Introduction: Overview of Diffuse Large B-Cell Lymphoma (DLBCL)

DR LOVE: Good afternoon, everyone. I’m Neil Love from Research To Practice, and welcome to Exploring the Current and Changing Paradigm for the Management of Newly Diagnosed Diffuse Large B-Cell Lymphoma, or “what do you think about the POLARIX trial” is another way to put it. We have a great faculty today to discuss this really landmark data set and more about diffuse large B-cell lymphoma. Dr Chris Flowers — Flowers from MD Anderson Cancer Center in Houston, Dr Neha Mehta-Shah from the Washington University School of Medicine in St Louis, and Prof Greg Nowakowski from the Mayo Clinic in Rochester, Minnesota.

As always, if you have any questions or cases you’d like to hear the faculty respond to, just type them into the chat room, and we’ll talk about as many of those as we have time.

If you’re into audio programs check out our Oncology Today podcast series, including a recent program with Dr Jonathan Cohen on CAR T therapy in non-Hodgkin lymphoma.

We do webinars all the time. Next Monday we have a great one on BCMA therapy in multiple myeloma. Not only the antibody-drug conjugate, belantamab mafodotin, but also the bispecifics. So much excitement about that as well as CAR T therapy.

We’re doing a program next Wednesday on small cell cancer. We’ll talk about immunotherapy and new agents in that disease. And a week from this Saturday’s our first all-day spectacular. We’re doing 6 webinars in a row, 12 investigators. We’ll cover 20 tumor types. Get your iPad, your phone, settle in on your couch or at the beach and spend the day with us a week from Saturday. It should be really an awesome time.

The following week, on Tuesday, February 15^th, right after Valentine’s Day, we’ll talk about immunotherapy in non-small cell lung cancer. And then we’re heading out to San Francisco for the GU symposium. We have a big program that’s going to be live simulcast on prostate cancer and bladder cancer as well.

But today we’re here to talk about diffuse large B-cell lymphoma and of course particularly the trial, the randomized Phase III trial just presented at the ASH Meeting. We’re so excited tonight because we have the opportunity to do something we really haven’t done before. We’ve used the technique we’re going to show you tonight to try to shift through these data, but we’ve never had the opportunity to do it just 6 weeks after these data were presented. So we’re really excited about that.

I worked with each faculty person separately to record their presentation and chat with them a little bit about the data in this area. You can check that out. We’ll send you an email with everything posted, including this webinar, for your colleagues as well. But we’re not going to spend a lot of time going through specific data slides tonight. We’re just going to talk about kind of what it means and where things might be heading after seeing this.

So what we did was over really the last week we were able to recruit 20 clinical investigators, including our faculty, to complete a survey about up front — mainly about up-front treatment of diffuse large B cell. We’re going to show the results of the survey and chat about a lot of the questions that docs have about the data set that came out with POLARIX as we go through this.

So here’s where we’re heading. The faculty’s going to be presenting cases today. Just a reminder, today we’re going to do 75 minutes, so an hour and a quarter, a few extra minutes. We have a lot to talk about today. We’ll start out, talk about a little bit of an intro and hear a case, kind of where things were in terms of R-CHOP. Then we’ll talk about the POLARIX trial, hear about a patient who was actually on the trial. Then we’re going to jump into this clinical investigator survey. We’ll talk about where things are heading in terms of future developments, and then we’ll finish up with a case of an older patient and talk about that challenging situation.

So just to get started, Neha, maybe you can talk a little bit about this 33-year-old woman that you manage who has germinal cell center diffuse large B cell. She actually ended up getting R-CHOP. Can you talk a little bit about what happened with her?

DR MEHTA-SHAH: Of course. She was — she had developed a supraclavicular adenopathy that came up over a relatively short period of time, otherwise was feeling completely well. And she underwent — she saw her primary care doctor, got an ultrasound, had labs that looked unremarkable, including normal LFTs and a normal LDH. And so when she saw us after getting a biopsy it showed germinal center phenotype diffuse large B-cell lymphoma. She had FISH that was negative for MYC, BCL2, and BCL6. And given how well she looked and felt we were a little bit surprised because she ended up having significant disease in the adnexa, as well as liver involvement in addition to other adenopathy in the mediastinum and hilum.

DR LOVE: So before you go on, I’m just curious, Greg. Any thoughts about what you’ve heard so far? How would you be thinking through her case a couple months ago? How are you thinking it through right now?

PROF NOWAKOWSKI: Yeah. So what’s interesting about this presentation, that she was a little bit surprised that there was liver involvement because it’s a GCB subtype presenting with cervical adenopathy. Somewhat unusual to see liver and adnexal involvement in this case. You wonder if the molecular profiling, apart from Hans grade was done, which actually showed that maybe this is indeed ABC subtype. Although histochemical specification is usually consistent with immunohistochemistry, and it can happen, extranodal involvement can also happen in the GCB subtype for lymphoma.

I think if you look at the IPI of this patient it’s going to be increased because of the staging studies we showed here, and in the view of the POLARIX data, and we can have the discussion later on, this is one of the patients that potentially would fit criteria for this trial to benefit from the addition of polatuzumab vedotin to therapy. And we can talk about some of the mutations and specifically in GCB subtype of the data set later on.

DR LOVE: So Chris, any comments on this case? And does the liver involvement change the way you view this?

DR FLOWERS: Well this is someone who presents with diffuse large B-cell lymphoma at an age that is dramatically younger than the typical population, and there’s a number of these features that suggest this is quite aggressive disease. As Greg mentioned, that liver involvement is one of those features that suggests that this is more aggressive than the standard diffuse large B-cell lymphoma. And as Greg mentioned, that this is someone who would have been a candidate for the POLARIX trial. And so those data that we’ll talk about is something you should take into consideration when considering treatment options for a patient like this in the future.

DR LOVE: So Neha, this is one of the slides you showed. We’re not — again, not showing all the teaching slides that you put in your talk, but maybe just comment — a little bit of an overview of diffuse large B cell.

DR MEHTA-SHAH: Yeah. So I think the important thing is that diffuse large B-cell lymphoma, although it’s named as 1 entity, really represents many different entities. We know that there are differences based in prognosis and in molecular subtyping and mechanisms of disease based on the cell or origin. I think we know even better now, based on gene expression profiling, that really you can’t lump it into 2 categories, and probably it’s more like 5 categories, and maybe in the future we’ll learn that there’s even more subtypes or better ways of classifying diffuse large B-cell lymphoma.

The categories in the WHO really are based on histologic phenotypes, so these would be T-cell histiocyte-rich diffuse large B-cell lymphoma, those that present in the skin, those that present only in the CNS. Primary mediastinal B-cell lymphoma is a subtype. And I think these are — and of course high-grade B-cell lymphoma not otherwise specified, which previously has been called double-hit or triple-hit diffuse large B-cell lymphoma. I think they’re categorized this was because the treatment for each of these — many of these subtypes is different from how we would treat other run of the mill diffuse large B-cell lymphoma. But certainly not all diffuse large B-cell lymphoma is made equal, as PROF NOWAKOWSKI was referring to.

DR LOVE: So Chris, as you mentioned, this is a very young patient, in her 30s, and she was interested in fertility preservation, actually wanted ovocyte preservation. I’m curious how you approach situations like this, Chris, both in men and women.

DR FLOWERS: Yeah. It’s definitely for any patient of childbearing age, both men and women. Fertility preservation is something that you want to discuss, and you want to discuss immediately at that first visit. That’s something, particularly for women, that needs to be initiated quickly and can be a little bit complicated to coordinate, and so organizing that as quickly as possible is important so that you can start on treatment as quickly as possible.

DR LOVE: So this lady actually got R-CHOP. Can you talk about, Neha, what happened?

