Prologue

DR LOVE: Good afternoon, everyone. I’m Neil Love from Research To Practice, and welcome to Challenging Cases from the Community, as our investigator faculty provide perspective on the optimal management of diffuse large B-cell lymphoma. We have a great faculty today for this program: Dr Jeremy Abramson from the Massachusetts General Hospital in Boston, Dr Jason Westin from MD Anderson Cancer Center in Houston, and Dr Soni Smith from the University of Chicago in Chicago.

We’re going to chat a little bit about where we’ve been in the past and where we’re heading, and then we’ll jump into some of the major controversies in the field. And as always we have a bunch of cases from docs in practice, general medical oncologists who see these patients all the time. They’ll be presenting cases, and we’re going to be making rounds with our faculty, which should be a lot of fun.

So we’re going to get started. Here are the docs. These are, again, general oncologists who will be presenting the cases today.

So Jeremy, just as a little bit of a prologue, it seems like we’ve been struggling to find a way forward in this very common lymphoma for a long time, a lot of unsuccessful attempts to go through — get past R-CHOP. And we’ll talk about the POLARIX study, a modest step forward that we can talk about what it means clinically. But I’m curious too because you starting to see things like this in a lot of cancers, Jeremy, all kinds of pathways and ways to attack the cancer. I’m just kind of curious what your global thought is and what we’ve learned about the biology of this disease. And from your point of view how we’re really going to make some substantial moves forward in the next 5 or 10 years.

DR ABRAMSON: Yeah, well we’ve made so many advances in diffuse large B-cell lymphoma in the last several years it’s almost made your head spin. After years of doing R-CHOP, and when that didn’t work we’d do R-ICE and a transplant or another type of chemotherapy. Now we use targeted therapies in the relapsed/refractory setting, targeted immunotherapies, and are poised to incorporate polatuzumab vedotin for higher-risk patients up front with DLBCL.

A lot of things have been tried. I think those — in DLBCL the biggest things that have moved the bar forward are those things that are targeting the cell surface. We’re looking at CAR T cells targeting CD19, bispecific antibodies targeting CD20, tafasitamab targeting CD19, polatuzumab targeting CD79b, and there are further drugs coming down the pike. Targeted therapies, things like BTK inhibitors, seem to work in small niches of patients, like patients with MYD88 and CD79b mutations, lenalidomide more selectively in ABC patients. But what’s striking is that it’s targeting the cell surface itself where our major advances have been made recently in our newly-approved targeted therapies.

DR LOVE: Jason, any thoughts?

DR WESTIN: Yeah. I agree with what Jeremy said, and it’s been very frustrating that we have this beautiful slide showing a handful of agents that are approved and a lot more that are coming and yet R-CHOP now 20-plus years after the addition of rituximab and nearly 40 years since the onset of CHOP as a therapy is still king. That is something that is daunting, and it’s probably due, as Jeremy mentioned, to the ubiquity of targets and the many, many subtypes of large cell lymphoma that CHOP works relatively well in. So I think we have a lot of work to do to figure out the right subtypes that potentially could benefit from something that’s more targeted and not just a 1970’s chemotherapy.

First-line treatment

DR LOVE: So Soni, I’m going to present a case in a second. I want to get your thoughts. These are 3 of the most-discussed issues. There are many others that we are going to talk about here tonight, but of course the POLARIX trial that came out last December at ASH using polatuzumab up front, and then immunotherapy, particularly with CAR T and bispecifics, we’re going to spend a lot of time on tonight.

And I want to start out with one of the docs, Dr Neil Morganstein from Summit, New Jersey. I sat down with him, and I said, “Well, have you had any diffuse large B-cell cases?” He goes, “Yeah, I’ve had 2 in the last week.” Just telling you what general medical oncology practice can be like, very different kinds of scenarios, because I was curious how the POLARIX scene is playing out in community-based practice. So he told me about the 2 patients, we’re going to talk about one in a second, but the first one I thought was relevant to POLARIX. Here’s Dr Morganstein.

DR LOVE: Any questions about the POLARIX trial and upfront POLA-CHP?

DR MORGANSTEIN: I’ve had 2 recent cases just within the last week. One was a straightforward young guy with a GCB diffuse large B-cell lymphoma.

And then I had an older gentleman with an activated B-cell phenotype, but his performance status just wasn’t good enough for me to utilize the POLARIX regimen.

What’s very interesting is that I believe there’s now a vincristine shortage, and vincristine’s getting exceedingly difficult to come by in our hospital.

Just got this memo. We have enough to treat existing patients, but they don’t know what they would for future patients.

DR LOVE: Wow.

DR MORGANSTEIN: So potentially this is where I might use it kind of because I don’t have anything else. I need a little nudge to get me moving towards it.

DR LOVE: So I didn’t know about the vincristine. I don’t know how widespread that is, Soni, but any thoughts about this clinical scenario he’s facing with a young patient with a lot of disease but a GCB subtype? We’ll talk about the POLARIX study, again, that was presented at ASH and then published in the New England Journal. Any general reaction? And how does it fit into your thinking now, Soni, since December?

DR SMITH: Yeah, so just to take a step back, the POLARIX trial was a randomized Phase III double-blind study of polatuzumab vedotin plus R-CHP versus R-CHOP standard chemotherapy, and it was restricted to high-risk patients, so essentially everybody had to have an IPI of at least 2. And the main primary endpoint was event-free survival, and there was a modest, as you alluded to, 6% improvement in progression-free survival and no difference in overall survival.

So the question now is how do we use this information. Do we use it generally or do we look at the forest plot and try to pick and choose the patient. And I think in general if — we saw that the toxicity was very similar other than maybe some increased infections in the pola arm. I think if it’s available that’s a conversation you have, and you use it.

I think in terms of the subgroup analysis, where it might be restricted to a non-GC or a GC patient, I think is more debatable. That was an unplanned subset analysis that was done, and I wouldn’t use that right now to pick patients. I mean there is a tendency towards more activity in the ABC subtype, but maybe it’s because those patients also tend to have worse disease. We know ABC is a negative prognostic factor. Maybe they have a higher IPI. So…

DR LOVE: So Jeremy, this are you a lumper or splitter kind of thing is throughout oncology. I feel like we talk about this every day about PD-1, do you use it in PD-1 low if the subset analysis doesn’t show any benefit. Any general thoughts about this approach, Jeremy? You could look at it as 5% or you could look at it as 25%, 30% relative risk reduction in the risk of recurrence without much in terms of toxicity. Any thoughts, Jeremy?

