled at the time of tazemetostat approval, which is listed here, although many centers will have their own testing capacity.

 

[01:34:09]

 

Tazemetostat in R/R FL: A Phase II Study

 

Tazemetostat was approved based on a pivotal phase II study that was performed in patients both with mutant EZH2 as well as wild-type EZH2. It enrolled patients who had received at least 2 prior lines of therapy. This is given in a pill format. One of the nice things about tazemetostat is it is very convenient. It gets taken twice daily until progression or intolerance.

 

For this trial, the primary endpoint was overall response rate.

 

[01:34:47]

 

As was probably not unexpected, the response rates were higher for patients who had mutant EZH2 rather than wild-type EZH2, and the overall response rate was almost double with 70% vs 35%. Interestingly, the median progression-free survival was not that different, regardless of whether or not patients had wild-type or mutant EZH2 status, and that ranged from about 11 to 13 months.

 

[01:35:20]

 

One of the most attractive things about tazemetostat as an option, it is very safe and tolerable. There are almost no grade 3 or higher toxicities associated with it, with the most common toxicities really being some constitutional symptoms, including nausea and diarrhea. So relatively safe oral option for patients.

 

[01:35:47]

 

It is moving forward in combination therapy. There is now a large phase III trial where it will be combined with R² compared with placebo R² in the SYMPHONY-1 trial, and this is ongoing.

 

[01:36:08]

 

Recently, we also had approval of tafasitamab in combination with lenalidomide and rituximab based on the inMIND trial. Tafasitamab, many of you are familiar with, is a CD19-directed monoclonal antibody. It has previously been approved for relapsed/refractory DLBCL in combination with lenalidomide.

 

In the inMIND trial, which really tested the possibility of dual targeting with monoclonal antibodies here, CD19 and CD20 in combination with lenalidomide, to see whether or not that can augment the immune benefit of R², which is commonly used.

 

[01:36:57]

 

The inMIND trial was a large phase III trial that enrolled patients with relapsed/refractory follicular lymphoma and marginal zone lymphoma, although the primary endpoint was looking at the follicular lymphoma patient population. Patients had to have at least 1 prior line of therapy, and they were randomized in 1-to-1 fashion to either tafasitamab R² vs placebo R². Both arms got up to 12 cycles of therapy. The primary endpoint was progression-free survival.

 

[01:37:32]

 

This trial met its primary endpoint with a significant improvement in progression-free survival with the addition of tafasitamab. We saw that the median progression-free survival was increased from 13 months up to 22 months with the addition of tafasitamab.

 

[01:37:59]

 

Importantly, the trial was stratified for patients that we consider to be of higher risk, including patients with POD 24 status, so those are the early relapsing patients; patients who have shown prior refractoriness to anti-CD20 monoclonal antibodies, and patients who had had multiple prior lines of therapy.

 

Importantly, in subgroup analysis, all of those patients benefited regardless of high-risk status.

 

[01:38:30]

 

What do we know about toxicities? Well, in general, the toxicities were quite comparable between the 2 arms, with the most common toxicity being neutropenia, which was pretty much the same in both arms. Although there was, I would have to say, a slight increase in the risk of pneumonia and COVID-19 in the tafasitamab arm, which is likely due to a deeper B-cell immune suppression.

 

Importantly, there was really no difference in the rate of discontinuation between the 2 arms. So it did not impede the ability to give the R².

 

[01:39:13]

 

This is a CD19-directed agent. We heard a lot about CAR T-cell therapy prior to this, which also targets CD19. One of the questions that people often have is, can I use CD19-directed antibody ahead of CAR T-cell therapy? Do I have to worry about whether or not I am going to lose antigen expression?

 

We are still learning about the loss of CD19, both related to the use of CAR T-cell therapy as well as tafasitamab, but we have learned quite a bit from its use in DLBCL, where it appears that tafasitamab has a low likelihood of inducing CD19 loss, and if it does happen, it is often transient.

 

This data is being collected from inMIND, and we only have some early information available. But in patients who did relapse, who went on to get biopsies after exposure on the inMIND trial, for those patients that had lymphoma detected who had been exposed to tafasitamab, 7 out of 8 still remained CD19-positive, and the 1 patient that was CD19-negative, looking at their initial biopsy, did have a CD19-negative clone at the time of entry into the study, and it may have been that that clone was selected for. But still, this is being collected and an important aspect that we need to pay attention to.

