 We’re talking about CAR [chimeric antigen receptor] T cells and how the responses are great and the durability looks great. But when it doesn’t work, when patients relapse or don’t respond, it reminds me a little of the [Henry Wadsworth] Longfellow poem about the little girl with the curl on her forehead. “When she was good, she was very, very good. But when she was bad, she was horrid.” What do we do about CAR T cells that are horrid, when they aren’t working? What’s our next step? Is it all these things that we’ve talked about? Is there anything that anyone favors? That’s a question that comes to me.

 That’s an excellent question. In addition to those relapses after CAR T cells, which can happen relatively early, those patients frequently have profound cytopenia from lymphodepleting therapy, which makes another candidate for many of the therapies that we use in this setting. It’s a very challenging population. Multiple reports show that survival of those patients is extremely poor, particularly if they have cytopenia, because it corresponds to more aggressive relapse. What do we do for those patients? What do you do in your practice?

 I like bispecifics in this setting, but obviously that means trying to find them on a clinical trial. I also like second cellular therapy trials, either CARs that target more than 1 tumor antigen or CARs that target a different tumor antigen. With allogeneic CAR T cells, we’ve seen some activity post autologous CAR failure. Those are my preferences, but I’m always trying to get those patients to an allotransplant because they’ve already proven to us that their remission isn’t going to be durable to an immunologic therapy.

When a trial isn’t available to me, or the patient isn’t a candidate for a trial, this is where I go to with or without bendamustine and Rituxan [rituximab]. As I said before, I’d also use tafasitamab and lenalidomide if the patient is still CD19 positive. It’s going to be interesting when more patients get polatuzumab in the front line. That isn’t going to be an option for either bridging before CAR or relapse after CAR, so it’ll be interesting to see how the landscape changes with new approvals.

 We don’t know the best treatment after failure of CAR T cells. That’s a huge unmet need because we’re seeing CAR T cells move up earlier. I agree with Caron. Getting them into remission is key. If you’re able to do an allogeneic transplant, that’s how I try to do it. But I’d also add that as we move them into the second line, there’s an outstanding question. After we’ve done CAR T, maybe in the second line for a patient, could they benefit from an autologous transplant if they progress on CAR T? We don’t know the answer to that.

 It’s similar. For example, we’ve had patients on the PILOT study, which was designed for people who aren’t candidates for stem cell transplant. But we’ve had people on that trial who progressed then had a transplant. We said, “You’re 73, which is the reason you went to CAR T first, but the performance status is good now, and we’ll try a transplant,” and we’ve had people who have had long remissions. We also try allotransplant in younger patients. I explain to patients that CAR T was derived from the idea of allotransplant, but now we’re talking about an educated T cell that’s going to treat their lymphoma. An allotransplant is an uneducated T cell that’s going to treat [their lymphoma]. Why is that going to be better? We try it, but I have this thing in the back of my head that says, “Why does that make sense?”

 In Hodgkin lymphoma, there’s some evidence to support sequencing an autologous transplant or going back to chemotherapy after CAR T-cell therapy in the second line that either led to partial response and then relapse or led to a complete response followed by a relapse. We definitely see that after patients get immune checkpoint inhibitors, they can respond to chemotherapy regimens that they didn’t respond to before the immune checkpoint inhibitors. There’s clearly a chemotherapy resensitization following immunologic therapies. I recently had a patient who relapsed a year after liso-cel [lisocabtagene maraleucel] in the second line, and she was primary refractory. She responded beautifully to chemotherapy and had an autologous transplant and did great. There’s a valid reason to try that approach.

 You’re touching on something very important with the sequencing of therapy and how the choice of therapy can affect subsequent therapies, or some of the gains in progression-free survival resensitize patients to therapy as well.

Videos

Drs Nowakowski and Gordon discuss treatment options after disease relapse on CAR T-cell therapy.

Treating Patients Who Relapse or Progress on CAR T-Cell Therapy

 Will bispecific antibodies replace CAR [chimeric antigen receptor] T-cell therapies too?

 I thought Michael Dickinson’s report [at the American Society of Clinical Oncology Annual Meeting] was impressive. I didn’t expect to see that.

 Do you think it would replace CAR, though?

 I don’t know. I never thought it would.

 Are you speaking to the glofitamab data? Is that what you’re referencing?

 Yes. I was more impressed than I thought I’d be.

 The median PFS [progression-free survival] was still 4.9 months. It has the baggage of obinutuzumab along with it. Granted, it’s 1 dose. I see it as a shepherd that replaces polatuzumab rather than a replacement of CAR T cell.

 The biggest advantage of bispecific antibodies is that you can combine it with other therapies at the same time. Those combinations appear to be quite feasible. The response rate is quite impressive. With already long follow-up, those responses appear to be durable from the initial studies and in combinations.