DR ABRAMSON: Yeah. I mean I tend to lump in thinking about was my patient eligible for the POLARIX trial that showed a progression-free survival benefit. There was no overall survival benefit, but I’ve never met a patient who would prefer a shorter remission or a chance to relapse, and so I think we’d all agree that if you can achieve a better progression-free survival without significant excess toxicity then we would do that.

Now obviously patients are heterogeneous within trials, and so you have to look at the overall result. The forest plot that you saw, those were under — those were unpowered analyses. So this trial wasn’t powered to show superiority within each of these subsets. And of course they’re univariable. They’re looking at a single variable as opposed to the overall patient. And patients are famously multivariable, right? Patients have gender and age and ABC subtype, and they have bulk or no bulk. And so I think in aggregate we have to say did a patient belong in this trial, which means did they have higher-risk DLBCL.

And so certainly an IPI patient of 2 or above, I think that’s a patient I would consider offering this regimen to. If a vincristine shortage were present, I think that would be a compelling reason to think about using the POLA-R-CHP regimen since it avoids vincristine, if they had a higher IPI score. But I think this is a regimen that offers a modest but real benefit, and I would use it in a high-risk DLBCL patient regardless of their cell of origin.

DR LOVE: Jason, any thoughts? You’ll hear in a couple minutes Dr Morganstein’s other case that he got last week of an older patient with congestive heart failure. We have this POLAR BEAR study. This is way up there on my list of favorite trial names. I like POLAR BEAR. But anyhow, looking at R-mini-CHOP plus pola. Do we need to see this, Jason, to actually use this strategy? And what are your thoughts about — in general about the POLARIX strategy, but also about using it in older patients who can’t get full-dose CHOP?

DR WESTIN: Right. I think we’re all in favor of using targeted therapy as opposed to unselected chemotherapies. Vincristine is not the most potent drug in the world for large cell lymphoma and being able to put a targeted drug in its place is great. Doxorubicin is, we think, a key part of the CHOP regimen, and that’s something that’s not been yet removed from the CHOP regimen of exchange strategy. But for some patients anthracyclines are dangerous, if they have a poor ejection fraction, and you really don’t think they can get full dose.

The POLAR BEAR study is a neat trial that’s basically building on the mini-CHOP platform, and that mini-CHOP or effectively half-dose CHOP has shown great potential in older patients who are not fit for chemo.

There are other studies in this space. There was a recent interesting study presented a few years ago at the ASH Meeting looking at the bispecific antibody mosunetuzumab, which is not something that’s yet approved, but nonetheless had great activity in elderly, unfit patients. There’s a new trial launching soon, actually it’s already launched, but opening at more and more sites across the US, looking at rituximab/loncastuximab tesirine, the CD19 antibody-drug conjugate as a front-line therapy. So a lot of work to do, but the POLAR BEAR trial is one of many studies in this elderly, unfit patient population.

DR LOVE: So yeah. I like the idea —

DR ABRAMSON: Neil, if I might say —

DR LOVE: Go ahead.

DR ABRAMSON: Yeah. I totally agree. It’s a great name for a trial. I would also say that I don’t think we need the results from that trial to be able to treat elderly patients with DLBCL. It’s adding polatuzumab to dose-reduced R-CHOP, and we’re used to treating elderly patients with dose reductions all the time, right? And so I’m comfortable giving an older patient dose-reduced R-CHOP, the R-mini-CHOP doses are perfectly acceptable. And I think it’s reasonable to add in polatuzumab because pola-R-CHP will be an approved regimen for those patients. And the elderly patients in the POLARIX trial garnered more benefit than the younger patients on that famous forest plot we discussed a moment ago.

So I think oncologists are used to dose reducing drugs to minimize toxicity in older patients, and I see no reason why we wouldn’t do that here as well.

DR LOVE: Soni?

DR SMITH: Can I just — just to put a little bit of a counterargument to using this off label? Or I don’t know if it’s off label because I don’t know if there was an older age limit. But there are some drugs that are more toxic. So for example, brentuximab vedotin, which has the same agent, has an increased risk of fatal pancreatitis in older patients. So to me I — for somebody who’s 80-plus I would try to find a good trial if I could rather than just adding the polatuzumab because you don’t know how much to reduce it, so…

DR LOVE: So the art of oncology —

DR ABRAMSON: Although yeah. I don’t think there was an upper age limit —

DR LOVE: In the indication, yeah.

DR ABRAMSON: — in POLARIX.

DR LOVE: I agree. I like the idea of up-front bispecific for an older person. That sounds pretty interesting, but I guess we’ll have to wait for some data on that one.

So speaking for waiting for data, I’m want you to hear about another case. This is from Dr Parsons, a big question a lot of people ask in practice, patients with double hit, and also he has questions about CNS prophylaxis. Here’s Dr Parsons with this 59-year-old woman.

DR PARSONS: This is a 59-year-old female, diagnosed with Double-Hit Stage IV diffuse large B-cell lymphoma.

She is just now reaching cycle 5 of EPOCH chemotherapy.

She has tolerated that well and she’s had a favorable interim PET CT scan.

The first question is, do you offer EPOCH chemotherapy to patients with Double-Hit lymphoma or do you stick with R-CHOP chemotherapy?

She presented with extensive disease burden and had just an amazing amount of bony involvement at her presentation. My second question to you is, when you have patients with diffuse large B-cell lymphoma with bone involvement, do you offer those patients bone modifying therapies like zoledronic acid? And then how long do you continue it for after you’ve completed your upfront induction therapy.

My third question to you is, with all the controversy around CNS prophylaxis in patients with diffuse large B-cell lymphoma, should I offer this patient high-dose methotrexate for 2 cycles or so after she completes her induction chemotherapy?

DR LOVE: So I told you you better bring a pen and paper because they throw a lot of questions at you. I’ll just mention also to Jason, I’m going to let you tackle this in a second, but also we like to refer people to good papers. We mentioned that we’re doing this meeting tonight in association with SOHO.

There’s a really good SOHO state-of-the-art update paper on CNS prophylaxis, and Jason, just to start with that, their concluding sentence is “The prevention of secondary CNS lymphoma remains an unmet clinical need and the standard approaches of delivering methotrexate intrathecally or high dose during front-line therapy are largely ineffective.” I would ask if you agree with that, Jason. If so, why are we still doing it? But anyhow, any thoughts about this case?

