Dr. Stephen Ansell: Welcome to The ASCO Post Roundtable Series on Advances in Follicular Lymphoma. I'm Stephen Ansell from Mayo Clinic. I'm privileged to have two of my colleagues, Dr. Loretta Nastoupil and Dr. Gilles Salles joining me for this discussion. I'm going to have them introduce themselves. Loretta.
Dr. Loretta Nastoupil: Great pleasure to join you today. I'm Loretta Nastoupil from the Department of Lymphoma Myeloma, the University of Texas MD Anderson Cancer Center in Houston.
Dr. Ansell: And Gilles.
Dr. Gilles Salles: Hello, I'm Gilles Salles from Memorial Sloan Kettering in New York. Very happy to be part of this program.
Dr. Ansell: Well, today we're going to be discussing recent updates in follicular lymphoma and integrating these into new developments highlighting three case series. Our final installment will focus on third-line treatment of follicular lymphoma. So, I'd like to highlight this with a case.
This is a 58-year-old male patient who sees you for an evaluation of multiply relapsed follicular grade I/II non-Hodgkin lymphoma. Three years ago the patient was diagnosed and was treated with R-CHOP chemotherapy for six cycles and then received 2 years of maintenance rituximab therapy.
Six months after completing the maintenance therapy, he had evidence of disease progression and was treated with R-squared, lenalidomide plus rituximab. He just completed that treatment 4 months ago, but now again has evidence of disease progression. A repeat biopsy has been done and this shows residual follicular grade 1/2 non-Hodgkin lymphoma, and notably, no evidence of large cell transformation. So, he's referred to you for recommendations concerning what's the next therapy. So, I guess Loretta, I'll start with you and ask, do you need more information treating this patient? What do you actually feel is important to know? Would genetic evaluations be helpful at this point?
Dr. Nastoupil: All good questions. So, in the third-line or later setting, the options get even more broad, and so having predicted biomarkers would be hugely helpful to help navigate all of those treatment options. There's potentially one, so having the EZH2 mutation status would potentially be helpful because we have tazemetostat now, which is an oral EZH2 inhibitor that's approved in that third-line setting for someone who has an EZH2 mutation. It has an interesting label, though. It's also approved in the relapsed setting, if you don't have an acceptable alternative standard of care. And so, if this patient was EZH2 wild-type, for instance, and had comorbidities that made the other treatment options less attractive, you could still consider it in that setting.
So, it's not truly a predictive biomarker in that regard because you can't expect to derive benefit from tazemetostat even in an EZH2 wild-type setting, which is more common than the EZH2 mutation. But I still think that information would be helpful, again, because it might provide additional insight into all of the variable options.
Dr. Ansell: Thanks so much. Gilles, what do you typically do as you're working this patient up?
Dr. Salles: Well, we have basically the intention to genotype this patient and get this information regarding is EZH2. Although, I will say this patient is young and I will really go for an option that brings this patient into an additional complete response. And we have to recognize that the complete response rate of patient receiving tazemetostat, even for those that have these EZH2 mutation, remains rather low. It's a 66% response rate, but I think the CR rate is in the range of 10% to 15%. So, I will not recommend that at this time. I think we have different options. We have the old classical option, and for instance, obinutuzumab/bendamustine in patients that were previously refractory with rituximab has led to quite interesting result and improvement of survival against bendamustine alone.
We have salvage chemotherapy followed by transplant. But nowadays, we have two other options that we need to consider, which are immunotherapy-based option. The first one that has been available will be CAR T-cell, cellular therapy, in the form of different products. And the ones that has been available since only a few months has been the bispecific antibody, mosunetuzumab, CD3xCD20, which has led to great response rate in this setting. So, I think we have the old classical options and the new options, and I'm guessing that's what we'll discuss.
Dr. Ansell: Absolutely. So, I think, to be frank, it's almost like an abundance of riches that makes it complicated. So Loretta, we've discussed old options, chemotherapy, newer options, CAR T-cell, bispecifics, less aggressive options, tazemetostat. How do you think about dissecting all of that and picking which patient benefits from what?
Dr. Nastoupil: I think when we get into later lines, the toxicity profile also becomes almost as important as the efficacy. So, we have a 58-year-old. We are assuming that this patient's otherwise young and fit. I do think that CAR-T can probably achieve the desired result, as you'll mention, where you probably can expect the highest rates of complete response. It's going to translate into a more durable remission. And so, for a younger, fitter patient without significant comorbidities, that's probably going to be my first thought. Is this patient a CAR-T candidate, yes or no?
