Austin Kim, MD, Matthew Weinstock, MD, Adam Olszewski, MD, David Fisher, MD, and Samuel Ng, MD, PhD, take audience questions and further discuss aggressive lymphomas in this panel discussion.
Excellent. So um it is 9.07. We'll get started with our aggressive lymphoma panel discussion. So we'll open it up to the audience um to ask any questions or difficult patients um that they may have about a few large B cell lymphoma or t cell lymphomas. Um If we don't have a lot of those questions we also have some cases um to discuss that um could um generate some discussion. So please don't be shy. Right well since we're not hearing anything yet um I actually um I know dr weinstock I'd like to introduce from Beth Israel Deaconess Medical Center. Um He actually had a case of second line large b cell lymphoma for someone who's transplant ineligible. Shin what frail that we can discuss. Hi everybody. Um Really excellent presentations so far. Great to see you all. Um Austin did ask me to to to bring a case and I'll share that briefly. Um One of the one of the instructive situations that we deal with in in the very real world of second line therapy um where we don't have the option to use those very exciting therapies that dr Schabowski just went through um very very well in at the first talk. So let me share my screen here um looks like I'm having difficulty sharing and I may have it if I can see. Let's see if I can can people see that. Yes. No. Yeah. Yeah. Yeah. Okay I can see it thanks. So again very real world situation. Um this is a patient of mine um at the time I met him he was 63. He's now I believe 68 um had a very large um pelvic mass that was biopsied and found to be consistent with diffuse large B cell lymphoma. You can see there um uh at the time of relapse the disease characteristics but um just to um note them at the beginning this was a non gcc phenotype by the hans algorithm. Um and you know history chemical profiling, um not gene expression profiling. Um This was a double express. Er I very much appreciated doctoral studies points to distinguish that similar sounding terminology from what we call double hit or triple hit. Um uh diffuse large B cell lymphoma. The hits refer to um trans locations, expression refers to immuno histone chemical um um uh staining and they do define different prognoses. So this was a double express er Which had a complex abnormal carrier type. A rearrangement in BCL six. Um but no rearrangements in Mick or BLEC two. And uh what becomes apparent in a moment was that the Epstein barr virus inside to hybridization. Study the ybor ish was negative. Um he was treated with our chopped for six cycles. He achieved a complete response which lasted for about 18 months. And then um he represented with fever night sweats and extensive retinopathy in the pelvis area as well as new split omega li this was biopsied showed very similar disease characteristics as at the time of presentation as I mentioned and um a very complex, complex situation um um alighting a bunch of the other stuff that was going on with him. But the main thing was that this patient had hypertensive encephalopathy which led to end stage renal disease about 20 years prior to the time of us meeting and required a kidney transplant. And at the time of the relapse, he had had progressive um alo graft dysfunction Of that kidney transplant and his creatinine was 3.7. Um This was not appreciably different than it had been um for quite some time. Uh slowly progressive but nonetheless really limits the options for what to do in the second line situation. Um They created an F 3.7 not really eligible to get a second line platinum based um chemotherapy or to go on to beam, which is the standard conditioning for high dose chemotherapy followed by autologous stem cell rescue and auto quote unquote transplants. um and similarly with the creation of of nearly four. certainly not a um very good candidate for car T cell therapy. So some of the tried and true second line therapies like um second line platinum based therapy followed by auto or even the more exciting therapies that we were starting to use at that time were not really available to him. So the question is what to do for for this gentleman um Dr Oshinsky mentioned a number of Alternative 2nd line therapies that we considered But the first thing was I had a very frank discussion with him about the dismal prognosis both in terms of the disease characteristics. Um history, pathologically um immune often a typically and psycho genetically and the lack of really a curative approach intent in this setting. He actually was really considering going to hospice, ultimately decided to try some steroids and some single agent rita oxen and did okay. Um and um uh eventually put him onto um second line therapy with R squared including Violeta might. He achieved a good partial response and then later developed um uh intra vitriol recurrence of the large cell lymphoma that was treated with intravenous methotrexate. Um uh and then about a year later actually maybe more like nine months later um developed another systemic recurrence and at that point was started on pole atoosa mob and wrote toxin avoiding the bending mustang because of the ongoing renal dysfunction. So this just gives a flavor of um some of the agents that we have at our disposal um in the second line therapy setting when patients are not eligible for auto and car. And I guess I would just open it up for questions about you know how we um situation, how we manage