DR MEHTA-SHAH: Yeah. So she had fortunately been asymptomatic and was able to get some steroids to carry her over through her ovocyte preservation, which was done successfully, and then she started on R-CHOP chemotherapy. She really did not have any complications of therapy, admissions, neutropenic fever. And then completed therapy and had a complete metabolic response. And she’s about a year out now; continues to do well and thrive. So she fortunately responded very well thus far to her treatment.

DR LOVE: Go ahead.

PROF NOWAKOWSKI: I just wanted to point to one thing, which — and then I’ll mention the beginning. I just want to make sure that our audience captured it because — I’ll mention that the FISH for MYC and BCL2 — or BCL2 translocation was negative, so this is not a double-hit or a triple-hit lymphoma. And that’s extremely important, particularly in these younger patients. So it’s definitely something which needs to be done in all patients with newly diagnosed diffuse large B-cell lymphoma, particularly younger patients, because if you have this double-hit or triple-hit lymphoma those patients would be a candidate for more intensive chemotherapy with either dose-adjusted EPOCH-R or CODOX-M/IVAC or some other Burkitt-like regimens which people use in this setting. And at least review of perspective case series indicates that those more intensive regimens are more beneficial in this setting.

It was also interesting that typically those double hits would actually happen because BCL2 translocation has to be present, so it typically would happen in GCB.

So in this case particularly there is a good reason to do that, and this was done appropriately. So I just wanted to highlight this, that this is the critical part of the workup.

The POLARIX Trial — Christopher R Flowers, MD, MS

DR LOVE: So we’re going to go on now and talk about the POLARIX trial. And actually, Chris, we’re going to start out with a patient who was actually in the trial. So we don’t even know what arm she’s on because she’s doing so well. But I’d be curious, maybe you can talk a little bit about this lady.

DR FLOWERS: Sure. This is a 71-year-old woman who I treated during the time when I was at Emory, before I moved to MD Anderson, who had Stage IV diffuse large B-cell lymphoma. She initially presented with a mass — really a mass under both arms, but it was most prominent under her right axilla, and you can see there that her PET scan showed involvement in a number of areas, most prominent in her right axillary, mediastinal, supraclavicular, and mesenteric regions. And the SUV at its maximum value on the PET/CT scan was 14.

She ultimately underwent a biopsy of that right axillary lymph node that showed a non-GCB subtype of diffuse large B-cell lymphoma using the Hans algorithm. And so this was one that was determined to be CD10 negative. She also had FISH analyses that were done that showed those to be negative for MYC, BCL2, and BCL6; so no evidence of what we would call a double-hit or triple-hit lymphoma. She had disease in her marrow, and at the time that she presented her most prominent symptom was being fatigued and to have about approximately 8 pounds of weight loss.

She did have some comorbid diseases, and those are shown there, having obesity and type 2 diabetes, had been a heavy smoker.

DR LOVE: So before we go on, Neha, any thoughts about what you’ve heard about the case so far? And again how you would think it through now as opposed to a couple months ago?

DR MEHTA-SHAH: Yeah. I think this patient firmly fits within the — clearly the criteria that were required for eligibility for the POLARIX study. She had multiple higher-risk features as well. So she has Stage IV disease with marrow involvement. She was found to have — she’s older as well. And so I think it was — I agree with Dr Flowers’ decision to put her on this study. And not to mention, sorry, that she also had non-GCB phenotype disease, which we know has inferior prognosis classically than germinal center phenotype disease.

DR LOVE: And that’s one of the interesting features to our survey that we’re going to get to in a second. But Chris, maybe you can just follow up on what happened with this lady and how she tolerated treatment and responded to it.

DR FLOWERS: Sure. So she was a woman who went on the trial, so we don’t really know which arm of the trial went on — she went on, but she achieved a complete response on therapy. She did have some mild to moderate nausea, and with one of her early cycles, cycle number 3, she had some prolonged neutropenia that was measured as Grade 3 in severity, did not have any infections with that, and proceeded through therapy without too many difficulties following that in terms of cytopenias. She did have — by the time she reached cycle 5 had some neuropathy that consisted of some tingling and numbness of her fingers. I did note that she had type 2 diabetes but did not have any symptoms of neuropathy related to her diabetes prior to starting the trial. That was ultimately determined to be Grade 1 peripheral neuropathy. When she was followed up after the trial all of that had resolved.

DR LOVE: So really interesting, and let’s talk a little bit about the data. But Chris, this is a slide in your talk that you went through kind of the clinical research strategies that have been looked at in trying to improve outcomes. It’s been a long time since we saw anything like adding R to CHOP, and that’s been a while. Can you talk about kind of where you see things heading?

DR FLOWERS: Yeah. So I think this is an important slide to consider kind of what the background that we are working with when we look at ways of improving upon R-CHOP. And so these are shown underneath this graph, are the 10-year follow up data from the original French trial that looked at CHOP, shown in the blue curve — survival curve, versus the R-CHOP arm. And what you can see there with those curves is there’s a fairly steep falloff in that first 2 years in terms of the survival for the populations in both arms.

And so approaches that have been tried to be able to improve upon that were to intensify the therapy. That included using approaches like R-CHOP14, condensing the therapy, intensifying the therapy with stem cell transplant. None of those were really approaches that worked.

Greg alluded to the approaches that tried to use predictive or evaluative criteria to identify populations like the non-GCB population or the ABC population, where we added additional agents like ibrutinib or bortezomib or lenalidomide to CHOP. None of those trials really have showed advantage over R-CHOP with those agents, those so-called R-CHOP plus X trials.

And so POLARIX is really the first trial to show an advantage over standard R-CHOP, and that’s why these data were so meaningful.

DR LOVE: So before we go back to the data and talk about it I want to start throwing in some things from the chat room. And some of this we’ll get into more with the survey. But Jitendra picking up on the marrow involvement of that last patient says, “With marrow involvement and higher-risk for CNS involvement, what info do we have?” I’ll ask Neha, maybe you’re aware of it, on pola and blood-brain barrier, pola in the CNS, Neha?

DR MEHTA-SHAH: Yeah. I don’t — I actually have to admit I don’t know of data to show the penetration of polatuzumab vedotin to the CNS. And I think on the study — the POLARIX study the rate of CNS relapse has not been reported separately. I think that’s of interest, and the authors are looking into that. But it hasn’t been reported in the paper or in the presentations quite yet.

DR LOVE: So Greg, Raje in the chat room wants to know about obinutuzumab in diffuse large B-cell lymphoma. Of course in CLL it’s a pretty significant difference compared to rituximab. What do we know about obinutuzumab in diffuse large B cell, Greg?

PROF NOWAKOWSKI: So interestingly this was compared in a front-line study called GOYA study. And the idea is that with the better CD20 antibody maybe we can improve over R-CHOP. And unfortunately this strategy did not show a significant benefit of changing the antibody from rituximab to obinutuzumab in this setting in the front line. There are also some combinations developed for refractory setting, but they were mainly Phase II studies. So we do not necessarily use it in diffuse large B-cell lymphoma, in contrast to low-grade lymphomas.

DR LOVE: So Chris, I’m calling the fall of 2021 the “ADC fall” because it’s not only this trial, but also in breast cancer we saw trastuzumab deruxtecan, much better outcomes in second-line therapy compared to another ADC, T-DM1. We now have an ADC approved in cervical cancer. I was mentioning about myeloma there’s an ADC. Can you talk about what polatuzumab is, what it targets, and how it works compared to other ADCs?

DR FLOWERS: Certainly. So polatuzumab vedotin is an antibody-drug conjugate that targets CD79b, and I think it’s a very important target for an ADC. So CD79b is something that’s ubiquitously expressed on diffuse large B-cell lymphoma. So the vast majority of all patients with diffuse large B cell will have this.