 What was amazing across the board, whether it’s glofitamab, mosunetuzumab, epcoritamab, or all the other bispecifics coming, is the non-hematologic toxicity. I often think that if I’m going to use it as a shepherd to cellular therapy, I’m looking for non-hematologic toxicity, like grade 3 to 4. I want disease stabilization without ECOG migration—meaning from 1 to 3 in ECOG score—so that when I’m doing lymphodepleting chemotherapy, my colleagues aren’t looking at me like, “Really?” That has an adverse event profile that satisfies me. I couldn’t care less about their temporary neutropenia or fever that they also had when they got their COVID-19 shot. It’s going to find its place. The real question is: if you get them to into a CR [complete response], then what do you do? Because that’s where there could be a potential for durability.

 Yes, the data were impressive with glofitamab, and that’s a therapy that’s probably going to end up as part of our standard-of-care armamentarium based on the data. But when I look at it, I don’t see it as a replacement for CAR T. I see a 35%-to-38% CR rate. For patients who had a CR, it’s very durable. At 2 years, 60% of them are still in remission. But 60% of 35% isn’t comparable with CAR T cell therapy. I wouldn’t think—at least in this current iteration—that it’s going to replace CAR T, but how we’re going to use it is an open question.

 About a third of the patients had prior CAR T and responded. But we don’t know the duration of that response in the post–CAR-T setting either. We didn’t have those data.

 They may have been driving some of the hematologic toxicities that were reported too, so it’s going to be very important to follow those data and watch it dichotomize between pre–CAR-T and post–CAR-T patient populations.

 I have 1 more thing to follow on your toxicity comment. Yes, the hematologic toxicity seem reasonable, but there was CRS [cytokine release syndrome] in that glofitamab data set, and it was 60% within the first few weeks. There was even a subset of almost 10% grade 2 CRS. We have to think about that in terms of how we administer those therapies and do it safely, whether that can eventually be done in the community or if this can be a therapy that’s done in sites like ours. But after the first month or so, it seems as if all those toxicities [dissipate].

 It makes me wonder what we would call this fairly predictable fever and hypotension that’s responsive to fluids if this class of therapy was developed outside a CAR T cell. What would we call it in the prior pre–CAR T-cell arena? First-dose rituximab [Rituxan] infusion—

 First-dose Rituxan. It’s another antibody.

 It’s a balance that we’ve shepherded CRS into this space. But is it really CRS?

 The close part is that there are T cells involved, and that might even be true with Rituxan.

 It has also been interesting to see how much tocilizumab is being used in this space and what a grade 1 or 2 CRS after a bispecific looks like.

Physicians speculate on the potential impact of bispecific antibodies on the treatment landscape of DLBCL.

A Closer Look at the Potential Impact of Bispecific Antibodies on the DLBCL Treatment Landscape

 There’s a new wave of real-world data from closely monitoring patients for a number of covariates. Some of this analysis was done in the setting of a tafasitamab-lenalidomide study. There was the RE-MIND study, which compared it with single-agent lenalidomide, and then RE-MIND2, which looked at frequently used regimens in the relapsed/refractory setting. What’s your take on studies like this? I’ll start with Matt.

 It definitely gave us the opportunity to discuss this analysis. It seemed as if they got traction from the agency. One major point of contention with this analysis is that it’s real-world data against clinical trial patients. If the analysis had been done in real-world tafasitamab and lenalidomide patients who were then matched to the other populations, then it would hold more water. But it certainly brought to the table the discussion about tafasitamab-lenalidomide and its place. It allowed some regimens to go under retirement. Single-agent lenalidomide is a good example. But I don’t think it’s going to retire CAR [chimeric antigen receptor] T-cell therapy.

 Some of these analyses started with CAR T cells because you had single-institution studies of CD19 CARs that were doing a phenomenal job of getting patients into remission, and it became unethical to think about a randomized trial. You had to set a benchmark. With a study like the L-MIND with tafasitamab-lenalidomide, I’m not sure it couldn’t have been a randomized study. They aren’t necessarily the same stakes. I don’t know that we should be adapting what worked to establish studies of CAR T cells into other pharmaceutical studies.

 In certain situations, the real-world look is important. CAR T is important. I was surprised to see that the data looked fairly similar to the clinical trial data. I thought the restrictions on CAR T on the trials were fairly strict, and I thought people would say, “Now that this is available, I’m going to give it to everybody.” But people are being pretty careful about it in the real world.

 First, I have a comment about SCHOLAR-1, which was an establishment of the baseline that Caron was mentioning. I agree, you don’t necessarily need that for all trials to establish. We didn’t know how a refractory patient population would do, so establishing that was important for CAR T. Now we have randomized trials, so we can look to those data.

