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Optimizing DLBCL Treatment: An Expert Roundtable on the Role of New and Emerging Targeted Therapies

DLBCL: Background and Overview

International Prognostic Index (IPI)

We do know for many years that all patients with DLBCL don't have the same outcome, and this was developed almost 30 years ago by Dr. Shipp and colleagues with the so-called International Prognostic Index, which remained valid in the rituximab era, and some patients clearly are more likely to be cured. I remember you said the IPI is based on five simple clinical factors, which are age, serum LDH, advanced stage, ECOG performance, and extranodal involvement. You can see this is a survival curve coming from a paper a couple of years ago in the rituximab era showing on the left the progression-free survival of this patient and on the right the overall survival data coming from many hundreds of patients in different places in the world.

We have tried to improve upon this index, rituximab IPI and NCCN IPI. I don't think many of those have really modified the stratification of patients. Maybe a couple of us are using something called the CNS-IPI, which, based on the IPI risk factors, the presence or absence of kidney or adrenal involvement, will evaluate the risk of CNS recurrence, as shown here on this slide, with a very low risk for the majority of patients, intermediate risk for some, and a high risk. And if you were in the session on aggressive lymphoma yesterday, you saw that there is a debate regarding the use of prophylaxis, which remains a question for many of us.

Biologic Heterogeneity of DLBCL: MYC Double-Hit and Triple-Hit Lymphomas

But this clinical heterogeneity is just a reflection of the biological heterogeneity of DLBCL, and we have learned a lot about that.

One of the first things we learned many years ago was that there were alterations, genetic alterations, including translocations involving MYC and BCL2 or MYC and BCL6, and with a couple of colleagues we were involved in this large study assembling more than 2,000 patients where we evaluate the outcome of patients with MYC double-hit or triple-hit lymphoma, showing that clearly those without a hit had this blue curve on the top in terms of PFS and OS. Single MYC has this black curve and double-hit this red curve. It's interesting to see the red curve in terms of progression-free survival. You see that it's clearly dropping during the first two years, but if after two years you had successful therapy, the risk of progression was not different from patients without this alteration.

So, this was one of the first stratifications and indications that possibly some patients may need a different strategy.

Biologic Heterogeneity of DLBCL: Molecularly and Clinically Distinct Subtypes

But during the same period, many colleagues developed genetic analysis and transcriptomic analysis based on gene expression profiling, and George Lenz at NCI and in the group of Louis Staudt looked at patients treated with rituximab trials based on the gene expression profiling so-called germinal center B-cell, GCB DLBCL, or activated B-cell, ABC DLBCL, and clearly showed that there was a very significant difference in the outcome of patients with GCB DLBCL who had a good likelihood to be cured, 75% at three years, versus the ABC DLBCL who had only a 40% chance to be cured. And this clearly indicated that this was an indication with a high need of improvement and a high need to focus on.

Evolving Classification of DLBCL by Cell of Origin

Obviously, this was done with gene expression profiling, which is not a technology that is available for routine care of patients and only in very specialized centers. There were several attempts to use more easily applicable techniques such as immunohistochemistry. And the one that really led the field was the so-called Hans algorithm, which is depicted here. If at diagnosis staining for CD10 is clearly positive, then this is a germinal center-derived B-cell lymphoma, GCB. If it's negative, we stain for BCL6. If BCL6 is negative, then this is a non-GCB. If it's positive, we have to do a third staining, which is MUM1. If it's positive, it's non-GCB. If it's negative, it's GCB. So, CD10-positive, GCB. CD10-negative, BCL6-positive, MUM1-negative, GCB. The other ones are non-GCB. And you know, it does reproduce at least partially the classification. And in fact, we learned from several studies that the concordance is in the range of 75-85%, but not 100%.

WHO Classification: Aggressive B-Cell Lymphoma

The different meetings that we have had with WHO, ICC, have really tried to continue to focus on how to differentiate this aggressive lymphoma, Burkitt lymphoma, high-grade lymphoma, which was a new denomination we gave to patients with MYC and BCL2 or MYC-BCL6 rearrangements years ago, and the other DLBCL, DLBCL not otherwise specified with ABC and GCB, not forgetting that there are other subtypes including the primary mediastinal B-cell lymphoma.

WHO Classification: Aggressive B-Cell Lymphoma

Just a little note that there is no consensus that what we call double-hit lymphoma is restricted to those carrying MYC and BCL2, and MYC and BCL6 are classified either high-grade or DLBCL NOS, probably in the future only DLBCL NOS, according to the work that is being carried out.

Newly Diagnosed DLBCL: Overview

DLBCL: Attempts to Improve Efficacy of R-CHOP

So, what happens to patients when they are treated in the first-line setting? With Dr. Sehn, a couple of years ago, we reviewed this data. What is shown on this curve on the left is the outcome of a large cohort of patients in British Columbia, Canada. I will bring your attention to the red curve. The red curve is the time to progression. That means this is the patients progressing. You know that in overall survival, in progression-free survival, there are other causes of death, other causes of events, but the time to progression really reflects that. The red arrow shows exactly what we have to achieve to bring this curve to 100%, meaning that patients that will be treated in the frontline will not progress. They may eventually have an intercurrent disease.

So, based on the rituximab CHOP study performed 25 years ago, there have been many attempts in the last 25 years to improve. We thought to intensify chemotherapy with transplant, with dose-intensive regimens, shortening the intervals between courses, continuous infusion. There were no consistent results for an improvement. We thought about adding some targeted agents, bortezomib, ibrutinib, lenalidomide. Again, no positive result. We thought about using maintenance to consolidate, and several studies with the drugs indicated here failed to show a significant benefit. Or eventually substitute one drug for the others, bortezomib or rituximab replacing respectively vincristine or rituximab. Again, it didn't work out.

What was also shown during this time period is that while R-CHOP was initially developed at eight cycles, six cycles were clearly demonstrated by data from Germany or from the GOYA study as being sufficient for patients with advanced-stage disease.

POLARIX: Polatuzumab Vedotin + R-CHP vs R-CHOP in Previously Untreated DLBCL

A study was published several years ago, which is called POLARIX, which is a study assessing the role of polatuzumab vedotin, which is an antibody-drug conjugate directed against CD79b. And this was a randomized double-blind study comparing rituximab pola-CHP, withdrawing vincristine, versus rituximab CHOP plus placebo in each arm and two cycles of rituximab at the end. This study was published in 2022 by Tilly and colleagues in New England Journal of Medicine, updated recently in Journal of Clinical Oncology.