The thing that makes this distinct and an important target for an ADC is that when you look at a cell surface marker, like CD20, which is the binding site for rituximab, rituximab binds to that site and it stays external to the cell and then stimulates an immune response against the cell. Unlike that, CD79b, when binding occurs with an antibody, it gets internalized into the cell. And so polatuzumab vedotin has tied onto the end of this antibody, the drug conjugate MMAE, and so when that gets internalized that kills the cell through microtubule inhibiting in fact.

DR LOVE: So Greg, before we go on with more of the data. We know obviously polatuzumab has been approved and is being used in diffuse large B cell in relapsed disease. I’m curious about what we learned there, but also what your clinical experience was with the drug, Greg, in terms of tolerability.

PROF NOWAKOWSKI: The drug is generally well tolerated apart from neuropathy which can developed after prolonged treatment in some patients, particularly if they have residual or pre-existing neuropathy either from previous chemotherapy or associated with other disorders like diabetes. What’s interesting about it is that the approval is actually in combination with pola/BR, which actually shows significant response rate, pretty high response rate and durability of those responses. In the real practice a lot of time the bendamustine dose is reduced or omitted, and this has to do with the fact that a lot of those patients could be cytopenic or having borderline performance status.

Pola has been also used quite a bit in so-called bridging therapy prior to CAR T therapy. So we have a number of patients which are potential candidates for CAR T cells but unfortunately have quite rapidly progressive disease, and a combination of polatuzumab and rituximab here, sometimes with the omission of bendamustine, to try to avoid the potentially T-cell toxic drug, was frequently implemented in this space, which will have some implications for the future because based on the POLARIX data if we use more polatuzumab up front in the management of our patients, then this creates this bigger need, as well, for bridging therapy. It was already there. We always need better bridging therapy. But I think with polatuzumab now moving to front line for a lot of those patients this will be an even bigger unmet need.

DR LOVE: So now it’s always hard to kind of dissect out some of the clinical issues involved in tolerability, for example something like peripheral neuropathy. I’m curious what your experience has been with polatuzumab, I guess usually in combination, which makes it even more difficult, but particularly related to the peripheral neuropathy in terms of the characterization of it, whether it resolves, and just in general any quality-of-life issues you’ve observed with polatuzumab, Neha.

DR MEHTA-SHAH: Yeah. So I think, as other have said, that the use of polatuzumab post chemotherapy-induced I think may be a little bit different than in the front-line setting. I have to admit that when I had patients on the trial similarly we could not tell which patients were receiving R-CHOP and which ones were receiving pola/CHP. And on the study they had not seen a significantly higher rate of neuropathy, which was certainly of very much interest for patients and investigators on the pola arm compared to the R-CHOP arm.

So there doesn’t seem to be a higher rate of neuropathy at least compared to vincristine-based therapy with the use of polar/R-CHP, which I think is very important for patients to know, and different from the experience with other ADC drugs like brentuximab.

DR LOVE: So Chris, it’s always a good sign when you can’t tell who’s on the experimental arm. And also, you were telling me that when you all really sat down, because you were on the planning committee and part of the team there, that actually the trial rolled out almost exactly as you anticipated, which I think is really awesome. Maybe you can talk a little bit about what the study actually showed.

DR FLOWERS: Sure. So before jumping to that I’ll make one comment on the point that Neha just made, and that’s around the toxicity. There will be data that will be rolling out at future congresses looking at the peripheral neuropathy specifically, including additional data on patient-reported outcomes, where we’ve assessed quality of life and assessed the neurotoxicity segment of patient-reported outcomes. So more data on that particular point to come in the next coming meetings.

DR LOVE: Incidentally, you mentioned — Neha mentioned B vedotin. Just out of — I mean, for example, in your own mind, how would you compare the peripheral — the issue of peripheral neuropathy, I don’t know if you can do this clinically, with brentuximab, for example, compared to pola?

DR FLOWERS: Yeah. So the microtubule inhibitor in MMAE is the same microtubule inhibitor. When year-old look at the very earliest trials of polatuzumab, when it was used as a single agent in Phase I studies or used in combination with rituximab the neuropathy appears to be cumulative neuropathy, meaning the more cycles you give the more likely it is to happen. That cumulative neuropathy typically happens after about 6 or 8 cycles of polatuzumab. And so in the POLARIX trial, as you see the design here, or maybe if you go back to that design slide, what we essentially did was to give pola/R-CHP for 6 total cycles followed by 2 doses of rituximab, so 6 cycles of therapy, as we typically would give in the United States, compared to R-CHOP for 6 cycles, followed by 2 doses of rituximab.

And I think this was a really well-designed trial from a 1:1 standpoint. I guess I can say that because I was on the design committee, where we planned to enroll 875 patients, with those patients being in the age range of 18 to 80 and falling into the IPI category of 2 to 5. And you can see the risk stratification factors, with the primary endpoint being progression-free survival.

And I think it’s important to note that progression-free survival is an established surrogate for overall survival in front-line diffuse large B-cell lymphoma. We took all of those negative randomized controlled trials that I had mentioned in diffuse large B-cell lymphoma that happened over the last 20 years and used those to validate progression-free survival as a surrogate for overall survival. So a really meaningful clinical endpoint that has been validated as well.

DR LOVE: So Neha, the other thing, if you look on the lower right there, is the central lab translational work, which I think should be really interesting. Any comments on some of the things you’re looking forward to seeing as the data comes out specifically looking for some of these biomarker correlations?

DR MEHTA-SHAH: Yeah. I think — and I think we’re going to talk about this in a little bit, about the differences in patients who had germinal center phenotype versus nongerminal center phenotype and differences in outcome based on cell of origin. Some of that work had been done at a local level and then validated at a central level. And additionally the study had incorporated looking at RNA seq data to correlate the immunohistochemistry use of cell of origin to the gene expression profiling data. I think that will be of interest in the development of future trials as well and how to incorporate the more sophisticated techniques in real time for patients.

DR LOVE: So Chris, can you comment on the primary endpoint here, progression-free survival?

DR FLOWERS: So when you look at the primary endpoint, the hazard ratio comparing the pola-R-CHP arm, shown there in black, compared to the R-CHOP arm, shown in red, was a hazard ratio of 0.73. So this has demonstrated that there’s a 27% reduction in the right of disease progression, relapse, or death. And then this shows that there was alignment of that primary endpoint with other secondary endpoints like event-free survival and duration of disease response.

DR LOVE: Do you want to comment on response rates also?

DR FLOWERS: Sure, yeah. I think one of the things that is interesting about this trial, and we’ll really need to delve further into it, is we did not really see differences in response rates and very high overall response rates for both the R-CHOP arm and the pola/R-CHP arm, with CR rates in the upper 80% range and very high overall response rates. But you can see there the clear separation in the disease-free survival curves as well.

DR LOVE: And of course I guess at this point we don’t see a survival benefit. Greg, any thoughts about these data? Do you think we’ll end up seeing a survival benefit? Treatment on progression has obviously changed, and we’re going to talk briefly about that. We could spend a whole hour talking about that after ASH, so I’m not sure how easy it is to even do survival. But Greg, any thoughts about what we talked about so far?

PROF NOWAKOWSKI: I think it will be probably unlikely overall — we’ll see a difference in overall survival, even with the longer follow up. And there are several reasons for it. Number 1, our therapy for patients with relapsed and refractory disease has changed dramatically and dramatically improved. So this a difference in overall survival could be much more difficult to show because of the subsequent therapies which patients may receive.

What Chris also mentioned is there’s a significant difference in the risk of relapse or death, but it really starts a little bit later on. It starts at about 6 months, and the CR rate, or response — overall response rate, is not so different. So the trial did not necessarily have an impact on the patients early on progressing, which are typically the ones which are most likely to die from their disease within the first year or 2.

