Dr. Stephen Ansell: Welcome to The ASCO Post Roundtable discussion on Advances in Follicular Lymphoma. I'm Stephen Ansell from Mayo Clinic and I'm joined today by two of my colleagues, Drs. Nastoupil and Salles. I'll ask them to introduce themselves. Loretta, please won't you start.
Dr. Loretta Nastoupil: Hi, happy to be joining you. I'm Loretta Nastoupil from the Department of Lymphoma Myeloma at the University of Texas, MD Anderson Cancer Center in Houston.
Dr. Gilles Salles: Hi, thank you for having me today with you. This is a great program with my colleagues. I'm Gilles Salles from Memorial-Sloane Kettering in New York. Happy to be there.
Dr. Ansell: Well, thanks to both of you for joining us. So today we are going to be discussing recent updates in follicular lymphoma and we are integrating these into three patient cases. This is our second one, and the second installment focuses on recurrent follicular lymphoma.
So the case we'd like to highlight is a 62-year-old male patient initially diagnosed with follicular grade I/II non-Hodgkin lymphoma stage IVA about 18 months ago. And at that time he received bendamustine plus rituximab and received six cycles and then achieved a complete response. Notably, based I guess maybe on the COVID pandemic, he did not receive any maintenance therapy.
Over the last 6 weeks, however, he's noticed an enlarging lymph node in his axilla, presented it to his physician, a re-biopsy was done of this lymph node and this shows recurrent follicular grade I/II non-Hodgkin lymphoma. Notably, there's no evidence of large cell transformation and a re-staging evaluation was done, which shows this not to be the only site, but multiple other sites of lymphadenopathy noted in the chest and abdomen. A repeat bone marrow aspirate and biopsy shows 20% involvement by follicular lymphoma. He now comes and presents to discuss management options. So Loretta maybe I'll start off with you and see what's your take on this case, particularly the relatively short duration of response. Is that a concern? And if you do believe it's a concern, why?
Dr. Nastoupil: Sure. So this gentleman had one of the most common front-line approaches, which is chemoimmunotherapy with bendamustine and rituximab. And unfortunately within 18 months, it is relapsing. Importantly, they pursued a biopsy to ensure that this is indeed follicular and not transformed to a more aggressive lymphoma. So we would characterize this as a POD24, an early relapse follicular lymphoma. Initially that was described after patients who commonly received rituximab in combination with CHOP frontline. But in that cohort of patients, the overall survival was quite short about 5 years on average as opposed to the other group patients that had a remission period that lasted well beyond that 24-month timestamp. We've seen similar results utilizing cohorts of patients treated with bendamustine; the Vancouver group reported that. Now once you exclude the larger proportion of patients who have transformed disease, again the prognosis is still not quite as good for those patients who relapse early. And so I am concerned about this patient having had an 18 month remission following frontline chemoimmunotherapy.
Dr. Ansell: Thanks. And so again, it would be very useful, Gilles, to know who this type of patient would be and sort of some way in which we could detect this upfront. Do we have any predictors of this high-risk group and do any of our genetic studies help us? And how do you think about managing that?
Dr. Salles:
Well regarding the prediction of patient failing a first-line chem immunotherapy, again, we have tried to combine some factors with the M7FLIPI with the 23 gene markers. And yes, we do identify a higher risk group, but this has not been installed in clinical practice. And these indexes may also vary according to the different treatment installed. So at this time we are essentially relying on clinical factors. I think during the last ASH meeting there was a very interesting presentation from the group of Mayo Clinic and the LEO Consortium, if I recall, while combining a couple of very simple biological factors in the large dataset to predict those patients that will have POD24. I think we are waiting for the final publication. But if this comes to life, this is a simple index based on several easy parameters. We are obviously disappointed that the advances that we have gained in understanding the biology of the disease have not been bringing some help in clinical decision. But it's how it is today.