this situation and and also I want to get the input of our other panelists to about um you know how others approach um challenging situations like this, right? And thanks for that case presentation. Um you know I mean I think at the end despite you saying it was a dismal prognosis is look like they're in a complete remission uh 2.5 years out. So uh yeah, I think that's yeah, it's hard then for the patient to say, hey doc, what do you mean? I'm doing great now, but it doesn't always end up that way, but it doesn't it doesn't always end up that way. Unfortunately, we do have some tools at our disposal. Um things that I didn't mention in this in this brief presentation would include the anti cd 19 therapies that are not car based. Um which Doctor Olsavsky highlighted as well at the time uh that the relapse initially occurred. Tafa Cinema was not available it now of course is um subsequently we have long cast ducks, mob kasserine. Um another um uh antibody drug conjugate that um as was highlighted earlier has has activity in this setting. Um So those are those are our next moves thinking ahead for this gentleman. Um Right now, of course, fortunate that he isn't isn't a cr and uh hopefully we'll stay there for a while in this case brings up several interesting issues. Uh One is that this was a relapse beyond 12 months. So actually anticipation would not qualify for the trials of cortisol versus the oldest and cell transplantation. So that may be actually a group with a better prognosis. Most patients in our clinical breakfast now with the relapse after art shop. It happens almost immediately or within a year. Yes. And the coral study that you highlighted really shows a differential uh in terms of uh you know second line therapy response even to auto for those patients who are truly primary refractory. But we will still remain in excellent standard of care for these patients to get a second line chemotherapy and as long as their chemo sensitive. But I think the second important issue is that which one is the end result is that um at the outset of of research on immunotherapy the companies just decided that patients who are immuno suppressed will not respond to these treatments. But we actually don't know that all patients with HIV infection with P. T. L. D. Or even autoimmune diseases or some you know suppressants are excluded from all these trials. This also appears to be including bi specific antibodies trials at least the ones that I've seen. But we actually do not know that. And I think you know we are quite comfortable with dropping immune suppression and patients with an adrenal disease or with post transplant when we treat the lymphoma. To low doses of predniSONE alone. Um and there actually is no conceptual problem with during the first meeting therapy stopping um immune suppression and allowing partisans to work at least for a couple of weeks when they actually do most of their job. But it hasn't been tested. It's we don't know how this might work but I think it would be an important question to ask in the future. Right? Can I can I ask a more kind of a practical question for this patient? Like how many cycles of polytheism of riTUXimab were given? I mean I know many of us kind of turned to that combination but the duration is kind of not clear given a great questions I've given him six. I agree that the duration is is not clear but that's what I've decided to do in this um real world, unusual, unusual situation. Um uh That's where we've we've elected on in terms of you know the duration of therapy, we'll see what happens going forward. Yeah. Alright so we have a couple of questions from the audience that I'll share and then um I'll ask dr fisher to um if we don't have any other questions just to review a T cell lymphoma case. So the first question um from Monica buckley is about supportive care strategies to limit or prevent neuro toxicity. Um As its common with many of the regimens, I'm guessing that means more um peripheral neuropathy not neuro toxicity necessarily from car T cell therapy which we'll talk about later. Um So I'll open that up. I know it's I guess we'll just say from my personal experience there's not great supportive care measures other than dose reduction or trying to be cognizant of that but I will open it up. Yeah. Yeah, I mean I agree with you with those reductions um is really in in terms of the in the moment um management strategy that I often use. Although I try not to of course um I've had quite good success on the ground with DULoxetine. Um uh more so than for example gabapentin or pregabalin um for patients who need a junked of therapy for peripheral neuropathy. Um But I'm also curious to hear if others have had successful with other approaches. There are some people that think that preventative dozing with alpha like poke acid might be helpful. Not well studied. I think his oncologist as we're using more political map, we actually have to start doing a regular neurological examinations on patients because I have certainly missed a few cases of neuropathy was developing during political map and I can just really badly flare up even after discontinuing the treatment of forgiving what you think was the last dose. So um I think my um thresholds to actually get the patient to the reflexes and understandable perception has now markedly lower than I do it more often. That leads to the next question we have from Andrew gillis smith about Polar the Polar eric's data and frontline management. It's not FDA approved