Having said so, the outcomes in the trial, in both control arm and experimental arm, particularly for the first year of therapy, is actually excellent. So I think it would be very difficult to show this early separation of the curves later on. But there’s a consistency. There’s a remarkable consistency here in all the time-dependent endpoints, so duration of response, progression-free survival, and event-free survival. That is also an important endpoint for me because some patients may initiate therapy without necessarily formal progression, and they’re all consistent and showing the benefit of adding polatuzumab in this trial.

DR LOVE: So one of the reasons we do these surveys, they’re always some surprises, and then we want to do another survey and ask questions we didn’t think about. And I was very surprised because I feel like almost any time since ASH that I’ve asked an investigator — we’ve worked with a bunch of investigators in the last 6 weeks, I feel like any time I’ve asked them what do you think about POLARIX, what are you going to do, everybody said to me, “Oh, yeah. I’m going to do that.” But that’s not exactly what we saw in this survey, really interesting subtleties there.

And Neha, anything you want to say about the subgroup analysis because one of the things that we saw was a difference of how people are at least thinking through data today. We’ll see what happens in 6 months, based on, for example cell of origin and also risk.

DR MEHTA-SHAH: Yeah.

DR LOVE: Can you comment on what was seen there and what you think about it?

DR MEHTA-SHAH: Yeah. So when you look at the forest plots you can see that — the 2 things that I’ve taken away from this. One is that IPI seems to impact the likelihood of benefit from polatuzumab-based therapy. The patients on this study could have IPI 2, and they were stratified in their randomization for IPI 2 versus 3 to 5, so they were equally represented on both arms. But those patients who had IPI 2 disease seemed to benefit less from the addition of polatuzumab. You could argue that those patients were likely to do well with R-CHOP alone, and that’s maybe the reason why we don’t see as much of a benefit in that population.

Similarly, when you look at the cell of origin, the patients who had non-GCB phenotype seemed to really benefit from pola/R-CHP over R-CHOP, but in the germinal center phenotype disease, again a better-risk population, that these patients had similar outcomes between R-CHP — R-CHOP and pola/R-CHP. So I think that’s important to consider.

I think the other point about looking at overall survival and progression-free survival is that we really are looking in this disease to wipe away the disease with their first-line therapy. Patients want to be done with their treatment for diffuse large B-cell lymphoma after finishing their first 6 cycles of anthracycline-based therapy, and lack of CR is failure of achieving adequate disease control. And then all those patients go on to other therapies, and that impacts both quality of life and cost of care and ultimately can impact survival as well. And so I think seeing improvement in CR rate is really important in this patient population.

DR LOVE: So we’ll get to the issues of tolerability in a second, but first maybe you can field some of the multitude of questions coming into the chat room. So Greg, Dr Malladi wants to know what was the rationale for the extra 2 doses of rituximab. Any thoughts?

PROF NOWAKOWSKI: I think Chris was on the planning committee.

DR LOVE: I guess I should ask Chris since you designed the trial. Sorry, Chris. Why did you put in the 2 extra doses there, Chris?

DR FLOWERS: It’s part of the kind of negotiations that goes in in designing any very large international trial. I think one of the challenges is that while R-CHOP for 6 cycles has been the standard of care in the United States, R-CHOP for 8 cycles was the standard of care in other countries. And so both the German groups and the French groups more commonly have used 8 cycles based on the original JALA trial that I showed you. And so those 2 extra doses just really got put in for our European colleagues.

DR LOVE: So I’m just kind of curious. Neha, are you going to want to use the 2 extra doses if this gets approved and you can use pola in this situation? Would you give the extra? And also, I’m curious, we could — again, I don’t want to get too far diverted, but I’m curious how COVID is affecting your approach to anti-CD20 nowadays, Neha.

DR MEHTA-SHAH: Yes. I think you bring up an excellent point. I usually do not in my standard of care setting give additional rituximab to a patient. Maintenance rituximab has not necessarily — has not shown a benefit in this patient population, and so I don’t think that the 2 extra doses of rituximab were the reason why the outcomes looked good, even on the control arm of this study. And I think in the setting of COVID and COVID vaccines and the unfortunate poor outcomes we’re seeing in lymphoma patients who are infected with COVID, being very cautious about when to use more CD20-based therapy than you need to is important.

There’s a number of studies now that have been done that show that vaccine response that occurs after rituximab-based therapy is less robust. This has been predominantly done with antibody-based therapy, which is not — antibody-based studies, which is not fully representative of the immune repertoire, but similar outcomes are now being seen amongst the T-cell repertoire as well. And so we’ve been, in DLBCL, where you don’t commonly use maintenance rituximab, it’s less of an issue. But on the topics of indolent lymphomas I think it’s very important to think about that as well.

DR LOVE: So Paramvir in the chat room wants to know “Is this trial practice changing?” Andrew says, “Is pola/R-CHP now the new standard of care?” I want to know that too, and I thought the answer was yet, but now I’m not so sure. So we’re going to get into that in a second. A couple more questions from the audience. Back to you, Chris. “With benda is there a concern for stem cell harvesting? What about pola affecting the ability to harvest stem cells in the future if that’s considered”, Chris?

DR FLOWERS: Well I answer your answered and asked question first, and that’s I think this is a practice-changing trial for any patient population that was eligible for enrollment, and you saw the eligibility criteria. When we think about bendamustine, that is something that may make it more difficult to harvest T-cells, in particular, for those patients who are undergoing apheresis for CAR T-cell therapy. And Greg mentioned this. Actually, I got a call from one of my clinical colleagues just a couple days ago, from someone who practices out in the community who’s giving polatuzumab with rituximab, so completely dropping the bendamustine, for a patient who achieved an excellent response and now is going on to harvest T cells. So dropping the bendamustine in that situation is reasonable, or dose reducing, as Greg mentioned.

We have no clear evidence that polatuzumab inhibits the ability to collect T cells or to collect stem cells prior to stem cell transplant.

DR LOVE: So Greg, Kenneth in the chat room — kind of reminds of questions we get about B vedotin in Hodgkin up front. So Kenneth wants to know if you use pola first line can you use it again later. Does the length of time between the pola and the relapse make a difference? Any thoughts about repeat use of pola, Greg?

PROF NOWAKOWSKI: So unfortunately we don’t have data in this regard, at least data that I would be aware of. I suspect the timing of the relapse would be very important in the future. We have seen it over and over again with different agents if you have a significant durability of response. In large cell lymphoma this would be somewhere between 6 to 12 months you can reconsider using the agent if the patients were showing no progression on this agent but actually achieved response, and then the responses are still seen. But because this is now just moving to the front line I’m not aware of any data on the retreatment in second or third line and the response rates to pola or a combination of polatuzumab vedotin with bendamustine/rituximab in this setting.

DR LOVE: So Greg, we were talking about tolerability issues. Anything you want to say? Anything else you want to say about what the data reported in terms of toxicity with this trial, Greg?

PROF NOWAKOWSKI: No. I think the toxicity looks very similar to R-CHOP. I was actually a little bit surprised. I was expecting that this combination would be a little bit more toxic, in particular in regard to neuropathy. And Chris mentioned that we may see additional reports and maybe deeper dive into the actual data, particularly patient-reported outcomes would be interesting. But it looks very similar to what we had seen with R-CHOP.

I would also point out that the growth factor support, right, is typically used with this combination as well, which hopefully likely avoids some of the infectious complications in this setting.

DR LOVE: So Chris, this is your conclusion slide from your talk. I highly recommend people to go through that, as well as all 3 of these talks. It really gets into the weeds, a lot of data from the trial. Can you summarize? We’re going to talk about this a little bit later, but just to precede that what your vision is moving forward, Greg, after seeing these data what the next step is.