POLARIX: PFS and OS Update and Response Summary

And you can see here depicted the outcome after five years of follow-up according also to the different estimates of progression-free survival on the left and overall survival on the right, event-free survival. You can see that the benefits that were shown initially, which was a benefit of 6.5% in favor of pola-CHP, was maintained over time. But there was no difference in overall survival even after five years of follow-up, even if there was a slight difference. There was no significant difference between the two arms in terms of overall response rate or CR rate. There was some associated toxicity, including an increased risk of neutropenia, febrile neutropenia and anemia, for those patients receiving pola-CHP, but still very well manageable.

POLARIX: 5-Yr PFS and OS Across Subgroups

So, there has been a lot of discussion regarding the interpretation of this study, based in particular on this analysis of different subgroups of patients that were accrued in the trial. And you can see the stratification according to age, to IPI, bulky disease, and a couple of other characteristics. And you can see that some categories of patients eventually, including those with some specific characteristics, such as being qualified as ABC using this molecular technique, appeared to benefit more from pola-R-CHP than the others, while for other patients there was no significant difference. This has to be taken with a word of caution, because a patient doesn't have only one characteristic. They have IPI-2 and non-GCB, or IPI-5 and GCB, and the way you interpret that to make your treatment decision is a matter of debate in several places.

DLBCL: Looking Forward

This was clearly a progress, but I will say, based upon the development of many new agents, many of the drugs were in development.

And I listed here a couple of trials that are ongoing. And on the top, this is the trial called SKYGLO, which is comparing pola-R-CHP plus or minus a bispecific antibody, a T-cell engager, CD3 by CD20, glofitamab. This is the only study using pola-R-CHP as a control. But there are many other studies using R-CHOP as a control, assessing other T-cell engagers, either CD3 to CD20, or very soon CD3 by CD19. There are other immune-based regimens, anti-CD19 antibody plus lenalidomide. We'll hear during this meeting the presentation of the frontline study, an immunomodulatory agent called golcadomide, or other antibody-drug conjugates. There is also the attempt to bring cellular therapy early on. But there is also, based on the biological aspects of the disease, attempts to improve the outcome of patients by introducing targeted therapy to specific cells.

Novel DLBCL Genomic Subtypes

And why is that? Because we learned that GCB-ABC is not sufficient to distinguish the molecular heterogeneity of patients. And based upon further work done in analyzing mutations, gene copy alterations, and things like that, there were some genetic subtypes that were identified in particular by the group at NCI, and by the group at Harvard, and reproduced by others, for instance, Dan Hodson in Cambridge. This is just one of the presentations showing that within the ABCs there are patients essentially segregating into the MCD, N1, A53, and BN2 clusters, the GCB essentially in EZB and ST2, whether MYC is present or not makes sense. But clearly it characterized different subgroups of patients which have a different outcome, as you can see from the overall survival. Some subgroups, such as ST2 in the middle, have a very – ST2 here has a very good outcome, while this patient MCD on the top has a poor outcome.

Settings Where Regimens Other Than R-CHOP or Pola-R-CHP May Be Preferable in Large B-Cell Lymphomas

So, there are also the settings where we know R-CHOP is not optimal, pola-R-CHOP is not optimal, whether these are older patients, frail, or patients with cardiac dysfunction, primary mediastinal, double-hit, primary CNS, primary testis.

PHOENIX: R-CHOP ± Ibrutinib for Previously Untreated Non-GCB DLBCL

But why do we go back to this targeted therapy? Let's go back to this PHOENIX study, which was evaluating the role of ibrutinib, the first BTK inhibitor that was developed, in combination with R-CHOP. This was a randomized double-blind study, patients receiving ibrutinib plus or minus R-CHOP. As you know, the primary endpoint was event-free survival, and the study was overall negative.

Evidence Supporting R-CHOP + Ibrutinib in DLBCL Subsets

And when people looked further into this study, there were a couple of messages. If you look at the two curves that are here on the top, you know, these two curves here, you saw that in patients that were below 60 years of age, there was an apparent benefit of adding ibrutinib to R-CHOP, which was not reproduced in older patients. And this may be linked to eventually some additional toxicity of using ibrutinib plus R-CHOP. Secondly, while the study recruited patients with non-GCB by the Hans algorithm, when patients were classified based on gene expression subgroup using molecular techniques as shown here, the true ABC appeared to benefit from adding ibrutinib. And finally, when genetic subtypes were characterized, you see that two genetic subtypes, the MCD subgroup and the N1 subgroup, clearly had the major benefit of adding ibrutinib.

ESCALADE: Acalabrutinib + R-CHOP for Previously Untreated Non-GCB DLBCL

So, based upon that, other studies have been run. One of the studies I mentioned earlier is this study called ESCALADE, which introduced acalabrutinib plus R-CHOP in previously untreated non-GCB DLBCL. This is a simple design with patients aged 18-65 years, non-GCB but confirmed by a central lab and will be analyzed by cell of origin using gene expression profiling. Patients could be treated with one cycle of R-CHOP before being allocated based on this result of gene expression profiling and central review to acalabrutinib R-CHOP or placebo R-CHOP. The study is different in that its maximum age at the beginning was 65 years. Again, cell of origin determined by gene expression profiling, mandatory G-CSF, and one cycle. We are looking forward to the results of this study in the near future, which has completed its enrollment some time ago.

GUIDANCE-01: R-CHOP vs R-CHOP-X for Previously Untreated Intermediate- or High-risk DLBCL

Another study that has been published by our colleagues from China was the so-called GUIDANCE studies, where a little bit the same principle, but this time all patients with DLBCL were analyzed genetically and they were stratified by genetic subtype with a classification which is very close to this so-called LymphGen classification developed by NCI. And you can see on the top eventually that this MCD and BN2 subtype receive also a BTK inhibitor, in this case zanubrutinib. Other agents were used for different cases based on what we do understand or think to understand about the biology.

GUIDANCE-01: Intermediate or High-Risk DLBCL PFS and OS

And this study has been published by Dr. Zhang and colleagues in Cancer Cell showing that if you look overall at the different, you put together all these patients, there was a significant benefit of adding specific targeted therapy for those.

So, there is probably a role for targeted therapy in this area that we need to further define.

Elderly Patients With DLBCL

A small word regarding older patients, we do know that R-CHOP is suboptimal and we are using a reduced-dose R-CHOP, which is R-mini-CHOP, but we clearly need to make progress because as shown on this curve, first of all, the median age of occurrence of DLBCL is close to 70 years of age, so quite advanced. And secondly, as you see on the bottom curve, the outcome of this patient is unsatisfactory. And there are many other studies evaluating different targeted agents, including acalabrutinib, in this setting.

