: To wrap up, Dr. Lunning, what has been your real-life experience with these patients with POD24 [progression of disease within 24 months]—do you recommend CAR T or bispecifics or transplant for those high-risk patients?

: Yeah, I think that it’s about sequencing and putting the best therapy that you think is going to be impactful to changing the paradigm of their disease. Because you don’t know about it when you’re first treating them. You only find out about POD24 within 24 months after the start of their therapy. That’s where you have to be very strategic. Right now with all of the therapies we have, I don’t know that they’re mutually exclusive. That one is going to rule out the other, so I have been thinking that bispecifics may come before CAR T in this scenario. I still think that lenalidomide could potentially come before bispecifics. I think there is some data to show that with R-squared you can get longer therapy or duration of responses than you did with the first line. And so, in a person [with whom] you’re trying to plan for decades, not for 2 years, of further of their life, like the case you described, the 53-year-old, you want to get them into their seventh decade of life. That’s part of the discussion. I’m laying out the table and playing the chess match against their disease. I don’t think that you always have to play the same piece all the time. Each patient has to understand the risk and the benefits of what you’re doing.

: No, no, that’s great. Well, thank you so much, Dr. Lunning, for this very insightful discussion. To our viewing audience, thank you for joining us today. We hope you found this 

® My Treatment Approach program to be useful and valuable to the management of your patients with follicular lymphoma. Thank you very much.

Videos

Key opinion leaders Sameh Gaballa, MD, and Matthew Lunning, DO, FACP, consider the evolving treatment landscape of follicular lymphoma and look toward future evolutions in the field. 

Relapsed/Refractory Follicular Lymphoma: Future Directions in Care

: Let me run a patient scenario by you. So, a POD24 [progression of disease within 24 months], for example. Again, POD24 [refers to] patients with follicular lymphoma who have disease relapse within 2 years of chemoimmunotherapy. For example, a patient walks in, they’re 53 years old. They were previously treated with rituximab bendamustine for bulky retinopathy above and below the diaphragm. Most of the SUBs were below 10. Patient had an excisional biopsy. At that time, there was no evidence of large cell transformation. They received 6 cycles of bendamustine rituximab. However, 18 months later, they noticed the cervical retinopathy with anemia and thrombocytopenia. Workup reveals that, again, they have bulky relapse with adenopathy above and below the diaphragm, now with bone marrow involvement as well. One of the concerns in these patients is to rule out transformation. For those who have disease transformation, that’s a different story because we would treat them similarly to how we would treat diffused large B-cell lymphoma. But, if indeed this is follicular lymphoma POD24, how do you treat those patients and do you treat them any differently? And maybe we could comment about the role of transplant as well.

: So this is a real case. It just happens in the minority of patients. I think POD24 was listed at 20% of potential follicular lymphoma population. I honestly believe that is probably really 2% of all follicular lymphoma patients. It’s just a log lower from that standpoint. That is what it is. You know, the case that you alluded to is a real deal. You can’t predict them when you started the BR [bendamustine and rituximab] of who’s going to be in this situation and who can’t. I think that’s been the crux of a lot of the matter of how to study this population. Coming back to how I would treat this patient, really is, do they need treatment? This patient does. But there are some patients who relapse who may not, who may go a year or 2 more without needing therapy for low-burden asymptomatic disease. This patient has cytopenias, they have bulky retinopathy, like you said, probably meeting GELF [Groupe d’Etude des Lymphomes Folliculaires] criteria. In this situation, again, I was alluding to the trial, which is looking specifically at this population, but even off of that trial, I think obinutuzumab [and] lenalidomide would be a reasonable option. R-squared would be a reasonable option. We really don’t know what obinutuzumab CHOP [cyclophosphamide, doxorubicin, vincristine, and prednisone] or what CHOP after BR does in relapsed/refractory follicular lymphoma. But to your question about transplant, really this is where you have that discussion. 