DR WESTIN: Yeah, so taking on the secondary CNS or the prophylaxis part of Dr Parsons’ questions up front, Dr Parsons keeps up with the data. There is a lot of controversy in our field. There have been multiple retrospective, large, international data sets now questioning the use of intrathecal or even prophylactic methotrexate for patients that have a high CNS IPI or high-risk factors.

In our practice I do still tend to use intravenous methotrexate for people that have high clinical risk factors, and this patient was mentioned having double hit, having a lot of extranodal disease, including bony disease. In my book that probably would benefit from methotrexate, but it would also depend on the fitness of the patient to tolerate an extra — additional therapy at the end of R-EPOCH.

Just to take on briefly the other questions, and then of course turn it over to my expert colleagues, we do use dose-adjusted R-EPOCH for double hit. There’s never been a randomized prospective trial in this patient population, but the general consensus is for advanced-stage double hit that R-CHOP is just not quite potent enough, even though there’s not compelling randomized data. There’s multiple retrospective series showing that EPOCH potentially is better there. It’s not any worse, and so if a patient’s fit we would use dose-adjusted R-EPOCH for these advanced-stage double-hit patients.

And then the final question from Dr Parsons regarding bone-modifying agents. We did a randomized clinical trial a number of years ago that kind of flew under the radar using zoledronic acid versus placebo in patients who were receiving R-chemotherapy. And first off, bone disease in the sense of osteopenia or osteoporosis is dramatically under-reported because we don’t look in patients who get R-chemo. But using bone-modifying agents is beneficial to maintain bone density, avoiding bone loss.

And in terms of how long to keep it, good question. I don’t know the answer for duration, but I would say at least during chemotherapy and perhaps for several months afterwards to continue to avoid osteopenia as a consequence of the chemo.

DR LOVE: So Jeremy, what about CAR T in a patient like this? Here’s the ZUMA-12 trial looking at axi-cel in these patients, a Phase II trial. Any thoughts about where this might be heading and now indirectly this might compare even right now to R-EPOCH?

DR ABRAMSON: Yeah, well I think this is very appealing data, and I completely agree with Dr Westin that I would give dose-adjusted EPOCH-R to most patients with double-hit lymphoma as initial therapy. That regimen’s been pretty much exclusively studied with intrathecal methotrexate, and on retrospective analyses that’s been associated with a better outcome, so I usually use double — dose-adjusted EPOCH-R with IT methotrexate for most double-hit patients. There are some very low-risk patients that I think R-CHOP is reasonable, and if they’re a rare patient with limited disease I would do combined modality therapy.

But for your question about CAR T cells, I think that — the ZUMA-12 trial is a very interesting study. It specifically targets high-risk patients, patients with either double-hit lymphoma or high-risk IPI scores, starts with R-CHOP, and for patients in less than a CR they transition immediately to axicabtagene ciloleucel. Their overall and complete response rate is extraordinarily high despite the high-risk population, and their progression-free survival looks excellent, though with limited follow up to date, and I think that’s going to be the key to monitor going forward.

Ultimately I think giving CAR T cells up front to all large B-cell lymphomas or even all high IPI risk large B-cell lymphomas is probably not a particularly practical or cost-effective strategy. But something like this that really does look for an early risk-adapted approach, whether it’s using PET scans or ultimately MRD assessments, I think that will evolve over time.

But I think this strategy is very appealing, trying to identify early on a patient with chemotherapy-resistant disease and pivoting to an active immunotherapy like CAR T cells. Not ready for primetime, but I think this tells us it is ready for a randomized trial in my opinion.

DR LOVE: So Soni, I want to move on to the next case. This is a patient of Dr Choksi, a patient with Richter’s transformation from CLL that had been treated successfully for CLL prior to that time. Here’s the case.

DR CHOKSI: I see a big change in him. He’s a golfer, was not able to do golfing anymore, had significant fatigue and some shortness of breath.

So at that point we decided to consider lymph gland excisional biopsy to see his status. And he has been found to have CLL transformed to diffuse large B-cell lymphoma with Richter’s transformation. He’s symptomatic, and this Richter’s transformation looks like aggressive in nature.

At that point we had presented him to the tumor conference locally here. And then decided to proceed with R-CHOP chemotherapy after consultation with the cardiologist.

I would like to know more from experts what are the treatment options would they suggest. Would they treat this patient any differently than R-CHOP?

DR LOVE: So we’re getting a lot of cases and questions in the chat room. I’m really looking forward to getting to that. Maybe we’ll do that towards the end. But Soni, what about patients like this Richter’s transformation? Also POLARIX in this situation. But generally how do you approach these patients and what kind of results do you see?

DR SMITH: Yeah. I think one of the more important pieces that we didn’t quite hear about is whether or not there’s p53 mutation or 17p deletion because I think that really predicts for failure of chemoimmunotherapy regardless of POLARIX — polatuzumab or any other agent.

I think R-CHOP is the right initial therapy, particularly if this is a de novo Richter’s transformation. If it is somebody who has a longstanding CLL that got treated, and we think this is — if it’s clonally related people tend to do worse. If it’s clonally unrelated they tend to do a little bit better, so if you can get those things set up.

But I think R-CHOP, or given that this is a 77-year-old an R-mini-CHOP, would be okay. What I have personally done for some of these patients, and this is anecdotal, is that if I can debulk them or at least get them through a couple of cycles they’re usually intolerant to too much chemotherapy because of their marrow disease, and then I have switched over either to a BTK inhibitor or to venetoclax. And it’s palliative, but there have been a couple of long-term remissions there.

DR LOVE: You mentioned p53, (del)17p, what do you do in that situation, Soni?

DR SMITH: Yeah, I mean more often than not no matter what you do the disease is not going to respond, but I would be more likely to add in a BTK inhibitor as the initial approach.

One thing that I think is going to be hopefully game changing in CLL within the next couple of years is cell therapy, and CAR T is currently investigational for CLL, but I do think — again, anecdotally I have patients who have done really well with that.

DR LOVE: With Richter’s transformation?

DR SMITH: With a Richter’s transformation, yeah.

DR LOVE: Interesting. Jeremy, any thoughts about this? And of course you also see we have cases that we didn’t put on the video today of people with FL who transform, people who present with mixed FL in diffuse large B-cell. How do you deal with that, Jeremy?

