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New and Emerging Therapies for Patients with Diffuse Large B‑cell Lymphoma

Dr. Gilles Salles (Memorial Sloan Kettering Cancer Center): Hello, and welcome to this podcast. My name is Gilles Salles. I am the Lymphoma Service Chief at Memorial Sloan Kettering Cancer Center, affiliated with Weill Cornell University, and joined by my colleague.

Dr. Pier Luigi Zinzani (University of Bologna): I am Pier Luigi Zinzani, Professor of Hematology. I am the director of the Institute of Hematology Seràgnoli in the University of Bologna, Italy.

Dr. Salles: Today, we are going to discuss this topic which is important and really changing rapidly regarding the therapies in diffuse large B‑cell lymphoma - A highly curable disease, but unfortunately, not all patients are cured and for these reasons, we need to have these new agents and know better how to use them.

We will first discuss the overview of the unmet needs, then we will discuss the expanding role of novel agents and how these targeted therapies are available for patients, how they can access within clinical trials or the access in academic and non‑academic centers. We will also emphasize the potential differences existing between patients living in different areas of the world, particularly in Europe and the United States.

We will approach a couple of ongoing trials and novel agents that are being currently investigated and what we may expect from them and also, discuss what was presented recently, either at the ASCO 2026 or EHA 2026 meeting, in terms of trials regarding DLBCL, and then we will conclude.

I think we have understood that there are a couple of unmet needs. I will say we can classify the questions currently at: what is the workup at diagnosis? Are there any differences? We have been adopting different lymphoma classifications. There have been, unfortunately, a few years ago different inputs by different groups of colleagues which are being unified right now. FISH has been implemented now since probably one decade in helping to identify those cases with double hit, and now we are moving towards delineation of some entities using molecular profiling. Obviously, with imaging we use PET scan, and we use classical prognostic index.

Pier Luigi, anything specific you would like to add regarding the initial workup? What we are missing at the present time? What will be the tools that we would like to see in our practice coming up?

Dr. Zinzani: As you said before, in terms of a histological classification, we are using the same that you are using in United States. Also, in terms of what to do in terms of staging before treatment, one point is quite important that I think is a little bit different so far when you compare Europe with United States is the role of MRD and ctDNA, because it could be important in the clinical trial, but so far in Europe in particular, or in the real life outside the clinical trial, we don’tt use.

Dr. Salles: You touched an important point, which is evaluating patient response. Worldwide, the use of Lugano Classification for evaluating the end‑of‑treatment PET has been used. However, we do know that some patients who present with a negative PET CT are still exposed to a risk of relapse. While sometimes we have difficulties in interpreting some result with PET, the Lugano scale and the Deauville scale being either 4 or 5, and with minimal lesions, and whether we want to use radiation, we want to use a biopsy ‑

Dr. Zinzani: Biopsy and so on. Another important point that could be different between the two continents is how to follow the patients after the first complete metabolic response, after the induction treatment. Normally in our institution, as in several other European institutions, we use the PET evaluation for the first at least two years every six months, and then we move from the third year to the fifth year with a PET every year. But I know that is a real heterogeneous field concerning this issue in the setting of United States, but also in the European countries.

Dr. Salles: If the patient has reached a complete response, usually the recommendation is to use CT only every six months for two years and interrupt after two years. There have been some discussions – even not to imaging patients – but most of us will image patients every six months. If there is any equivocal data on the final PET, we will use potentially another PET or two, but try to move quickly to the CT.

I think you mentioned the role of MRD and ctDNA. ctDNA has been a new tool. It has been developed, and there have been now several reports indicating that it will be highly discriminant to identify patients with a high probability of cure, probably above 90%, versus those who have a high risk of disease recurrence in the 20 to 40%, depending on the technologies and things like that.

All these data came from mostly studies performed with either companies developing these tools or potentially some academic labs. We have seen that in the UK and in the Nordic countries. How do you see this field evolving in the near future, Pier Luigi?

Dr. Zinzani: Could be important, could be interesting to combine with a PET evaluation to really understand the response or the potential risk of progression of the disease. But, at the end of the day, right now, there is no real perfect method that we can use in this situation. Outside some clinical trial, or the potential support from some company could be difficult in terms of economic point of view to use this kind of evaluation.

Dr. Salles: The field will be moving a little bit faster here, given the fact that one or two of these companies are approaching very quickly the FDA and may have the test being approved. In the near future, this might change.