Regarding the management of the patient, I may be a little bit nuanced. I think, as Loretta said, all the POD24 patients showing that this patient had an adverse prognostic kind of mix of those patients that transform and do not transform. And I feel more reassuring when I have a clear feature of patient without any histologic transformation, such as this one. He had a bone marrow biopsy, he had a biopsy of a node. He has no clinical symptoms for transformation and I'm not sure that this patient have such a very different prognosis from other relapse and this have to be probably settled in further study. So clearly this is very important distinction. Has this patient been transformed and in this case we have to manage them differently. If they have not been transformed, I think there are different options are probably not very sensitive to chemotherapy, but I think we have other tools for these patients.
Dr. Ansell: Very good point. So Loretta, what's your approach? Do you regard these POD24 patients nontransformed as not as concerning as Gilles is mentioning.
Dr. Nastoupil: I think he raises a good point that we've all been debating. Part of the challenge is that this was described as from an observational cohort of patients where we were able to dichotomize patients into two groups. Because they weren't well studied in terms of excluding those patients that were transformed, we haven't been able to do as good a job as prospectively outlining how high risk they are in risk stratifying these patients into specific treatments. I do try to prioritize getting them on trial because I do worry about a patient who has a shorter remission following what I would consider an effective frontline approach than a patient that has a 10- or 8-year remission period. So this does convey a little bit more concern on my part, but I also feel that some of those early descriptions maybe fell short at fully characterizing what is the outcome for those that are still follicular lymphoma just within early relapse.
Dr. Ansell: And Gilles, what do you actually offer to these patients? And I guess while we are talking about treatments, PI3 kinase inhibitors often were used in this space, but they've fallen a little out of favor right now. So I wanted to get your thoughts about your treatment choice and do PI3 kinase inhibitors feature in that?
Dr. Salles: Well, I think I've never been a proponent of PI3 kinase. Having said that, I was part of the initial study with the first one, but I didn't brought them in my regular practice for this patient. I think, again, these patients are probably not very good candidate for another line of chemotherapy. And the idea of bringing this patient to CHOP because he has received bendamustine is not a very good idea for me. I think we have some data suggesting that, again, an immunotherapy-based approach may be suitable in this patient and whether we can combine either rituximab or obinutuzumab with lenalidomide, which is approving the second-line setting for this patient is, I will say, an interesting approach.
We have actually data suggesting that those patient with proven follicular lymphoma entering those trial ask where obinutuzumab and lenalidomide, whether they were POD24 or not, didn't had a very different outcome. So at this time, this is my preferred option, monitoring these patients closely for the response. If they don't respond, then we'll have to switch to another approach. But if they do respond well, I will continue this kind of approach. PI3 kinase will come much later as an option with the only ones that remains available nowadays.
Dr. Ansell: Gilles, you said something about chemotherapy not being such a great option. So Loretta, I wanted to ask you, some people would say this is a kind of patient where you want to intensify chemotherapy and go down the role maybe of an autologous stem cell transplant. So what would you say? Would you say that's a wise decision or would you say we need to go in a totally different direction?
Dr. Nastoupil: It actually follows Gilles' logic in that if, again, if I don't have concern for transformation, I have a situation where a patient had a good chemotherapy backbone and didn't get the remission duration I had hoped for, I do like to switch it up and I generally do prefer lenalidomide as one of my preferred second-line approaches. I have to reconcile that with, as you mentioned, there are clearly others that would take a very different approach and intensify the chemo, give a platinum-based chemotherapy, and then proceed with high dose therapy autologous stem cell transplant. We have retrospective CIBMTR data that those outcomes can be quite good if it's done within a year of that POD24 event. All the caveats of a retrospective study and a CIBMTR database. So I do struggle a little bit with how to reconcile those approaches that are so vastly different.