 

[01:40:44]

 

The other major small molecule inhibitors that we use routinely in CLL and other areas of lymphoid malignancies have been the BTK inhibitors. We do know that follicular lymphomas are highly dependent on the B-cell receptor pathway, and it seemed logical to test BTK inhibitors in the treatment of follicular lymphoma. Early on, ibrutinib was tested both as a single-agent and in combination with rituximab and yielded actually disappointing results.

 

I think there was low enthusiasm initially to think that these drugs were going to be beneficial.

 

[01:41:28]

 

Then we saw the data of the ROSEWOOD trial. The ROSEWOOD trial actually tested the next-generation BTK inhibitor, zanubrutinib, with obinutuzumab and compared it in this randomized phase II trial against obinutuzumab alone. This trial enrolled patients who had had at least 2 prior lines of therapy, and the treatment with zanubrutinib was to progression.

 

[01:41:54]

 

The primary endpoint was the overall response rate and this trial led to a significant improvement in overall response with zanubrutinib and obinutuzumab, so a response rate of almost 70%, and a CR rate of approximately 40%. In many of these patients, durable benefit was seen.

 

[01:42:20]

 

You can see also that the progression-free survival was markedly improved in the combination arm, with many patients actually achieving rather durable benefit with the combination.

 

[01:42:35]

 

We are quite familiar with the toxicities with zanubrutinib and obinutuzumab as it is commonly used in other settings. So no surprising toxicities here. Generally well-tolerated.

 

Regarding the toxicities of interest, there was really a low rate of atrial fibrillation seen, low rate of hypertension, no major bleeding complications. Probably the biggest risk for patients receiving this type of therapy, of course, is infections based on the immune suppression.

 

[01:43:09]

 

There is a phase III trial that is currently ongoing that will further validate the benefit of zanubrutinib and obinutuzumab. This now is being done in patients after at least 1 prior line of therapy, and it is being compared head-to-head against R².

 

[01:43:34]

 

Just a brief mention that there are other trials also exploring other BTK inhibitors. There have been several trials recently looking at acalabrutinib. These trials have been actually combined with R².

 

[01:43:56]

 

There was 1 trial in the relapsed/refractory setting where the acalabrutinib again here was given to progression and showed actually quite notable response rates with different doses of lenalidomide being tested as well as some durable benefit for some patients.

 

[01:44:08]

 

Again, quite a tolerable combination.

 

[01:44:14]

 

It also in other trials is being tested up front now. This was a more time-limited type of treatment, so only given up to 13 cycles for the acalabrutinib and 12 cycles for the R².

 

[01:44:32]

 

Again, in early data with small numbers of patients, what we are seeing is really high response rates and some durable benefit for patients.

 

[01:44:40]

 

Pirtobrutinib, the non-covalent BTK inhibitor that now has emerged for treatment for CLL and mantle cell lymphoma is also being tested in follicular lymphoma, with some intriguing data looking at response rates, seeing overall response rates of 50%, with modest CR rate of 16%. But this is early data.

 

[01:45:08]

 

Quite a well-tolerated agent. No new safety signals.

 

[01:45:16]

 

We also have a novel non-covalent BTK inhibitor, nemtabrutinib, that is also showing some interesting data with, at this point, modest response rates of 41% and a low rate of CR. Right now it looks like BTK inhibitors may have some role to play in follicular lymphoma. They may need to be combined to improve efficacy, but there are many trials that are still ongoing.

 

[01:45:45]

 

I will just mention 1 other data set, and that comes from really a small trial looking at the antibody drug conjugate, loncastuximab tesirine in combination with rituximab. This was performed in a patient population with relapsed/refractory follicular lymphoma after at least 2 prior lines of therapy. It had really intriguing results with a high overall response rate of 97% and a CR rate of over 75%.

 

Many of these patients again had durable benefit with quite a high flat line and progression-free survival. This actually combination has been added to the NCCN guidelines and is undergoing further testing.

 

[01:46:36]

 

Really to conclude, there is an increasing number of therapeutic options for our patients with relapsed/refractory follicular lymphoma. As we balance out which option is best at any given time for our patient, we really do need to consider patient characteristics, the disease behavior, some of the prognostic indicators, what our goals of therapy are, and ultimately what our patient preferences are.

 

It is also important to think about, in the relapsed/refractory setting, what patients received previously, how they benefited, whether or not we want to move on to an alternative mode of action.

 

For optimal treatment sequencing, since many of this data that we are looking at today are showing highly effective options, but none of them have really been compared against each other, as clinicians, probably we need to manage what we know about comparative benefit and toxicity. Ultimately, I think moving forward into the future would really be interested in having biomarkers that allow us to select these treatments with greater biological rationale. But I think we are not quite there yet.

