Andy, are there any other new CAR [chimeric antigen receptor] T-cell therapies that you’re excited about that might be applied to follicular lymphoma? We’re seeing a variety of second- and third-generation drugs that are coming through with improved adverse event profiles, perhaps even in vivo expansion of the cells. Any thoughts there?

I think you’re exactly right, and it’s all of the above. In terms of new therapies out there, there’s a third that’s hopefully going to come to market. It’s been slowed a little, at least in the diffuse large B-cell space, because of COVID-19 [coronavirus disease 2019] and inspection reasons. But yes, there are double engagers. There’s a CD19/CD20 drug being studied. There are natural killer [NK] cells—NK CAR T—at Loretta’s institution and many others that are being studied. It’s an exciting time to have all of these targeted therapies being explored. And then of course, maybe to wrap it up a little, how do you ultimately sequence or even combine these? Should we combine lenalidomide or other rational drugs to CAR T-cell therapy, whether during therapy or as maintenance therapy? So these are really exciting times, Ian, in follicular lymphoma, in terms of therapeutics.

Great. I think that’s exactly right. Let’s go around the bend here and get your final thoughts on things that you’re excited about. Thank you, Andy, for leading off. Loretta, what excites you most? Any final thoughts here this afternoon?

I think each year it’s better news for patients. We have more and more treatments that are effective. We’re getting better at managing the toxicity profiles of these drugs. My expectation is the bispecific antibodies will be approved, and they’ll probably move into combination strategies. And so, this whole argument of CAR T versus bispecific therapy will probably be short-lived. But again, good news for patients.

I think follicular lymphoma is one of the most heterogeneous lymphomas we treat. Just like Loretta said, having many different tools that fit our many different kinds of patients is what is really exciting about this.

And Caron, I’m going to leave you with the last word here.

It’s hard to follow a lot of these forward-looking comments in the field. I echo everyone’s optimism. With each year we have 2 or 3 new fields of therapy that are transforming the landscape. We have all been concerned about patients in the third line and beyond, and now we’re concerned about patients in the fifth and sixth line. That’s progress.

Perfect. Well, thank you again. And to our viewing audience, we hope you found this 

® discussion to be useful and informative.

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A panel of hematologists/oncologists remark on the transformations occurring in relapsed/refractory follicular lymphoma as newer, novel therapies continue to emerge.

Novel Therapies for R/R Follicular Lymphoma

Andy, I think we’d probably all agree that this is an exciting and evolving field, but who should be evaluated for CAR [chimeric antigen receptor] T-cell therapy? Also, equally important, who should not?

I was not an author of that study, but I can say I was as impressed as Caron was. They were fantastic data, and she gave a great presentation at ASH [the American Society of Hematology annual meeting]. I think it will immediately move ahead of any transplant, maybe for a young patient like we talked about with terrible disease.

To me, assuming we have bispecific antibodies in the near future, that’s going to impact a lot of the decision-making—CAR T, bispecifics. I’m not sure it would be ahead of R2 [rituximab/lenalidomide], but listen, I think this is where decision-making with the patient will factor in—shared decision-making. It at least looks as good as bispecifics, and looks at least as good, if not better, than R2 [rituximab/lenalidomide].

Also, this is a one-time treatment. Yes, it’s more aggressive. Yes, there’s more acute toxicity, and I don’t mean to minimize that at all. But you would talk to a patient and say, “Listen, you could be vein to vein in 3 weeks and be recovered 3 weeks after that.” Many of the other therapies we talked about are not just a year, sometimes they require indefinite treatment. So I think there will be different patients for different situations, but it will be another kind of treatment for use in our armamentarium to discuss with patients along the way.

I’m really glad you brought that issue up, about the CAR T cells. It’s good to have the problem of trying to figure out which is the best therapy here, based on having so many choices hopefully in the near future.