In the real-world setting for CAR T, Caron and I published 2 complementary papers in 

] showing real-world data from consortiums that we helped put together. This was specifically for axicabtagene ciloleucel, which we and the centers had the most experience with. The results showed that the PFS [progression-free survival] and OS [overall survival] curves look almost superimposable on the ZUMA-1 trial that led to its approval. We’re being careful, but the majority of those patients wouldn’t have been eligible for ZUMA-1 because of some comorbidity or factor. The curves look the same.

It raises the question of why they’re doing the same if they have more comorbidities. My interpretation is that the ZUMA-1 trial allowed for refractory patients, patients who were getting active therapy and had progressive or at best stable disease or relapsed after an autologous transplant. In the real-world setting, we’re getting patients who responded to second-line therapy and then relapsed 4 months later. If you stratify by refractory disease vs relapsed disease, you can see that those with refractory disease don’t do as well. That’s why we’re getting those relapsed patients and why those curves look so similar.

 In our series, when we did the PFS curves for patients who were eligible for ZUMA-1 vs those who were ineligible, the group that was eligible did better than the patients on ZUMA-1. It’s probably because of what Fred is saying.

 Because we’re getting real, let’s talk about the curves. You mentioned it. Is there a tail or is it a tale? This is an important dichotomizer, because the real issue is what I call the brain-to-vein time, which is when you want to do a CAR T-cell therapy to when you can do an apheresis. Those data aren’t in the clinical trials or the real-world experience. It shows the evolution of commercial cellular therapy. How quickly can you get a person for whom you want to do CAR T-cell therapy into the machine and get those T cells pulled out?

In my opinion, in our Medicare territory, the fastest brain-to-vein time is Medicare with a supplement. But if you have a third-party payer, it’s been very hard to negotiate single-case agreements. That’s a 2-way mirror, your institutions negotiating that with a third-party payer. But that’s the true denominator of CAR T. That’s the true access issue. Until we start counting that period of time, which requires institutions to show their cards of the brain-to-vein time, I’m not sure we have the true denominator, the true impact that cellular therapy is bringing us in the real world.

 We also have that for clinical trials. There’s always delay getting somebody through the process of a clinical trial.

 But the biggest Achilles’ heel is the concept called off the shelf. Whether it’s a cellular therapy, a bispecific, or lenalidomide-tafasitamab, that’s off the shelf. All these things are in play. They’re all semantics, but they’re topics that we should be discussing in a forum like this.

 Brain-to-vein is an interesting concept. We’ve thought a lot about this at our center. The problem is: how do you define that? When does brain-to-vein start? At our center, we have a consult process for CAR T, so we know it’s intentional that this is a patient who we think could be eligible and bring them forward. But other centers may not do that. You’re seeing different kinds of patients in your clinic. When do you decide to do CAR T? How do you record that? We try to work with centers in Europe to look at their brain-to-vein time because some of their outcomes look different from ours. We say, “Maybe this is the issue.” Even there, it’s hard to capture when brain-to-vein starts. They have central reviews across the country or regionally.

 Everybody’s brain is different. That’s true. But institutionally, you can set your own brain-to-vein time, and the importance of this time period is maybe not understanding your own evolution. We all think we should be shortening that brain-to-vein time. If you do it at a single center and you know you’re shortening it, then you’re doing justice to your patients by comparing Moffitt [Cancer Center] with the University of Nebraska or Moffitt with the entire country of France, which may be different. But if we aren’t having this conversation, then we aren’t being impactful to the whole patient population. Do the PFS curves that we’re reporting in the clinical trials and real-world experience have true trails on the curves? I think they do, but this should be an intent-to-CAR discussion rather than “I got apheresed, and I got infused.”

 We’ve had this in the transplant world forever.

 How do you do that? I agree that it’s something we have to think about.

 There are also differences among the different manufacturers and products in terms of what allows you to have the shortest brain-to-vein time, because it isn’t just the insurance carriers that delay access to manufacturing slots.

 You’re sitting there ready to go and you have an apheresis slot that’s 2 weeks away.

 There are plenty of factors and variables that go beyond the institution or the payer, but we need to have those explained to the patient. Because right now, the patient feels this time. They’re feeling the vein-to-vein time and the brain-to-vein time. If we’re going to get true access into the community, we need other providers’ brains, the presynaptic brain-to-vein time between a community oncologist to a cellular therapy doctor or a lymphoma doctor to realize and make that synapse that they can be part of the shortening of this period.

 That’s where these kinds of forums help. You’re going to see people who know that this may be a second-line therapy, and referrals will come faster. At least part of this raises the question of what we do in the future. You mentioned off the shelf. Where are allogeneic CARs going to go? Maybe a bigger question is: in the next 10 years, are we going to still be sending cells to manufacturers across the country? Or are we going to be doing this at our own sites?

