Austin Kim, MD, Philippe Armand, MD, PhD, and Patrick Johnson, MD, take audience questions and discuss cases of elderly indolent lymphoma CAR-T cell therapy in this panel discussion.
Alright, well I think dr Jacobson virtually, she will be joining us soon. Um and uh we are actually five minutes ahead of schedule uh which is I think unheard of. Uh So um I think at this time, well maybe just get started with the panel discussion and dr Jacobson will join us. Um So we will field any questions. Um If there are not any we will bring up some cases that we have prepared things so far. I mean I'll introduce uh it's because the talks were so limpid that there's just no more question to ask. Yeah, we we we touched on all salient points so there's there's there's nothing to ask. I will actually introduce dr Philippe Armand he is um the chair of our lymphoma group here dana Farber and was instrumental in helping getting this symposium together. Um So it will be our fourth Panelist here. Um I can share my screen if you want if you we can talk about front line therapy of follicular lymphoma and and so can everyone see on this slide? Okay, all right, so um I can read this and I'm actually curious to hear what what people will say. So this is a 70 year old female who presented four years ago with the auxiliary osteopathy. Um So stage 38, grade 1 to 2. Um Don't always get a bone marrow, so we that was not done. Um She has four sites of disease, all less than three centimeters. So at that time did not meet any of the Guelph criteria for treatment she was observed for four years but now has retro peritoneal lymph nodes 4-6 cm Axillary lymph node four cm now is slightly fatigued as a lot of our patients say they are. Um and their past medical history includes rheumatoid arthritis um on methotrexate and colon cancer two years ago. Uh So um the question is how would how would we um kind of managed this patient at this time? At this point the patient does meet um Guelph criteria with three lymph nodes more than three centimeters. Again these are guidelines but um and it does seem like she is somewhat symptomatic. So um maybe we'll start with dr Herman. I was hoping to start with you guys but I think you you you already touched on what what I see as the the interesting questions in this case is what are the criteria to initiate treatment? And where do golf criteria mean? And so as as as you guys know, golf criteria were not evidence based criteria designed to okay to lead to decisions about initiating treatment. They're just bulk of disease criteria. So should they determine whether patients starts treatment especially when the symptomatic indications like in this case the borderline and someone with our a and fatigue may or may not be related. And the second part which I'm interested in your take on is so there is this this sense I think in in clinical practice that patients who have Guelph criteria positive should get chemotherapy and and those with lower burden disease can get away with just single agent or toxin map for example. But is that true? Is that how you guys practice? So so maybe uh pick a new kind of effort to start. So so what what do you think? Do you think this this patient needs treatment And if so, do you think there's a strong reason to choose one treatment or another? I think those are all great questions. I think that for this specific case, I think the crops is a pretty robust patient clinician clinician discussion just because I think You have to be clear about all those things. You know, four centim actually node I recognize maybe it's not symptomatic at the moment. But a lot of times patients before senator actually note if we if we really tease it out, you do wonder if that's bothering her symptomatically how it looks, how she's feeling with that. I think teasing out the fatigue a little bit more can be helpful and being clear about what's going on with the patient. I definitely wouldn't consider that a clear indication for therapy. You know, I feel like You you have you have to be clear that there's no way we're gonna know what this fatigue is and there's about 55 other things and you know, I think if you reach a point where um where after a clear discussion that we feel like there are symptoms that could be contributed and the patient wants to pursue with therapy, that's kind of where I would pull the trigger. I wouldn't do it based purely off of off of the size criteria, especially in the context of kind of this where we've got multiple sites of disease that have been monitored over time. It's not like we have a new presentation where we don't have pace of disease either, where maybe we could be a little more concerned about the rapidity of growth. So I think that standpoint from treatment and in terms of therapy actually think you're by no means were mandated to do chemotherapy. I think for for me it's a it's a it's especially in the era of of covid it's even more complicated. But I certainly think a land based regimen is something that you could consider. For example, um if you want to try to avoid chemotherapy and you make a decision that you want to do treatment. I also would say that um sometimes just time limited based treatment with chemotherapy is what is what is attractive to the to the patient and sort of maximizing the remission and and that's fine. Um as well. And then obviously if there's a clinical trial that is chemotherapy sparing, I think that's it. This may be a time where if there's a a gulf criteria oriented trial that's chemotherapy sparing in the frontline setting, I do find those