We spoke a bit about some of the obstacles of administering bispecifics in the community office. Although that certainly seems to be getting better with each year. Each publication, each update on the Mosun [mosunetuzumab] data looks better than the last about giving it in a safer manner. There are also real access problems in this country in terms of getting CAR T-cell therapy, whether it’s a financial barrier or a logistical barrier in getting patients to come to these larger centers. So it certainly would be a major step forward if we had bispecific antibodies that could be administered in the community that seemed to be approaching the efficacy that we’re seeing with CAR T-cell therapies.

With that said, Loretta, who are candidates and who are not for CAR T-cell therapies? It’s not the same as when you think of giving high-dose chemotherapy. It’s different. If you’re going to give a message to referring doctors, what do you tell them about when to send the patient, and what does that patient look like?

I think what’s different with follicular lymphoma as opposed to large B-cell lymphoma is we generally do have more time. And so, I don’t believe that argument that these patients are crashing before they can get to the referral center and get financial approval is as strong of an argument in follicular lymphoma. And in my opinion, any patient who’s beyond third-line therapy, because those outcomes are so poor even with some of our modern therapy, even the Mosun [mosunetuzumab] PFS [progression-free survival] wasn’t phenomenal. We’re still looking at about 11- to 12-month PFS. And so, I do think there is an argument to be made for CAR T-cell therapy, particularly in the fourth-line setting, for just about any patient.

Now, there are barriers. Sometimes there is a requirement for patients to relocate to another city. They have to have a caregiver. They have to be away from work and employment for a minimum of 4 weeks. Even in my practice, I recognize that there are patients for whom it’s just not feasible. I’m going to exhaust other therapies that don’t require as big of an impact on their day-to-day life.

But as Andy mentioned, it is a one-time therapy. So if you have folks who are willing to commit to it, I do think it probably gives us the best PFS we have available in that fourth-line or later space.

The other intriguing thought is, we could potentially even lead up to this with our PI3 kinase inhibitors and see if we could further impact that T-cell fitness. I’m a little bit more optimistic about that in follicular lymphoma, which might be contrary to others.

Yes, that’s an interesting thought. Caron, could you comment on T-cell fitness? Does it matter what line of therapy someone gets CAR T? I worry about treating with bendamustine and all of these other therapies that are tremendous T-cell depleters, much less the fitness of the therapy. Is there an art to the timing of giving CAR T-cell therapy in patients with follicular lymphoma, as well as making decisions based on prior therapy?

I wish I had data from ZUMA-5 to think about time from bendamustine, because I think that’s a really important point. In large B-cell lymphoma, we believe that collecting after earlier lines of therapy is a good thing. There are data that show those T cells do have a more attractive phenotype and have a better doubling time. That may mean they’re fitter and better cancer-fighting cells. In follicular lymphoma, most of our subsequent lines of therapy are not cytotoxic chemotherapy. Many of them are immunomodulatory in a favorable way.

I agree with Loretta, that even in follicular lymphoma you may find that the later you do it, the better it is. You’ll have more time from traditional bendamustine-containing chemotherapy. And actually, some of the agents that you may cycle through in between can actually improve outcomes. So stay tuned. We don’t have a lot of correlative science from these early phase 2 studies yet, but I think we’ll learn more in the coming years.

Yes, there are studies in other disease states looking at co-culturing the CAR T cells with PI3 kinase inhibitors to try to improve efficacy there.

Krish, I realize there are no head-to-head data, but do you think there’s a reason to use a 4-1BB construct versus a CD28 construct in follicular lymphoma? Is there any theoretical reason why one might be better than the other in that setting? Honestly, it’s ultimately the clinical data that are going to play out here.

Yes. I think your point is an important one, Ian, which is that the data will tell us. But I think if we kind of borrow the concepts that are applied in large B-cell lymphoma, we know that CD28 CAR T cells typically expand faster. There’s perhaps some increased cell kill, if you will, earlier on. The 4-1BB CAR T cells have more persistence. I think in a disease that we don’t cure, an indolent disease where, for example, not all of the clones that are present are perhaps present in the same immune microenvironment or are proliferating in the same way, this concept of persistence might have some differences. I think that’s speculative, but perhaps there is a reason to believe that CAR T cells that persist for a longer period in an indolent disease might be different than those that don’t. We’ll have to see.