yet but we do expect that it will be how we're going to apply that data um And then also for double hit lymphomas. Would anyone consider giving cola are chip instead of our epoch, I personally believe in epoch for double hit. Um That's what I've done and I don't see anything in politics. That would make me change that practice right now. Dr Osofsky highlighted the subgroup analyses which have garnered a lot of attention but I would be I personally I'm being very careful about that and for me, double hit, triple hit, I'm still using epoch dose adjusted epa car. Um And the other question was about, what was that exactly was how you would use the Polaris data, assuming it is FDA approved. Um Who would you give that to for frontline management of large cell lymphoma? I think that the future maybe maybe with polaris. But um as I just said for the very highest risk patients I would I would at least right now reserve an intensified therapy with with dose adjusted Deepak are at least from my the brief subset analyses and polarity. It did not appear that patients with um double hit triple It lymphoma did particularly well with polar our chips. So I would agree I probably would not um give that front line for a patient with double hit lymphoma. I I would think just I would probably apply the data Um to the patient eligibility from the trial IPI 2-5 um advanced stage. Um I would consider I would strongly consider and unable to probably switch my practice to that but that's I think that is something that we're going to have to decide very soon. I would agree. I would say that you know you can think of those are just a car as a regiment that was developed for high grades including Burkitt lymphoma. Only the closing moments of the burkett. The higher the higher potential benefits at least as it appears we have shown some analysis high grades to be someone from N. O. S. At the ash this year. And also the the group that that has potential benefits from the adjusted back is the market like group. So I agree that um even though I really do not have prospective data on epoch that would compare it to our job and actually seeing patients relapse immediately after impact or in the middle of the pack. Um So but this is not a separate disease. This is no longer the so we really should not be tweeting at right so dr fisher I don't know if you have a case you wanted to share. I just have one slide. Sure. Perfect. Mhm. I can share. I just want to talk about can you see that slide? Yep. Perfect. I just want to talk about transplant in first remission for our aggressive t cell lymphoma. Just working off of SAm's cases that who do we transplant and when um certainly um we consider this for mostly aggressive t cell lymphomas. Certainly people under at least age 75 with adequate organ function. Of course there are a few groups that we would not recommend transplant for and that's pretty much all our positive anaplastic lymphomas as they have a much better prognosis as you know. Um Out negative lymphomas uh tend to do better than the other aggressive t cell lymphomas decides from out positives. The deaths 22 positive group do the best As you know. TP 63 is a poor prognostic finding. So perhaps the out negative desk 22s would not consider transplant in general, patients with 01 I. P. I tend to have good prognosis with most of the aggressive T cell lymphomas ptcl ah and A. I. T. L. For higher I. P. I. S. Uh We do tend to consolidate first remissions whether it's off of chopped tv or chew up or whatever. Sam had to come up with for higher I. P. I. Certainly 3 to 5 to a little more controversial depending on sort of the extent of the disease their age or comorbidities. All these things to consider. Um So the main point is just to consider consolidation, high dose chemotherapy and so you may then ask what's the data for this uh And there is no randomized trial looking at this to give us definitive answer like we had with uh Parma study back years ago with B cell lymphoma. This is mostly from single arm studies mostly retrospective analyses post hoc analysis. Certainly looking at patients in echelon to and a post hoc analysis those that had consolidation with transplants seem to do better of course there's selection biases etcetera. So um a randomized trial would be wonderful but I doubt that's going to happen. I think what we need is SaM points out is better upfront therapy. I know SaM has any further thoughts. No. David, I'm in pretty good agreement with that stuff and you know, you certainly and I personally have followed this sort of kind of recommendation that you outlined in general acknowledging that the data is not, you know, particularly what we would want it to be to make those recommendations. But you know, I think at this point, just given, you know many of the outcomes that we've seen for these patients, that adding transplant is very reasonable. One of the things I wanted to add that I meant to mention during, during my presentation was, you know, one thing you might ask is how do we even know like about these dust 22 rearrangements, how can we find out um at least within the wider MGB system. Um Over at MGH Valentina Nardi has helped to establish with archer a fusion protein detection panel that you can send out to um over there if if you're really interested if you have an alka negative patient who you might be might want further prognostic information for um and the turnaround for that is not terrible usually. Um a few weeks um and I don't think you would