 Or are we going to be injecting something into the patient, and CARs are going to manufactured in vivo?

The panelists discuss the importance of using real-world evidence in addition to data from clinical trials to inform decision-making.

Comparing Real-World Evidence With Data From Clinical Trials

 In those patients who can’t go to CAR [chimeric antigen receptor] T-cell therapy and aren’t transplant eligible, but [where] it’s second line, I like tafasitamab and lenalidomide because often if they’re chemo-refractory, that’s the fastball; I want to throw them a curve ball. A CD19 monoclonal antibody plus an IMiD [immunomodulatory imide drug], like lenalidomide, is an attractive option.

If you look at the L-MIND data, there were some interesting pieces that people should know about. One of them is 1 to 3 prior lines of therapy; initially, patients with primary refractory disease weren’t allowed. The double-hits and triple-hits; we’ve discussed before that there were some sprinkled in there. They looked at those with a creatinine clearance greater than 60 mL/min and performance status. I’m not afraid to give lenalidomide to a patient who has a creatinine clearance of 40 mL/min. I just need to dose adjust the lenalidomide appropriately.

Tafasitamab is negligible. It’s an active agent that’s front-loaded, so it has the opportunity in aggressive disease to capture response and potentially have durability if you can get them into a CR [complete response], and I think that’s what the data support. There are a multitude of other agents that I think are going into retirement, including single-agent ibrutinib. I think R2 [rituximab, lenalidomide] is probably in retirement. Pola-BR [polatuzumab vedotin, bendamustine, rituximab]: the smartest thing that the NCCN [National Comprehensive Cancer Network] guidelines did was polatuzumab plus or minus rituximab plus or minus bendamustine. Gone are the days of giving a milligram of bendamustine so that you can give polatuzumab-rituximab. But if POLARIX hits and we all switch our practice, then what’s going to fill the space of polatuzumab? Bispecifics are on their way. I’ll stop there.

 Caron, Matt mentioned the tafasitamab and lenalidomide combination. What’s your experience with this combination? What’s your take on its efficacy and potential toxicity?

 We’re using it largely in patients who have gone to CAR T-cell therapy and subsequently relapsed. Often, we like to rebiopsy them and confirm that they’re CD19 positive, which many are at the time of relapse. Sometimes it’s used for patients who are not CAR T-cell candidates or autologous stem cell transplant candidates. As Matt said, it’s one of his preferred regimens for those patients. The points that Matt made are valid; that some of the patients who went on that study are some of your healthier patients with relapsing large B-cell lymphoma with a better prognosis. When we’re using it for CAR relapses that are often double- and triple-hit lymphomas, I don’t think we’re necessarily seeing the same responses. But we’re definitely still seeing responses in the clinic.

Other than the adverse effects of the lenalidomide, which you can dose adjust in order to overcome, the regimen is pretty well tolerated. I’m glad it’s in our armamentarium, but it’s a little challenging to understand how to sequence it at this point, given that I believe CAR T-cell therapy cures people with diffuse large B-cell lymphoma and I don’t want to jeopardize that, and we don’t know how it affects sensitivity to CAR if you use it before CAR T-cell therapy.

 To follow-up on a couple of things Matt and Caron said, I fully agree that referral shouldn’t be for modality. Referral should be for an opinion about management of lymphoma and then the modality gets placed in its appropriate position. If you look at the people who have relapsed within a year or have primary refractory disease—Fred can speak to this—based on the data from ZUMA-7 and TRANSFORM, in at least those 2 studies, it looks like CAR T-cell therapy offers a better progression-free survival and better response rate than autologous stem cell transplant.

That said, there are probably some patients whom you might still consider giving a transplant. For example, if you expect a patient with early-stage disease to be in CR at the end of treatment, you give 6 cycles, and there’s still a small residual mass in the axilla and nothing else. Those are patients who might be OK with radiation and maybe an autologous stem cell transplant. Maybe they’d be OK with only radiation. There are some patients whom I’d still think about giving an autologous transplant. I have the same criteria for transplant as Matt does, and we like to see people in CR or near CR. When we were looking at ZUMA-7, that was a concern of mine, because all people needed was a PR [partial response], which to me isn’t enough to go to transplant. But as it turned out, only 30% of people in ZUMA-7 wound up going to transplant, and you can speak to this.

The comment about tafasitamab and the clinical trial and picking the best patients is true, but I’m afraid that applies to many clinical trials that we do. Are we really doing clinical trials in patients who we see every day? Or are we doing clinical trials in a subset of robots? The way we do clinical trials and the way the FDA [United States Food and Drug Administration] requires us to do clinical trials has always been concern of mine. That’s why some of the real-world data are important to look at.