Factors that should be considered when evaluating patients with relapsed/refractory follicular lymphoma for CAR T-cell therapy.

CAR T for R/R FL: Treatment Considerations

Loretta, I know your institution, The University of Texas MD Anderson Cancer Center, has used a variety of CAR [chimeric antigen receptor] T-cell therapies in follicular lymphoma. There was the ELARA trial that was presented at ASH [American Society of Hematology] in 2020 by Nathan Fowler. I don’t know if you had patients on that trial, but what is your take on that data? They were pretty exciting data as well.

I share Caron’s enthusiasm. We have both the ZUMA-5 and the ELARA study, and I saw similar things in that the response rates were quite favorable. The toxicity profile is also more favorable. I completely agree with her explanation that this is disease related and is not just us getting better at it. The durability is also very favorable. We don’t have the long-term follow-up we’d like to see to make this have a bigger splash in the treatment landscape, but I really think there is a role for CAR T-cell therapy for some of these patients with follicular lymphoma.

Do you foresee it changing, for instance, your use of autologous transplant or even allogeneic transplant in patients with follicular lymphoma?

Absolutely. At our center, for any patient who we’re considering a stem cell transplant, we will consider CAR T-cell therapy. I expect the allotransplants, particularly, to disappear.

Yeah. Krish, where do you see this therapy fitting in the landscape of treatment for patients with follicular lymphoma? We talked about the different groups of patients. We spoke about those who do well and tend to have a near-normal life expectancy, and those patients who unfortunately who don’t do well. Do you think it’s going to be used only for those early progressors or those people who are not responding, or can you see a more broad application of it?

In the short term, for that population of patients we’ve already talked about, who have poor-risk follicular lymphoma and POD24 [progression of disease within 24 months], if you look at the response rates and the outcomes for that group of patients compared with patients who didn’t have those features, it really does seem to be a remarkable therapy. It overcomes some of that poor prognosis. In the long term, as others have alluded to, we really want to understand whether this is a treatment that potentially cures a fraction of patients with follicular lymphoma. That alters this thinking about the risks and toxicity compared with the benefits. In the short term, it is probably among the most promising treatment options we have for patients with POD24. But in the long term, we’ll have to see whether there are other subgroups of patients for whom this therapy is the optimal choice.

Caron, Krish brought up an important thing. Is it too early to know whether there’s a plateau or not in these curves? You had only 17 months of follow-up, or something along those lines.

We know that it’s better than what we have available to us. We can say that at this point. We don’t know if there’s a plateau in this disease. What we do know is that some of the early, single-institution phase 1 first-in-human studies of these CD19 CAR T-cell therapies did treat some patients with follicular lymphoma, some of which are 10-plus years out. That’s proof of principle that a subset of these patients are going to be cured with CAR T-cell therapy. I just don’t know if it’s going to be 5%, 40%, 70%. I don’t know.

Implications for adding CAR T-cell therapy to the treatment armamentarium for relapsed/refractory follicular lymphoma in the near future.

CAR T-Cell Therapy for R/R Follicular Lymphoma

We’re going to change gears and talk a little about CAR [chimeric antigen receptor] T-cell therapies. We’ve now seen CAR T cells approved for large B-cell lymphoma and mantle cell lymphoma. There are a number of CAR T-cell therapies under investigation in follicular lymphoma. Caron, you presented data at ASH [American Society of Hematology Annual Meeting] on axi-cel [axicabtagene ciloleucel] in patients with follicular lymphoma—the ZUMA-5 study. Can you talk through some of that trial? Why is it being conducted? What results are being seen, and where do you see that therapy fitting in for follicular lymphoma?