There has been CIBMTR [Center for International Blood and Marrow Transplant Research] data looking at transplant within the first year in the POD24 population [who] may derive benefit, but I think it is that time where it’s a go or no-go discussion. I know that transplant has fallen out of vogue because of CAR T cells and bispecifics coming. I still think off of a clinical trial, I’m using R-squared on a clinical trial. I’m looking for a combination that has a lenalidomide backbone in this population. Is O-chemo [obinutuzumab plus chemotherapy] a wrong answer here? I don’t think it is, but I think you’re still asking that question after 2 to 4 cycles. Should I consolidate with an auto transplant in this scenario? Because this is a young person where, in my opinion, you’re trying to get more time with their second-line therapy than you did with their first. So that’s what the conversation I’m having is—you’re battling against that disease biology, which is the law of dimension returns, right? First line is longer, second line shorter, third line shorter. You’re trying to be impactful at the second line [where] you’re getting a longer period of time than you did with the first-line treatment. What that strategy is can differ. It’s a very long discussion, and these consultations are not in 20 minutes.

: No, definitely not. My personal position on transplant is, so for follicular lymphoma, it’s not a curative treatment. I mean, allogeneic transplants, you certainly see a plateau in the curve and the relapse is lower. There’s certainly some cure. But with autologous transplant it’s not going to be a curative intent treatment. 

So, I personally would go for CAR T prior to an auto transplant. But transplant is certainly an option, particularly in patients with POD24. Patients who are younger, and who have high risk disease, sometimes I can even consider allogeneic transplants. But these are patients typically [whose diseases] failed CAR T, have failed bispecifics; these are higher-risk patients. In terms of the CAR T data, we have 2 approvals. We have axi-cel [axicabtagene ciloleucel], we have tisa-cel [tisagenlecleucel]; as you had mentioned, there is the [phase 3] ZUMA 22 study [NCT05371093], which we have at our center, which will randomize patients with relapsed follicular lymphoma as early as second line for POD24, to standard of care chemoimmunotherapy or R-squared versus CAR T-cell therapy, in this patient population. But I agree with you, it’s going to take a number of years before we get a readout, particularly [for] these patients with POD24, [who] only represent about 20% of patients with follicular lymphoma. I think the other interesting approach in these patients is bispecific antibodies. We’ve all seen the data with mosunetuzumab, which again, is now approved. We have response rates close to 80% with about a CR of 60%. But again, we need longer follow-up on the data. Same thing with the iCAR [inhibitory CAR] R-squared, which looks, again, very interesting and results were just updated at this ASCO [American Society of Clinical Oncology meeting].

Centering discussion on a second patient scenario of follicular lymphoma, key opinion leaders consider best therapy for patients with early or aggressive relapse. 

Patient Scenario 2: A 53-Year-Old Man With Relapsed/Refractory FL

: Having talked about the different options and the relapsed/refractory setting, we now have CAR [chimeric antigen receptor] T-cell therapy, we have bispecific antibodies. Copanlisib is still available. [The] PI3-kinase inhibitor tazemetostat is available, which is an oral therapy. So could you elaborate a little bit more about which patient profiles would fit in tazemetostat? Are we looking here for efficacy or safety? Do you look at the 

 mutational status? There’s also been recently a comparison—a propensity score matching of the patients in the trial [who had 

 wild type. Because, as you remember, the problem with the study was that the patients on the mutant arm or the 

-mutant arm were very different, and then [there were] those who were easy to wild type. Could you give us your thoughts in a nutshell?

: I think that tazemetostat certainly is an option in follicular lymphoma. It’s just finding the right patient in the right situation where that drug can be used. I personally see tazemetostat as a drug that you would be using when you’re trying to gain confidence in a patient who’s coming off a prior regimen that you thought was going to work in follicular lymphoma, but they had intolerance or an adverse event that led to the withdrawal, yet they still need another line of therapy next. I think that’s the advantage of tazemetostat, its toxicity profile is there, and it does have the potential for not only efficacy but durability, if efficacy is seen. I agree with you with the match, with the propensity analysis. 