We’ve discussed the diagnosis, the initial response - obviously, we have a major concern for those few patients, 5‑10%, who have early refractory disease and we will see how we manage the relapsing patients. A patient that experiences disease recurrence in the near future.

Dr. Zinzani: This is a very important point because we can obtain in the most part of the patient a complete metabolic response during the induction treatment in front line. Of course, the real problem is to identify as soon as possible the potential patients considered refractory or early relapse.

But now, if we compare with the last 5 or 10 years, we have a very important therapeutical option also for these patients. In particular, the CAR T second‑line. This could be another important point. The control of the response during the front line treatment, in particular the interim evaluation with PET and/or CT scan after three or four cycles of the induction treatment could be very useful to really understand if there is no response or a very small response, why not to move directly to CAR T second line, or to evaluate very strictly this patient with a final evaluation after the front line treatment after the sixth cycle, not after one month or one or two months later, but after two or three weeks to really understand if the patient obtains a final complete metabolic response.

This is fundamental to stratify as soon as possible the potential patient for the second line and, in particular, of course, for CAR T or for a good chemo‑free regimen in second line with good alternative in terms of treatment.

Dr. Salles: Yes, we are in perfect alignment on this topic. Let us maybe dive a little bit towards these new agents. I hand it to you, Pier Luigi, to introduce this topic.

Dr. Zinzani: We are really in a new era concerning new agents in the setting of diffuse B‑cell lymphoma. Now, the therapeutic algorithm of this disease is incredible. It is quite close to the multi‑myeloma Sudoku in terms of new agents and could be sometimes quite difficult to decide what to do in terms of vision when you start the treatment of diffuse B‑cell lymphoma, a very long list of novel targets and agent according to monoclonal antibodies, CAR T cells with three different products, all of them CD19 and all the bispecifics. The most part, of course, CD23, but now we have also a new CD19/CD3 that could be very important in terms of some alternative in terms of targets, the surovatamig. Of course, the list of the antibody drug conjugate is loncastuximab tesirine, polatuzumab vedotin, brentuximab, and also zilovertamab.

And all the intracellular agents, such as BTK inhibitors, the CELMoDs of third generation, golcadomide, BCL6 degraders, IRAK-4 inhibitors. And the other targets are CD22 or CD37. Also, the CD70 with some new potential bispecifics, and as I said before, of course, CD20, CD19 and CD3.

And I think it is important at this point to stress if there are some differences between Europe and the United States. For example, what is the current role of BTK inhibitors, for example? Another important issue concerning the potential role in the setting of relapsed‑refractory diffuse large B‑cell lymphoma. Why not in the future, and also in front‑line?

Dr. Salles: At the present time, none of these drugs has received a formal approval for patients with diffuse large B‑cell lymphoma in any line of therapy, although we do know that there are specific subsets of DLBCL that may have a selective sensitivity to this drug. After the result of the PHOENIX study in the first‑line study, there have been other studies using acalabrutinib, which is accompanied with less toxicities and probably more manageable in combination with chemotherapy. We are awaiting the results of the randomized study called ESCALADE, combining rituximab‑CHOP versus rituximab‑CHOP + acalabrutinib. It is a double‑blind study. This will be very important.

I will say that sometimes in the relapsed setting, we might have access to the use of these drugs if insurance approves it either alone or in combination with lenalidomide. Might not respond, but in not heavily pre‑treated patients, you may see some transient response in maybe one-third of the patients, and this remains sometimes useful to bridge for another form of therapy.

Dr. Zinzani: Yeah, I agree with you that the potential role of ESCALADE, if the trial will be positive, will change, finally, the concept that we can use in frontline in combination with conventional chemotherapy, or second‑generation BTK inhibitors, such as acala, because it is less toxic or ibrutinib. There was a difference in terms of inclusion/exclusion criteria when you compare with the PHOENIX, because PHOENIX included patients until eight years old, and in this case, for ESCALADE, they use at the beginning to 60, and then in the last six months, they put eh check in term of age at 75.

Surovatamig. As I said before, surovatamig, a CD19/CD3 bispecific, could be very important. Of course, there are several ongoing phase I, phase II study, not only in diffuse large B‑cell lymphoma, but also in follicular lymphoma. What is your opinion in the United States concerning the potential pivotal role of this new target in the setting of the list of bispecific monoclonal antibodies?