This is a phase 2 open-label study of axi-cel [axicabtagene ciloleucel], which is an anti-CD28/CD19 CAR T-cell therapy that’s been approved for adults with relapsed/refractory large B-cell lymphoma. It leads to long-term remissions in about 40% of those patients. This has really become definitive and revolutionary therapy for patients who didn’t have other curative or successful treatment options. There’s no reason to think you can’t apply it to other CD19-positive diseases.

As we started discussing at the beginning of our discussion, follicular lymphoma is an incurable disease. While there are a lot of unmet needs in follicular lymphoma, 1 of them is the elusive cure. The hope is that by using immunologic therapies like allotransplant, although maybe a little safer than allotransplant, you could change the natural history of this disease.

The ZUMA-2 study looked at patients in the third-line setting. We spoke about PI3 kinase inhibitors leading to about an 11-month progression-free survival in that setting. We treated patients with a single infusion of axi-cel [axicabtagene ciloleucel].

The trial included both follicular lymphoma and marginal zone lymphoma patients, but when you look just at the follicular lymphoma cohort, the response rate was 94% with an 80% CR [complete response] rate. That’s probably 1 of the highest CR rates we’ve seen in this multiple relapsed/refractory setting. What’s more important is, of course, not the CR rate but the durability of response. The median follow-up for duration of response was 17.5 months. Looking specifically at 12 months, 72% of patients with follicular lymphoma remained responsive to treatment.

Of course, we need longer follow-up data in a disease like this to understand if this is a therapy that can equally change the natural history of this disease and transform outcomes for these patients in later lines of therapy, but the early results are very encouraging. These responses were seen across all risk groups, including the POD24 [progression of disease within 24 months] patients.

One of the most notable things about it is that we talked about CRS [cytokine-release syndrome] and neurological toxicity when we talked about the CD20 bispecifics. We know what the CD28 CAR T-cell therapies can do in large B-cell lymphoma, in terms of rates of high-grade cytokine release syndrome and neurological toxicity, but this had a more favorable safety profile than what we saw in large B-cell lymphoma.

The rates of grade 3 and higher CRS, which is ICU [intensive care unit]–level cytokine release syndrome, were only 6% in the follicular lymphoma cohort. The rates of grade 3 and higher neurological toxicity were about half of what we see in large B-cell lymphoma, about 15%.

From personal experience, these patients had a much easier course. The fevers started later and didn’t last as long, and many of these patients had no neurological toxicity. Overall, I’m very optimistic about where CAR T-cell therapies are going to fit in this landscape, but I may be a little biased.

You have to have the courage of your convictions. I want to just stick with you for a second. Is there a biological reason why there’s less severe adverse events in follicular lymphoma compared to large B-cell lymphoma, or are we just smarter and better at giving these—intervening earlier and getting better at administering the therapy?

There’s absolutely a biological reason. We know that high-grade CRS and neurological toxicity is increased in patients who have high pretreatment inflammatory markers. In our patients with follicular lymphoma, the pretreatment CRP [C-reactive protein] and ferritin and IL-6 levels are much lower than what they are in large B-cell lymphoma. The testament to that being disease driven is the fact that in large B-cell lymphoma, with axi-cel [axicabtagene ciloleucel] 95% of patients have grade 1 CRS with a fever. In follicular lymphoma, only 77% had grade 1 CRS. You can’t prevent the onset of CRS. We’re not good at doing that yet. If we were, we’d be better at managing this in large B-cell lymphoma. That speaks to the fact that with these patients, the disease interfaces with inflammatory response in a much less significant way than large B-cell lymphoma. Whether that’s microenvironment or the disease itself, I don’t know.

Caron A. Jacobson, MD, MMSc, of Dana-Farber Cancer Institute, comments on current data demonstrated by the ZUMA-5 trial in relapsed/refractory follicular lymphoma and the potential use of CAR T-cell therapy moving forward.