It really, again, is what drove me to maybe stop checking for 

 mutational status, because if I’m going to use the drug, I’m going to use the drug, but we are going to watch. I think you have to watch out for dysgeusia with tazemetostat, asking them how [they are] eating, and monitoring…quality of life issues. Because it is a population, like I said, that where I’m kind of dipping my toe into the rituximab isn’t working anymore as a monotherapy, but your follicular lymphoma needs treatment because it’s impacting your quality of life. But I do think it’s that therapy, but I also think it is a [variable] regimen. So I think that it is something that can be combined with other agents. Is it going to be the main course? Probably not, but it’s a good dessert to the regimen. Sometimes dessert still can taste good and can be impactful to the disease durability, so I see it as a drug that not only can be used commercially, but also in the clinical trial realm, perhaps as a maintenance therapy or after a bolus of a lead-in, whether or not that’s bispecifics, [lenalidomide-rituximab], so on, and so forth.

: Previously in terms of patients who require, who’ve asked for oral therapies for different reasons, we had some of the PI3K [PI3-kinase] inhibitors in this setting, although the toxicity was a concern. But now, most of the PI3K inhibitors are not available; the only PI3K inhibitor for follicular lymphoma that’s still available would be copanlisib. Although [there was] the copanlisib-rituximab trial, the company’s not moving forward with trying to get it approved. It may change in the future, but I think one of the issues with the PI3K inhibitor class as a [whole] was toxicity. We’re seeing some autoimmune manifestations, colitis, pneumonitis. Some of them were intravenous, like copanlisib, for example. They were having some issues with hyperglycemia or hypertension. So I think a lot of patients at this time are either thinking of bispecific antibodies, CAR T-cell therapy, tazemetostat, or, if they’ve not seen rituximab-lenalidomide previously, that’s still obviously one of the options.

A brief discussion on the respective roles of EZH2- and PI3K-targeted therapies in patients with relapsed/refractory follicular lymphoma.

Relapsed/Refractory Follicular Lymphoma: EZH2- and PIK3-Targeted Therapies

: Let’s now review the options available for patients with relapsed/refractory disease. Over the last 2 or 3 years, we’ve really had a lot of changes. In terms of the options available, as we discussed previously, you could rechallenge again with single-agent rituximab, obinutuzumab. There is chemoimmunotherapy. So a patient, for example, who’s had R-bendamustine could get R-CHOP [rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone] again. But again, my personal approach for these patients is [to] typically reserve the R-CHOP for patients where I’m suspecting disease transformation. For patients with relapsed/refractory disease, the most common regimen that currently I use is R2 [lenalidomide and rituximab] in the second line, and that’s based on the AUGMENT [trial; NCT01938001] data. The results have been updated at the last ASH [American Society of Hematology] meeting, and there’s now an overall survival advantage. Not all patients are going to be good candidates for R2. Patients with renal impairment, for example, or some patients who are elderly or infirm. For those patients, I may recommend something like [tazemetostat] in the second line just because of its superior safety profile. In the third line and beyond, we’ve now had mosunetuzumab, just approved in December in the US. It was previously approved and available in in Europe. CAR [chimeric antigen receptor] T-cell therapy is also available for these patients. We have axi-cel [axicabtagene ciloleucel] and we have tisa-cel [tisagenlecleucel], but that patient profile typically is patients who [maybe have] more high-risk disease, younger patients [who are] expected to have a long survival, and you might want to proceed with a therapy that provides you the longest remission duration. Bispecifics are interesting because we’ve all seen the data where with mosunetuzumab, we need longer follow-up. 

There is data for [INAUDIBLE] as well combining it with lenalidomide, and the results look very interesting. As a matter of fact, they look very close to what we’re seeing with CAR T, but the problem is the follow-up duration is still short. It was just updated at the annual ASCO [American Society of Clinical Oncology] meeting, but we need longer follow-up to really try to tease out where will this treatment really fits. I see in the not-so-distant future where bispecifics, either alone or combination with other agents, would be used in earlier lines in follicular lymphoma, even before CAR T. That’s very different than diffuse large B-cell lymphoma, because in diffuse large B-cell lymphoma, we’re trying to cure their disease. Right now, the most data that we have is really with CAR T. But as we get longer follow-up for patients on bispecifics, I think that will help clarify that question. What has been your approach for these patients with relapsed or refractory follicular lymphoma?