attractive. And so that's one where I really would sort of sit down and say man if I've got access to that and can use this as a time to initiate therapy for something that's truly truly novel. Chemotherapy sparing. I'd be attracted in that as well. Austin. How would you how would you treat her? You you go straight to chemo for someone like this or I was actually fairly attracted to single agent riTUXimab. Um I think one of my questions is always you know, you see the reviews on follicular lymphoma, it's like low tumor burden the toxin or observation, high tumor burden our chemo. I mean do they is high tumor burden that means Guelph criteria or I guess I never really understood. I haven't heard anyone define what that means to me. So um I think for this patient I probably would um start treatment just because of those retro perennial nodes. I mean as they get larger, I would be a little concerned about them potentially causing um your literal um compression. And so those lymph nodes I get a little more nervous about. Um So if I were to treat I I would be attracted to doing single agent riTUXimab. Um especially because the fatigue is you know, she's not that symptomatic really. Um So I just feel like with as Connor pointed in his presentation in about 60, response rate with toxin. It's not as durable as Arlen or chemotherapy but um I think just four weeks. Um I don't think you lose anything by doing it and um hopefully you can get a response and just delay any subsequent therapy. That's that's that's what I would do. But I don't think, yeah, I mean there's Arland or some people would do our chemotherapy. Um I think that you could make an argument to observe. Uh so um I'm guessing maybe this is a patient of yours sleep right? But I think you guys I completely agree with what you're saying and the importance of of what kind of described of of the the patient engagement on this decision, which and we always say importance of patient engagement, but this is really one where it's all about how they feel and how they want to feel and what they want to put up with. Because pretty much nothing we do in physical informa other than adding mattocks map, it's gonna it's gonna affect overall survival. Right? So so really it's up to her and I think that is really a key point that kind of made. And then the other thing which I think Austin you you pointed out in in which we so our group has been probably more um a more avid proponent of single agent riTUXimab because of the the influence of dr Friedman who has been a venerable leader for many years and and who used a lot of single agent riTUXimab. And I think he often makes the point that you make of what do you lose if you do reduction and it doesn't work because it's true that reduction that may not work well in bulk your disease. There's some some data about that although it's not great data. But so if the toxin that doesn't get you to what you want then you can add chemo or or liability might um and you probably haven't lost anything. This is not large cell lymphoma on the on the level. In my point that's also it's it's very interesting because for us at least in the dana Farber group I think we very rarely use land based frontline therapy although the there is a variable interpretation of the of the relevance trial and whether that means it's as good an option or not. My my take on it is that because of the length of therapy, the side effects which even though they're different from chemo are still not negligible. And because of the fact that most of the patients on the chemo arm had job or CP which is not what we use and then we use Benda Mustang based therapy typically. And compared to Bend a must in our land seemed a little bit less good at least in terms of PFS. So I think for us I feel like we haven't used much land based therapy although it's definitely but it's an option for patients who want it and you can get the the insurance approval for sure. So it's interesting. I know some people or groups of people are more prone to using that approach and I decided I agree. You know, I think if if it comes down to it after that patient discussion, I probably would use venom mustang based therapy if I want to sort of truly achieve Maxwell durable control of disease and feel like the patient's symptomatic. And then I think if you feel like a trial over tax and monetary, but you could always adventure mustang for example, after that if you don't have. And so I think that's a pretty good sort of patient discussion option for a case like this. Um and I think the the other point that I'd like to echo that that you made Connors is Covid. And and at least for me two years ago I thought Covid would be a temporary problem, but it doesn't seem to be. And our vending machine is probably as bad as we can do in terms of chemotherapy, chemo, immunotherapy treatment really we we we make our patient's immune cripples from the covid standpoint of covid vaccination. And I think we've all had patients after our vendor who get in real trouble from infection and and don't have good theological response to boosters etcetera. So that is a that is a really important part of the discussion. I think these days. Yeah, go ahead, go ahead. I was gonna say also neither of you mentioned which is also of interest because technically one could use OKemo right, Which is approved and has some some PFS benefit. So what what do you guys think about that? I gather you don't use it from your responses. But but why you know I mentioned that I tend to, I'd say on the spectrum of follicular form of patient if the the younger