 You touched on something very important. Real-world data can inform some of those treatment decisions and compare the patients. It’s always difficult to make intra-trial comparisons and conclude which regimens are better, because the inclusion criteria have risk factors that vary quite a bit in those studies.

Oncologists discuss the efficacy and safety of a tafasitamab plus lenalidomide for relapsed/refractory DLBCL and share personal experiences relevant to its use.

Tafasitamab plus Lenalidomide as a Treatment in Patients With R/R DLBCL

 Right now, the reality is that about 30% to 40% of our patients will relapse after R-CHOP [rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone], and typically, those relapses happen relatively soon after therapy. Those are associated with poor prognosis. Caron, how do you choose treatment for patients with relapsed/refractory disease? What are your pathways in the clinic?

 Because of some of the randomized studies in the second line of CAR [chimeric antigen receptor] T-cell therapy, the first question is: how soon did they relapse after their frontline therapy? If it’s within the first year and they’re a candidate for CAR T cells, 2 of the studies, which we’ll talk about later, would say we should be moving forward with CAR T-cell therapy in that setting.

If they’re relapsing after a year from their initial therapy, then I ask myself: are they an autologous stem cell transplant candidate? In which case, I’d treat them with second-line chemotherapy—either standard options like R-ICE [rituximab, ifosfamide, carboplatin, etoposide] or R-DHAP [rituximab, dexamethasone, cytarabine, cisplatin]—or a clinical trial, because there are clinical trials with some of these new agents that we started to talk about today—looking at them in combination with standard chemotherapy. If they have a good response, take them to autologous stem cell transplant. If they don’t, then it’s CAR T-cell therapy. That’s how I usually approach it.

 That’s exactly how we do it at Moffitt Cancer Center as well. That brings up the question of who is a candidate for CAR T-cell therapy versus transplant? There has been some thought that they have similar eligibility criteria, but in reality, we’re able to get some of the older patients with more comorbidities through CAR T-cell therapy—patients on whom we wouldn’t have necessarily done autologous transplant. It’s important that those patients get referred in and considered, and at least have the conversation and discussion rather than make assumptions about it based on what we’re used to in the transplant setting.

 I take pause when I get a CAR T-cell referral and I say that this is a large cell lymphoma referral. It’s part of my job to look at the landscape and understand that CAR T cell is 1 piece of the landscape in relapsed/refractory diffuse large B-cell lymphoma. Because while the disease may be shunting you toward CAR T cell, other factors may not. What are those? Logistics, caregivers, financial ramifications, and insurance ramifications. All those things are factored in. You may want to do CAR T-cell; the intent may be to do CAR T cell, but you just can’t do it, so you have to be able to pivot, and maybe give another therapy while you work on or fine-tune their CAR T cell ability in that situation. It’s incredibly frustrating when you want to go to CAR T but you can’t, but we all sometimes live in this reality.

There are meaningful therapies that have response rates and can have some durability in the relapsed/refractory setting. But we have to be very choosy in what those therapies are, because if they’re going to engage the same antigen that the CAR T cell is, what are the ramifications of that? Often in the short term—maybe if you can have time away from those therapies—there may be less of an issue, but we’re in a relative data-free zone in regard to that. This is a major chess match against a grandmaster opponent in this situation. What piece you move matters, even if the queen is your CAR T cell.

 I like your comment that we should look at the whole picture as large cell lymphoma referral rather than CAR T cell referral because it fits in the landscape of rapidly changing therapies in this space. What therapies are you typically considering in your patients who aren’t CAR T-cell candidates due to medical reasons, insurance, logistics, or just refusal?

 The landscape has been a landslide from the standpoint of what was there has flown away, and we’re looking at new territory in regard to relapsed/refractory diffuse large B-cell lymphoma. What they did in their first-line setting or second-line setting, how they tolerated certain therapies, and what they received matters. Personally, it also depends on my intent. Is my intent to go to CAR T-cell therapy? Are they not a transplant candidate? Because usually the reasons that they aren’t is because their disease is refractory, not that we didn’t want to take them to an autologous stem cell transplant in certain circumstances.

Caron Jacobson, MD, and Matthew Lunning, DO, FACP, assess the available treatment options for patients with R/R DLBCL.

Selecting Among Available Treatment Options for Patients With Relapsed/Refractory DLBCL

 R-CHOP [rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone] has been there for 20 years. Fred, do you think that outcomes are improving with frontline therapy? Because if you look at the initial studies that were published, the survival curves and progression-free survival [PFS] curves were somewhat lower than we see in the modern studies. Do you think it’s due to patient selection for the studies? Or are we better at supportive care and what we do in patient selection, where patients are doing better overall with frontline therapy?