Circulating Tumor DNA

What is changing also is a new way we can assess the response to therapy for patients. I'm just pointing to one of the ways which is circulating tumor DNA. We do know that all cells release in the bloodstream fragments of DNA, and some are non-tumor-derived, others are tumor-derived. We'll talk here about circulating tumor DNA, which can be detected in the plasma from a simple blood sample, can be quantified. It's a non-invasive technique. It provides genetic information.

ctDNA: Prognostic Utility

And my colleague, Dr. Mark Roschewski, published this paper a couple of months ago, showing that if you look at the end of treatment after completion of six cycles of R-CHOP, those patients that are undetectable for circulating tumor DNA clearly had a very favorable outcome. This is shown on the blue curve, where those patients that had detectable ctDNA after six cycles clearly had a very poor outcome.

Clinical Trial Opportunities With ctDNA Assessed at EoT

And this is the base for further work in this area, including trials, assessing eventually new therapies to potentially consolidate the treatment for those with detectable MRD, while those that didn't have that eventually can go for surveillance.

Relapsed/Refractory Overview

High-Dose Chemotherapy + ASCT in Relapsed NHL

Just one word regarding – yes. The timer is not working, by the way. I will try to advance quickly. But in the relapse setting, we have learned that high-dose therapies are working.

Overview of the Treatment Landscape for R/R DLBCL

But we have learned also, and I think this will be detailed by Dr. Budde and colleagues, that many options, including CAR T-cell therapy, autologous stem cell transplant, and new therapies are in this area.

Conclusions

So, we will discuss during this meeting the immune-directed therapies and treatment-based approaches that transform the field of patients with DLBCL, including different immunotherapies, CAR T-cell therapy, antibody-drug conjugates, bispecifics, and I think this will be the debate. I think I went clearly over time, and I'm sorry for that, and I hope the timer will be helping us.

Now, Let’s Retake Our Survey

Posttest 1

So, I think we will adjust to this survey very quickly before transitioning directly to Dr. Budde and keep the question and answer for the end to keep us on time.

So, again, patients with DLBCL eligible to enroll in the ESCALADE trial, which one of these criteria was not an inclusion criterion for enrollment in the study?

I think there was some progress with that.

Thank you for your attention, and Dr. Budde, I think I invite you to the podium for the second presentation. We'll skip the first discussion because of time.

Toward a New Era in DLBCL: The Expanding Role of Novel Agents

Let’s Consider a Patient Case and Quick Question

Dr. Elizabeth Budde (City of Hope National Medical Center): Good morning. So, let's first take a look at a patient case and some quick questions.

Patient Case: 73-Yr-Old Woman With R/R DLBCL

So this is a patient, a 73-year-old woman with relapsed/refractory diffuse large B-cell lymphoma who was diagnosed with Stage IIIA, IPI-3, and the patient had a biopsy-proven CD19-positive, CD20-positive, and appears to be a non-GCB type. And she was treated with pola-R-CHP for six cycles, achieved CR. Unfortunately, the lymphoma recurring eight months later. She was then treated with axi-cel, achieved a partial remission at day 30. By day 90, the patient progressed and also became symptomatic. But she continued to have good performance status and organ function. Biopsy again demonstrated recurrence of diffuse large B-cell lymphoma. The cells continued to be CD19-positive and CD20-positive. Now, Ki-67 went up to 75%.

Pretest 2

So, if you look at the questions. So, at this time, which of the following is the next best treatment for the patient?

1. Glofitamab;
2. Lisocabtagene maraleucel;
3. Rituximab;
4. Surovatamig;
5. Selinexor.

All right. Most of you picked glofitamab.

Pretest 3

So, next one is what is the mechanism of action of surovatamig?

1. Is it an anti-CD20/CD3 bispecific antibody?
2. Or is it an anti-CD19/CD3 bispecific antibody?
3. Or is it a BCL6 degrader?
4. Or is it a Cereblon E3 ligase modulator?

Wow, you guys have done really well.

The Current LBCL Treatment Landscape

All right. So, here I show here is the current large B-cell lymphoma treatment landscape. You can see that there are many, many advances from first-line to second-line to third-line and later. So, look at the third-line and later. From 2017, since the CAR T-cell approval, we have seen many other novel treatments being approved, including antibody-drug conjugates, PD-1 blockade, as well as bispecific antibodies.

Novel Targets and Agents in LBCL

So, we know that if you look at from a different way to look at how we're targeting large B-cell lymphoma, it can really be largely categorized into either we target cell surface antigens, this is on CD19, CD20, CD79b, BAFFR, CD70, or we can target intracellular targets, such as BTK inhibitors, CELMoDs, BCL6 degraders, and many others.

Classes of Novel Agents in LBCL

So, I'm going to touch on the four classes, CAR T, bispecifics, antibody-drug conjugates, and intracellular agents, in the next 20 minutes or so.

ASCT Consolidation in R/R DLBCL

So, we know for many years, autologous stem cell transplant has been the standard care for patients with relapsed/refractory diffuse large B-cell lymphoma. Based on patients' response prior to autologous stem cell transplant, the transplant will really provide outcomes if those patients had complete response before moving to autologous stem cell transplant. And those patients who got transplants will definitely feel much better than those patients who did not receive autologous stem cell transplant.

CD19-Targeted CAR T-Cell Products in DLBCL

But we know with the CAR T-cells that enter into diffuse large B-cell lymphoma treatment, the landscape has really been changed. So here, there are three CD19 CAR T constructs. They all target CD19, the same binder, but various different designs, which confers to the activities and toxicities.

CAR T-Cell Therapy: A New SoC in Early Relapsed DLBCL

Now, back in 2022, we know two Phase III studies, ZUMA-7 and TRANSFORM, looked at CAR T versus the standard salvage chemotherapy followed by autologous stem cell transplant, asking the question, which is the winner in those patients who have primary refractory large B-cell lymphoma or early relapse. In both Phase III studies, CAR T is clearly the winner. You see the curves separated very beautifully. Now, this led to the approval of these two CAR Ts in the second-line use, which also has become the standard of care.

Classes of Novel Agents in LBCL

And subsequently, bispecific antibodies entered into clinical development for relapsed/refractory large B-cell lymphoma patients.

CD20/CD3 BsAbs in B-Cell Lymphomas With EMA or FDA Approval

And here are the four bispecific antibodies in clinical development that have gone pretty far. And there are two common features of these bispecific antibodies. One is that they all target CD20, so they are CD20, CD3 T-cell engaging bispecific antibodies. And second is that they all have this immunoglobulin G, so Fc-based region, which really confers a much longer half-life, allowing intermittent dosing for this bispecific antibody, which is very different than the first-generation bispecific antibody, the BiTE format. And the two in the middle, epcoritamab and glofitamab, were approved for patients with third-line plus relapsed/refractory large B-cell lymphoma.