Dr. Salles: In the United States, bispecific has taken place probably more in academic centers and in large community centers than in small community practice, given the management of this drug. CD3/CD20 antibodies, whether they are used alone or in combination, start to be routinely used. Unfortunately, this is not sufficient. Having a new one with a new target is important. We are also awaiting the time where potentially the CD3/CD20 will be entering first line of therapy, and then having at our disposition a CD19/CD3 will be very important. We are awaiting the phase II and the registration of this drug and I think it will take another one to two years. So, the results we have seen are very promising in terms of CR rate and in terms of duration of CR, but more to come with final results and evaluation by health authorities.

Dr. Zinzani: Yeah, I agree with you. The same situation is in Europe because academic center, but also the major hospital with the institution of Department of Hematology, they are using bispecific CD20/CD3 in third line according to the official indication. Sometimes I prefer to use bispecific instead of CAR T. This is another important point that I know is quite similar, this problem also in United States. Of course, with a potential future where the CD20/CD3 will be included in frontline, and there is a risk of CD20 loss – could be important to have another target such as CD19.

Antibody‑drug conjugate, I think there are some differences when you compare the United States versus Europe in terms of do you use polatuzumab frontline in the setting of patients with diffuse B‑cell lymphoma, according to the POLARIX study?

Dr. Salles: It is used in about 35 to 40% of the patients newly diagnosed. Some centers will restrict the use of patient with what they will call non‑GCB based on immunohistochemistry, while other centers will use it according to the market approval. It is more a philosophy that clinicians will take.

Dr. Zinzani: On the contrary, in Italy, the use of Pola‑R‑CHP in frontline is close to 60‑65%, and some hematologists prefer to use this in the elderly patient, according to the registration study, according to the IPI, say 3 or more than 3, according to the cell of origin. But, at the end of the day, at least 60% of the patients are using Pola‑R‑CHP in front‑line.

Back to the CAR T issue we discussed a little bit before, but I think the situation is quite similar to the United States. In Europe, we have several problems to use CAR T – to receive as a CAR T center, for a patient from the referral center in third line. Sometimes we have several problems also in second line because they prefer to use the classic conventional chemoimmunotherapy treatment plus auto‑stem cell transplant to avoid to lose the patients, to maintain their local visibility. No more than 35%‑40% of the patients are eligible for CAR T move to the CAR T center.

Dr. Salles: Yes, we do know that in the United States, the size of the country, the insurance, the cost, the different buyers exist, and the penetration of the number of patients, candidates that receive CAR T is probably about 20%. So, I don’t think this will be moving dramatically in the near future. As you said before, antibody-drug conjugate, bispecific antibody T cell engagers are making inroads into this area. We will see. I think it’s still an area where it had become a little bit easier with some regulatory change regarding proximity from the treatment center with the availability of products that are efficient and well tolerated. Recently, the US consortium reported 1,000 patients treated with liso‑cel and with quite a good result. But, at the end of the day, CAR T only cures one out of two patients, whether in second or third line. There is still a lot of space to improve upon that.

Dr. Zinzani: Sure. The last two points we can put together that the potential role of CELMoDs in particular, of course, the third generation of golcadomide, and also the BCL6 degraders. There are several clinical trials concerning the role of these two new agents. That could be a very important new potential targets for our patients with diffuse large B‑cell lymphoma. What do you think? Which is the role right now in the United States?

Dr. Salles: No, I think there is no difference. Maybe they are a little bit more investigator‑initiated studies being run out, but we need to see more data to discuss what is the potential of these for patients in the near future.

Dr. Zinzani: Yes. There are some preliminary interesting data with golcadomide, of course, and in diffuse, but also in follicular lymphoma. We are only at the beginning of the story concerning the potential role of BCL6 degraders. Also in our institution, we have two phase I studies in this moment, but could be another good opportunity we hope in the future for our patients.

Dr. Salles: If we move to the ongoing trials in DLBCL, what we are expecting in the relapsed setting are a few publications regarding data that were presented, for instance, at the EHA. We will touch upon that later. We heard about the role of loncastuximab randomized trial, epcoritamab, but more importantly, we just heard also recently about epcoritamab and lenalidomide, and as we said, surovatamig.

I think what is making us a little bit in a situation which is exceptional is the fact that there are probably eight or nine trials in the first‑line setting. The first one was the FRONTMIND trial, which results have been presented and published with tafasitamab.

Then the bispecific antibodies, there are three clinical trials with epcoritamab, glofitamab, and with odronextamab that are being run in the frontline setting. We discuss already the ESCALADE trial with acalabrutinib. In addition to those, there is golcadomide being investigated in a phase III trial, which I think has completed accrual, as well as ZUMA‑23, which is assessing the role of early intervention with CAR T in patients with very high risk.