If they're not, then my next choice is going to be, is the bispecific antibody going to be something that's a good option for this patient? I fully agree that you can go through the list of more traditional therapy such as chemotherapy. The one caveat I might raise is for bendamustine in this setting, if I'm going to use it now, I have to consider what that next treatment might look like. And if it's a T-cell engager, either an autologous CAR or a bispecific, I may have some reservation about introducing that therapy too soon after bendamustine. And so, the other concept to consider is not just the toxicity profile, balancing that with the efficacy we hope to achieve. But also, what does it look like if my next therapy is an immune therapy–based approach, do I want to use a bendamustine option right now? So, those are the nuances in the challenges with follicular lymphoma.
Dr. Ansell: Yeah. I mean, you make some good points. And Gilles, I mean, you commented on this earlier, but CAR T-cell data in a young patient like this would obviously be a good candidate. The data look really good. But now that the data are maturing more for bispecific antibodies, those data look really good. How are you selecting between CAR T-cell and bispecific?
Dr. Salles: Well, I think it's very difficult to compare the result cross trials. I mean, these were not necessarily the same patient that were including this trial, but let's give it a general figures. CAR-T therapy is a rather rapid treatment. These patients often are very different from diffuse large B-cell patients. They don't need bridging and you need to harvest the cell, you can bridge them nonaggressively or not bridge them, and they will receive the CAR-T. And after the initial period of surveillance, they will be out of therapy. So, within 3 months, basically, the work is done and the response rate is in the range of... Complete response rate in the range of 70% to 90% depending on the product and the studies. And I will say, let's put it like 80% CR rate. So, it's a very high CR rate. The bispecific mosunetuzumab in a phase II study with 90 patients had achieved in the third line and third line plus setting an overall response rate of 80% and a complete response rate of 60%.
This is a different treatment. It's completely outpatient. It's ready off the shelf. And while there are some side effects, especially during the first months and the first infusion such as short-term CRS, this can be managed rather easily in an outpatient setting by most physicians. So, the burden of that is that, obviously, are repeated injection and this will be either eight cycles every 3 weeks or 70 cycles if the patient does not reach a CR. So, it's a prolonged treatment. I think we have no long-term data. It's probably that the median PFS on the last communication was 24 months, which may appear shorter than the PFS achieved by CAR T-cell in the same population. But again, these are not necessarily cross trial comparison. And I think we have a long discussion with a patient like we have in the tumor board nowadays regarding these two strategies.
Dr. Ansell: Yeah. So again, very valuable comments. Loretta, your thoughts, you mentioned toxicity and that being important to you. So, CAR T-cell therapy, highly effective, but all of us are seeing prolonged neutropenias and other things. Does that play into your decision-making or do you really have a preference one bispecific versus CAR T?
Dr. Nastoupil: I think it's absolutely going to factor in. I think the other consideration is that when you're considering an aggressive lymphoma, their survival's going to be so short if you don't have an effective treatment. It's not the same natural history with this disease. Now again, most patients with follicular lymphoma will actually have their highest risk of death being follicular lymphoma, but that's on the time span of years, sometimes decades. And so, you do have to balance that toxicity with the desired efficacy. And so, the other point to make is that you have two CD19-directed auto CARs right now that probably do have differential safety profiles with the construct of tisa-cel likely having much more preferable toxicity profile. So, no grade 3 or higher cytokine release syndrome observed.
One patient had grade 3 or higher neurotoxicity that fully resolved. When we balance that with axi-cel, though, the success rates with manufacturing with axi-cel are so high, you do expect about 15% of patients with follicular lymphoma might have neurotoxicity that's grade 3 or higher, which means they're going to likely be in an ICU for a period of time, at least for close monitoring. And so, that's just a different mindset. And so, generally, the patients where I'm going to favor something that's going to be more resource intense, it's going to be a lot of managing expectations, timelines. I'm going to use that in a patient where I feel like the risk is justifiable. And so, that tends to be a younger, fitter patient with more aggressively behaving disease.
Dr. Ansell: Very valuable. And Loretta, you made a comment earlier about your choice of therapies impacting the sequence of things. So, being cautious about, for example, bendamustine, if you're going to do a cellular therapy. I guess, Gilles, I'd like to get your thoughts. We keep targeting the B cell going after very similar targets on it. So, is there a preferred sequence in your mind where you go, "I like to do this and then go this way." Or do you go... Just hammer away at the same thing because that gets you a better result?