DR ABRAMSON: Yeah. I mean I think we’re certainly left with primarily R-CHOP as the initial therapy in a patient with a large cell lymphoma regardless of what it’s transformed from. We’ve historically seen worse outcomes in the Richter’s transformations, meaning transformed from CLL, but it’s hard not to give a shot at chemoimmunotherapy since the biggest problem is not that they don’t respond, it’s that the responses aren’t particularly durable.

But I always try and get them into a remission. If you can get these patients into a remission, and they are p53 mutated or 17p deleted, and they’re transplant eligible, those are still some of the few patients I would think about an allogeneic stem cell transplant with. For a p53 or 17p-deleted Richter’s transformation, if they’re clonally related, I totally agree that post-chemo immunotherapy venetoclax does have some responses in Richter’s transformation. BTK inhibitors, they’ve usually been exposed to, but if not they’re worth a shot. Usually in single agents the response rates in Richter’s are pretty disappointing.

But CAR T cells, coming back to, I agree completely. We did have a handful of these patients included in the TRANSEND trial of third line or later large B-cell lymphoma, and the FDA label for liso-cel includes patients with DLBCL transformed from any indolent histology. And I would think about taking those patients in the third line or later setting to liso-cel if one had access. But I agree, it’s hard not to start with R-CHOP, but then think about venetoclax and CAR T cells as available options in the future.

DR LOVE: So Jason, we’ve got a case here in the chat room that I think you could be helpful with. This is from Lillian, who has a 69-year-old woman, diffuse large B-cell, IPI 4, GC subtype, having a great response to R-CHOP based on the PET after cycle 2, but struggling with neuropathy and still has 2 cycles left. She wants to know should she stop the vincristine. Any thoughts? Have you seen this happen in this way, Jason?

DR WESTIN: Yeah. This unfortunately is more common than I think we report in the studies. Vincristine is a quite toxic drug, and we talk about that with some of the antibody-drug conjugates that neurotoxicity is a concern. Vincristine, the vinca alkaloids, it’s a big problem.

Dropping the dose, especially in somebody who’s already had a great response, is certainly appropriate and has plenty of precedent to either drop the dose in half or omit it altogether for the remaining cycles. I would do that and wouldn’t lose any sleep over it for this patient who’s already achieved a great clinical benefit.

DR LOVE: So Soni, a follow up to your thought about p53. Dr Mallady in the chat room has a patient who died last week despite multiagent chemo, BTK inhibitors, p53 positive, stem cell transplant, CAR T was planned, but the patient wasn’t able to make it. There have been some p53-specific strategies that have been out there. I know there’s APR 242 or whatever, and of course a lot of the biologics are effective. Any thoughts about how patients like this maybe can be more successfully treated, Soni?

DR SMITH: Yeah. I mean I think there are a number of agents that are in development. It sounds like Dr Mallady did everything possible for this patient, and it’s terrible that it — we just run out of tools at some point.

In terms of targeting p53 specifically, in lymphoma this is not even close to primetime. I mean this remains an unmet need, and even agents like APR — I know there are other agents in development trying to target NDN, for example. Nothing is really far enough along for me to comment on that specifically.

DR LOVE: So Jeremy, a couple of other things in the chat room. Can you give dose-adjusted R-EPOCH to elderly people over age 70? Is there an age limit? And also Dr Kumar wants to know is there an entity of diffuse large B-cell not otherwise specified? And if so, how do you treat it?

DR ABRAMSON: Sure. So the answer is we can give dose-adjusted EPOCH-R to very elderly patients, and we’ve certainly given it to patients in their 70s and 80s. I think we’re all clinicians, and the art of oncology also includes dose reducing where necessary. It is a unique regimen in the sense that the infusional component of it tends to reduce some of the peak toxicities.

But the cumulative toxicities do build up. It’s very important to dose reduce the vincristine for neuropathy with dose-adjusted EPOCH-R. I’d have a low threshold in a very elderly patient to nudge down the doxorubicin and cyclophosphamide and etoposide, as we would do in an elderly patient given R-CHOP.

But I certainly think that those patients with an eligible histology like high-grade B-cell lymphomas and double-hit lymphomas should be offered a chance of cure, but obviously with personalized attention to their comorbidities and their performance status.

As far as the question of DLBCL NOS, DLBCL NOS is the most common subtype of diffuse large B-cell lymphoma. In the wisdom of the WHO, DLBCL not otherwise specified is further specified as either germinal center or nongerminal center subtype, ironically enough. But we treat them as of today the same with R-CHOP.

I think there’s another entity of high-grade B-cell lymphoma NOS, and that’s a much spicier meatball as far as knowing what to do with it. There’s long been an entity that just looks nastier than DLBCL and not quite meeting criteria for Burkett lymphoma. It’s been called Burkett like. It’s been called B-cell lymphoma unclassifiable. More recently it’s called high-grade B-cell lymphoma NOS, whereas the other subtype of high-grade B-cell are those with the double-hit cytogenetics.

We really don’t know what to do with those patients. At a genetic level they’re probably just diffuse large B-cell lymphomas that look a little angrier under the microscope. But in the absence of definitive therapy, if a patient is eligible for dose-adjusted EPOCH-R I tend to err on the side of giving them dose-adjusted EPOCH-R, but I suspect that in the next WHO iteration that this category of high-grade B-cell lymphoma not otherwise specified may no longer exist in the current form.

DR LOVE: I’m having a really good time with these chat questions. Maybe we’ll just dump the rest of the script and just let the audience run the conference. Soni?

DR SMITH: I was just going to add to Jeremy’s points that I actually find the steroids and the vincristine to be the most toxic part of dose-adjusted EPOCH-R. You can dial down — we always forget to dial down the steroids, but I find especially when they’re done with treatment, because people tend to — they want to get through the therapy, so they mask their weakness, and then all of a sudden you’re left with a lot of profound toxicity, so don’t forget to reduce that.

DR LOVE: All right. Let’s get back — let’s bet back to our docs on the video, Dr Ku. This is for you, Jason, a patient with Stage II disease. Here’s the case, a 66-year-old woman.

DR KU: 66-year-old woman. She’d be a non-bulky Stage II and also has a good risk revised IPI score.

The question that I have is for these types of earlier stage patients, if she were to receive a complete response after 3 cycles of R-CHOP, would the preference be to complete just 1 cycle of R-CHOP? Or depending on if there’s just a single site left on PET, proceed with ISRT alone? And just acknowledging her location with the lymph node involvement in the left groin and if that would be very morbid to do radiation.