 

[01:47:58]

 

Let us reconsider our patient case.

 

[01:48:05]

 

          Patient Case: 75-Yr-Old Woman With FL

 

Again, the 75-year-old woman who now needs second-line treatment after short progression following her BR.

 

[01:48:16]

 

          Posttest 4

 

I will ask you again to answer the question. Which of the following do you think is the most accurate statement regarding this patient's specific situation? I will ask you to replace your vote now.

 

Okay, I did show you the data from the inMIND study that shows the benefit of adding tafasitamab to R². I have to say that, what we are seeing is that although R² was a preferred option previously, adding to R² with some of these novel agents like tafasitamab, and more recently, epcoritamab is really improving benefit. I think R² will soon go by the wayside for some of these novel and improved outcome combinations.

 

[01:49:22]

 

Okay, we are happy to answer some of your questions. I will see whether or not anything has come in here.

 

This is an interesting question, actually, and maybe I will throw it out to my colleagues. Do BCL2 inhibitors have any likelihood of being used in the future?

 

We all know that 1 of the key features that factors into the diagnosis of follicular lymphoma is that these patients do have BCL2 rearrangements, but we know that there has been some exploration of venetoclax. Surprisingly, it did not have big efficacy, although there are other BCL2 inhibitors in development.

 

Do we think that that is going to emerge as a possible option? Peter?

 

Dr Martin: As you say, it is an intuitive target, but has been disappointing. Certainly single-agent venetoclax at doses that were so high, they were almost intolerable, were still minimally effective. Then combining it with other agents like chemotherapy have been challenging. There are some trials with lenalidomide in mantle cell lymphoma, and there may be some role.

 

Right now, although there is a clear rationale, I do not know that there is a clear role for it in follicular lymphoma, particularly with the other agents we have available. I know that there is a very strong preclinical data from Lisa Roth and Wendy Béguelin to combine EZH2 inhibitors and BCL2 inhibitors. But despite that rationale, I do not know whether there is a real role for it.

 

Dr Smith: I was just going to say, I think biologically we know that BCL2 is necessary, but probably not sufficient. There is other steps. So probably it is no longer the driver. But my pet theory is that eventually we are going to find that there is a clonal cell, and we may be eradicating it with the BCL2. You do not see it when you treat the bulk disease, but maybe that is going to be the key. That is my pet hypothesis. I am hoping it will be proven someday.

 

Dr Sehn: This is an interesting question. I showed you data from the inMIND trial, and 1 of the things that was noted in that trial was that R² by itself seemed to have relatively low progression-free survival. The question is, is that our expectation currently with R², and do we have an explanation for that?

 

Many of us maybe anticipated what R² can do based on results from the AGUMENT trial. But the AUGMENT trial, to remind everybody, really included patients who were still rituximab sensitive. In inMIND, many of the patients enrolled were actually rituximab refractory. It was a very different patient population.

 

Similarly, in clinical practice, inMIND enrolled the patients that we are seeing in clinical practice. Expectations with R² probably are less optimistic than we saw in AUGMENT. But Gilles do you want to comment on that?

 

Dr Salles: Well, I think you stress the point. I mean, the AUGMENT had a particular selection of patients. R² is a very active regimen, but probably not for patients with early failure or refractory to other lines of therapy.

 

I will say the second difference is that there is clinical trials and there is patients that are monitored during clinical trials, and having a lymph nodes that change from 1.2 centimeters to 1.8 centimeters is a progression of disease, and it is an endpoint of the trial. In our real life as clinicians for patients who are not enrolled in clinical trials, having lymph nodes that change from 1.2 centimeters to 1.8 centimeters usually does not change the management of these patients.

 

Again, there are variety of patients. They are diverse in their presentation and things like that. What you want to achieve for some patients and whether what the proof of success or not can be judged with some cautions in perspective.

 

Dr Sehn: Maybe I will just throw out 1 last question. This had to do with EZH2 inhibitors. How often do you consider using EZH2 inhibitors in patients that have wild-type follicular lymphoma?

 

Dr Salles: This is a drug that I was involved in the early development of this drug, and I found that this drug was an oral agent that was modestly active. Because again, there is a response rate modest as a single agent. Duration of response is about 1 year. With the new tools, we have, this is, I will say, a little bit outdated. Combinations are in process, but there have been also a few warning signals regarding the possibility of patients developing myeloid malignancies when maybe prolonged treatment is given.

 

I will say, we need to know more about this drug before my opinion using widely and right now I rarely used it outside of clinical trial.