Glofitamab Following CAR T-Cell Therapy Failure in DLBCL

So when we look at the bispecific antibodies, and one of the natural questions is, how does it perform in those patients who already received CAR T-cell treatment? So, I want to highlight the LYSA study, which is a Phase II study of glofitamab for patients with relapsed/refractory DLBCL that have progressed or relapsed after at least one month of CAR T-cell therapy.

So, in this study, 46 patients were enrolled, and most of these patients already had elevated LDH, and a third of them were refractory to a prior line of treatment, and the median time from CAR T-cell was four months, ranging from one to 60 months. And we can see the progression-free survival in the middle showed a median progression-free survival was 3.8 months. The complete remission rate, actually quite high, is 46%, and the median duration of complete remission is not reached. And this study actually had a pretty reasonable cytopenia profile with a very low CRS rate, ICANS rate, and tumor flare was only in 9%. So this is a reasonable regimen in those patients who failed CAR T.

Phase III Trials of Bispecific Antibodies in Aggressive BCL Established Later-Line Role: Earlier-Line Momentum

But bispecific antibodies did not just stay as a later-line treatment. It has entered into earlier-line treatment, and here are the four Phase III studies comparing bispecific monotherapy or bispecific combination therapy versus the chemo control arms in patients with relapsed/refractory large B-cell lymphoma in the second-line setting. The first two studies have completed and the results were available already. So we're going to focus the next slide on these two studies.

STARGLO: Glofitamab + GemOx vs R-GemOx as 2L Therapy for Transplant-Ineligible R/R DLBCL

So, STARGLO is a Phase III study comparing glofitamab plus GemOx versus R-GemOx in patients with at least one prior line of therapy, and those patients had DLBCL NOS, so it does not include patients with high-grade B-cell lymphoma. So, patients were randomized to either glofitamab plus GemOx versus R-GemOx. That is a fixed-duration treatment for the experimental arm, and it's a total of 12 cycles. The primary endpoint is overall survival.

STARGLO: Glofitamab + GemOx vs Rituximab-GemOx as Second-line Therapy for R/R DLBCL

So, here we look at the response rate. On the right is the result from glofitamab plus GemOx. CR rate 58.5%, more than double of that from R-GemOx, and the safety profile looks pretty standard. The CRS is very similar to single-agent glofitamab. Some infections, which are common in bispecific-containing regimens. ICANS is quite low, and this study met its primary endpoint. Now, we see improvement in progression-free survival as well as overall survival in both overall patients and also in those patients concentrating in the second-line treatment. Most of the patients in the study actually received this as a second-line treatment. Unfortunately, this study did not receive FDA approval due to insufficient patients in the U.S., but it's NCCN listed.

SUNMO: Mosunetuzumab + Polatuzumab Vedotin vs R-GemOx for Transplant-Ineligible R/R DLBCL

So next one, the SUNMO study, which is a little bit different than the STARGLO. Here we were looking at a chemotherapy-free pair, so mosunetuzumab plus polatuzumab vedotin versus GemOx. Now this is also in patients with transplant-ineligibility, but this study included around 20% of patients with high-grade B-cell lymphoma as well as transformed large B-cell lymphoma. Patients were randomized to mosunetuzumab plus polatuzumab vedotin versus GemOx for a fixed-duration of 8 cycles, and the treatment was given in the outpatient setting. There are two primary endpoints, including overall response rate and progression-free survival.

SUNMO: Mosunetuzumab + Polatuzumab Vedotin vs R-GemOx for R/R Transplant-Ineligible DLBCL

And if we look at the results, both primary endpoints were met. For the complete remission rate in the mosunetuzumab arm, CR is 51%, which is more than double of that for GemOx, which was 24.3%. And this novel combination has the lowest cytokine release syndrome among all bispecific-containing regimens. And you can see on the right upper over here, you can see the CR, cytokine release syndrome is typically in the first cycle, and the progression-free survival as the other primary endpoint was also met. It's more than three times that of the GemOx group. Therefore, this regimen now is listed in the NCCN guidelines and also is going through the regulatory pathway.

Phase III Trials of Bispecific Antibodies in Aggressive BCL Established Later-Line Role: Earlier-Line Momentum

So bispecific antibody combos have also entered first-line development. These are the three Phase III studies using a bispecific-containing regimen versus standard of care. We don't know the results yet, but so far I think it looks encouraging.

Surovatamig (AZD0486): Novel CD19 x CD3 Bispecific Antibody

So moving on to a novel bispecific antigen, which is the agent surovatamig, which is a novel CD19, CD3 bispecific T-cell engager. It also has the Fc portion, allowing a longer duration of half-life, allowing glasses or intermittent dosing. Again, it targets CD19.

Efficacious after prior CAR T or anti-CD20 BsAb Surovatamig for R/R DLBCL

And this study is still early during development, but a Phase I study with 106 patients gave us very encouraging results. In those patients who have prior CD20 bispecific engager, this agent appears to be able to induce a CR in five out of 11 patients. And in prior CAR T-treated patients, 11 out of 31 patients also get into a complete remission. And if you look at the different dosing regimens here, since this is an early phase study, so you can see that when you go up the bispecific antigen dose, then the CR ratio went up from 38% to 54% when patients received 25 mg as the full dose. And we look at the safety profiles, it's actually quite reasonable. Cytokine release syndrome is pretty similar to other typical bispecific antibodies. The ICANS is a little bit higher, but still remains low compared to CAR T. This is probably because it's targeting CD19. So there are some questions remaining to be answered. It appears maybe a good salvage regimen after CD20 bispecific or CAR T treatment, but can you replace CAR T? We don't know yet. We also don't know the mechanism of resistance since we haven't really learned anything about the CD19 negativity after patients relapse. But nevertheless, it's a very encouraging molecule.

Classes of Novel Agents in LBCL

Moving on to antibody-drug conjugates.

ADC Mechanism of Action

Now, we know an antibody-drug conjugate is really a targeted chemo. Basically, it brings the payload into the lymphoma, the target cells, and this payload will then be released and kill off the target cells. And the payload can also kill off the tumor cells in the surrounding area, the so-called bystander effect.