and less concerned about toxicity and the more that I feel the patient wants a PFS benefit as the major goal of therapy. I'm more inclined to give Inabinett based regiment for that. The I want to use age numerically given my talk but the patient, the biologically older, the more I'm concerned about infectious complication, the more reticent I am to use um open and tourism based therapy. And so for example, I have a case now of a younger patient with um uh disease that's threatening some major blood vessels and who's, you know, good, quite, quite fit and active. And so I think maybe PFS benefit for that. I might include. I'm including amenities mob their, you know, their survival benefit of course not. But maybe given the threatening blood vessels and he's very active and he sort of has just as fit as a fiddle. I'm a little bit less concerned about acute complications. I had an older patient in their seventies who's got some cardiac comorbidities And um who? I chose riTUXimab because I was more concerned about toxicities and I wanted to get him through through sort of a minimal impact and I'll say because of the COVID-19 pandemic? I I have not been doing maintenance therapy um although that's always an interesting discussion to hear different folks approaches to that, right? And also to put a spin on that is if you're not doing maintenance therapy, it's also less clear what the PFS benefit of the magnetism of edition Israel. Yeah, I agree with that. And I tend to shy away from open and to sin mob also because that study I mean was done with two years of maintenance riTUXimab afterwards and I always feel a little uncomfortable, you know, going away from that and then I figure okay, how much are we really getting from that comparative? Er um especially with with Covid. So wow, Yes. one question I had with because I feel like we had talked a little bit in our internal pathways discussion of using linen linen meid riTUXimab frontline um is as you pointed out, Connor in your talk about the relevance trial, it was um It was at least you know, it was like 18 months of lanolin hmeid and then it was like six more doses of maintenance or toxin mob. However like in the augment study where you use in relapsed follicular lymphoma, it's you know, 12 months? Um I don't know if you if you do use it, do you have you used it just for 12 months and kind of or I guess do you feel obliged you have to follow the study and do the 18 months. I mean I guess you maybe need to if that's you're going by that data but I guess that's why maybe that regimen is a little bit less attractive just given the time you're on therapy totally. And I honestly I typically save our land for the relapse setting most of the time and use it more and augment. Um I included you know because I do think it is it's it's good to know it's available for a patient that you really really have concerns for whatever reason about chemotherapy toxicity but you also you know you try riTUXimab and and you're not getting the response you need or for whatever reason you feel like you need that that augmentation of therapy. I think it is a good option but I tend to use it in the majority of time in in my clinical practice and the relapse setting and follow the schedule. Thank you doctor. Thank you Connor Philippe uh pointed me to the question. I'm sorry I didn't see that question. Let me I can stop sharing my screen now um From Andrew Gillis smith with the approval of car T. Cell therapy. What role do you see a large genetic transplant for relapse refractory mantle cell lymphoma. Um So I do think that is a good question. So um I still think there would there is a role for a lead genetic transplant. but I would say it's and relapse after car T. Cell therapy. So um in my talk I do think the sequence as of now is still our chemo At relapse of B. T. K. inhibitor and then 3rd line car T. Cell therapy. Um And then at relapse after car T. Cell therapy you often need some some treatment to try to um control the disease and hopefully achieve a remission. And then I would say Allah genetic transplant is when I would um see the role there. I wouldn't um I personally would not use it before car T. Cell therapy just given the long term side effects. Um I think the challenge is getting those patients who relapse after car T. Cell into remission. Um I think that's um often they're not able to get to transplant at least in my opinion or at least in my experience. Um So that's that's at least how how I see how I see its role. Um And unfortunately so dr Jacobson's talk when she had the patients with mantle cell lymphoma was actually my patient. Um So he was primary refractory to be our our chemo um A collaborative and then achieved a three year complete remission after Brexit. Captain Jean or two parties. He just recently relapsed um I'd say like four months ago. Um So he had a three year remission two car T. Cell therapy. So it's kind of we're starting to see I think we're going to be seeing these relapses post car. Um So I did um he did go on to a bi specific antibody trial um that he didn't respond to. He's currently responding to single agent veneta clacks. Um And he has seen our transplant team but he's not in a remission yet. So this is kind of the role I see for our transplant. Um And that's just my thoughts. I don't know if Philippe or Connor you have anything else to add. Thank you. You make very good points and and the the fundamental point that I think you make other than head to head that carty has clearly better safety efficacy um Compared to toxicity ratio. But but also that carty is