: I think that I have tried to be a steward of the POD24 [progression of disease within 2 years] concept, but truly the POD24 [patients who] are progressing within 24 months of the start of their therapy. I’m not classically scanning them. It’s the person at a year after therapy, so at about 18 months, and they’re coming in and their disease is coming back, that in my mind is a real POD24, and I’ve tried to put them on the SWOG trial or have the discussion about the SWOG trial. Let’s say they got BR [bendamustine plus rituximab] first. That’s a randomized trial now with obinutuzumab, lenalidomide versus chemo, and we still have this discussion, right or wrong, about [autologous] transplant consolidation. The sweet spot is in their second line, where we, at least historically, at our own institution has have seen plateaus on that curve. Obviously, it’s a different era now with many more therapies than that. I think that if you’re going to have that discussion, it should be done in the second-line setting, from a clinical trial. I think R2 is the backbone for me, either off a clinical trial, because the data has shown that POD24 really hasn’t mattered necessarily in that setting to the opportunities for long-term disease benefit. But if they’re not on a clinical trial, which is R2 plus something, whether it’s tazemetostat or epcoritamab, as you alluded to from the Merryman abstract from just this year at ASCO, which looked very impressive. 

Where are we going? There’s also the discussion about CAR T-cell and where is that going to fit into the equation? I 100-percent agree with you. I think [epcoritamab or epcoritamab-mosunetuzumab]; those trials are going to jump ahead of CAR T-cell in follicular lymphoma, whether or not it’s single agent or if it’s in combination. CAR T-cell [therapy is] going to be reserved for that patient who still has follicular lymphoma on a biopsy but is behaving like a large-cell lymphoma, or, very rarely, probably less than 5% of follicular lymphomas are double refractory, right? You got their BR [bendamustine plus rituximab] and they still had progressive disease, and then they got R2 and they didn’t respond. In my mind, that’s a CAR T-cell patient, especially after I biopsied them probably both times, and it’s still follicular lymphoma. So I know the real-world data is out there from Caron Jacobson and colleagues showing that we can get people the CAR T-cell [therapy] in the real world. In the real world is completely different than the clinical trial world in lymphoma, just in general about how you get people to CAR T-cell [therapy]. But also I think it’s going to be a challenge. ZUMA-22 is coming up, it’s a [phase 3] planned trial [NCT05371093] looking at axi-cel versus standard care and relapse/refractory follicular lymphoma. That’s going to be a trial that’s probably going to take years to read out, right? Because it’s a clinical trial population, and it’s probably going to be the population that can wait to get on a clinical trial. So I think there are a lot of moving pieces on the chess board right now in follicular lymphoma, and I don’t think we know when to move the rook and when to move the bishop, but it’s a fun situation to be in where we have a lot of therapies to offer our patients when they are in need of therapy.

Switching focus back to relapsed/refractory follicular lymphoma, Sameh Gaballa, MD, and Matthew Lunning, DO, FACP, consider the list of available treatment options in this setting.

Relapsed/Refractory Follicular Lymphoma Treatment Armamentarium

: This is an area where there’s a lot of heterogeneity in terms of practice. What do you do after you’re done with induction? You get an end-of-treatment PET and the patient is in CR [complete response]. How do you monitor these patients? How often do you get imaging? I agree with you, in the real world, there is a lot of heterogeneity. I’ve seen referrals come in with patients who’ve had scans every 3 months for several years. But for me personally, I agree that less imaging would be my approach. Because this is not a disease where if you catch it early, it’s going to necessarily change your treatment algorithm if the patient is asymptomatic. So what I’ve done is at least maybe every 6 months, maybe for a year or 2, and then afterwards, it’s either maybe an annual scan or just scan on an as-needed basis. A lot of this is driven by a discussion with the patient because different patients will have different attitudes about monitoring. Again, we explain to them that even if there’s…[a] relapse, we would not jump to treatments right away. But some patients want to feel more in control. For those, if they’ve been in remission for a year or 2, typically, I would say, Well, we could get imaging maybe not more than annual, and others [are] OK with doing an as-needed scan. So this is an area where there are, again, a lot of different approaches in the real world, and [it] also depends on how the patients take it. In terms of maintenance therapy, there have been randomized studies—maintenance treatment does have better PFS [progression-free survival] and a longer time to next treatment. But again, the survival is the same. In the era when we had COVID-19, I basically stopped all maintenance therapies. Previously I used to discuss the risks and benefits, and I’ve certainly seen risks from maintenance therapies including increased infection risks, and some of these infections can sometimes be serious. So at this time, I do not recommend maintenance therapies again because of COVID-19 and increased infectious complications. But we used to do it more often prior to COVID-19.