DR FLOWERS: Yeah. So I think there a number of things listed here, but I’ll maybe focus on just 1 issue that we’ll talk a little bit more about, and that’s DTI, or diagnosis-to-treatment interval, and that’s something that Greg alluded to earlier. And it’s an important factor in diffuse large B-cell lymphoma that maybe is a little bit underappreciated. With diffuse large B-cell lymphoma what we know is those patients who have a shorter diagnosis-to-treatment interval are actually those patients that fare worse, and those particularly who have a diagnosis-to-treatment interval of less than 14 days. And that flies in the face of everything we know about cancers in general, that you want to treatment faster. But it’s really those patients who need treatment faster are those patients with diffuse large B-cell lymphoma who have worse outcomes.

And so we really need to think about therapies and approaches in clinical trials moving forward that allow us to get those kinds of patients on clinical trials. And I described a number of agents that can be incorporated into clinical trials, shown there, some of which have already been tested and may be retried in trials and some that may be incorporated into trials moving forward.

Clinical Investigator Survey

DR LOVE: So let’s move forward now and talk about this survey that we did. And in fact, the first question we asked these investigators relates to what we were just talking about, which is how quickly do you need to treat. This is our top 10 list. I think we could have made about 30 or 40 questions, but we only have an hour and a quarter. So these are the ones I thought people would most be interested to hear about.

And first, this gets into this issue of speed of treatment. Greg, you brought this up when we did your session, the question of do you need to treat the person right away on a Friday night, or can he wait a couple of days? And it looks like, again, you see a little bit of variability. I’m curious what your thoughts are and what you do, Greg.

PROF NOWAKOWSKI: Yeah. So this is an aggressive lymphoma, which typically moves relatively fast, so you definitely don’t want to wait weeks. Having said so, there are very rare situations where you would actually need to treat patients on Friday night. And actually, over the years a number of pretreatment strategies which can stabilize the patients have been developed. You can use steroids in some of those patients. Actually, steroids in newly diagnosed diffuse large B-cell lymphoma have a very high response rate by itself. You can use combination of steroids and rituximab or vincristine, as our German colleagues have shown.

In fact, some of the data from Europe indicate, from our German colleagues, again that this pretreatment may even improve the outcome and decrease the mortality the first cycle of chemotherapy because you’re improving patient performance status and sometimes cytopenias which could be related to the disease.

So yes, there are some patients, let’s say with critical airway obstruction and some other features which would make you pretreat patients on a Friday night, but most of the time with those pretreatment strategies you can actually stabilize the patient.

What Chris has mentioned is also very critical in terms of the prognostic — prognostication of these patients because the patients who progress so rapidly, the ones which tend to come to your office on Friday afternoon with a lot of symptoms, are the ones who tend to do worse with chemotherapy later on. So those are the patients who have the most to gain from adding new agents, maybe participation in clinical trials. And here is another reason why considering some of those pretreatment-like strategies to try to stabilize the patients and then maybe allow the patient to enter a clinical trial or combination chemotherapy in this setting is something which should be considered.

And one more point which I would make here in regards to the rapidity of the treatment, particularly in younger patients, you really would like to have the FISH for double-hit lymphoma, as well, as you’re making the decision. Occasionally we don’t have it, and we just have to move with the treatment. Again, in a majority of the patients with those pretreatment-like strategies you can achieve disease control.

And most of the current studies actually do allow pretreatment. So we know that most of what I’m calling modern designs of the clinical studies a variety of the pretreatments, including steroids, rituximab, and vincristine, is allowed.

DR LOVE: So Chris, I was interested in your comments about the importance of rapid treatment. You were 1 of the 2 people who checked off ASAP. I’m curious, are there any data from the real world in terms of how this is really playing out in the community, how long it takes? I’m sure at MD Anderson you get your workup back a lot quicker, I think. But what do we know about delays in treatment in real world?

DR FLOWERS: Yeah. So probably the best real-world evidence we have actually comes from Matt Maurer and the Mayo group that really described this well and looked at their diagnosis-to-treatment interval through their Iowa Mayo data set that was a precursor to our large 8-institution LEO study that actually all of us on the call are part of. And that data set showed that the median time from diagnosis to treatment in several hundred patients was about 21 days in that group and about 28 days in France. So that would speak to some of the data that you just showed — saw from — from your participants in terms of practicality of getting treatment started.

And as Greg mentioned, it’s those patients who fall in the less than 14-day category from that group that have the worst prognosis in diffuse large B-cell lymphoma, and those are the ones that are most important to get started on treatment sooner. So ASAP is really a practical matter, is that you really do want to treat a patient as soon as it’s feasible and reasonable. And we really want to shorten those times to treatment so that we can get those patients who need treatment most and need to be on clinical trials most treated faster.

DR LOVE: So a couple more findings from the survey I want to run by the 3 of you, first of all about the POLARIX study. So Neha, here are a couple questions we asked the faculty. This is getting pretty close. When we see everybody giving the same answer we call it a consensus. We see 4 different answers, we go okay, well, that’s interesting. Maybe not so much a consensus. This one’s getting there. We said, “Suppose there is no survival benefit, with long-term we don’t see — is it still — would you still prefer using R-CHP” and most of the investigators say yeah. I mean I guess if there’s no difference in tolerability/toxicity, I guess maybe cost might end up coming to be an issue.

We also asked people what their sense was about, going beyond the data, about tolerability of pola. And they all believe in the data pretty much, or most of them do, that there’s really not much difference. A couple people thought R-CHOP may be less of an issue.

And also the question of the reversibility of pola-induced peripheral neuropathy, Neha. Most people say it is reversible. I’m curious about your thoughts on these questions, Neha.

DR MEHTA-SHAH: Yeah. I think like we were alluding to earlier, that the — even if the study doesn’t show an overall survival benefit, if patients are able to be cured with 1 line of therapy as opposed to more than 1 line of therapy, I think that’s very important for patient care and ultimately then trickles down to cost of care. I think one of the major discussions that’s been had is how could the approval of pola/R-CHP impact cost of care for diffuse large B-cell lymphoma. I think you have to be very careful when you do those cost effectiveness analyses to make sure you’re looking not only at the cost of first-line therapy but what would the cost of second- and third-line therapy be.

And then looking at quality of life, to do really a quality-of-life adjusted analysis to then articulate what the impact of therapy is on day-to-day life and returning to work and returning to your day-to-day activity. I think most of our patients who have survived diffuse large B-cell lymphoma and have undergone multiple lines of subsequent therapy, like CAR T cells and autotransplant, will say that those therapies have impacted their quality of life and their ability to do what they want to do on a day-to-day basis. And so that all has to be considered. And I think that’s why the survey results look like they do, that there’s not a significant toxicity, and there seems to be a benefit in the number of people who go onto second-line therapy.

DR LOVE: So Chris, we talked about this with Laurie Sehn, very involved also with the trial. She said, “Well, we’re looking at avoiding 1 out of 4 relapses.” I mean not exactly that. The hazard rate’s 0.73. So you’re avoiding 1 out of 4 relapses, 1 out of 4 people getting CAR T and other expensive therapy, so it’s going to be real interesting to see how that plays out. Incidentally, do you say that to your patients, Chris, by using this newer therapy you may avoid — 1 out of 4 change you’ll avoid a relapse?

DR FLOWERS: Yes. I mean that’s a very good way of thinking through the hazard ratio and making it interpretable to talking to patients about it. I think the other way of looking at it is kind of at the 2-year progression-free mark where we saw that that was about a 6 1/2% difference for the group that got pola/R-CHP versus R-CHOP, so 76% versus 70% at that timepoint.