ADCs and Their Payloads in R/R DLBCL

So there are at least four antibody-drug conjugates used in the relapsed/refractory DLBCL setting: brentuximab vedotin, loncastuximab tesirine, and polatuzumab vedotin, as well as zilovertamab vedotin. And three of the four have MMAE as a payload. The loncastuximab tesirine has the PBD as the payload.

ECHELON-3 Study of Brentuximab Vedotin Plus Lenalidomide and Rituximab (R 2) vs R2 Plus Placebo

So, ECHELON-3 is a study combining brentuximab vedotin, a CD30 antibody-drug conjugate, plus R-squared, which is lenalidomide and rituximab, versus R-squared plus placebo. And this study, the patient population is a little bit different than those Phase III trials that I mentioned earlier. These are for patients who either are not eligible for transplant, relapsed post-transplant, or patients who have had CAR T-cell treatment already. Patients were randomized into BV plus R-squared versus placebo plus R-squared. The primary endpoint is overall survival.

ECHELON-3: OS and PFS in ITT Population

And you can see here, the study actually matches the primary endpoint. There's an overall survival benefit favoring BV plus R-squared.

LOTIS-5: Loncastuximab Tesirine + Rituximab vs R-GemOx in R/R DLBCL

And moving on to – so this is the LOTIS-5. I think some of us probably learned that just now on June 3rd, the company announced top-line data from LOTIS-5, this is such a positive study. We don't really know enough about the details here, but just, this is a Phase III study looking at those patients with transplant ineligibility. Some of them received loncastuximab tesirine, a CD19 antibody-drug conjugate, plus rituximab, versus GemOx in patients with relapsed/refractory DLBCL and transplant ineligible. All patients received a fixed-duration treatment. And this study actually matches the primary endpoint. So, we need to learn a bit more about the risk and benefit ratio before we can really be able to put it in the landscape.

Loncastuximab Tesirine + Glofitamab in R/R DLBCL

A quick word on LOTIS-7, which is a rational combination of loncastuximab tesirine, a CD19 antibody-drug conjugate plus a CD20, CD3 T-cell engager in patients with relapsed/refractory large B-cell lymphoma. As a single-arm study, cohort one is looking at third-line plus, cohort two is looking at second-line plus. And all patients received a fixed-duration treatment. And you can see here the overall response rate is quite high, 93%. With a CR rate of 87%, and this combination has a very favorable side effect profile, low cytokine release syndrome. Most of them, all of them are grade 1 and grade 2. And very few patients had any ICANS, and currently the study is going through Phase III expansion, planning to enroll around 100 patients. It probably has the potential to be best-in-class if the efficacy and toxicity profile continue to remain consistent.

POLARGO: Polatuzumab Vedotin + R-GemOx in Patients With Transplant-Ineligible R/R DLBCL

And a word on the POLARGO study, which this is your typical traditional chemotherapy plus another smart chemo, so it's more intensified chemo in patients with transplant-ineligible relapsed/refractory DLBCL. So this is also looking at the second-line plus setting. Patients were randomized one-on-one to either pola-R-GemOx versus R-GemOx for a total of up to eight cycles. The primary endpoint is overall survival.

POLARGO: Pola-R-GemOx vs R-GemOx in R/R Transplant Ineligible DLBCL

This is another positive study, met its endpoint. The CR is 40% in the pola-R-GemOx group versus 19% in the R-GemOx group as a control arm. And if you look at the progression-free survival, the curve on the top upper, over here, and looking at the overall survival, both curves really separated very early on and maintain to be separated. So this is a positive study. The efficacy is quite encouraging, but as a chemo backbone plus more chemo, it appears to be a little bit more toxic than R-GemOx, but it's a good regimen for those patients who do not have access to CAR T or more complex therapy.

Other Third-Line and Beyond Treatment Options for R/R DLBCL

And this one, this slide is here just to tell you that selinexor, which was approved in large B-cell lymphoma, however, this was taken out of the market, so it's no longer available.

Classes of Novel Agents in LBCL

So moving on to the last part of my talk, which is focusing on the intracellular agents: BTK inhibitors, CELMoDs, or BCL6.

Investigational Approaches

These are very exciting intracellular agents that really broaden the available new agents for patients with relapsed/refractory large B-cell lymphoma. And all of these agents are currently undergoing investigational development –

Advances on the Horizon

– but it really has broadened the availability of new agents for this patient population.

BTK Inhibitor: Mechanism of Action

So, BTK inhibitors, we all know how BTK inhibitors work.

BTK Inhibitors for DLBCL

So moving on, I'm just going to focus on – now, this slide is really summarizing the ongoing clinical trials testing BTK inhibitors, not so much focusing on ibrutinib, which is the first-generation covalent BTK inhibitor. So the current newer trials really focus on second-generation covalent BTK inhibitors, acalabrutinib or zanubrutinib, in combination with other partners, either with chemoimmunotherapy, like in the ACCEPT study, versus also in patients who are elderly and frail to see whether BTK inhibitor incorporation can further improve the outcome in this patient population.

Other Trials of Acalabrutinib in DLBCL

And here are these – if you are interested in learning about the background of this, some of the studies were already performed and completed. For example, the ACCEPT study, which really showed a much higher, very encouraging CR rate. So this is, but still, this is an early phase study. I think a later phase study will tell us whether adding a BTK inhibitor in this setting will be able to benefit a certain patient, or is it just focusing on the ABC subtype.

CELMoD Agents: Mechanism of Action

So moving on to a very exciting new agent on the block, which is really the CELMoD agent. We know lenalidomide has long been the only CELMoD available for patients with lymphoma, but nowadays there are several CELMoDs in development, and they have much higher binding specificity to inhibit modern Cereblon E3 ubiquitin ligase complexes. And this really leads to a very specific regulation of the Ikaros and Aiolos pathways, and which as a result, it modulates immune cell function, it inhibits cell proliferation, and so promotes apoptosis.

CC-99282-NHL-001: Efficacy of Golcadomide for Patients With R/R DLBCL

And this is a study looking at a molecule, the so-called golcadomide, in patients with relapsed/refractory DLBCL. So this is in combination with rituximab. When you look at these agents given at a low dose, 0.2 mg, that's already a pretty encouraging CR rate, 18%, but if you look at when you give a higher dose, 0.4 mg in combination with rituximab, the CR rate went up to 43%. And the follow-up is still quite short, but nevertheless, I think the efficacy is very encouraging, and especially when you look at those patients who have prior CAR T-cell treatment. This is in a third of patients, 33% of patients had a complete remission, which is a little bit lower than the patients who are CAR-naive. And the most common side effect that was associated with this agent, golcadomide, is neutropenia. And so far, it looks like the safety profile is a lot more favorable than lenalidomide. And these agents are being tested in the frontline setting, the GOG-3026 study, and also in the relapsed/refractory setting, combining with antibody-drug conjugates, combining with bispecific antibodies, certainly an agent to watch out for.