: Yes, I agree with you. I pulled almost all of my patients off maintenance rituximab in follicular lymphoma. I think the 1 scenario, outside follicular lymphoma, where I still have the conversation is in mantle cell lymphoma, especially after an auto transplant, but different disease, different beast in some situations in regard to non-Hodgkin lymphoma and its occult management. I agree with you, though, about scans. Scan anxiety lives on the spectrum. You have patients who fear that they aren’t watching it and want to scan, and you have people who just walk into the room or the building that they’re going to have a scan and are [vomiting] and need their Zofran because they’re so concerned. But if you don’t do a scan, they’re fine. So this is where the relationship in these follicular lymphomas—which, yes, it’s a lifelong condition, and you can remember the patients who surpass with follicular lymphoma because your goal, as their oncologist, is to have them live with their follicular lymphoma and only treat it when it’s impacting their quality of life. If it transforms, then that’s one of those prognosis-changing events, but that’s where our job is following their follicular lymphoma to look for what triggers that biopsy that shows transformation. That’s just a whole different beast in itself and where our therapies evolve in this situation. So it’s one of those things like, Why do you have to see me? And it’s like, I have to see you because I need to make sure that you’re not—I’m always walking in the room going, Is this patient transforming? And do they need a scan? And that’s why we see [patients with] follicular lymphoma even when they’re years out from their initial therapy.

Before closing out their discussion on first-line management of follicular lymphoma, experts consider the importance of patient monitoring and discuss the diminished role of maintenance therapy.

Follicular Lymphoma: Patient Monitoring and Maintenance Therapy 

 One of the areas of follicular lymphoma that I was surprised about, since we’re talking about oral therapies, has been the ROSEWOOD trial, which looked at obinutuzumab and zanubrutinib in relapsed/refractory follicular lymphoma. I saw this as a dark horse trial, like something you really didn’t see coming, and then you saw the data and you’re like, “Well, this is very interesting.” Because we had expected that ibrutinib should work, and then it didn’t. But then we come around to zanubrutinib, a next-generation BTK [Bruton tyrosine kinase inhibitor], perhaps a bit easier on the AE [adverse event] profile, and then partnering it with obinutuzumab in a randomized trial, I was taken aback. So it’ll be interesting to see, I know that’s going further into clinical trials, if a BTK can add or fill the gap that it appears that PI3 kinase inhibitors are leaving. I’m not too much of a user of copanlisib right now, just because of its schedule. It reminds me a bit of like romidepsin, where you’re multiple weeks on and it’s IV [intravenous]. In this patient scenario, they’re traveling a distance, it’s a lot to ask to get IV therapy. I don’t know your thoughts on where BTKs may end up in follicular lymphoma, is there going to be room?

 I completely share your excitement here. I did not see this coming. We’ve all seen the ibrutinib data in follicular lymphoma. It does work, it’s just that it hasn’t been as exciting as we would have thought. The data with zanubrutinib, although it was a smaller randomized phase 2 study, not a phase 3 study, the PFS [progression-free survival], there’s certainly an advantage there in zanubrutinib. The question will be, are we going to see a more confirmatory trial, a phase 3 trial, to try to tease out that question? That combination, it would make a lot of sense, not just in follicular lymphoma, but also marginal zone lymphoma, where zanubrutinib is approved in the relapsed setting. But combining it with obinutuzumab is certainly a combination of interest there. Yes, the more options we get to fill the gap of PI3 kinase inhibitors, that will be a welcomed change. At this time obviously it’s still not approved. But the data look very interesting from the ROSEWOOD trial, and it’ll be interesting to see.