ZUMA-5 in R/R Follicular Lymphoma

I’m going to end this section by bringing us back to sequencing. Andy led off about this earlier. I don’t think any 1 patient is the same as the next, and we do customize our approaches based on age, comorbidities, and everything else. But I often start with chemoimmunotherapy—perhaps BR [bendamustine, rituximab]—as frontline therapy for many patients with follicular lymphoma.

If I have 1 go-to regimen for second-line therapy, it’s often an R2 [rituximab, lenalidomide] regimen. Maybe some of you agree or don’t agree with that approach. What about for those POD24 [progression of disease within 24 months] patients—who are progressing early, whose natural history of the disease suggests they’re going to have a major impact in survival compared with those who have a longer initial remission?

Andy, do you buy into that sequence for the non-POD24s? How do you modify your therapy, your approach in patients who do have early progression?

I have a similar overarching—I guess you could say treatment paradigm. That said, we always think about low tumor burden, high tumor burden. Sometimes you have these gray zone patients who don’t fit. They aren’t quite low, but they aren’t quite high. Maybe you’ll think about single-agent rituximab in this case. Besides that, yes, I agree.

Just to circle back to our discussion, Ian, about biopsies, we finally published our ECOG-ACRIN E2408 study. We tried to add bortezomib and lenalidomide to BR [bendamustine, rituximab], and it was a negative study from that standpoint. The PFS [progression-free survival] was not improved. Actually, trying to give 20 mg of lenalidomide right on the heels of full-dose BR [bendamustine, rituximab]—6 cycles—was tough. There were a lot of cytopenias.

We looked at POD24 patients. Among the patients in this follicular lymphoma frontline study with POD24, almost all of them were biopsied and half had transformed. That’s something that is always important to consider. They would require different treatment, as we talked about, if they are transformed. Let’s say they’re not transformed. Then our approach would be similar to what we talked about. We would at least think about autologous stem cell transplant. If that’s not an option for 1 reason or another, I would really look at targeted therapy. There is an ongoing national study looking at PI3 kinase–based therapy, and that would be a valid option as well.

Approaches to sequencing therapy for patients with follicular lymphoma who experience progression of disease within 24 months (POD24).

Treating Follicular Lymphoma With Early Progression

Andy, let’s turn the discussion to new agents that are being developed in follicular lymphoma. We’re going to talk at length about CAR [chimeric antigen receptor] T cells in a few minutes. Aside from CAR T cells, what are some of the other exciting things that you’ve seen? There were a couple of publications on bispecific antibodies at this year’s ASH [American Society of Hematology Annual Meeting]. What’s your take on that data, and how likely is it that these agents are going to be used?

The data for bispecific antibodies are extremely encouraging. As you said, what does 

 mean? It’s a fully humanized CD20xCD3 bispecific antibody, so it is attaching to the CD20 B-cell lymphoma and then attracts T cells to hopefully engage against the lymphoma. You mentioned ASH. I don’t think I’ve ever seen so much about this topic at ASH. There was 1 session that presented on 4 different bispecifics, back to back to back to back. Four different products, and they were all similarly efficacious. Rutgers Cancer Institute of New Jersey has helped lead the Regeneron Pharmaceuticals, Inc product. Dr Rajat Bannerji has been a part of that.

There are 2 others I’ll highlight. One product is mosunetuzumab, the Roche product. You might recognize that. That was presented in CAR T failure at ASH 2019. The UPenn [University of Pennsylvania] group led that and Dr Stephen Schuster.

In follicular lymphoma, these are incredibly active. Looking across all 4 of the drugs, we’re looking at an overall response rate from 70% to 100% in some of the studies in follicular lymphoma, with a fairly decent CR [complete response] rate—some rates over 50%.

Another compound is epcoritamab. What’s unique about this drug is it can be given subcutaneously. That can be of some potential benefit. Someone might ask, “What about CRS [cytokine-release syndrome], neurotoxicity, etc?” It is seen with these bispecifics, but as someone who’s probably put 10-plus patients on at least the Regeneron product, the rates of occurrence are markedly less. And this is mostly, if not completely, an outpatient treatment.