I think another question is if she achieves a partial response on PET, would you give the R-CHOP for 3 cycles and give further ISRT regardless? Would there be a situation where if there’s just isolated left groin avidity that you only proceed with ISRT and not complete further cycles of R-CHOP?

DR LOVE: Jason?

DR WESTIN: Yes. This is a scenario that comes up a lot in terms of how to manage localized or limited-stage diffuse large B-cell lymphoma. And the reason it comes up is because we’ve got options to consider here, unlike for advanced stage where it’s time 6 cycles for everybody, rinse and repeat. Here we’ve got the potential for using 6 cycles of R-CHOP or 3 cycles followed by radiotherapy if the Stage II is within a radiation field.

And then we had the FLYER trial, which looked at younger patients, up to age 60, with low IPI disease that gave them only 4 cycles without radiotherapy showing equivalent results to 6 cycles.

So the way I often customize therapy for my patients is based on how they’re tolerating the R-CHOP. If they’re tolerating R-CHOP beautifully and having very little side effects, then there’s less incentive to stop R-CHOP early or to use a different therapy like radiation that may or may not have toxicities for the patient. It also depends on where the radiation field would be. As we heard in the case, some patients do have morbidity after radiation therapy depending upon what you radiate, and that could steer you to use more chemo, or if they’re in an area where radiation’s not going to be so bad, to consider using radiotherapy in lieu of the final 3 cycles.

I do use the FLYER trial in patients who are a little bit older than age 60. I know we all say follow the rules of the protocol, but I think our age cut for that trial was a little bit arbitrary. So for a patient like this who’s doing beautifully response wise from their chemotherapy so far I think you’ve got all of the above as options.

We heard the question of what if the patient has a partial response. In that situation it’s a little bit harder to argue de-escalating therapy early or stopping chemotherapy after 4 cycles or to use radiation alone. I think in that situation I’d want to keep chemotherapy going, and if the partial response was still there at the end consider getting a biopsy to see if that’s active disease. We know that positive PET scans are fraught with false positives. I don’t ever trust a positive PET scan without a biopsy at the end of R-CHOP therapy because false positives unfortunately are way too common.

DR LOVE: So Jeremy, a second opinion, and you’re not allowed to say I agree with everything that Jason said.

DR ABRAMSON: All right. I agree with most of what Jason said in that case. And so yeah, I think for non-bulky limited-stage patients, really independent of age, my most common therapy is R-CHOP for 4 cycles without radiation therapy. Beyond the FLYER trial there’s an NCTN trial led by SWOG, and there’s 2 French Cooperative Group studies, all of which looked at a shorter course of R-CHOP in non-bulky limited-stage patients. Some of them were mostly younger patients, some of them were limited to lower-risk patients. They were all non-bulky, and they were remarkably concordant, with a PFS of about 90-plus — just over 90% across these trials.

So if a patient is responding nicely to R-CHOP, and they’re achieving a PET CR after 2 or 3 cycles, I’ll finish 4 total cycles and finish out. And if they still have a positive PET scan I agree, I think the question then there is do you continue chemotherapy for 6 cycles or do you stop after 4 and radiate, and I think I tend to — if the patient is having a more sluggish response I tend to push more to 6 cycles if they’re tolerating the R-CHOP well, and then, as Jason pointed out, get a biopsy and radiate if they have persistent disease.

Bulky patients, those patients we don’t stop short at 4 cycles. For a bulky patient we’d continue to a full 6 cycles.

Bispecific antibodies

DR LOVE: So we’re going to go on to another case. Actually this is the second case of Dr Morganstein. We have a thing we do sometimes, we call a day in the life, where we put the schedule of a general medical oncologist up on a slide, and you start thinking about all of the things that they have to think about as they go through seeing patients. Imagine him seeing these 2 patients in the same week.

This is the other side of the spectrum, a 75-year-old man with severe heart failure. I use this case. Of course it’s hard to find a patient who got bispecifics in the community on a trial, but it’s a case I was curious whether you think a man like this, or a patient like this theoretically might be eligible at some point if he progresses, to get a bispecific. But Soni, I’m also curious about how you would manage this case up front. This is — he has a very poor ejection fraction, presented with a pulmonary nodule and regional adenopathy that was diffuse large B-cell. Here’s Dr Morganstein again.

DR MORGANSTEIN: 75-year-old gentleman, multiple comorbidities, severe congestive heart failure.

His EF was about 20-25%, presented grossly volume overloaded. Creatinine was 2.8.

Activated B-cell diffuse large B-cell lymphoma.

He was initially hospitalized, given his first dose of chemotherapy in the hospital. There was worry about giving his rituximab just because of the volume, so he had an aggressive diuresis. He was treated with Cytoxan, gemcitabine, very dose-reduced vincristine, and steroids, tolerated it not well, multiple hospitalizations, dose delays.

Ultimately got him through 6 cycles. He’s now in CR, now dealing with his cardiac issues.

DR LOVE: He went into CR with all that?

DR MORGANSTEIN: Yup. Yup. PET-negative.

DR LOVE: Wow.

Any questions about what to do if and when he progresses?

DR MORGANSTEIN: What kind of performance status, comorbidities, and who should be evaluated and where should they be evaluated for CAR T-cell therapy, okay?

Bispecifics, what are the toxicities for elderly, poor performance status or just where in general does it fit in?

When bispecifics come out for diffuse large B-cell lymphomas where are these medicines going to be given?

Office, hospital? And then the education for nurses, staff, and hospital needs to happen.

DR LOVE: So if you could summarize that in about an hour and a half, Soni. Just kidding, but maybe just a few — we really do need another hour for this. Anyhow, any thoughts about this? First of all the up-front treatment of this patient.

DR SMITH: Yeah. I think this is an older patient. He’s 75 with multiple comorbidities, elevated creatinine and lower ejection fraction. I think the regimen that was chosen was a good one. Alternatives when people have a cardiomyopathy or pre-existing heart failure, I typically go with R-CEOP using etoposide instead of the anthracycline. And for this particular situation I probably would have reduced everything by 50%, so really an R-mini-CEOP and then escalated as possible.

I think the choice of gemcitabine instead of CEOP makes sense given the renal insufficiency and the toxicity with etoposide in that setting, so I think both are very, very reasonable, and I’m amazed that this patient made it through and did well.