And I think if you look at those downstream therapies there was more use of CAR T therapy in the group that got R-CHOP in the trial. There was more use of stem cell transplant. I think the challenge, perhaps, if you want to call it a challenge, with diffuse large B-cell lymphoma is that for those patients who are not cured in the first line that we can still cure them in the second line with autotransplant and maybe CAR T-cell therapy, and we can still potentially cure them in the third line with likely CAR T-cell therapy there. But if you were — if I were a patient with diffuse large B-cell lymphoma I want to be cured with my first-line therapy and not need to go to those second- or third-line therapies.

DR LOVE: So let’s get to the heart of the matter. And again, we were kind of surprised. Somehow I wasn’t anticipating there’d be a difference based on cell type. I guess I should have. I figured people don’t look at those subsets that much if the overall benefit’s positive. But it turns out a lot of people do, at least in our survey.

So we presented a younger patient with ABC subtype, and you can see the vast majority of the faculty say yes to pola. But then we flip it to germinal, and we see a very different picture. Neha, any thoughts?

DR MEHTA-SHAH: Yeah. I think it alludes to what we were talking about by dissecting the forest plots. The study was not powered for such subset analyses, but it was stratified for patients based on their risk factors. And this is a very large study in diffuse large B-cell lymphoma that showed a — that was done very well, and well executed, and I think when we see that the patients with nongerminal center phenotype disease really looked like they benefitted from pola/R-CHP more than the germinal center phenotype disease, I think we take that into account for patients. Especially if they fit multiple low risk categories, I think we have a different discussion with those patients compared to patients who have nongerminal center phenotype and IPI 4 disease.

DR LOVE: So Greg, I see you actually don’t seem to change based on cell type, that you use pola for both. What are your thoughts?

PROF NOWAKOWSKI: Well, I think as Neha mentioned, this is a subset analysis. So in general we would adhere to the study eligibility criteria in the first place with selection of the patients which can benefit from this regimen. Biologically I have a difficult time understanding why this would be more active in ABC subtype of diffuse large B-cell lymphoma. Maybe it has to do with the cell signaling and importance of the surface receptor for it. But maybe it’s just because the outcome of patients with ABC subtype tends to be worse, and this was the one which showing the difference was easier.

We can speculate in many ways why this is — why we’ve seen this subset impact in ABC particularly. But again, this is a subset analysis. The overall — the goal of the study was to look at all comers, this is how the study was designed, and in all comers it did show a difference.

DR LOVE: So it reminds me of an argument we were having last night about upper GI cancers the FDA approved something would the investigators think doesn’t work, and a big argument about IOs, whether to do that. Anyhow, let’s keep moving down our list. Actually, Neha has a great case, an 87-year-old that we’re going to present at the end. But I want you to take a look at the data from the survey. And you can see there’s a consensus.

I guess over age 80 couldn’t even get in the pola trial, right, Chris?

DR FLOWERS: Over the age of 80 couldn’t, but this 80-year-old patient could.

DR LOVE: Would. An 80-year-old patient should. But in any event, Neha, you can see there’s a consensus about what to do. Just kidding. You got to 3 different — 4 different docs you’re going to get a bunch of different issues. Any thoughts about where this is heading? I know there’s a trial looking at R-miniCHOP — CHP plus pola, but what about right now? What are you thinking, Neha?

DR MEHTA-SHAH: Yeah. I think — I think one of the things is that not all 80-year-olds are made equal. There are some 80-year-olds who look fitter and act fitter than some of our 60-year-olds, and then some of our 80-year-olds who have multiple comorbidities and their day-to-day life, even prior to lymphoma, suggest that they’re much more sedentary. And I think those are very different patients in their tolerability. The geriatric lymphoma studies have shown that, like that predictors of simple things like get and go suggest — are better indices of frailty than purely looking at age. I think that’s part of the reason why I think everybody when they read this question thinks about a different 80-year-old patient who has Stage IV disease. And everybody remembers their 80-year-old who you hope to aspire to be when you’re 80, and those who would have a difficult time with treatment.

DR LOVE: We had a case presented the other day of a 93-year-old who was on no meds, no meds, 93 years old.

DR MEHTA-SHAH: Yeah. I want to be that person.

DR LOVE: So I think we’ll put that one in and say what would you do for that person. It’s interesting, though too, you see, again, a little bit of a split even in the 80-year-old in terms of pola based on cell type. ADC you can see a bunch of people are saying pola, but we flip it over to GCB and pola drops way down. So to be continued.

Greg, I want you to take a look at the findings, what we heard from these docs as it relates to specific subsets, particularly double hit, which we’re getting tons of questions. We’re getting tons of questions on CNS. We’re getting there. So Greg, double expressor. Most people are saying R-CHP/pola. Double hit, dose-adjusted R-EPOCH. What are your thoughts?

PROF NOWAKOWSKI: Yeah, well for a 65-year-old the more intensified regimens like dose-adjusted EPOCH-R would be preferred for double-hit lymphoma, even with the data which we have seen with POLARIX that the number of patients with double-hit lymphoma in this study was very small. So we can not necessarily conclude that the addition of polatuzumab would actually improve over R-CHOP significantly to consider those patients for this combination rather than dose-adjusted EPOCH-R or some of the other escalated chemotherapy schedules in this setting.

It is important to remind — to remind that there is really no head-to-head comparison, there’s no randomized study in double-hit lymphoma which would show that dose-escalated chemotherapy is actually better. The only trial, which was performed by CALGB Alliance, didn’t show a difference in common variety diffuse large B-cell lymphoma versus dose-adjusted EPOCH-R and R-CHOP. Having said so, there’s a lot of retrospective analyses and prospective Phase II studies which show that with more intensified chemotherapy regimens we see better results than we would expect of R-CHOP. And I think for the foreseeable future that’s something that we will continue doing in practice.

DR LOVE: So Chris, we’ll talk a little bit about CAR T later. Hopefully we’ll have at least a couple minutes to talk about that versus transplant trials. Those were incredible presentations. Any thoughts or comments about the use of CAR T in these high-risk situations? We saw a press release from the ZUMA-12 study with a 78% complete response rate. Anything you want to say about that, Chris? And do you think we’re moving in that direction? Do you think we’re going to get there in the next couple years?

DR FLOWERS: I certainly hope so. I think — the ZUMA-12 trial was presented at the ASH Meeting by my good friend and colleague, Sattva Neelapu, and this really has been fantastic work for a high-risk diffuse large B-cell lymphoma population utilizing CAR T earlier in the line of therapy. And we know that those are patients that when they progress on standard therapy that they’re very difficult to treat and get responses that are durable. And so very promising data.

DR LOVE: So we have a whole bunch of questions that we’re not going to show, but if you want to check out in the slide set we have posted in the room, and when we distribute this you can see. I hear some of the comorbid situations we asked about, I’m not going to discuss them because I want to get into some other things, low LVEF.

But what I want to talk about now is transformed disease, Neha. So we said, “A 65-year-old patient with a history of CLL who has Richter’s transformation.” Most people say R-CHOP. Do you agree, Neha, and what about pola/R-CHP in this kind of patient?

DR MEHTA-SHAH: Yeah. So I think in this patient population people who had — people who were on the POLARIX study were — could not have transformed indolent lymphomas with prior treatment for those indolent lymphomas, and I think in this patient population currently R-CHOP remains the standard. And so that’s what I would do in this situation, at least with the current data that we have available.

DR LOVE: Chris, any thoughts? And also we asked the question what about FL with transformation to diffuse large B-cell lymphoma. And now you see a little bit more of pola/R-CHP. Any thoughts about these 2 situations, Chris? And also where things are heading.

DR FLOWERS: Yeah. In FL I think the answer is the tried-and-true R-CHOP for the vast majority of those patients. I think that’s also a population, though, that tends to have GCB lymphomas and one that is particularly prone to the potential risk of double-hit diffuse large B-cell lymphoma, and so you need to think about what — that and making sure that you do the FISH studies and determine whether that patient population needs dose-adjusted R-EPOCH in that event.