I may forget some, but this is probably the major landscape. There are differences in the trials. Most of them use R‑CHOP as a control arm, except the trial with glofitamab, which used Pola‑R‑CHP as a control arm and as a backbone to which glofitamab is added.

I should also mention that there is at least one trial that assessed the role of an allogeneic CAR T in patients that are MRD‑positive at the end of treatment, but there are a few projects either with bispecific or with other CAR Ts to be done in this setting. So, at the end of the day, maybe, Pier Luigi, we can predict the result of these trials. But what will be the key elements in a nutshell of how we are going to interpret those and what will be potentially the key decision factors, whether to use this new agent versus that new agent versus another new agent?

Dr. Zinzani: This is a very important question because, except ESCALADE and also the ZUMA‑23, for all the other seven or eight ongoing phase III studies, the inclusion and exclusion criteria are the same in terms of age from 18 to 80, and in terms of IPI from 2 to 5.

This could be a problem at the end of the day, when we hope probably most of them will be positive, and how it is possible to stratify the use of these different trials in our setting of patients with diffuse B‑cell lymphoma? And, it could be easier in the United States, the role of the drug agency, but I do not know in Europe, EMA. Do you think EMA will accept all these different trials in the same setting of patients where most of them are quite similar? I mean, R‑CHOP plus bispecific in at least five or six of them. This could be a very important point for the future because, except ESCALADE and ZUMA‑23, where they have a different study population, for all the others, the study population, including the trials, are the same.

Dr. Salles: This is a very important point, but as we know, usually drug companies make commitments with the agency, and this commitment has to be fulfilled as long as the results fulfil the expectation.

My point of view is that both agencies, but also the reimbursement in Europe, in different countries, as well as the guidelines in the US and potentially some insurances will look at the side effect profile of these different drugs and the constraints. We already had this discussion with tafasitamab and R‑CHOP, where patients had to come every week to receive the infusion of the CD19 antibody. That is a constraint. This was associated with lenalidomide and R‑CHOP with a significant toxicity. It is a positive trial. It improved PFS, but the burden for patients and the toxicity are high. We will have to balance that when these results come.

R‑CHOP has been easy. It is patients were coming every six weeks. Pola‑R‑CHP is the same. Patients are coming every three weeks. One of my colleagues said there is not only constraints for the patient, but also for the clinical team seeing the patient every week and having to evaluate the counts, the cell counts, the side effects, a little bit of fever. What to do with that? That’s a lot of constraints.

Dr. Zinzani: This is another logistic problem. Yes, of course.

Dr. Salles: So, I  hope for patients that some of these trials will really show benefit, and maybe looking at some subgroup biologically or differently will be guiding us on what to use. It is a complex area.

Dr. Zinzani: Yeah, it could be more difficult. You have to know very well all these trials, all these data, and to have a very important vision when you start with the treatment in front line with, as you said at the beginning, to decide what to do in front line and to be sure that you have a good opportunity of treatment potential in second line with a different target if there are some CD20 loss, for example.

Dr. Salles: I should mention that the trial, combining surovatamig with R‑CHOP, is just on the initial steps of implementation at several centers and will attract also a lot of investigators. I was fairly impressed to see that many of these trials have accrued patients in one year and a half, 18 months to two years, even 500, 600, 800 patients. The field is moving very quickly. These are good opportunities for patients. Surovatamig has this peculiarity of targeting CD19 while we are targeting CD20 with rituximab. The question of antigen escape is probably less an issue with this drug, but again, we have to see the results.

Dr. Zinzani: Now we move to the key presentation/results of the last EHA meeting in Stockholm. Which presentations at this meeting were of particular interest and practice‑changing? I think there were some interesting presentations, of course, as you said before this, there was at the EHA, but also at ASCO, the final presentation of the FRONTMIND trial by Georg Lenz was the first new phase III trial in front line. The setting of advanced diffuse B‑cell lymphoma.

There was a very interesting presentation also by Dr. Bouzani concerning the role in frontline of Pola‑R‑CHP plus golcadomide. The preliminary results, because they included 58 patients, all untreated patients advanced disease IPI 3 to 5, there was a randomized study concerning the comparison between different doses of golcadomide 0.2 mg versus 0.4 mg. At the end of the day, preliminary result, of course, evaluable no more than 28 patients, but was incredible, the result, when you use 0.4 mg in terms of complete metabolic response roughly to 90%. Independence by the high‑risk patient on the basis of the IPI or the presence of bulky disease, also, according to the COO.