 That’s a great question. For full disclosure, I’m a transplanter and a CAR [chimeric antigen receptor] T guy, so I don’t give the frontline therapy until we’re going to talk about CAR T maybe as a frontline treatment. But I see that as well, and we, at ASH [American Society of Hematology Annual Meeting] this year, had the POLARIX data showing that adding polatuzumab to a CHOP [cyclophosphamide, doxorubicin, vincristine, prednisone]–like regimen could improve PFS, but it’s a very small difference with a lot of patients. We’re making incremental small changes.

The part I don’t fully grasp is that yes, we have these ways of looking at patients and knowing who’s likely to need dose-adjusted EPOCH [etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin] or the more intensive hyper-CVAD [cyclophosphamide, vincristine, doxorubicin, dexamethasone]–like regimen, but it isn’t clear to me that those are defining features that tell us that these patients are going to do much worse—like so bad that we need to do CAR T-cell therapy for those patients. We need to do more to figure out how we can stratify those patients in the frontline setting, because if we’re curing 60% or 70% of patients with R-CHOP or by adding other agents, who do we need to give CAR T-cell therapy to in the frontline, at least in the clinical trial setting? Obviously, it would be a clinical trial.

 Sattva S. Neelapu, MD, at The University of Texas MD Anderson Cancer Center, published some data that addressed that as part of the ZUMA studies, where they looked at 2 cycles in a high-risk group getting dose-adjusted EPOCH and then a PET [positron emission tomography] scan, and if that wasn’t satisfactory, they went to CAR T. It’s almost first-line.

 That’s the ZUMA-12 study. It was published in 

. They call it frontline, but to me, it isn’t frontline if you gave 2 cycles of chemotherapy, did a PET, and saw that there’s still PET-positive tumor there. That’s a viable strategy, though. But the question is, how do you pick those patients at the front end and do that?

 That’s a great question. That’s the question.

 Some interesting data out of that study, though, are the high and durable complete response rate and attractive T-cell population that was recovered from the patient in order to make the CAR T cells. It may even be that finding patients who are in partial response with 2 cycles of chemotherapy may lend them to do better. Maybe frontline isn’t the way to do it. Maybe it’s to do 1 or 2 cycles, catch them in response, and then take them to CAR T. It will be interesting to see. We’ll get some data.

 Yes, I like that strategy, and it changes the way we interact with our community colleagues if that ultimately does become a strategy. It requires another trial to show that, not just ZUMA-12. But I agree, those response rates are impressive, better than anything we have seen with axicabtagene ciloleucel.

 It’s going to be interesting. If those data and that situation are going to go forward clinically in the real world outside of a clinical trial, how are we going to do it? Because we all know that CAR T-cell clinical trials aren’t anywhere comparable with when we commercialize or use a commercial product from that gap in time between apheresis manufacturing and in some cases the preapheresis therapies that are needed for these patients.

Preapheresis chemotherapy and how that affects the T cells is an underexplored area in cellular therapy. This lends to a discussion about preapheresis in a newly diagnosed large-cell lymphoma population, like can we identify who we should be doing apheresis for at the time of diagnosis? We all have robust apheresis groups now. Can we identify and enrich for [them], and is that the best T cell that you’re going to get? Whether or not it’s using it as first-line Deauville 4-5 or if it’s in the second line based on TRANSFORM and ZUMA-7? We’re going to get there, but how do we change the architecture of our cellular therapy algorithm?

 One thing this brings to mind actually what Caron suggested and what the Nature Medicine paper did was when you go back to the origins of autologous stem cell transplant and diffuse large b-cell lymphoma was a paper by Thierry Lamy. Their group looked at people who weren’t getting an adequate response—based on CT scan—to their initial chemotherapy, which was CHOP, for the most part. They were randomized to either continue the same therapy or go to autologous transplant. It isn’t a big difference.

I’ll remind everybody that it isn’t a huge difference, but that’s what we base autologous stem cell transplant on: that initial observation. This is similar. It's the same question. If people aren’t getting a good response, would you go to CAR T? I agree with Matt that I’d like to have T cells available that we’ve collected early. Anecdotally, there’s a patient whose couldn’t be collected, but we had previously collected stem cells a year before that we froze. To remind everyone, there are about 20% T cells in the usual 5-million bag. CAR T cells were able to be manufactured from that, saving them, hopefully. We’ll see what the response is. The issue of having some stem cells around [is important]. Convincing insurance companies that’s a good idea is a whole different story.

 It was on a trial with an exception. Out of spec.

 But to this discussion about how we operate in collecting cells, can we collect them earlier? Will it make better T cells for CAR T? We also have to keep in mind that there’s a cost to collecting and doing apheresis and holding on to cells. That cost to hold on to it isn’t necessarily covered by the insurer.