Back to the CLL question, I think the other potential area of advancement that could have come there are the role of PD-1 inhibitors particularly in that transformation event. And I think — thinking about PD-1s, particularly on clinical trials, offer those CLL patients that have evidence of transformation, where we’ve seen high levels of response rates in those trials.

DR LOVE: Interesting. So Greg, again, we’ve got tons of questions about CNS prophylaxis. There was a really interesting paper at ASH I’m curious of your thoughts on in terms of circulating DNA. But when we asked about a couple of cases in the survey. So we have a 65-year-old man with right testicular involvement, GCB, no marrow involvement or distant disease. Would you recommend CNS prophylaxis? Most people say yes, high-dose methotrexate. 65-year-old patient, GCB, LDH is 300, PET scan reveals diffuse marrow involvement. There was a question about this in the chat room. Would you do CNS? Most people say no. Go ahead.

PROF NOWAKOWSKI: And you’ve captured it in those 2 cases very well, the differences in our understanding of CNS prophylaxis in this setting. So the difference is the first patient had testicular involvement, which is typically associated with a very high risk of CNS involvement. And we know from some of the studies, retrospective studies but also from prospective studies from International Extranodal Lymphoma Study Group that methotrexate prophylaxis is very important for those patients. I think most of us with testicular involvement, other gonadal involvement or adrenal involvement, would still consider those patients for CNS prophylaxis with high-dose methotrexate, systemic methotrexate.

Now the field has changed quite a bit in regards to prophylaxis of patients without involvement of those sites, but with high so-called CNS IPI. So those are the patients who frequently have high LDH and multiple sites of extranodal disease. There is a higher risk of CNS relapse in those patients. In the past a lot of us were strongly considering CNS prophylaxis with systemic methotrexate in those patients. Most recent data from multiple groups now, from retrospective case series, are indicating that really this high-dose methotrexate did not prevent CNS relapses.

And what was also evident from this data, that introduction of methotrexate, particularly in between R-CHOP cycles, is resulting in additional toxicity, sometimes R-CHOP delays, which actually can affect your control of disease in the first place. And that’s still patients with a high CNS IPI have high IPI overall as well. So there are still more likely to be affected by disease relapse or die from relapsed disease than from CNS relapse. So maintaining the R-CHOP intensity is really critical.

So in these 2 cases you reflected very well this change in pattern how we are approaching now those patients. For testicular involvement, other gonadal involvement, ovarian involvement or adrenal involvement, yes, but I think for the patients with just high CNS IPI most of us would not consider CNS prophylaxis with high-dose methotrexate anymore, based on the studies which we have seen.

DR LOVE: Neha, any comments? I’ve heard people talk about using high-dose methotrexate after the R-CHOP. Is that something you would consider? And what about circulating tumor DNA? That makes a lot of sense. We saw some data. Any thoughts?

DR MEHTA-SHAH: Yeah. So I think with regards to the high-dose methotrexate after R-CHOP I’ve certainly started to do that for some of my higher-risk patients, or at least talk about it. That decreases the — that changes the likelihood that the methotrexate would impact the dose intensity of R-CHOP, and so that’s important. I think the — there are multiple retrospective, very large studies that have now shown that high-dose methotrexate prophylaxis does not change the risk of CNS disease, although it’s a complication that we’re all very scared of, and I think that’s a hard habit to break. But I agree with PROF NOWAKOWSKI that in the patients who are very high risk I have started to move it to the end so that kidney injury or low blood counts doesn’t delay their dose intensity of R-CHOP.

You had asked about the CNS — CNS disease and cell-free DNA. So there is an important paper that was at the ASH Plenary Session that looked at cell-free DNA in the peripheral blood, as well as cell-free DNA in the CSF, to look for CNS disease that seemed to be highly specific and sensitive using error-corrected method sequencing. There are plans to expand on this effort to better understand how to best utilize it. But the hope would be to be able to diagnose primary CNS lymphoma without taking patients to a brain biopsy is the ultimate dream goal of a project like that. Most of those patients really had primary CNS lymphoma not secondary CNS lymphoma though.

Ongoing Trials in DLBCL — Grzegorz Nowakowski, MD

DR LOVE: So we’ve got a lot more that we were going to cover, but I think I want to talk about more taking care of patients. And so let’s go to another case. Greg, you’ve got a 22-year-old man. Go ahead.

PROF NOWAKOWSKI: Yeah, so this is a 22-year-old male who was previously healthy, really has no past medical history, and presents with dry cough, night sweats, and some weight loss. Physical examination is remarkable for actually a mass protruding from the chest. And chest x-ray shows this large intrathoracic mass. Laboratory evaluation shows that LDH is elevated, and he’s anemic. If you can go to the next slide.

And this is the staging PET scan. What you can see here is this very large intrathoracic mass with areas of central necrosis, particularly within the lung. You can also see some evidence of disease below the diaphragm here on the PET scan, as well, in the perihepatic region. If you go to the next slide.

So this is the pathology, which showed that this is a diffuse large B-cell lymphoma. It is negative for CD10 and non-GCB by Hans algorithm, and again FISH was performed for MYC and BCL2 and was negative.

In a case like this with a very dominant mediastinal mass, the differential is between primary mediastinal large B-cell lymphoma, which a lot of us would think about because of young age of this patient, versus the secondary involvement of the mediastinum by lymphoma. And this is the example where the current molecular classification can help us. So there is an assay called Lymph3Cx, which looks at the expression of 58 target genes, and that helps you distinguish between primary mediastinal large B-cell lymphoma and DLBCL. And if you do have DLBCL it helps you distinguish if this is a GCB versus ABD subtype.

And in this particular patient this was a non-primary mediastinal B-cell lymphoma, like signature, consistent ABC DLBCL, something which clinically I would not necessarily suspect from initial presentation. I think I would still worry about primary mediastinal lymphoma without this molecular subtyping.

So this patient later on went on therapy in one of the ongoing clinical trials which is using a combination of lenalidomide with R-CHOP, so R2 CHOP plus tafasitamab, the anti-CD19 antibody. So this study’s called First-MIND. It was really a study which provided foundation for currently ongoing randomized study of this strategy versus R-CHOP alone called Front-MIND. And the patient achieved remission and is doing well.

DR LOVE: So before I get Chris and Neha’s response to the case, just kind of curious, I hear this with the young patients in this situation. Was there delay in his diagnosis? Did he delay? Did the medical system delay? Or was he diagnosed promptly? Greg?

PROF NOWAKOWSKI: Yeah. That’s a great question. So what happens is we actually frequently see it in young patients. If you’re young you can compensate a lot. And what’s interesting about this patient, he’s actually a construction worker. He’s a carpenter, and very active, and he did notice shortness of breath, sure. He did notice some weight loss, but he kept working until really his symptoms go to the point he ended up in the emergency department. So some of those younger patients can get to medical attention very late, primarily because they’re young, but it’s particularly if they are physically fit can compensate for so long for those very large masses.

I can guarantee you that if I had this mass, even half of it, I would probably be very symptomatic much earlier because I’m not nearly in as good physical shape.

DR LOVE: So Neha, Danny in the chat room wants to know do you use pediatric protocol on a 22-year-old, but I noticed you were smiling while he was describing the patients, so I’m guessing you must have had a patient like this yourself.

DR MEHTA-SHAH: Yeah. It’s every few weeks I feel like we see a patient quite like this, and I would agree with PROF NOWAKOWSKI that like these patients, not only do they compensate better. One of my favorite patients is a — is like a professional biker and bikes like 50 miles at a time every day, and he could compensate for a very long time with a very large mass in his chest.