BCL6: A Master Regulator of the Germinal Center Reaction

And last but not least is the BCL6 degrader. Now, we know BCL6 serves as a master regulator of the germinal center reaction. So what it does is it regulates the germinal center cells' activity. Basically, it rescues the cells from DNA damage checkpoints, allowing the cells for rapid progression and somatic hypermutation, which leads to lymphomagenesis. So if you shut down BCL6 by degrading it, allowing these abnormal B-cells to die or to differentiate.

CA123-1000 Monotherapy: Efficacy and Safety in R/R NHL

So, how does it perform in the clinic? CA123-1000 is one of the BCL6 degraders. In the first-in-human, first Phase I clinical trial, we see this degrader actually work quite well. Now, we get here in the overall patient population, 48 patients, the CR rate is 21%. And you see responders in both the DLBCL and follicular lymphoma. And we know this is only single-agent activity. And time to first response is actually quite short, only 1.8 months. And duration of response so far is 5.8 months. And duration of CR, those patients who achieve CR, most of them continue to remain in CR. And the response so far appears to be subgroup agnostic, so it doesn't matter if it's different cell types or whether prior CAR T-cell treatment, you continue to see good responders. And the most frequent treatment-related AE, one of them is arthralgia, which is in 21%. But this molecule is still early in clinical development. If the toxicities continue to remain the same, no worse, and if the combinational therapy allows it to combine with bispecific antibodies, with rituximab, with other agents, so I think this one is very encouraging. Definitely gives us more tools in how we manage patients with relapsed/refractory large B-cell lymphoma.

Conclusions

So just to conclude, we think the therapeutic landscape in diffuse large B-cell lymphoma is rapidly evolving. More and more novel agents are available now, either as monotherapy or in combination. And rational combination approaches really have shown very promising efficacy, which so far are within manageable toxicities. It is an exciting time to have access to novel treatments via clinical trial enrollment.

Now, Let’s Revisit Our Patient Case and Quick Question

So now back to our patient case.

Patient Case: 73-Yr-Old Woman With R/R DLBCL

So remember, this is a 73-year-old woman with relapsed/refractory DLBCL, who was treated with R-CHOP-pola, had a very short CR, eight months, primary refractory, received CAR T shots as a second-line treatment, but did not quite get into a durable remission, relapsed at month three, and the patient now is looking for a third-line treatment.

Posttest 2

So here is, which of the following is the next best treatment for this patient?

1. Glofitamab;
2. Lisocabtagene maraleucel, which is another CD19 CAR T-cell treatment;
3. Rituximab;
4. Surovatamig;
5. Selinexor.

Wonderful. Well, this may be an option here if it's available in a clinical trial.

All right, let's move on to the next one.

[00:51:42

Posttest 3

Oh, okay, what is the mechanism of action of surovatamig?

1. Is it an anti-CD20/CD3 bispecific antibody?
2. Is it an anti-CD19/CD3 bispecific antibody? Or
3. Is it a bidirectional BCL6 degrader? Or
4. Is it a CELMoD modulator?

Wonderful. Thank you all.

Dr. Salles: Thank you so much, Elizabeth, for keeping in time and then allowing us to keep the whole session on time. We have time before Dr. Zinzani, maybe for two questions. If there is one from the audience, we'll take it. Otherwise, I have one question for you already. You know, we learned clearly that CAR T-cell therapy was allowing to cure patients. And based on the data that you see today, do you think that in general with the concept of T-cell engagers, or so-called bispecifics, but T-cell engagers, do you think these drugs, either as a single agent or as a combination, also offer potential for cure for patients with relapsed DLBCL?

Dr. Budde: I actually do think so. I think now we have, you know, we're seeing five-year follow-up from patients treated with glofitamab, you know, four-year follow-up from patients treated with epcoritamab, and, you know, there are also patients, the subset of patients who are on the mosunetuzumab plus polatuzumab vedotin combo from the early Phase I, Phase II studies, now we're seeing our subset of patients continue to remain in complete remission five years, or even higher, you know, after the treatment. So, definitely, I think a subset of patients benefited from very durable remission, and I think some of them are possibly cured.

Dr. Salles: So, I don't see any questions from the audience. I saw that the timer for Dr. Zinzani had started. Maybe it can be rebooted to zero. And I think Pier Luigi Zinzani will present to us how do we access these new treatments, how are they moving forward. Please don't hesitate to ask questions online. We'll answer them during the Q&A final session. And please, Pier Luigi.

Expanding Access to Targeted Therapies and Clinical Trials in Non‑Academic DLBCL Practice

Dr. Pier Zinzani (Alma Mater Studiorum-University of Bologna): Thank you, Gilles. Good morning to everybody.

A Quick Survey

So, we'll start with a quick survey.

Pretest 4

It's which of the following investigational agents is an allogeneic CD19-directed CAR T-cell therapy?

1. Cema-leucel;
2. This one is so difficult, 4-1BB, Interleukin-18;
3. Prizlo-leucel; and
4. Zam-leucel.

Please vote.

Interesting. We can discuss later.

DLBCL: Role of Clinical and Biologic Features Let’s Start With a Patient Case

Okay. Good morning in the CAR T, second-generation world.

Patient Case: 78-Yr-Old Man With Resistant DLBCL

Our patient case is a 78-year-old man with resistant diffuse large B-cell lymphoma. He has a history of prostate cancer and ischemic heart disease. He's diagnosed with bilateral testicular diffuse large B-cell lymphoma. With an activated diffuse large B-cell lymphoma phenotype, of course, CD20-positive, MYC-negative, BCL2-positive. PET positive with some localization to both adrenal glands, skeleton, liver, epicardium, and skin. The IPI at the end of the stage was four. The CNS-IPI was five. The patient received in terms of frontline treatment pola-R-CHP after being considered eligible for anthracycline-based therapy related to the normal heart function. There was no response after six cycles. It was considered, of course, a primary refractory disease with persistent localization to adrenals and skin, although this was confirmed by the biopsy. The patient received as a second-line treatment the conventional R-GemOx with a good tolerance after two cycles. But, of course, the patient obtained only a stable disease.

Patient Case: 78-Yr-Old Man With Resistant DLBCL

The third-line included loncastuximab tesirine. After two cycles, the patient received a PET scan that revealed an increase of FDG uptake, lesions in both adrenals and new areas of FDG uptake in the skin. And there was also an increase of hypermetabolism at the persistent PET-positive cutaneous sites. The patient, at this time, remains CD20-positive. Overall, the patient is in good clinical condition with adequate cardiac function, 62% with normal ventricular kinetics, no systemic symptoms, no cytopenia, and no present infections.