a treatment transplant is a consolidation. You can't photograph someone with active disease. I mean you cannot you cannot grab somebody in pr maybe but you can't photograph someone with growing disease and that's a big difference. But unfortunately that means that when you when you use therapies and you get farther down, it's harder to get patients to out there trying to fly. And there is still an important treatment still a curative treatment for You know how depending on what series you want to look at somewhere probably around 40% of patients. I think one thing which which I I see as a very important place of aloe is the incomplete car response. And so right now we have these crude tools which is pet scan. Okay you get a pR and early pRS many of these patients were convert made PRS fewer but there has to be a way to distinguish the PRS. We're going to progress from the PRS warrant. Maybe it's C. T. D. N. A. If you knew that if you had a patient Pr who you thought had a higher chance of progressing. I think that's actually a good candidate for a loan for something like mantle cell When you're not sure you can get the patient back in remission. That's true for large cell lymphoma as well. I think the importance of getting patients in metabolic complete response for alot is much less than for auto. So that I hope is someplace where we can get to as we understand better the predictors of later failure after card. You don't have a whole lot to add. You know I think the allergenic transplant, it's a it's a narrow and narrow slice of the pile overall therapy. I also just add um you know I agree. I think you need to it's a consolidated therapy and so you are dependent upon an induction regimen. And so the trick is do you have an induction regimen and postcard setting that can really get you where you need to go. I'm also interested in the future to see, you know, how do we incorporate by specific and car together to try and achieve permission and what what kind of induction strategies do we employ um to try to achieve MRG negativity and build sort of rational basis of consolidated therapies around that. I think the by specific integration with car T cells and how we go through that will be an interesting sort of set of trials that come up in the future. Right. I don't see any other questions on the chat. Um mm hmm. One question I guess I don't have a slide for it. But maybe something I will bring up is um since we didn't have a talk specifically on follicular lymphoma but Connor you kindly touched on it as well as Karen did for car T cells. Um Where I guess what is the role of chemotherapy ah and auto transplant now in follicular lymphoma? I think that's something I struggle with. So before car T cells we would let's say give br um someone relapses within a year or their primary refractory, then we would maybe give art shop for three cycles. If they're in a complete remission, then we would consolidate with an auto transplant and hopefully get Maybe 4-5 years. We we hope um now with car T cell therapy um it seems like in general we've been doing less of the chemo and auto um And I guess maybe as much as I'd like to think. Car team maybe curative and follicular I I'm kind of not as optimistic about that. Um maybe I should be but um I guess that that's a question I had. I wonder uh what what do you guys have been doing or what your thoughts are? Um Because I do think as you said, Connor using our land a lot more second line. Um is there still a role for our chemo and transplant? You know it's it's a great question I think for your for your young patient who's p. o. d. 20 for um I think it's you at least have to have the discussion around around that as a potential therapy. That young patient whose PNG 24 is ideal for a clinical trial in my opinion. So if you have something, you know, just like we're talking about how that will be included and in some of the confirmatory randomized trial for different studies that I think that's a great place for for a trial. But in the absence of a trial, I think that's the patient where I'm thinking about that for patients who are the other options for patients who you know have had a relatively recent relapse in the setting of the toxin exposure is actually open a twosome app with Lynn um with the Galen trial. That's another sort of thing to consider. And we obviously don't have high level data to say what's what's best in that scenario. But those are things that I'm at least thinking about in patients who've had recent exposure to toxins. And I'd say the fit young patient who is not yet eligible for car T. Cell therapy but has a PNG 24 that is one where else I would still consider chemo immunotherapy with transplant and that slice of patients sleep. Any um Anything else you have to add our thoughts? I think you're right. I think the the major driver of this decision is how you think about car if it weren't for car I think you can make a good decision still to autograph patient. The purity 24. I'm not a huge party 24 fan as as you guys know I think what is basically telling you is a patient is chemo refractory and that's it doesn't mean they're gonna be refractory to other treatments. There's a slight you know we have now the carty data on Prd 20 for both the one care and published the electorate trial, There's a slight deck criminal and overall response or duration of response for pure 24 but it's pretty slight and slight enough that I don't think that by itself warrants using auto transplant just to avoid that sacrament. So So if you think that you will get the patient to car T and that