 

[01:55:29]

 

ASH 2025: Key Studies in Follicular Lymphoma

 

Dr Sehn: Okay. Moving forward and thinking about the ASH meeting this year. It is going to be really fascinating to see some of the new data that is coming out in the context of follicular lymphoma.

 

Prior to this session, we actually pulled faculty and said, which abstracts are you most excited about looking at and seeing the details out of this meeting? We have got a short list here just to bring your attention to look forward to the meeting.

 

One of the highlights of the meeting probably is going to be the first phase III trial, looking at moving bispecifics forward now into the second-line setting. That is the trial of EPCORE R² vs R². We heard that that is recently been FDA approved but is based on data that will be presented for the first time in full format here in the meeting. So probably 1 of the abstracts that we are all most excited about.

 

Beyond that, I think what also is exciting is that we have got longer term data coming out of the CAR T-cell therapy trials, but also longer term data coming out of the monotherapy trials. We will see longer term data from TRANSCEND and ELARA. Now 5-year data from mosunetuzumab will be shown in a poster.

 

There is also an intriguing abstract looking at outcomes in the second decade following a follicular lymphoma diagnosis looking at data from Iowa and Mayo Clinic. That will be an interesting natural history observation. But of course, it may be that that will be the baseline that will compare against when we move forward and think about how our patients are doing several decades in with all of these novel therapies.

 

[01:57:45]

 

We also have some long-term data from FOLL12 coming out, which examined different chemoimmunotherapy options, looking at the possibility of rituximab and epcoritamab in the frontline setting. There is an interesting novel CAR T-cell therapy that will be described targeting BAFFR, particularly for patients who have already failed a CD19 CAR or patients who have CD19-negative disease.

 

A novel first-in-class BCL6 degrader, which may be 1 of the next new things we need to keep our eye on, as well as more data coming out on EZH2 combinations here with CAR T-cell therapy. So lots to look forward to at this meeting.

[01:58:29]

 

          Poll 3

 

Just a couple of questions. Final survey before we move forward. Based on today's discussion, do you plan to make any changes in your clinical practice based on what you learned? For our own information, and to learn from how to create these symposia moving forward, we would like you to answer yes, no, or uncertain. If you can answer that now.

 

[01:59:19]

 

          Poll 4

 

Then 1 final request we have is, just maybe take a moment and add a text comment in if you are planning to make a change, what change do you think that you will make based on the education that you receive today?

 

[01:59:48]

 

Okay. At this point, we actually are pretty close to the end of the symposium. Maybe I will ask our esteemed faculty if they have any last comments based on the data we have seen and any words of wisdom for the audience today. Mitch, I will start with you.

 

Dr Smith: I think come away from this really with a good overview of all the options and complexities of the decision-making for physicians as well as obviously for patients. I applaud you guys for covering a huge area in each of those sections in such a concise way.

 

Dr Salles: Very briefly, I think we alluded to the abstract by Jonathan Day from the Mayo Clinic and it reflects a prospective collection of patients diagnosed with follicular lymphoma. And it reflects another paper that has been published by groups in Europe.

 

When next week you meet patients and you meet a newly diagnosed follicular lymphoma patient, there are 2 or 3 messages coming from these studies. Living apart, the very low tumor burden or the localized stage patients. But even for advanced stage patients, there is a large proportion of patients 30% to 40% who will receive over the lifetime 1 single line of therapy. The median number of lines of therapy received by patient is 2, and it is only less than 30% of the patients that receive 3 or 4 lines of treatment or more.

 

I think the concept that it is an incurable disease and patients will all be treated with several line of therapy need to be reconsidered with the active regimen we are delivering, taking also into account that these data are coming from the last 20 years, and we are seeing what has been presented with new age. I think we should bring hope to our patients and confidence in the future and continue to individualize the management.

 

Dr Smith: Can I just respond to that? I think you are absolutely right. But what is missing is the biomarker to tell that patient is going to do well, that they are going to do well, and they are not sitting there worried constantly for the next 10 or 15 years. If we could give that, then we would be in much better shape.

 

Dr Salles: I fully agree.

 

Dr Sehn: Peter?

 

Dr Martin: The 1 thing that I am continuing to dwell on in my own mind is the idea of shared decision-making in follicular lymphoma and involving patients, and also as physicians and researchers, understanding more about what it is that patients want. I spend more time reading studies now about those kinds of outcomes, and maybe spending a little bit less time dwelling on small differences in progression-free survival or overall response rate.

 

There are a number of large, well-organized cohorts around the world now. We will see more and more of those data emerging. That is where I will be spending a lot of effort diving into those papers in the future.