A brief review of BTK inhibitor therapy and its potential role within the relapsed/refractory follicular lymphoma treatment landscape. 

Role of BTK Inhibitors in Relapsed/Refractory Follicular Lymphoma

 Let me give you a patient scenario. Let’s say you get a patient who’s in their 80s, for example, an 83-year-old. They come in, they were diagnosed with low grade follicular lymphoma, grade 1 or 2, 3 years ago. At that time they got rituximab single agent, they had relatively bulky disease. They achieved a PR [partial response], and they’re stable for the next 2 to 3 years. But now they’re slowly progressing for the last year. Say they’re symptomatic, they have lower extremity edema from pelvic adenopathy. This patient, say they’re elderly and they live far away from an academic center. What would be your approach for such patients? Would you consider single-agent rituximab again, obinutuzumab, or an oral therapy? How do you treat these patients?

 That’s a very practical case scenario in follicular lymphoma. Not all follicular lymphoma is bad follicular lymphoma that’s rapidly progressing when you’re sitting here asking yourself, is there transformative disease? But you can have that slow, insidious follicular lymphoma, as you alluded to here, which in patients, we have to remember that the median age is in the late 60s, early 70s. These patients’ odds are that they’re going to die with their follicular lymphoma, not of their follicular lymphoma, but still it could be quality of life altering, as it is in this patient. So looking at this subject, who got rituximab monotherapy and had disease control, but as you would expect, coming out of our monotherapy had some residual adenopathy. Then you’re asking the question, is it still behaving like a snail, or is it transforming into a cheetah? From the case description, I always ask myself, do I think this patient is transforming? Because that sets the tone for the discussion, and it sounds like it’s still acting like a snail, but even snails can cross the treatment finish line again.

In regard to using rituximab monotherapy again, I’m a bit hesitant, just based upon the RESORT [trial] data, that I’m going to get good mileage out of rituximab again. In the second and the third line, you do see the law of diminishing returns with rituximab. It’s not to say that it can’t work, but I wouldn’t use it to say that we’re going to get a couple more years out of rituximab again. So then do you partner something with rituximab or switch to obinutuzumab-based combinations? Or is there a different therapy that could be well tolerated in that case? If I’m thinking about adding something to a CD20 backbone, I think that lenalidomide, as in the AUGMENT [study], would be a reasonable discussion, but I think a lot of the toxicities are driven by the lenalidomide. In an 83-year-old individual, I would pay very close attention to their creatinine clearance. In the AUGMENT trial, patients were allowed to go on the study if their creatinine clearance was less than 60 [mL/min], but you had to dose adjust lenalidomide appropriately from 20 mg down to 10 mg. Truly, there’s a right dose for everybody for lenalidomide. I’m just not sure in follicular lymphoma that it’s always 20 mg. Patients better tolerate it if they’re appropriately dosed for their lenalidomide, understanding that now we can go all the way down to 2.5 mg based upon our NDS [National Drug Control System] availability of that dose. That would be part of the discussion.

The other discussion truly is tazemetostat in this population of a patient who wants an oral therapy that, based upon the data and the clinical trials, could be well tolerated and could have the potential for activity. One of the things I find interesting about tazemetostat is when patients are progressing, it doesn’t appear to be transformation that they’re progressing with, it appears to just be their follicular lymphoma. I don’t think you lose anything or you take anything off the table by giving tazemetostat, or sequencing it as R-squared [rituximab and lenalidomide] followed by a plan of tazemetostat. Still it sounds like this patient might be a clinical trial candidate, if they’re willing to travel for some sort of trial from that standpoint.