I generally think that for patients, again that are young and fit, lenalidomide is quite well tolerated. For older frailer patients, lenalidomide is quite well tolerated. So it happens to be my preferred go-to second-line approach. But I will highlight that there was a SWOG study done to try and attempt to answer this question with three options, PI3 kinase inhibitor–containing option, chemotherapy switching up to the backbone of the chemo, meaning if you had bendamustine frontline, you'd have CHOP second line, and then a lenalidomide-based approach, all combined with obinituzumab. And you had the option to take those patients onto high-dose therapy auto transplant if they were responding. And it has been incredibly difficult to complete that study, so much so that I less optimistic that that will ultimately answer this question.
Dr. Ansell: Yeah, so I think again, you highlight the diversity of approaches, but I think again, created maybe a little bit of guidance as to how to think about it. Maybe to change the discussion a little bit, we focused here on a POD24, so early progressing patient, but Gilles, more typically, most patients actually benefit substantially from treatment. So if we changed the scenario and we said the patient got R-CHOP, let's say, and had an excellent response and 8 or 10 years later, the patient is now progressing, would you have a different approach and what would you recommend now at this time?
Dr. Salles: Oh, when a patient had a 10 years’ time without disease, I think all the approach is on the table, and it can be using rituximab single agent if the patient has a limited tumor burden, and this can work. In this case, I usually what I call the Swiss Scheme, which is a four plus four scheme, four weekly infusion and consolidation with another four infusions one every 2 months. PI3 kinase copanlisib may be an option for this patient, but it's cumbersome, so they have come often to hospital; there are still some side effect. We do know that copanlisib plus rituximab is better than copanlisib alone, but it's not one of my favorite approaches. It's a little bit early to start for this patient thinking about EZH2 inhibitor, which is approved only later in time of therapy. And obviously repeating chemotherapy can be an option.
If I go back to the opposite scenario, if I may, Steve, which is the patient that had had a PR after R-CHOP or R-benda. And is here with not proven transformation, but had a residual significant lesion and progressed within 3-6 months of achieving therapy, that will be the patient in which I will consider probably most likely a salvage approach and a consolidation. Whether nowadays we would like to consolidate patient with autologous stem cell transplant while there are other alternatives such as CAR T-cell will be another element to consider in the discussion that obviously enrich our strategy and enrich our discussion with patients and probably widen the opportunities for these patients.
Dr. Ansell: Thanks, and yeah, valuable comments there, but coming back for a second again, finally, Loretta, to the good responding patient with a durable remission, what's your preferred approach in that case?
Dr. Nastoupil: I agree that you have so many options. It depends. If they're a low tumor burden, I might actually even observe them for a period of time. I do tend to use a little bit more single-agent CD20 in that setting than any other setting. You could make the argument they had such a good remission following, for instance, they had R-CHOP, you could consider four cycles of bendamustine and rituximab in that setting. So I do think it opens the door to more options. Again, it is a little bit more reflective of what we typically see.
Dr. Ansell: Well, thanks for those insights. So again, I guess the key takeaways for me from our conversation is POD24, EFS 24, whatever you'd like to call it, is a poor prognostic group, but we made the case that exactly who's in that group might actually impact how poor or less poor the prognosis is. And the important point is getting a biopsy to be sure there's not a transformed lymphoma, because a number of the patients may well be transformed to a more aggressive histology. Those that have a much longer remission than the short 2-year remission; actually, there're data to say their overall survival may be very similar to the national averages. So I think that's an important thing to remember as you're choosing therapies. And again, both Loretta, you and Gilles made the case that as the remissions get longer, the options become greater.
And then finally, second-line treatment is very heterogeneous. And so this is where, and I think both of you made the comment, conversation with the patient, engaging them in the decision-making and basing the decision on characteristics and time to progression and whether the disease was relapsed versus refractory, and obviously what you gave before are all factors that would go into treatment choices. I guess the good thing is there are many treatment choices and many patients may actually have a good outcome.
So that brings us to the end of our case. We'd like to say thank you for listening and participating. Please see the other segments for additional conversation about the latest data for follicular lymphoma or visit ASCOpost.com. But thank you to my two colleagues for a very useful and insightful discussion. Thank you.