I think this is a very important point for the future. We have a very short‑term follow‑up, no more than 16 months, a few patients. However, the inclusion in frontline of this third generation of lenalidomide could be very, very interesting because at the same time, the safety profile is very good.

What do you think about these preliminary data, Gilles?

Dr. Salles: I think, as you said, they are preliminary. I try to bring things into perspective, you know, when we have seen the results of bispecific as single agent three or four years ago, we said, "Wow, that is fantastic." In the relapsed setting, we get this 40% response rate, and this CR rate, and that appeared to be stable. This was true also for combination with GEMOX, with polatuzumab, with other agents, I kept saying these results are early and we don’t know whether these will really cure patients.

One of the presentations at EHA was the long‑term result of patients receiving glofitamab single agent. It shows that overall, it is about 50% of the patients receiving the active dose and reaching a CR. Not all patients entering the trial, but those that reach a CR who had a maintained complete remission up to five years. Clearly, after two years, 24 to 36 months, the curves look pretty flat, showing that patients do not relapse.

We have seen emergent results with surovatamig and others. The question to me, which is also related to the question you asked regarding this combination trial, is that the complete metabolic response is an important endpoint, but we would like more and more to see the evaluation of ctDNA in these first‑line trials. Looking at that with the appropriate technologies, given that we have learned now the appropriate technologies using different nucleotides close by, but it can be different approaches and are really the most sensitive.

Looking at this phase II data is very exciting. We have already seen R‑CHOP‑epcoritamab with 100% overall response rate. We have seen polatuzumab‑R‑CHP and glofitamab also 95% PFS at one year. Now, I think we will like, before the randomized trial and even when the randomized trial will be presented, to be paying interest to this new data on ctDNA. We do know that in these clinical trials, this will be collected and probably presented.

Dr. Zinzani: Yes. I totally agree with you concerning the fantastic data at five years of glofitamab in the setting of relapsed‑refractory patients with diffuse large B-cell lymphoma in the third line because these data right now with this long follow‑up, are quite close to the data of CAR T in third line.

And this is a very important point. Bispecific fixed duration, for example, with glofitamab, you can obtain the same results in terms of a curative treatment at five years when you compare with CAR T. In terms of potential toxicity, question mark, but in terms also of cost could be a difference. It is a very important point. For this reason, there are several new combinations, new regimens, including bispecific plus, for example, ADC monoclonal antibody, moving from the third line to the second line in these preliminary data, for example, LOTIS‑7, glofitamab plus loncastuximab tesirine. The preliminary results in the phase II study are really impressive because the CR rate is 85%. Of course, we need the evaluation of the response, you need, as you said before, the evaluation of the ctDNA in this patient.

There is a new kind of regimen in the second‑line setting in diffuse B‑cell lymphoma, all chemotherapy‑free with this concept of bispecific plus other monoclonal antibody, in particular, ADC/monoclonal antibody. This could be, in the future, also a big competitor with the CAR T in the same setting of second line.

Dr. Salles: Yeah, I am fully aligned with your statement. We are getting close to the end of this podcast, and I would like you, Pier Luigi, to give what do you feel is the most exciting concept, most exciting drugs in the setting of new and emerging therapies for DLBCL?

Dr. Zinzani: Surovatamig could be very interesting because of the new targets. The concept of combining chemotherapy‑free regimen in second line, like I said, LOTIS‑7, glofitamab plus loncastuximab tesirine. I think about the very long list in frontline, ZUMA‑23. ZUMA‑23, because on the basis of the phase II study, ZUMA‑18 was where the data were really incredible for high‑risk patients. I mean, IPI 4 and 5. This setting of patients represent the patient with early relapse or refractory to the frontline treatment that normally are resistant or refractory to the second line with CAR T.

Dr. Salles: Yeah. Thank you. I share, obviously, your enthusiasm for all these studies. I will add to that that the targeted therapies, oral agents such as BTK inhibitors, including acalabrutinib, but also CELMoDs or BCL6 inhibitors – are a new family of drugs, which can be combined with some of the active agents, may have the potential to improve the efficacy of bispecifics.

As we said, we do know that this bispecific T‑cell engagers are encouraging, and this is an important message in the last year – alone, or in combination. We do know that investigators and companies are moving extremely fast with the field of providing the manipulation of T cell in vivo. This was one of the late‑breaking abstracts for EHA, where a few patients were receiving what is called in vivo CAR T, basically the ability to transduce T cell in vivo. We do know that this could be also transformative therapy.