 I completely agree, Dr Lunning. These patients are always not the same, you have to personalize each decision. Just as you mentioned, patients could come in with comorbidities, or they could be coming in like an 83-year-old patient, but functionally speaking, they’re functioning at a much younger age. Or they could have a lot of comorbid conditions that make us try to think about which treatment is appropriate for such a patient. In terms of single-agent therapy, obinutuzumab can sometimes be an option as well for these patients. This patient technically is not rituximab refractory, but exactly as you mentioned, you get diminishing returns with each subsequent line of therapy. Sometimes what you need is more of a stable disease. Although with this patient, I agree with you, you probably want to be a bit more aggressive since they’re symptomatic and you need to shrink their lymph nodes because of the lower extremity edema. I completely agree, something like tazemetostat oral therapy can be an option here as well, if the patient wants an oral therapy, they don’t want to come in for infusions, they live a bit far away from an academic center or from a local oncologist. Bispecific antibodies probably will have a role there. For the elderly patients, at least the CRS [cytokine release syndrome], particularly within the first 2 cycles, we’ll have to think about how do we care for these patients in the community? At this point, at least where I’m practicing, the bispecifics are still done more at academic centers, but I see in the near future, these treatments being done within the community setting as well.

 I agree with you. I think that bispecifics are going to have a steep learning curve. There are some institutions who learn through the clinical trials and are adapting it to the commercial environment very well. But the slope of that curve will flatten over time as it gets out there and you dip your toe into the water with the appropriate risk-benefit patient, and then we’ll see the full impact.

Centering discussion on a patient scenario of relapsed/refractory follicular lymphoma, key opinion leaders consider how they would select best available therapy in this setting.

Patient Scenario 1: An 83 -Year-Old With Relapsed/Refractory FL 

 Dr Lunning, this is a good segue into my next question here, which is, how do you see the management of relapsed follicular lymphoma evolving? Now we’ve been getting more and more approvals. There are more options now, including approvals for bispecific antibodies, we have CAR [chimeric antigen receptor] T-cell therapy, we have chemoimmunotherapy. When you get a patient with relapsed/refractory follicular lymphoma, what’s typically your approach?

 It depends upon how they’re relapsing and what they received in the first-line setting. I’ve characteristically used chemoimmunotherapy, typically bendamustine and rituximab, in the front line. I haven’t used a lot of obinutuzumab backbone in the first line, despite the GALLIUM study data. I haven’t been as big of a fan, going through and coming out of COVID-19, of maintenance rituximab, even in a metabolic CR [complete response] coming out of induction chemotherapy. Coming back to the to the relapsed/refractory setting, I am a believer in POD24 [progression of disease within 24 months from diagnosis], if you follow the POD24 characteristics. Over time, the POD24 designation has been watered down in the relapsed/refractory setting, where it wasn’t quite following the original paper by [Carla] Casulo, [MD]. It was very hard to tease out that population of patients who truly fit that higher risk relapsing disease. But if you do have a patient who received chemoimmunotherapy and their disease is telling you it’s coming back within a year or two, or they’re relapsing on maintenance rituximab, if you so choose to give it within 2 years from the start of therapy, I think that may color my discussion with the patient. But if they’re having asymptomatic relapses at 3 years, I’m not too keen on moving them into therapy, until they prove that they need therapy again.

I’m very conservative in the relapsed/refractory setting. I have characteristically used lenalidomide and rituximab, especially if I’ve used chemoimmunotherapy in the front line, as my second-line therapy, especially off of an AUGMENT [study]-like approach if they are rituximab sensitive. I do think that lenalidomide has a nice fit there. Obviously, clinical trials are quite appealing right now in the second-line setting, in regard to tazemetostat combining with lenalidomide in a randomized trial. I know there are bispecific trials moving into the second line. Also, I think that bispecifics will eventually challenge in the frontline setting. Are we seeing the evolution like we did in CLL [chronic lymphocytic leukemia] with putting novel therapies before chemoimmunotherapy? Are we just going to be slightly delayed in follicular lymphoma by 5 to 10 years before we are looking at getting to these chemotherapy-free regimens? When you talk about chemotherapy-free, you’re talking about your classical chemotherapies, like your CHOP [cyclophosphamide, doxorubicin, vincristine, prednisone], your bendamustine, and whether those are getting pushed further and further aside. I really like the movement that’s happening in follicular lymphoma. I think we’re approaching this in a very unique way.

A broad view of the current treatment paradigm for relapsed/refractory follicular lymphoma and how the field has been evolving. 