I will say that geriatric assessment and geriatric optimization are 2 pieces that need to become standard of care. And there’s actually a prospective SWOG now intergroup trial of R-mini-CHOP with or without oral azacitidine that fully integrates geriatric assessment and frailty assessment at diagnosis. And hopefully that will give us some tools, positive or negative, to take forward for other settings. So I’m glad the patient did well.

Now for the second line, this is still — I mean the fact that he’s in a CR initially is great, there is some chemosensitivity there, but when it comes to using a bispecific for this patient remember that that first cycle does include cytokine release syndrome and the immune effector cell-associated neurotoxicity. And he has a significantly increased risk for complications if he becomes hypotensive, for example, with the CRS. So I think that this is somebody that if a bispecific is considered a specialized center is needed.

Down the road I do think that giving bispecifics in the community is feasible. People will have to be comfortable with using tocilizumab, initiating steroids, having a 24/7 ability to evaluate a patient. And if you don’t have that, then I think it’s going to be difficult to integrate bispecifics into a practice.

DR LOVE: Jeremy any thoughts? And also the idea, and I’ve seen this in other situations, where maybe the patient starts out in a tertiary center and then once they get through a cycle or 2 goes back to the community. Any thoughts in general?

DR ABRAMSON: I think that’s very feasible for bispecifics, to be sure, get through the early dose escalations, the ramp-up dosing where pretty much all the CRS and neurotox occurs. The incidence of both of those is lower than with CAR T cells typically, and you get them out of the way. And so that’s absolutely entirely reasonable. Ultimately I think regional centers will be able to give bispecific antibodies safely, they’ll just need the training and resources to manage the CRS and neurotox, which compared to CAR T cells are typically much shorter lived than CAR T cells, which of course continue to circulate and expand as opposed to a drug which you can just stop administering.

For the patient that was just presented, this is one of the few patients I think I would really not think would be a CAR T-cell candidate. It would be very tough to get them through the volume issues should they develop CRS and even bispecific antibodies I think could be challenging. God forbid they were one of the few rare patients who had severe CRS and not being able to handle the volume.

So low EF, uncompensated or incompletely or poorly compensated heart failure, I would avoid those. I do think we have a good alternative. Tafasitamab/lenalidomide is approved in the second line and later setting. It has a very good response rate in the second line setting particularly, and fairly remarkable durability. That has a PFS for the entire population of close to a year, and for responders the duration of — the median duration of response is like close to 4 years. It’s really quite impressive. And so my first choice, if a patient is CAR eligible, and they meet those criteria, is to give a CAR T cell. I think it offers the best curative intent.

But not every patient is, and not every patient has access. In a patient like this we always have to remember we do have other options. I think taf/len in the second line would be a very good option if this patient recurs.

DR LOVE: So Jason, can you talk a little bit about what we know right now in terms of toxicity, complications, tolerability issues with bispecifics compared to CAR T?

DR WESTIN: Sure. They have similarities but important differences, and we’ve heard a little bit about these in that the similarities are the cytokine release syndrome and neurologic toxicity. But the differences are that the severity generally is much less, and the timeframe for when they occur is a little bit — it’s within the first cycle or 2, but that goes along with the idea that you’re dosing these for much a longer timeframe, which are a one and done type infusion. Bispecifics are often given for 8 cycles, 12 cycles, or until progression or toxicity. But that long tail of infusions of treatment schedule usually is cruise control in terms of risk for cytokine release syndrome. It’s in that first few cycles.

Generally, my impression is that if we didn’t have CAR T cells we probably wouldn’t call these reactions CRS. This is more like an infusion-related reaction, almost like a bad rituximab reaction. Those are things we generally know how to manage. They’re a little bit more significant than that. I don’t mean to undersell it. People do have fevers. People do sometimes have hypotension, rarely might require an ICU admission. And so as mentioned earlier in our discussion tonight, knowledge of how to use tocilizumab is really important in the off chance that you need to use it. But that’s going to be much less common than with CAR T cells, where it’s a live chance that you might actually need to administer tocilizumab.

So I think, as we’ve mentioned, bispecifics have a huge role to play for patients with large B-cell lymphoma. Perhaps the strategy of ramp up, get out of the weeds in terms of risk of cytokine release syndrome, and then go back home to your infusion center, your regional cancer center, that may be a way that we can get around this. But it is that long-term dosing, where you’re getting it for 8 to forever cycles, that is the hamstring, I think, of bispecifics right now.

DR LOVE: So Jeremy, these are 4 of the bispecifics, particularly — I’ve heard — we’ve heard a lot about the top 3. They all have CD3 and CD20. Can you talk a little bit about how these agents work? I’m going to, as you talk about it, clip through some of the slides we have in the slide deck for people to check out in terms of specific data. But more broadly how they work and how — the degree of effectiveness that we’re observing.

DR ABRAMSON: Yeah. This is a very exciting class of drugs. All target CD20 and CD3. We’re used to targeting CD20, of course, with rituximab and other CD20 antibodies in other lymphomas, but the CD3 binding is really what makes this an active immunotherapy. I think of this as an antibody that binds to the tumor cell with CD20 and throws a lasso around the patient’s own T-cell, brings it in for a kiss to activate the T cell, and destroy it. And so it’s really a way to harness the power of the patient’s own T cell against their lymphoma.

That of course is what CAR T cells are doing as well. CAR T cells are different. They include costimulation, and they’re I think a souped-up version. But this is a way to really help directly engage a patient’s T cell.

And the efficacy is looking quite encouraging, both in follicular lymphoma and in diffuse large B-cell lymphoma. We’re seeing CR rates with these drugs that are up to — as high as 40%, as you can see here, with this glofitamab Phase II trial. Overall response rate of 52%, 30 — nearly 40% of patients having a complete response, with rates of CRS and neurotoxicity that are actually very low and usually quite fleeting, and the use of rescue medications, such as CRS and dexamethasone, is actually quite uncommon, unlike in CAR T-cell therapy.

We don’t yet have long-term data on durability. That’s something we still need because that’s how we’re going to compare it to the one and done treatment of CAR T cells that Jason pointed out.

Mosunetuzumab was also studied in DLBCL. I’d say it had a lower, generally, overall and complete response rate but does look particularly good in indolent lymphomas where it’s likely to get an FDA label.

And epcoritamab recently had their Phase II data presented, as well, in relapsed/refractory DLBCL. This is a subcutaneous drug, unlike glofitamab, and you can see the majority of patients responded, and at last follow up have been in ongoing response with a low rate of severe CRS.