 And the majority of the patients will never need it.

 There’s a cost, and there isn’t enough room in our freezers for all the cells.

 Maybe there’s a business opportunity. Maybe we should sign a CDA [confidentiality and disclosure agreement] and start a company where we collect and store these things. But there have to be changes in the way business is done to make that sort of thing happen. To the point of 2 cycles of chemotherapy and whether we could roll in the CAR T, we have to interact with our colleagues in the community. If they’re giving R-CHOP or whatever in the frontline setting, seeing that, we have to be able to get that patient in quickly. We have to work closely with our friends in the community in order to get that patient CAR T if that’s what we’re going to do. We also need trials to verify that’s the way to go.

 All of us have seen the POLARIX data, and there was some improvement in progression-free survival. So far, there’s no overall survival difference. There are some other exciting studies going in this space. We have bispecific antibodies added to R-CHOP, and other targeted agents: tafasitamab plus R2-CHOP [rituximab, lenalidomide, cyclophosphamide, doxorubicin, vincristine, prednisolone]. Those are all interesting studies, and hopefully they’ll move the bar.

Drs Locke and Gordon explain how outcomes for patients with DLBCL have improved as treatments continue to evolve.

Improving Outcomes in Patients With DLBCL

®titled “Applying New Data to Treatment Selection in Patients With Relapsed/Refractory Diffuse Large B-Cell Lymphoma.” I’m Grzegorz Nowakowski, a lymphoma physician and a professor of medicine at Mayo Clinic in Rochester, Minnesota. I’m joined by a panel of my colleagues who treat patients with DLBCL [diffuse large B-cell lymphoma].

 Hi, my name is Fred Locke. I’m coming to you from Tampa, Florida, where I’m the vice chair of the department of blood and marrow transplant and cellular immunotherapy at Moffitt Cancer Center.

 I’m Caron Jacobson from the Dana-Farber Cancer Institute in Boston, Massachusetts. I’m a lymphoma physician and the medical director of our cell therapy program.

 I’m Matt Lunning from the University of Nebraska. I’m a lymphoma physician and the medical director of our cellular therapy program.

 I’m Leo Gordon from Northwestern University at the Robert H. Lurie Comprehensive Cancer Center in Chicago, Illinois. I’m a professor of medicine and the director of our stem cell laboratory.

 Let’s start with the frontline therapy of diffuse large B-cell lymphoma. We know that DLBCL is extremely heterogeneous in clinical presentation and molecular characteristics, which results in heterogeneous outcomes. How do you use this classification and risk stratification in everyday care of patients with DLBCL? I’ll start with Dr Gordon.

 Thanks, Greg. This has been somewhat of an evolution. In the early days, we evolved to treatment with CHOP [cyclophosphamide, doxorubicin, vincristine, prednisone], initially based on factors that were identified by Margaret Shipp, MD, in about 1993 or 1994 with the International Prognostic Index [IPI]. Those were the clinical features that we had. We had done a study comparing CHOP with m-BACOD [methotrexate, bleomycin, doxorubicin, cyclophosphamide, vincristine, dexamethasone] a couple of years before then and identified LDH [lactate dehydrogenase] as a major prognostic factor.

We had the International Prognostic Index. We had clinical factors like that and LDH. We also had limited treatment options; so over the years, we have evolved. Obviously, we have more understanding of the molecular biology of the disease and the microenvironment to where we now have cell-of-origin analysis and molecular analyses. All of that was identified about 20 years ago. We’re still, in a way, stuck with CHOP or R-CHOP [rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone]. At the moment, we’re still using fairly simple classification schemes. Things are evolving, mostly for clinical trials. I don’t think that practice has changed yet based on cell of origin, but what we have is fodder for new clinical trials for some of the new understanding that we’re getting.

 Thank you. Matt, you mentioned that R-CHOP has been there for a long time. Is there any other clinical situation where you’d use R-CHOP for treatment of your patients with newly diagnosed diffuse large B-cell lymphoma?

 It’s important to realize that once that diagnosis is rendered, there’s a second step: taking the tissue and analyzing for what we call double-hit or triple-hit biology in the new WHO classification. That’s high-grade B-cell lymphoma with 

. It’s important to note that it’s got to be 

 in order to fall into that category. In those situations, I’d still use dose-adjusted EPOCH-R [etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, rituximab]. It’s an infusional regimen. It’s a little more resource intensive, but despite some of the dose-adjusted EPOCH-R versus R-CHOP, the CALGB [Cancer and Leukemia Group B] study, I still favor that regimen in that population.