But the — I think the other part with regard to access to care is many young adults don’t necessarily see their primary care doctor. They’re not necessarily plugged in. So it takes a while for them to get in, and they often will see people who they don’t have a longitudinal relationship with, like so people in the emergency room or the urgent care, where the focus of the triage is different, which certainly leads to some delays. And they also have — they’re more likely to have something that’s not malignant, so on the part of the provider when they’re deciding what it is, you would think that a 20-year-old more likely has mono before you think they have lymphoma.

DR LOVE: Yeah. We’ve had a bunch of cases like that. Chris, what about — I’m not sure exactly how pediatric diffuse large B cell’s approached. Is it different? I mean if he were 18 or 16 would you do it differently?

DR FLOWERS: Yeah. I think probably not. I think it’s actually a little bit more common in the lymphomasphere for those who fall in the borderline or in that adolescent/young adult population to be treated with adult regimens, unlike diseases like ALL —

DR LOVE: Right.

DR FLOWERS: — that get moved towards pediatric regimens, where pediatric regimens have been shown to be better.

DR LOVE: So Greg, this slide is from your talk. We have a contest going for best trial name, and I’m going to enter the POLAR BEAR study into this one for sure. I already love GLOW. You know there are 2 GLOW studies in oncology, not just CLL? But anyhow, Greg, this is what you were talking about before, pola with mini-R-CHOP. But what about bispecifics, Greg? We’re hearing so much about that. I was mentioning we’re doing this program next week with myeloma. Where do you see that heading? Do you see them coming into the first line?

PROF NOWAKOWSKI: Yes. So they are definitely very active in relapsed/refractory lymphoma, and they have such single-agent activity with overall response rate exceeding 50%, and durability of those responses as well. You definitely would like to consider moving it to front-line therapy.

I think what’s really appealing about bispecifics, in contrast to CAR T cells, you can actually combine it with other therapies. And this year we have seen a number of reports where they are being combined with other agents, including polatuzumab, in relapsed/refractory setting, but also now moving to front-line setting in combination with R-CHOP or R-CHP. So there are a number of studies being planned and already going for the design — final design stages, and I think this will be definitely one of the most promising approaches to watch for for the future.

DR LOVE: So yeah, this idea. Glofitamab, so much excitement about that, combining it with R-CHOP or pola/R-CHP sounds really exciting. I’d love to see what that trial’s going to show. You go through a lot of the new strategies, bringing agents like tafa, which we were talking about before, into the up-front setting.

Up-Front Treatment for Older Patients with DLBCL — Neha Mehta-Shah, MD, MSCI

DR LOVE: But I want to make sure we get this 1 last case in because any case that starts out 87-year-old man’s got my interest, Neha. Can you tell us a little bit about this patient?

DR MEHTA-SHAH: Yeah. So this is an 87-year-old gentleman who is not the healthiest but lives his best life. He has CAD and had multiple stents, as well as occlusion of some of those stents, but had a preserved ejection fraction. He has a known AAA. He had prostate cancer over a decade ago and underwent prostatectomy without any detectable PSA.

And he presented with weight loss and then on further questioning he said he was having some early satiety but no nausea, no vomiting. And he undergoes a CT scan that shows a fairly large splenic mass, as well as some lower FDG-avid periportal lymph nodes and axillary lymph nodes. He underwent a biopsy that showed nongerminal center phenotype diffuse large B-cell lymphoma. His FISH was also negative for MYC, BCL2, and BCL6, and his labs had demonstrated he had some kidney injury with an elevated calcium at the time of diagnosis.

DR LOVE: So before we go, I want to see what Chris would be thinking about in the patient. I’m also curious, audience, if you like our new approach putting the docs on the side of the slides. We took that off of the Manning Monday Night Football approach. Let us know if it works for you.

Chris, what would you be thinking about with this patient?

DR FLOWERS: Well, Neil, I told you I like the approach as long as I could play Peyton. So really a challenging patient. I mean any time you see someone over the age of 80 it’s going to be challenging. This is a particularly frail and infirm patient, and so somebody that you’re going to need to think about some of those approaches that Greg described at the beginning, so giving some prephase treatment with something like prednisone. I’ve sometimes sprinkled some rituximab in there as well.

In any situation when you can give an anthracycline you would like to because that gives the patient the best chance. And so I think mini-R-CHOP is a reasonable approach for this patient if you can get in that cycle of anthracycline as a portion of the care.

DR LOVE: Greg, second opinion? And also, let’s throw in the variation of this many had double hit.

PROF NOWAKOWSKI: If this patient had a double hit the chance of remission would be probably much lower because of aggressiveness of the disease and lower response rate in those patients. Having said so, this is a lymphoma, diffuse large B-cell lymphoma. It’s definitely worth trying. And I think he would be a candidate for R-miniCHOP even with the age and comorbidities. And even this regimen, although at reduced — dose reduced, is still producing significant responses and durability of response in a large number of patients.

So I guess the message is don’t give up because diffuse large B-cell lymphoma is responsive to a number of treatments, and R-miniCHOP even, if the patients cannot get full-dose of R-CHOP, can actually be a good treatment for a lot of those patients.

DR LOVE: So Neha, I can imagine you taking a deep breath and walking into that man’s room and saying, “Here’s the plan I’m going to propose to you.” So what happened with this patient?

DR MEHTA-SHAH: Yeah. So we admitted him to the hospital to get some IV fluids and get the ball rolling. He got prephase steroids for just 4 days while we got everything lined up and repeated his echo. And he got R-miniCHOP. He completed 6 cycles without any further complications or admissions or neutropenic fever. And he is now 2 years out, still thriving and enjoying watching football on Sundays, so…

DR LOVE: So yeah, last week we had Eddie Garon from UCLA. He was all pumped up. He’s got — he had tickets to the game on Sunday. He’s trying to get a ticket to the Super Bowl. We’ll see what happens here.

Chris, any final comments about this case, and really just reflecting back on what we’ve been chatting about today, Chris?

DR FLOWERS: Yeah. A really exciting time for patients with lymphoma. We’ve talked about a lot of exciting data. There’s even more exciting data that we didn’t get a chance to talk about in the CAR T-cell field, so really looking forward to the future of these trials playing out in clinical practice.

DR LOVE: Yeah. I didn’t even get a chance to ask you guys what you think about the CAR T — let’s do that. 30 seconds, real quick. Greg, are you ready to give CAR T second line in diffuse large B cell? Would you like to in spite of the fact that 1 out of 3 trials was negative?

PROF NOWAKOWSKI: Yes. If I was to answer in 30 seconds I would say yes. There would be some factors of patient selection now for patients who achieve CR maybe with bridging therapy I would consider still for high-dose chemotherapy and stem cell consolidation. But overall I think it will be a practice-changing — those 2 studies are practice changing.

DR LOVE: Neha, agree/disagree or in between?

DR MEHTA-SHAH: No. I agree. I would say especially for the primary refractory patient population, the very high risk, this seems to be very important, an earlier incorporation of CAR T cells now has repeated evidence of benefit. I think the key is the logistics of making sure we’re able to do that efficiently and get CAR T cells into patients quickly as opposed to having lots of lags in that process.

DR LOVE: And having spaces to treat them, which I think may be an issue. And we’re going to actually be talking on Monday about myeloma. We’ll be talking about CAR T, as well as bispecifics in the discussion with Dr Berdeja and Raje.

Neha, Chris, and Greg, thank you so much for joining us tonight and sharing your experience with us. Audience, thank you for attending. We’ll see you tomorrow night — Monday night, same time, same place, 5 pm. We’ll keep up the Monday night format if we get good feedback on it. Be safe, stay well, and have a great night. Thanks, Chris, Neha, Greg.

DR MEHTA-SHAH: Thank you.

PROF NOWAKOWSKI: Thank you.

DR LOVE: Thank you.