Dr. Salles: Well, I think this is really a field that is growing with some information that are here and there. When we use CAR T-cell therapy against CD19, there have been reports of CD19 loss after CAR-T therapy, but this was with essentially permanent in patients with acute lymphoblastic leukemia. It's probably less frequent in patients with diffuse large B cell lymphoma. Results are variable according to series and the way you examine CD19 expression. With flow, probably a minority of patient had lost CD19. With bispecific antibodies, obviously, you still have to have patients that express CD20 on the surface. And we have discovered that maybe for patient like that, about 5% of them, before receiving anything else, may have very diminished or lost CD20 expression. And it seems like after exposure to bispecific antibodies, a significant proportion of this patient, maybe 20%, that's actually one number from one study, may have lost CD20.
Well, the good thing is that, basically, we have CAR-T for CD19 and bispecific for CD20. The other thing to consider is that we do have data regarding the use of bispecific after CAR-T and this probably rescue number of patients that have not responded to CAR-T often in follicular. It's a real minority of patients. While we don't have data right on the opposite sequence. But I agree, this is a young patient, probably POD24 or just relapsed after the end of maintenance, had a very short duration of second line. If I have any concern regarding possible transformation, anything like that, the question of cell therapy will be there on the table. If it's a patient that will be having obstacle to a CAR T-cell therapy, I mean, you have to be close to the center for 1 month, you have to have caregiver support, you are exposed to a couple of short and long-term complication, including sometimes long B-cell depletion time. I think bispecific could be a good option. So again, we'll discuss that in length with the patient and relatives.
Dr. Ansell: Thank you. So Loretta, any comments you'd like to make related to sequencing? Because I guess this is what we're all working with in our practices.
Dr. Nastoupil: The challenges, how can we apply the knowledge that currently exists to answer that question and the challenge is that the novel therapies are utilized in such small number of patients that it's not until we get more experienced, larger sample size that we can really then start to interrogate what are the outcomes with a certain sequence of treatment. I agree with everything that Gilles said. We have to factor in, what is the patient's goals of this treatment? What is the therapy that's resulted previously in them getting to this time point? And we just personalize it. Over time, I'm hopeful that we'll get more data where we then can start looking at outcomes to try and answer some of those questions because we have a lot of hypotheses that, yes, if you use a therapy that's going to eradicate B-cells and T-cells for a prolonged period of time may have an impact on what your next treatment approach is going to look like.
Is the target there? What is the health or fitness of those T-cells you're asking to do a lot of heavy lift? We still don't have a great understanding of even how you sequence bispecifics in CAR's right now. Not to mention all the other targeted agents. And maybe we might even get better at utilizing things like PI3 kinase inhibitors or EZH2 inhibitors to optimize those patients for an auto CAR. So, I'm optimistic that over time we'll get better at answering this question. We're just hindered right now by the limited number of patients that have been exposed to these novel treatments.
Dr. Ansell: No, I totally agree. And Loretta, would you say that... Let me ask you, what's the role for autologous and allo transplant in follicular lymphoma? Does it have a role or are we basically kicking that to the curb?
Dr. Nastoupil: I think it has a role, but I think there are diminishing situations where I think we need those therapies to overcome a real challenge. I think there will probably always be a role for a small subset of patients for an allogeneic stem cell transplant, particularly if they're young and fit, maybe even post–CAR-T. The auto, in a sense, is probably going to have less of a role over time, just giving us more intensive chemotherapy, potential risk for second cancers down the line. And so, I think Gilles illustrated a perfect scenario where you might still consider it, but I think, over time, you'll just see less and less of it used.
Dr. Ansell: Well, thank you to both of you for your insights. I guess my takeaways from our conversation was there are multiple effects of therapies in third line for follicular lymphoma. That's a good thing. I think we have a number of novel new therapies which are pretty exciting and highly effective, particularly CAR T-cell therapy and bispecific antibodies. We made the case of really weighing up our goals, the patient's goals, and also the toxicities because they do have more toxicities and do require specialized management.
But there are a variety of other agents, EZH2 inhibitors, lenalidomide, PI3 kinase, multiple CD20 antibody options, all of which are reasonable alternatives. So I think, again, strategizing with the patient and, obviously, thinking ahead to utilize these therapies effectively is really the main way to go. So, that brings us to the end of this case. Please see other segments for further discussion about follicular lymphoma or please visit ascopost.com. Really grateful to both of you for your insightful comments. Thanks for being with me and thank you for your time.