I’m glad you brought that up about: the outpatient therapy. Loretta, it’s 1 thing to do something at The University of Texas MD Anderson Cancer Center. But to treat in community oncology offices around the country, how low does the AE [adverse event] profile need to get for a community physician to feel safe treating patients with the drug in their offices? It’s not a big deal for us to have a little CRS. We can easily handle it. But I’m not sure that’s true in some of these other offices.

The critical thing is how you’re going to handle that toxicity. If you need to administer something like tocilizumab, it’s probably a deal breaker for most community and even academic centers. If it’s infusion-related symptoms such as fever and chills, these can be monitored and managed with something like Tylenol or Benadryl. That’s a much different scenario from a patient who needs to be in an inpatient unit monitored, potentially needing things like tocilizumab or even ICU [intensive care unit] care.

Those subtle differences are hard to tease out when you’re looking at the rates of grades 1 to 3 CRS. More important, we need to know what strategies were employed to really manage some of these toxicities. Any strategy that can be employed that will reduce the rates of grade 2 or higher CRS is critical, such as more aggressive premeds with dexamethasone, these ramp-ups, or these debulking strategies. All those need to be explored and need to be very effective before you can roll this out to larger centers.

Yeah, that’s true as well. I was impressed with some of the data in terms of looking at the neurotoxicity. For instance, when reading the details for mosunetuzumab and X-number of patients with neurological toxicity, insomnia was considered a neurotoxicity. So we’re probably overestimating some of that from what we would really think of as neurotoxicity.

Were there other agents that we haven’t talked about that are in the pipeline and are coming? Krish, is there anything that you think is really exciting that’s going to make its way through the developmental pathway in the next few years to treat patients with follicular lymphoma?

Yeah. There are a number of immunotherapy approaches that look pretty exciting. Regarding what we’ve been involved with that seem exciting to watch for are the use of anti-CD47 agents, so-called macrophage checkpoint inhibitors. They certainly seem to be well tolerated and have some meaningful activity in a broader array of lymphomas, including follicular lymphoma. In particular, other cellular therapies like natural killer cell-based therapies look exciting. These are another potent platform to use. Immunotherapy approaches, at least from the early data that have been published for small studies, seem to have a very distinct toxicity profile from T-cell–based immunotherapies.

 Caron, what about BCL2 inhibitors? You think of a disease that was set up for a BCL2 inhibitor to work well in, but so far we haven’t seen a lot of data on using venetoclax, at least as a single agent, and sometimes even with the combination of bendamustine and rituximab. It doesn’t really add much to that. Do you think that’s true as a class? Or is there anything else that’s in development for antiapoptotic approaches?

I think you’re right. The single-agent data look as though it leads to meaningful responses in about 20% of patients. But those patients who do respond actually have quite durable responses, and some of those responses last 2 or more years. This gets to the point that Loretta made earlier, which is that we really are lacking biomarkers to understand who’s going to respond to which therapy. I would hate to throw away a whole class of drugs for a group of patients who could get an average 2 or more years’ remission duration from them. There’s more to understand for drugs like venetoclax in this disease, in terms of patient selection, but it doesn’t seem to be a blockbuster drug as we would have expected. The biomarker is not the 14;18 translocation.

Yeah, I was sort of taken aback. I didn’t predict that was going to happen with that drug in that disease.

An overview of novel therapies under investigation for the treatment of relapsed/refractory follicular lymphoma and special considerations regarding treating patients with newer, novel agents in the community setting.

Ian Flinn, MD, Sarah Cannon Research Institute

Articles

Novel Therapies for R/R Follicular Lymphoma

CAR T for R/R FL: Treatment Considerations

CAR T-Cell Therapy for R/R Follicular Lymphoma

ZUMA-5 in R/R Follicular Lymphoma

Treating Follicular Lymphoma With Early Progression

Emerging Therapies for R/R Follicular Lymphoma