So I think these are all exciting compounds. I think the ones that are looking particularly appealing in DLBCL are the glofitamab and epcoritamab, and I’m excited to see those move forward and hopefully ultimately get a label and ultimately, of course, move forward in combining with treatment in the front-line setting.

DR LOVE: Can you talk a little bit more, Jeremy, about what agents are being combined with bispecifics and what we’ve seen so far?

DR ABRAMSON: Yeah. There are several combination strategies. There’s a couple of trials getting up and running in the up-front setting looking at combination with R-CHOP. And so kind of like polatuzumab did, polatuzumab substituted for vincristine due to the overlapping toxicity. This study here with epcoritamab is looking at it, of combining with R-CHOP, or in some settings replacing the rituximab. That’s a very appealing option, amping up the immunotherapy part of chemoimmunotherapy in the up-front setting.

There’s this other interesting trial in the relapsed/refractory setting combining polatuzumab with a bispecific antibody. I think about coming at the tumor cell from a cytotoxic element and an immunotherapy element in relapsed/refractory disease, I think that’s very appealing. And then there are a number of other potential options. We have some early data combining with lenalidomide, which we know has an immune-stimulating, activating, and modulating effect. And so combining lenalidomide as we know do with rituximab, for example, what about combining it with a more active immunotherapy like bispecifics?

We have some early evidence that that’s looking pretty exciting, as well, as well as a newer generation of these cell modifying agents are coming along. So I think we’re at the infancy of bispecific antibodies. We’re going to see these improve a lot as single agents, and I think we’re going to see some exciting combinations.

DR LOVE: So antibody-drug conjugate and bispecifics, it’s not chemotherapy anymore folks. What an incredible thought.

CAR T-cell therapy

DR LOVE: All right. Let’s talk a little bit about CAR T therapy. Again, we could spend the whole hour on this. Dr Yang has a patient who actually did great with CAR T, you’ll hear about, but then has had prolonged pancytopenia. Here’s the case of this 73-year-old woman and his questions about CAR T.

DR YANG: R-CHOP chemotherapy, she relapsed 6 to 12 months later, had R-ICE/autologous stem cell transplant, relapsed very quickly, went to CAR T. She’s been in a complete remission.

What’s interesting is that she has severe pancytopenia after the CAR T. And I’ve talked about it with the academic center is this a direct effect of the CAR T treatment. They said potentially it could be. They also said that they’re starting to see a lot of patients who have myelodysplasia. And they say they believe that the myelodysplasia is not related to CAR T, but myelodysplasia is related to all the previous chemotherapy treatments I also see some dissonance among the centers that give CAR T about how much chemotherapy to give before CAR T, I recall one of the academic centers had told me you need to have a bit of disease present for the treatment to work.

DR LOVE: Soni, any thoughts?

DR SMITH: Yeah. I think that in terms of the myelodysplasia, just to touch on that, I think that’s really hard to say. This might be — we had talked a little earlier about CHP, but I think that there’s probably a population of patients who are predisposed to multiple malignancies, and the prior therapy probably has something to do with it. I don’t think it’s the T cell itself, but they may have a risk of that.

I think the other piece of it, though, we talked about the hypogammaglobulinemia and the prolonged cytopenias, I mean I do think this can take a long time to recover, and they need very aggressive supportive care with prophylaxis, IVIg, potentially, if they don’t have MDS, to also give them some growth factor support.

But one piece I wanted to touch on was the number of cycles of chemotherapy. You showed some of the second-line diffuse large B-cell lymphoma trials. So we talked a little bit about ZUMA-7. We talked about TRANSFORM. We really didn’t talk about JULIET — I’m sorry — about BELINDA.

But essentially axi-cel, there was no real bridging therapy, there was minimal chemotherapy. It was just steroids. And in the TRANSFORM study it was maybe 1 cycle of chemotherapy on average, whereas with the BELINDA trial it was like at least 2 cycles of chemotherapy. And you see the efficacy of CAR T really diminish the more chemotherapy you give them before you get to the cell therapy. And I think that’s something we really have to understand more, but I think the message is the sooner you get those T cells collected before exposure to too much chemotherapy and the less bridging therapy you need the better patients do.

DR LOVE: Wow. I have not heard that one before. That is very interesting.

So let me go back to 1 more case and then we can talk a little bit more about CAR T therapy. Before we do, though, Jeremy, anything you want to add? We put up that slide of long-term potential complications. There are also neurologic long-term complications, hypogammaglobulinemia. Any other comments about delayed or long-term complications of CAR T, Jeremy?

DR ABRAMSON: Yeah. I mean there’s no question cytopenias are one of the big ones. Now they usually do recover, in the vast majority within 3 months of CAR T cells are Grade 2 or better. They might not be normalized. But we do see patients with prolonged profound pancytopenia. We’re clearly doing marrows in those patients. These are often heavily pretreated patients, and of course they got fludarabine with their lymphodepleting therapy, which is like a flame thrower to the bone marrow. And so we can see MDS or just a prolonged period of marrow aplasia. But with growth factor stimulation and support we usually do see recovery.

I will say that the goal of bridging therapy is really just that. It’s to buy some time for the product to be manufactured, and it should be used, in my feeling, as little as necessary. If the patient doesn’t have bulky, symptomatic, rapidly progressive disease the best course of strategy can be just to wait for their CAR T cells to be ready. Not all patients need to be bridged.

If they do need to be bridged, think less is more. Think about polatuzumab and rituximab, things that aren’t going to induce a lot of cytotoxicity. Think about radiation to an isolated area of symptomatic disease. Is this a patient that just a short course of steroids can bide them along. And if they do need chemotherapy a single cycle of chemotherapy should be enough to get their cells back.

In the unlikely event they go into a complete remission I still give them their CAR T cells when they’re ready. We do know that those patients are not in a minimal residual disease undetectable state, and we have some anecdotal evidence that those patients do expand their CAR T cells. The goal is not to induce a CR with bridging therapy, but if they happen to get a CR, their cells are manufactured, I still give them to them. They’re not going to have a durable remission from bridging therapy alone. The CAR T cells are still going to help them with a chance of cure.

DR LOVE: So speaking of bridging with polatuzumab, that’s what happened with this 45-year-old patient of Dr Mushtaq. And Jason, I’d like you to listen to some of the — this is a patient who basically was refractory to R-CHOP, again was on the way to CAR T when I talked to him, but he had some interesting comments about his experience with CAR T being in the community. Here’s Dr Mushtaq.