Poll 3

Next questions. What is the most significant parameter that may inform the choice of polatuzumab vedotin plus R-CHP as the frontline treatment for this 78-year-old man with CD20-positive activated diffuse large B-cell lymphoma?

1. IPI score at diagnosis;
2. Age and/or level of fitness;
3. Cell of origin, and also the last and
4. Preserved cardiac function.

Please vote.

I think we are quite close, because at the end of the day, as was said before, there are some controversies in these different subsets of patients inside the POLARIX study, in particular, of course, the activated B-cell cell of origin, and also the high IPI, intermediate high IPI. Okay.

Epidemiology of DLBCL: Age, Presentation, and Survival Rates

Some epidemiology of diffuse large B-cell lymphoma, the age, presentation, and survival rates. The median age at diagnosis is roughly 65 years, and presenting with stage – advanced stage in at least 55% of the patients. At least one-third of the patients present systemic B-symptoms at diagnosis, and in at least two-thirds of the patients, there is an elevation of the LDH. In at least 40% of the patients, we can observe an extranodal involvement, and bone marrow involvement, at the end of the day, there is a range between 10%, at least more than 30-35%. The CNS involvement, yes, there was a debate concerning the prophylaxis, and this is roughly 4%, and roughly 2% at relapse. And the five-year relative survival is close to 65%, according to this evaluation with patients between 2013 and 2019.

Comparison of Clinical Prognostic Indexes

And as was said before, of course, in terms of clinical prognostic index, the historical IPI, but I think is, of course, the best. Also, there were also the revised IPI, and the last one was NCCN-IPI, but at the end of the day, there are no real significant differences among these three different prognostic indexes, and I think the IPI, the historical one, is the best one.

DLBCL: Role of Molecular Subtyping

New WHO Classification of DLBCL

Role of molecular subtyping, I think we can skip this slide, because as was said before, there are some modifications, in particular, the last WHO/ICC classification, there was a reunification of the two different pathology groups, at least four years ago. Now, something we are changing, in particular, in a smaller definition of some subsets of patients.

A Summary of Prognostic Factors in Newly Diagnosed DLBCL

In terms of prognostic scores in untreated patients, so as I said before, the clinical IPI, revised IPI, age-adjusted IPI, the disease bulk, metabolic tumor volume, time from diagnosis to the therapy, and of course, the metabolic tumor heterogeneity.

The response-based is included. The end of therapy PET is mandatory to do at the end of the induction treatment, the PET evaluation. You can do also the CT scan, but of course, with a PET scan. The interim PET is fundamental, in particular now that there is the possibility to use in these patients in second-line CAR T-cell therapy, it's quite important to know as soon as possible if the patient is a potential primary refractory patient or with a very slow response during the treatment. Be important also at this time to use PET instead of a CT scan. And MRD, MRD is of course very important, very common in clinical trials, could be more difficult to use in the real world.

Molecular cell of origin, of course, the classical historical cell of origin, translocations in MYC, BCL2, BCL6, as was shown before, the BCL2 and MYC expression and some molecular clusters.

Poll 4

Other polling question: which of the following is an appropriate strategy to consider to improve outcomes for a patient with high-risk diffuse large B-cell lymphoma after progression of frontline treatment?

1. Addition of a bispecific antibody to a chemotherapy backbone;
2. The use of CAR T-cell therapy if the patient has a high-risk, high IPI score risk; or
3. Enrollment on a clinical trial.

Please vote.

Quite easy. We'll see. Okay, so C is 30% clinical trials. Yes, because as Elizabeth presented before, also we see some – we present some slides concerning there are some new ongoing Phase II studies, including chemo-free regimens such as, I mean, for example, LOTIS-7, which could have very interesting preliminary data in terms of efficacy, but we need more data in terms of duration of the response. Of course, CAR T at this moment is the conventional treatment for this kind of patient.

EPCORE NHL-2: Response With Epcoritamab + R-CHOP in Previously Untreated DLBCL

EPCORE, this kind of trial was the EPCORE NHL-2 trial, looking at the combination of epcoritamab plus R-CHOP in untreated large B-cell lymphomas. This was from a presentation by Dr. Lorenzo Falchi. And I think the data are really impressive. There is a fixed-duration epcoritamab plus the conventional R-CHOP. And you can see here with a median follow-up of roughly 28 months, the evaluation is on 47 patients. The CR rate is 85%, and the overall response rate is close to 100%, 98%. And in particular, the percentage of complete metabolic response is between 85-90% in all the different subsets of patients: double-hit, triple-hit, IPI-3, IPI-4 and 5, and also patients with bulky disease more than 10 cm. And the median duration of exposure of epcoritamab is roughly one year.

Navigating Access Across EU Healthcare Systems

SKYGLO: Polatuzumab Vedotin + R-CHP ± Glofitamab for Previously Untreated LBCL

And the SKYGLO. SKYGLO is another important ongoing Phase III trial. As was said before, it showed the very long list of this Formula One race concerning several ongoing Phase III studies in the setting of advanced untreated diffuse large B-cell lymphomas. SKYGLO is one of them: pola-R-CHP plus glofitamab versus the conventional pola-R-CHP. As said, it's the only one of these ongoing Phase III trials where the standard arm is pola-R-CHP because in all the others it is the conventional, the historical R-CHOP.

ZUMA-23: Axicabtagene Ciloleucel vs SoC in High-Risk LBCL

ZUMA-23. So you remember the publication by Sattva Neelapu concerning the role of frontline axi-cel in the high-risk patient population, IPI-4 and 5, including all the double-hit, triple-hit. CR rate was more than 80%, and the two-year progression-free survival was roughly 80% on the basis of this very interesting Phase II data. They started with the ZUMA-23 study, a Phase III randomized trial. I was involved in this study. It's not so easy to include the patient anyway. Very easy ratio, one-to-one. The standard of care is R-CHOP or DA-EPOCH-R for six cycles. And of course, the study arm is axi-cel, one shot. And probably the accrual will be closed at the end of this summer. And we'll see in the next two years probably the first analysis.

Poll 5

Another polling question. After receiving frontline polatuzumab vedotin added to pola-R-CHP, the patient received second-line R-GemOx, good tolerance after the first two cycles, but only with a stable disease situation. Which of the following is an alternative to second-line R-GemOx for this patient considering his age, 78?

