Dr. Stephen Ansell: Welcome to The ASCO Post Roundtable Series on Advances in Follicular Lymphoma. My name's Steve Ansell from Mayo Clinic and I'm joined today by two of my colleagues who will introduce themselves in just a minute. Dr. Loretta Nastoupil and Dr. Gilles Salles. Loretta, go ahead and introduce yourself please.
Dr. Loretta Nastoupil:
I am quite excited to join this panel of some renowned experts on follicular lymphoma. Loretta Nastoupil from University of Texas, MD Anderson Cancer Center in Houston.
Dr. Ansell: Gilles.
Dr. Gilles Salles:
Hello, good afternoon. My name is Gilles Salles from Memorial Sloan Kettering in New York and I'm also excited to be part of this meeting with esteemed colleagues.
Dr. Ansell: Well, thank you both. And today we'll be discussing recent updates in follicular lymphoma and we'll be integrating them and these new developments into three specific cases and case studies. And as we start off, our first installment is really going to focus on newly diagnosed follicular lymphoma.
So our first case is a 64-year-old female patient who presents with increased lymphadenopathy in the neck, axillae mediastinum and retroperitoneum. And the lymph nodes in the back of the abdomen have actually amalgamated into an 8-cm mass when measured. A biopsy is done of one of these cervical lymph nodes and shows follicular grade 1/2 non-Hodgkin lymphoma and a bone marrow aspirate biopsy was done and that shows 30% involvement by follicular lymphoma. The patient is generally in good health with an ECOG performance status of 1 and presents to discuss treatment options.
So as we start off, I think it's really important for us to get a sense of what do we regard as indications for patients who need treatment with newly diagnosed disease with follicular lymphoma. And Loretta, I'm going to ask you to start us off. Just give us some idea of what do you think about when you're thinking about a patient like this and who actually needs to get treated?
Dr. Nastoupil:
This case illustrates a pretty common presentation. So this lady first notices lymph nodes out in a peripheral region, probably brings that to the attention of her physician. After undergoing further imaging, we see there's a larger amount of tumor underneath the surface, particularly in that retroperitoneal space. So generally when I approach these cases, I want to know what is their tumor burden status? Is the therapy side effects going to be justifiable in a sense? And we generally follow the GELF criteria, which Gilles has much more intimate knowledge than I do here in the U.S. But essentially having a mass over 7 cm would be an indication that this patient would benefit from treatment.
Dr. Ansell: Thanks, Gilles, you want to comment on that seeing you were part of that original description?
Dr. Salles: Well, I was a bit coming later, but having said that, I think the GELF criteria that include a couple of clinical criteria regarding the tumor size and eventually biological criteria such as cytopenia or elevated LDH. I think they have to be taken a little bit with caution and I think many colleagues also interpret the GELF criteria with the dynamic, the pace of the disease. And sometimes we have patients that are borderline and they are stable for 3, 6 months, 1 year, and we may not initiate treatment immediately. While sometimes are patients that have grown from 3 cm to 6 cm within 3 months, they don't necessarily reach 7 cm, but I will initiate. So it's criteria, it's not dogma and I think they have to be interpreted clinically.
Dr. Ansell: Yeah, so totally I understand and agree with you. I guess the question is obviously criteria for treatment versus predictive prognostic factors. And so Loretta, maybe you want to comment on how do you marry those two concepts and what prognostic or predictive factors do you think really matter?
Dr. Nastoupil: I think this is actually a critical concept that is sometimes hard to describe to patients, but in general, what we're trying to do is assess risk. And so commonly in my clinic I will calculate a FLIPI score which takes into account clinical factors such as age, stage, LDH, number of nodal regions. There were attempts to try and refine this a little bit further with the FLIPI-2 that not only took into account the number of nodal sites but also the largest diameter of a node with a cutoff of 6 cm and then incorporation of beta 2 microglobulin and refining stage IV versus others. And so I think those are clinical tools that help us really assess risk across populations and importantly help us interpret study findings.
For a given individual obviously they want us to be able to predict the future so that they can also make plans in terms of what their next few months to years is going to look like. And so I do walk patients through their FLIPI score. I advise that that is a tool that we use to try and risk stratify patients but doesn't help us predict what's the best treatment course for those patients. We're going to take in other factors which I'm sure we'll get to, but also patient specific features such as comorbidities, performance status, et cetera. And so it is a marrying per se of the prognosis but also the amount of tumor and when observation versus treatment is important, there have been attempts to refine that further with incorporation of biology. We have the M7FLIPI score which took into account the status of seven genes and so I'm hopeful that over time we'll get even better at using more biology to inform that risk. But you're right, it is prognosis primarily with some of these risk scores married with amount of disease that helps us help a given individual navigate this.