DR MUSHTAQ: How do the community physicians should depend or rely on the CAR T centers when CAR T rate is very low?

At least in the community, what I have seen is CAR T is not as streamlined as bone marrow transplant.

A lot of patients we send, they are a good candidate for CAR T. There’s a delay. They cannot get it.

Sometimes I feel like we are just referring too many patients for CAR T, and a very small percentage is getting CAR T.

Which one is better than the other? There are I think 3 different CAR T. And I want to send my patient for the best CAR T.

DR LOVE: So any thoughts, Jason?

DR WESTIN: Yeah. I think early referral is really important, and I think the question implies that we’re losing patients or patients who are being referred are not getting CAR T cell. There are multiple steps, including getting the financial approval and then getting the appointment for apheresis and then waiting for the cells to be manufactured. Nobody gets a CAR T cell next week with the current CAR T cells we’ve got. And so early referral really is key, and ideally doing so before a bridging chemotherapy is administered so that the T cells and the leukocytes are present, not having to wait for recovery of counts.

I think if you can refer a patient early on with a direct communication with the CAR T-cell center, not having your nurse call somebody at the 1-800 number and having the patient wait for a month to get an appointment but calling somebody and saying this person needs to be seen ASAP because they’re a CAR T-cell candidate. We’ve had greater success with getting patients through the gauntlet of getting through all of the logistical steps at that timepoint.

In terms of the question for what is the best CAR T cell, unfortunately we don’t know. We’ve not had a randomized trial comparing the CAR T cells. And so what we’re left with is analyses like the one here on the slide from Mark Roschewski’s New England Journal review paper or from our Blood review paper that Laurie Sehn and I had earlier this year which compare the randomized trials to each other but not directly, not actually having studies that are looking at liso-cel versus axi-cel versus tisa-cel.

So I think a lot of what happens is what your center is used to using. If you have 1 CAR T cell that you have muscle memory with or have ability to get an apheresis appointment quickly, many CAR T cells are chosen based on logistics not so much based on efficacy. There does in the second line appear to be a pecking order, where axi-cel and liso-cel were highly effective, and in the randomized studies hands down, in my opinion, beat the standard of care. Tisagenlecleucel did not. But all 3 are approved. All 3 are available. And if your patient can only get a CAR T cell getting any of them is better than the alternative.

DR LOVE: So Jeremy, any thoughts? Right now a lot of times it’s just like get whatever you can — what might be available, but if you had the option of choosing, let’s just talk about a straightforward situation of a patient maybe who’s already had a transplant, any preference? And any difference in what you would choose in a younger, otherwise healthy patient and an older, kind of borderline candidate?

DR ABRAMSON: Yeah. It’s a good question. I completely concur that the best CAR T cell is the one you have access to. That’s clearly the most important thing. But if we have a decision to make, and we can choose among multiple products, we have to think about both patient- and product-specific things.

Axi-cel is extremely effective. It does have the highest rate of cytokine release syndrome and neurotoxicity and the highest rate of severe CRS and neurotoxicity and might not be preferred for an older, frailer patient. I will say that there’s more recent data looking at prophylactic steroids with axi-cel in that circumstance; clearly does reduce the rate of severe cytokine release syndrome, and I would recommend using that.

I’m typically choosing between liso-cel and axi-cel. I think those have the best efficacy data in the relapsed/refractory DLBCL setting. Axi-cel has the quickest turnaround time. And so for a patient whose disease is such that you need the drug yesterday then axi-cel is typically my treatment of choice. But I think both liso-cel and axi-cel are extremely effective products. Those are typically the ones I’m going to based on the aggregate data that we have across the DLBCL indications.

DR LOVE: So one more thing I want to cover, but before I do just one other question in terms of — I flipped through the slides, and I recommend the audience check out on all the papers that came out at the last ASH looking at transplant second line versus CAR T. I just want to ask you, Soni, one of the things about the approval and about the trials was that it focused on people either progressing on R-CHOP or who relapsed within a year. In general is that your preference at this point? And what about the patient who relapses at 2 years, Soni, assuming you could access it?

DR SMITH: Yeah. I think for anybody with primary refractory disease or early relapse the SCHOLAR-1 trial — analysis and other data sets show us that the median survival is only 6 months, and now we have randomized data showing that CAR T is superior. So that is definitely my treatment of choice.

Beyond 2 years there’s actually very good CIBMTR data showing that chemosensitive disease in the relapsed setting, with a late relapse, it’s extremely effective to do an autotransplant. So that’s when I would use autotransplant.

DR LOVE: But again, just to be specific, at 2 years transplant or CAR T, theoretically, at 2 years?

DR SMITH: For the first relapse I would do an autotransplant.

DR LOVE: Yeah.

DR SMITH: Yeah.

DR LOVE: So final question. We didn’t get to see the video, but we had a case of a patient who wasn’t eligible for CAR T or transplant, Jason. Of course we have a bunch of options available. This patient happened to go on pola-BR, but before Jeremy mentioned tafa/len. We have the antibody-drug conjugate lonca-T, selinexor. Any comments about how you choose between these and how you sequence them, Jason?

DR WESTIN: Yeah. We have a good problem to have that we have a lot of weapons, and hard to choose between them for these patients who are not eligible or have already had, in relapse after a CAR T or a stem cell transplant. Pola-BR is an effective regimen. However, it the patient is potentially eligible for CAR T cell in the future, if they’re ineligible now because they’re lymphoma symptoms make them unfit, but you think maybe if you tune them up you can get to CAR T cell, I probably would not choose to use the bendamustine because we think that’s quite toxic to the lymphocytes, potentially damaging the ability to make a quality CAR T-cell product.

Tafa/len also could be problematic there in that you’re targeting CD19, and then you’re going to go back to CD19 again. But for most of these patients where we’re talking about non-CAR or nontransplant, they’re not going to tune up and get to that. They’re elderly. They’ve got organ dysfunction, or they just don’t want to pick up and move to a CAR T-cell center. So I think pola-BR, often I omit the benda even if I’m not going to give CAR T cell because I don’t think bendamustine’s particularly effective there. Or tafa/len or lonca/rituximab tesirine all are highly active agents in this noncell therapy population.

DR LOVE: So Jeremy, Soni, and Jason, thank you so much for joining us tonight. Be safe, stay well, and have a great night.