Evolving Treatment Landscape of Relapsed/Refractory Follicular Lymphoma

 program titled, “My Treatment Approach: Expanding Treatment Options for Relapsed/Refractory Follicular Lymphoma.” I’m Sameh Gaballa. I’m an associate member at Moffitt Cancer Center, in the lymphoma section within the department of hematological malignancies. I’m joined today by my colleague, Dr Matthew Lunning. I would like to welcome him to introduce himself.

: Thanks. Matt Lunning, from the University of Nebraska Medical Center. I’m an associate professor here in the division of hematology oncology.

: Welcome and thank you for joining me. Today, we’re going to discuss approaches to treating patients with follicular lymphoma. We will present 2 hypothetical clinical scenarios and discuss our treatment plan to illustrate how we incorporate some of the recent data into our practices. Let’s get started.

: Dr Gaballa, we know that follicular lymphoma is our most common indolent lymphoma. Many times this disease lives on a spectrum, from being incidentally diagnosed based upon a CT scan done for some other reason, or patients come in with symptomatic bulky disease, and on a biopsy it’s follicular lymphoma. We’ve seen a lot of movement in the NCCN [National Comprehensive Cancer Network] guidelines around follicular lymphoma. Has your testing for newly diagnosed follicular lymphoma changed at all with the recent NCCN guidelines?

: Thank you, Matt. In terms of newly diagnosed patients, we have not been testing for 

 mutations. Even for the relapsed/refractory setting, the recent NCCN guideline updates back in March, they don’t require it at this time. That makes a lot of sense because if you think about it, the situations in which you’re going to need to know what the 

 status is are very limited. For example, if you have someone coming in who’s older, in the second or third line, and they’re not going to go for bispecific [antibodies] or CAR [chimeric antigen receptor] T-[cell therapy], they’re looking, for example, for an oral therapy. This is a patient situation where you’re going to be recommending something like tazemetostat regardless of the 

The other scenario is in the third line and beyond, the NCCN now also is not mandating the 

 testing. It comes down to the same situation. In most of the patient clinical scenarios, you’re not going to need to know the 

 mutational status. We know that, for example, tazemetostat will have activity in both wild type and 

 mutated status. You’ll have to think about the patient scenario, is this a patient who will need more intense therapies, like bispecific antibodies or CAR T-cell therapy, or are you looking for some less aggressive therapy? In this situation, you really don’t need to know the 

 mutational status. That’s also important because a lot of the PI3 kinase inhibitors that were previously indicated for follicular lymphoma, are now not available for follicular lymphoma. That doesn’t leave a lot of oral options available for these patients anyway.

: I agree with you. There have been some seismic shifts recently in relapsed/refractory follicular lymphoma, not only with the introduction of mosunetuzumab in the relapsed/refractory space, but also having tisa-cel [tisagenlecleucel] and axi-cel [axicabtagene ciloleucel] from a CAR T-cell standpoint. But if I’ve etched those out of the equation for the management, based upon likely patient characteristics more so, and I’m looking for an oral therapy for a patient who’s either frail, advanced age, or has other comorbidities that preclude them from CAR T-cell bispecifics, I had been doing 

 mutational status just to have the discussion about whether they were in that 20% who had mutated 

 over wild type. Perhaps they would have better odds of response. But if you look at the data, the duration of response was fairly similar regardless of mutated status or wild type. The only thing that seemed to drive it, at least in the clinical trials, was maybe a slightly higher overall response rate. But I think that’s being further called into question. I know in the matched analysis set in this patient population, maybe that wasn’t the case. I think that may have been driving a bit more the relevance of checking 

I still have the conversation. It’s become easier over time to get the test. It was an uphill battle to get the test results. Now as data emerge, your practice evolves. If our practice isn’t evolving, then we’re not using the data to help inform us, and therefore inform our patients.

Experts Sameh Gaballa, MD, and Matthew Lunning, DO, FACP, reflect on recent updates to the treatment guidelines for patients with follicular lymphoma. 

Sameh R. Gaballa, MD, Moffitt Cancer Center

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