Dr. Ansell: I think that's we're very well said. And Gilles, I don't know if you want to add to that a lot of work has been done to try and refine the FLIPI score and utilize that and do you find that useful in your practice? Do you actually incorporate that into your decision making?
Dr. Salles: Unfortunately, not really. I think first of all when I talk with the patient, one of the first thing I discuss is that the future is pretty encouraging for this patient with most of the patient with advanced stage disease like this patient stage IV, 80% to 90% of them will be alive at 10 years. They will have received one or several lines of therapy. But this is encouraging and again, as Loretta said, the prognosis is here to help what is the risk of failing primary therapy and having to receive another therapy but not necessarily associated nowadays with major differences in survival if they respond to first-line treatment, which is the case in the majority of patients. Coming back to biology, I think the mutation describing the M7FLIPI, gene expression profile that we did together with the Mayo Clinic and other indicators such as infiltration by different T cells, these are very useful to understand the biology, but I can't take them into my clinic.
What I'm paying a lot of attention to my clinic is however, if the patient may have some features that are associated with a high risk of histologic transformation and I think beside advanced stage, the presence of B symptom, grade IIIA rather than grade I/II, a higher LDH, and more importantly, the PET/CT features at diagnosis are also some criteria that I take into account for the decision of different therapies.
Dr. Ansell: I think that's a very important point and Loretta, maybe you want to comment on this. So typically a PET scan would maybe have an SUV of about let's say 8 or something, probably 10 or less would be typical. Would it matter to you if you suddenly had somebody who had a PET with an SUV of let's say 20?
Dr. Nastoupil: Challenge is as you illustrate, where is the line in the sand? I do think we all utilize PET to help us try and assess how confident are we that sampling one lymph node or maybe one site within the bone marrow is going to be entirely reflective of what we're seeing in front of us. Absolutely agree with Gilles. We also take into account some of those clinical features such as lab findings, symptoms, calcium for instance. And so it is actually constellation of all of those features. Now what I do put emphasis on the PET is if there's a big discrepancy, for instance, we see the majority of the lymph nodes have SUV in that 4 to 8 range, but we have a mass that's 35. Clearly I'm going to be suspicious that that high SUV mass is not consistent with all the others that I'm seeing is going to be highly concerning for having a discordant pathology and more likely to have aggressive lymphoma there.
However, I don't feel as confident saying, okay, all SUVs that are 20 or higher are associated with risk of higher-grade lymphoma. And I think some of the challenge lies in that we often don't get good representation of all of those lesions in terms of histopathology to observe. As we get more data and more experience with PET, maybe we'll feel more confident having a discreet cutoff, but as of right now I take that as one aspect into consideration with all the others.
Dr. Ansell: Thanks so much. So based on what we know about this case, Gilles, what would you say would be your treatment approach? Would you jump in with chemoimmunotherapy? Would you observe the patient? Would you go with antibodies alone? Do you have a preferred regimen? Do you have a preferred antibody? So just your approach and how you think about this and then love to get what Loretta thinks as well.
Dr. Salles: So I think this patient is 64, have a significant tumor burden in term of lymph node. She has an ECOG performance status of 1 and assuming this is linked to the disease, I think all these features may be indication for initiating therapy and initiating therapy to have a greater chance of achieving a complete response and a sustained complete response. So I think in this area we have different options that include two chemotherapy regimen, CHOP or bendamustine, eventually CVP; two antibodies that are rituximab and obinutuzumab and a non-chemotherapy approach, which is a combination of rituximab, of lenalidomide, the R-squared regimen. Nowadays, and given the fact that it's part of the NCCN recommendation and that I'm pretty used to this regimen and that this regimen has shown equivalent to immunochemotherapy, my first approach for this kind of patient without aggressive symptoms, without high SUV or higher histology, is to propose R-squared, which is a non-cytotoxic approach. Other than that, I think I have the discussions of the pro and cons regarding the different chemo regimen and the different antibodies benda is very popular. We still treat a few patient with obinutuzumab and CHOP.
Dr. Ansell: Thank you very much. Loretta, what do you do in your institution?
Dr. Nastoupil: I can echo all those comments. There's not one standard approach for all patients. We do take into consideration their underlying comorbidities. If you're going to use an anthracycline-based approach, obviously in older patients who want to make sure that they don't have cardiovascular risk factors where that may make that a less attractive approach. I generally do like chemoimmunotherapy in this setting where you have a large retroperitoneal mass that you want to shrink quickly so that you reduce that risk for organ compromised. I've had good experience with lenalidomide and rituximab in high tumor burden states. But I think sometimes in these areas where you're worried about even maybe if you had tumor flare and what would that do in terms of risk of hydronephrosis for instance, I lean a little bit more towards a chemoimmunotherapy approach. And how I choose between bendamustine or CHOP is based off of patient-specific characteristics. Some disease features, I do agree that if you have grade IIIA, I'm a little bit more inclined to lead towards an anthracycline-based approach versus bendamustine. And then how I choose between the antibodies again is based off of age and how likely they are going to tolerate the toxicities with one antibody versus another. So I consider all of those options and then I try to personalize it as much as I can.