What’s a little tougher is when you have 

 rearrangement but you don’t have that partner. Where is that and what you do? That’s still a territory that makes me uncomfortable, but sometimes I’ll err on the side of giving dose-adjusted EPOCH-R. Sometimes I’ll give R-CHOP, but I use the IPI score to help guide me in that situation. The other learning point is that “dose adjusted” is in EPOCH [etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin] for a reason. That’s the recipe. I’m not sure you’re getting the same results if you don’t have the intent to dose-adjust up, and you could be more toxic to the regimen if you aren’t checking CBCs [complete blood counts] twice weekly and not dose-adjusting down to that regimen.

 Double-hit lymphoma and triple-hit lymphoma is definitely associated with worse outcome when treated with R-CHOP. At our institution, we tend to use Burkitt-like chemotherapies for patients younger than 60. Have any of you been using the same practice?

 We haven’t. We have probably used dose-adjusted EPOCH, but a lot of this is based on retrospective data. Adam Petrich, [MD,] did a paper in 2014, and the best regimen—all retrospective—was hyper-CVAD [cyclophosphamide, vincristine, doxorubicin, dexamethasone]. It wasn’t actually dose-adjusted EPOCH. It’s a good question. We haven’t done that. Like Matt, we have also used dose-adjusted EPOCH. But the caveat is there haven’t been—and I’m not sure there will be—any prospective studies comparing the regimen. These are all retrospective. In fact, there have been some retrospective studies comparing CHOP with dose-adjusted EPOCH without much difference. That brings about a question. There are some data—I think from the Lunenburg Lymphoma Biomarker Consortium—suggesting that if the 

 partner isn’t an immunoglobulin partner, the outcome is maybe not as dire. Do any of you use that to help make decisions?

 I’ve tried to talk to my pathologist about looking to see if the partners, the kappa or lambda light chain—there’s literature on that as being the mysterious partner in those—but I too remember seeing those data that said that if the partner isn’t there, then you can give R-CHOP–based therapy.

 Sometimes in people whom I’m surprised to find are double-hit—for example, somebody who’s 78 years old with stage I DLBCL and underlying comorbidities—I’m looking for that information to give myself a reason to perhaps not use dose-adjusted EPOCH. That’s the way I’m doing it at the bedside. I first make the decision and then I support it by the data, if you will.

 Dr Jacobson, do you use IPI? The FLYER Study showed that younger patients with low-risk factors can be treated with abbreviated chemotherapy. Do you use it in your practice?

 I do, but I find that there are still a lot of exceptions in the patient population that was put on the FLYER Study. I feel like all the patients who come in with a low IPI have an unusual extranodal site that I feel less comfortable giving abbreviated chemotherapy for. I definitely would do it for the right person, but there are some exceptions to it that I’m not sure the study was robust enough to evaluate.

Experts in lymphoma discuss how they risk stratify patients and the currently available options for first-line diffuse large-b cell lymphoma treatment.

A Focus on Frontline Treatment in Patients With DLBCL

Matthew A. Lunning, DO, FACP, assistant vice chair of research in the Department of Medicine, assistant vice chancellor of clinical research, and associate professor of internal medicine in the Division of Hematology and Oncology at the University of Nebraska Medical Center, discusses how the FDA approval of lisocabtagene maraleucel (liso-cel; Breyanzi) expands treatment options for patients with large B-cell lymphoma (LBCL).

On June 24, 2022, the FDA approved liso-cel as second-line therapy for adult patients with LBCL, including diffuse large B-cell lymphoma (DLBCL) not otherwise specified (including DLBCL arising from indolent lymphoma), high-grade B-cell lymphoma, primary mediastinal large B-cell lymphoma, and follicular lymphoma grade 3B.

The indication is specific to patients who have refractory disease to first-line chemoimmunotherapy or relapse within 12 months of first-line chemoimmunotherapy; or refractory disease to first-line chemoimmunotherapy or relapse after first-line chemoimmunotherapy and are not eligible for hematopoietic stem cell transplant (HSCT) due to comorbidities or age.

CAR T-cell therapy has proven effective in patients with DLBCL who relapse after 2 primary therapies, Lunning says. The phase 3 ZUMA-7 trial (NCT03391466) led to the first approval for CAR T-cell therapy in the second-line setting with axicabtagene ciloleucel (Yescarta) in patients with high-risk primary refractory disease or quick relapse after completion of therapy, Lunning adds.

Many high-risk patients may not survive long enough to be eligible for CAR T-cell therapies that are only approved for those who have received at least 2 prior lines of therapy, Lunning notes. The approval of liso-cel in the second line and beyond offers greater treatment availability to a vulnerable population, Lunning says. Cellular therapists now have another option to use with patients in the commercial setting, Lunning concludes.

Matthew A. Lunning, DO, FACP, discusses how the FDA approval of lisocabtagene maraleucel expands treatment options for patients with large B-cell lymphoma.

Matthew A. Lunning, DO, FACP

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