change treatment with BB chip. Um It would be more you know that the front line or the consolidated transplants that that would be something that might hinge on a result like that. So you know that's something that that can be considered is sent out for a fusion protein detection. If if that's what some providers are interested in. I guess one um scenario that I've come across that's been a little bit not clear to me is so you have someone let's say um out positive A. L. C. L. Um who meets criteria for who's transplant eligible but has an I. P. I. Of let's say four. Uh And they go into remission with the V. Chip. Um Would you transplant that person or not? And I think I came across that scenario and clinic and I think in my mind I said well I probably should recommend it but when I spoke with the patient it was really hard for me to really sell it to not sell it to them. But to convince myself and convince him that You know that's it's going to be worth maybe that five maybe that 10% increase in curate. Um So that was something I've struggled with and I don't know um how you guys have handled that or what you do. Um Since we're using more BB chip now upfront in general for a positive and a plastic which are always young patients their outcomes. even with high I. P. I. Tends to be very good with chopped based therapy. So I tend not to transplant those patients at first remission keep in mind that there are a few patients that have out positivity who are a little older. I think if you're out positive over 35 or so you probably don't do any better than someone who's out negative. So there may be some exceptions to older patients, the rare ones that are out positive. Yeah so my patient was an older patient like in him he was 60 without positive cl cl which is rare but um he did remit to BB chip and had a high I. P. I. Score. So um you know those those patients tend not to do any better than someone who's out negative. Ah And so they would fit the transplant paradigm. Think in some ways that he was very against transplant to begin with um when he came to see me. So it made the console for me a little bit easier but I think it would have been harder for me to try to if the patient was a little more like whatever you tell me doc um I I kind of struggled with what the right thing to recommend there was and I don't know if there is a right answer but um I just felt like the book answer what we should tell patients is you should transplant for some reason it's it's hard for me. It was hard for me to be like yeah definitively you should that's what we should do. And I think that maybe that's that's where we're at. I suspect that since I recommended transplant and he didn't have it that it did well. Um I actually don't know how he did. It was a second opinion. Um So yeah All my detail patients for the past years have declined transplant when hearing that the benefit would be in the range of 5-10%, which I found surprising. But even younger patients felt it was not worth it. Maybe we gather up enough to see what the outcomes are. Yes. We have a few minutes. I wanted to ask the panel if there's any thoughts about sequencing the novel large cell lymphoma therapies after car t cell failure. Um tapas, unmanned Len blanca pola, Is there a reason for any type of sequencing or preferred? I don't know if others have have observed this but I've seen people go into very durable remissions with the bi specific antibodies after car failure. Um This was I believe it was a plenary session at Ash Maybe two years ago or so with the most awesome ab and we've been using the Lotronex to nab Regeneron product on trial previously here and had some very good success there. So if that's available um on trial, that's what we've been. We've been preferring as far as the agents that are already approved um anecdotal. But I think my my experience has been that politician map based regimens seem to behave the best in terms of efficacy and are well tolerated. So that's that's usually my first go. Um curious to hear what others have to say about that as well though I would have struggled with it because I want to know and I have actually sequenced probably most of my relapse, diffuser, visual and Thelma. I want to know the genetic makeup but I admit that on a practical level they will. The choice of therapy does not depend on it. I can't think of a good rational to choose the land over Polaroid toxin up. Um for someone's albums on the basis of their genetic makeup. I'm probably when when they really look like high grade lymphomas, I start to worry about all of them and just trying to think about allergenic transplantation. That's um these are rare cases. Yeah, that's a I think a really outstanding point adam is for many people who are who are fit. I really try to get them to and aloe and um I've had several cases of very long term um permissions such as they can be given how long cars have been out um after car failure if if the patient's fit and can get them right to an aloe. Um after getting them into remission, It was about a patient who had P53 mutation complex cardio type is just the worst possible when somebody could think of and went into complete remission with astigmatism map and politician happens. Um That was the last time we heard something. All right. Um well, it's 9:35, so I think we'll um give everyone a 15 minute break. Um I want to thank everyone um who presented in this session and our panelists. And for you guys, you can hopefully enjoy the rest of your weekend.