Dr. Ansell: That's very valuable. Gilles, your thoughts on rituximab versus obinutuzumab? There have been randomized studies looking at that. Has that impacted your practice?
Dr. Salles: Well I think the GALLIUM study was a study where patients were receiving either CHOP or bendamustine with either rituximab or obinutuzumab. There was no randomization between the chemo regimen but only the antibody and overall there was a benefit in term of progression-free survival for patients receiving obinutuzumab who were also receiving rituximab. And in both arms of the study there was a consolidation with maintenance like we did in PRIMA, one infusion every 2 months for 2 years. The legal issue we have with this result of this study was that there was an excess of toxicity in those patients that received obinutuzumab/benda, followed by obinutuzumab maintenance. And we weren't sure whether this was linked to the chemo, I think with the combination of chemo and antibodies. And I will say in general I keep away from the combination of obinutuzumab/benda. At the same time we have been also through an area of the COVID pandemic where we have stopped applying rituximab maintenance or obinutuzumab maintenance for many patients during 2 years.
Now we are coming back especially for the patient with a high FLIPI that have a higher incidence of relapse within 5 years. So I think again it's a question of patient's individualization. You have young patients that you feel the infectious risk or other morbidities are very low and I will be fine to give obinutuzumab/bendamustine and other patients where I feel they're frail or may have risk for infectious complications or other kind of medical complications I will stay away. And if I prefer benda for this patient, I will use this with rituximab. When we use CHOP, usually we do obinutuzumab/CHOP because this additional toxicity was not really obvious for patients receiving CHOP-based chemotherapy.
Dr. Ansell:
Thanks so much. And Loretta, may be coming back to the maintenance therapy, especially as we now emerge from the pandemic and are thinking about that again. Is that something you're recommending standardly for your patients or is there a population you select it in or do you just never do it?
Dr. Nastoupil:
I actually discuss it with every single patient, recognizing that the trials were done for those patients who were responding to frontline chemoimmunotherapy. The challenge are those patients who've had a partial response. And so we want to make sure that that's still either inflammation or follicular lymphoma and not transformation, but if I am confident that it's still follicular lymphoma, I do discuss the risk/benefit. Similarly, for those patients in a CR it's a little bit easier in a sense to talk about what is the added benefit of extending out the CD20 antibody, what is the potential risk? Generally speaking, the risk pertains to viral infections and prior to COVID that was less of a concern. I do think we're on the backside of the COVID infection where I'm not quite as fearful as I was 2 years ago about potential infectious complications that could be life-threatening, but it's still a risk/benefit discussion.
The benefit is their remission period is going to be likely double what it would be if we observe them. It's hard to describe that in the sense that overall survival right now is not likely to have a major impact by doing the 2 years of maintenance. We balance that with the potential risk for viral infections. So as long as we're doing an adequate job with prophylaxis for shingles and they're counseled on watching for any upper respiratory or lower respiratory infections that might need closer attention. I do consider it in, again, mostly because of that first remission duration being prolonged.
Dr. Ansell:
Well really appreciate both of your comments. So I think key takeaways for me from what our discussion highlighted was obviously as you're thinking about a newly diagnosed patient criteria for treatment, not everybody needs to be treated. But those that do our commonly, those with more bulky disease, organ involvement, compression, constitutional symptoms, circulating cells, and then increased disease markers. So I think we highlighted the GELF criteria, but expanded the fact that there are actually a lot of other symptoms and features that we need to be considering. We then spoke about prognostic and predictive and we spoke about FLIPI and highlighting that as a way to determine prognosis. Additional work coming out now with genomic and genetic information, M7FLIPI, then thinking about how to treat people and pretty much there being three groups if you like, those that don't need treatment can be observed, there are those that we didn't talk much about that maybe could just get away with an antibody-based therapy. But we spoke about the R-squared regimen with lenalidomide and rituximab or a chemoimmunotherapy process, the R-CHOP regimen, R-bendamustine, Dr. Salles mentioned briefly RCVP, but I think the other two regimens more commonly used now and then. We highlighted here at the end, maintenance therapy improving PFS but not necessarily overall survival. And there is some variability about whether it's given based on the fact that the overall survival advantage hasn't been seen and the risk in recent years of infections as Dr. Nastoupil very kindly outlined.
So that really brings us to the end of this case. Please see other segments for more discussion and all of the latest data related to follicular lymphoma or please visit ascopost.com. So thank you very much for joining us and thank you to both of you for your commentary.