they are likely to have a 5060% cure rate if you think that then it's harder I think to to justify the toxicity of auto especially non negligible chance of of downstream consequences like treatment related. Myeloid neo plasm which isn't really that when that happens that's a that's a major major major problem. Um And then now, you know, with the increasing data that a lot of those patients have transformed disease et cetera, I think it further decreases the the The enthusiasm for autographing routinely all patients just because they're purely 20 for having said that. I think like Connell, I agree it is an option that has to be presented, it's still a reasonable option. And if you are in a place where you don't have good access to investigational therapies or car, then it's something that strongly consider because there is data for those patients and you know, the PFS median PFS about five years if they go to transplant, it's not bad five years in in the world of the lymphoma, given the pace of research and stuff is pretty good. Um So I think it's something that needs to rethink thank you sir. Go ahead. I was gonna say. And and the other thing I think about often and struggle with is you know, if you're thinking about car T cells for third line and then somebody's had be our frontline, you could do, you know, our R squared or you could do Olin and you pretty good data uh and then that sort of reserves your functionality for car T cells and you know, obviously chemotherapy is still around and so we don't necessarily burn bridges, you know, obviously it's not it's not following the exact data in the sense that we don't have randomized trial data of how to sequence these types of things. But generally speaking, I don't think you're truly burning chemotherapy bridges. And so I do find myself leaning more and more towards that type of sequencing. Um and then, you know, I think for somebody who really is chemo refractory early, I think that's the optimal place to get them into a study to try and get an investigator agent investigational agents second line macarthur. All right. And I don't see Karen here to defend herself. But um I think what I will say with the Zuma five data And and maybe it's the the median PFS of about 40 months um and maybe with longer follow up that will still be, you know, maybe those are the 50% that will continue to be in remission 678 years from now. But I guess I was kind of hoping or thinking that PFS would have been longer than just Um three years and three months. I don't know what you're guys thoughts were I was somewhat disappointed, but you're talking about five. Yeah, maybe median PFS is not the is not the best marker of car t performance or transplant performance or anything where there's an inflection potentially in the survival curve. Right? So If you had a therapy in follicular lymphoma where everybody progressed at one month, 60% of people progress that one month and everybody else was cured. So we love it, but the median PFS will be one month and so, so I think cars a little bit like that. Again, it depends what you believe system is. If you think that those curves are flattening and they're going to remain relatively flat then And I think that, you know, it just tells you maybe that maybe that flattening will occur below 50% but that wouldn't be, it's different if you think it's a continuous pattern of failure And the patient on on Zuma five were pretty heavily pre treated reasonably more than on LAra and many of them now the studies now that we're seeing for example by specifics, our studies with patients have received pretty light pre treatment and I say to me that's the most important risk stratification I felt. Right, what line of therapy we had the first line therapy NFL you have to have, you have to find something effective. Mhm. I agree totally. I mean, the only other thing I'll say is this in follicular probably even more so than large sell the existential question of car T cell versus by specific will it's true for true for a lot of lymphoma, not just not just particular but that's definitely that's definitely something that's on my mind as as we continue to move closer and closer towards towards really having multiple different by specific psychotherapy products available, you could argue and I don't know how you guys feel about it. But I know this question comes up a lot, but you could argue that it's not really a question that is relevant for patients because by this fortunately now the existing ones don't hit the same target because we don't use blender and NFL. So, so at least you, let's say you don't worry so much about impairing the future ability. My specifics are probably going to find their way in front front line or second line therapy Car. Maybe stay in 3rd line, maybe hire a second line. So you do both, right? You give by specifics and on failure or whatever you give car and and perhaps nothing lost. And if you cure patients upfront with by specific. Great, great. So I don't know that from a patient standpoint. I don't know that they compete with each other, but Alright, so it's 1146, we're still four minutes ahead of schedule. So um I think we're maybe done riffing here. Uh So uh I will say we should adjourn for a break and we'll plan to come back uh Maybe a couple of minutes after 12, we'll say 1205 um to pick up and we'll finish our last session on Hodgkin lymphoma. CLL S. L. L. And then give you guys the rest of your weekend. So um I want to thank Connor and Philippe. All right, for the discussion that's pretty much everybody every weekend. Thanks you too