1. CAR T therapy;
2. Bispecific antibody plus conventional chemotherapy;
3. Bispecific plus targeted therapy;
4. Observation; or
5. Palliative care.

Please vote.

70, I mean, 68% CAR T. In Italy for me it's quite impossible to use CAR T because there is a cutoff of 75 years only for diffuse large B-cell lymphoma, not for mantle cell, not for CLL, not for follicular. I don't understand why, I mean, anyway. Okay.

STARGLO and EPCORE NHL-2 in R/R DLBCL: PFS and OS

STARGLO. STARGLO and EPCORE, already Elizabeth presented these two trials that are very interesting, the concept in second-line to use the conventional chemotherapy, GemOx and a CD20, CD3 bispecific, glofitamab or epcoritamab, and the data are really interesting and are quite similar in both studies.

LOTIS-7: Loncastuximab Tesirine in Combination With Other Agents in R/R B-Cell NHL (Arm E)

LOTIS-7, I said before, is very interesting. The concept is loncastuximab tesirine, an ADC anti-CD19 monoclonal antibody plus the conventional glofitamab. I'm involved in the trial. We will close probably next week the accrual with 100 patients and the preliminary data in the first 48 patients is an 85% complete metabolic response. The most part of patients were in second-line, at least 60% of the patients and the other 40% received at least two prior lines of treatment. The trial included not only diffuse large B-cell lymphoma but also a very important number of high-grade B-cell lymphomas.

Investigational and Approved Bispecific Antibodies in B-Cell Lymphomas

And some investigational bispecific antibodies, and you know very well the long list also as was presented before: mosunetuzumab, epcoritamab, glofitamab, and odronextamab, all of them are CD20, CD3 bispecifics. And the new one, the CD19, CD3, we need a new target according to the unbelievable therapeutic algorithm that is quite similar to the Sudoku of multiple myeloma, surovatamig, of course, anti-CD19, CD3.

EU vs USA: Barriers to CAR T-Cell Therapy

So, some barriers to CAR T-cell therapy with the comparison between the European countries versus the United States. I am a CAR T center, and I think it's quite difficult for several reasons, technical reasons such as rapid disease kinetics, complex manufacturing and coordination of care, accessibility to treatment centers, toxicity management, cost, and various factors. But at the end of the day, when you treat for several months in a year, CAR T-cell therapy is quite easy to obtain a good result with a very good management of this patient. The real problem in Europe, but I know also in several academic centers in the United States, is that sometimes, I mean often, it's difficult to receive the potential patients eligible for CAR T from the referral center for several reasons and this is a national and international problem.

Evolving Treatment Algorithm in DLBCL: Sequence Approved ADCs With Other Available Therapies for DLBCL

I mean, this is the classical algorithm of what to do from frontline, second-line using CAR T or bispecifics plus something, or bispecifics as treatment for patients who failed CAR T.

Optimization of CAR T-Cell Therapy

And I think it's very important the optimization of CAR T, optimize the stem cell memory phenotype to prevent exhaustion and improve efficacy, speed up manufacturing. This is another important step. Prevent antigen escape and reduce, of course, the toxicity.

Advances on the Horizon

And there are some advancements on the horizon: earlier CAR T and bispecific antibody therapy, and you know this combination of bispecifics, glofitamab plus pola, glofitamab plus loncastuximab, glofitamab plus RG6026 for this co-stimulatory antibody, and also new specific monoclonal antibodies, bispecific monoclonal antibodies, surovatamig, of course, anti-CD19, CD3. BTK inhibitors, first-generation and also second-generation. And of course, the data presented by Elizabeth concerning one of the BCL6 degraders and of course golcadomide.

New CAR Ts on the horizon: the rapcabtagene autoleucel, zamtocab autoleucel, GLPG5101, the ATALANTA-1 study, and the 4-1BB Interleukin-18, the KITE-363 and the cema-cel, CAR-NK cells and also many others, the CAR in vivo, for example.

Rapcabtagene Autoleucel

This is a very long list. This is rapcabtagene autoleucel, a next-generation autologous CD19-directed CAR T-cell therapy with a rapid manufacturing platform to preserve the T-cell stem cell memory phenotype, and the expansion is comparable to T-cells at day 25 for a lower dose. It's a Phase II trial in relapsed/refractory diffuse large B-cell lymphoma. Only 60 patients so far are evaluated for response. The complete metabolic response is 65%. And in terms of CRS grade 3 or more than 3, it's 6%. And the neurological toxicity grade 3 or more is 3%.

Zamtocabtagene Autoleucel

Zamtocab autoleucel is another autologous CAR T-cell, CD19, CD20, with a two-week vein-to-vein time. And DAILY II is the name of the Phase II study in patients with relapsed/refractory patients with diffuse large B-cell lymphoma after at least two prior lines of treatment. So far they included roughly 60 patients and you can see the preliminary data in terms of efficacy. Roughly 51% complete metabolic response and the overall response rate is 73%.

GLPG5101

The ATALANTA-1 study, Phase I/Phase II trial, there were fantastic results in particular on mantle cell lymphoma, 100% complete metabolic response. The last meeting, but two months later in March, the enrollment was closed, and of course, the trial was stopped.

KITE-363

KITE-363 was the first presentation at the last ASH meeting. It was an autologous CAR T, CD19, CD20. And you can see here the preliminary results, a very high level of complete metabolic response, close to 80% and close to 90% overall response rate.

Prizloncabtagene Autoleucel (JNJ-90014496)

And prizlocabtagene autoleucel is another CD19, CD20 CAR T-cell, autologous CAR T, Phase I study, again in diffuse large B-cell lymphoma, but really preliminary data and you can see also in this case the CR rate is more than 75%.

huCART19-41BB-IL18

This is another, it's a fourth-generation autologous CAR T-cell that secretes Interleukin-18. There is a Phase I trial in the setting of relapsed/refractory lymphoma including indolent and also aggressive disease. You can see here in terms of response for diffuse large B-cell lymphoma it is close to 40%.

Cemacabtagene Ansegedleucel

And this is the only allogeneic CAR T-cell, I'm sorry, according to the polling questions. It's a Phase I and Phase II study. The overall response rate so far is close to 70%. The CR rate, the complete metabolic response, is close to 60% in this Phase I, Phase II trial.

Should We Use MRD to Target CAR Consolidation?

And I can skip this, which was presented before by my colleagues, the concept of ctDNA detected or not detected according to the really recent publication by Mark Roschewski.

ALPHA-3: Cema-cel as an “MRD Eraser”

And the ALPHA-3 trial is another important concept. Cema-cel is an MRD eraser and is like a consolidation, I mean, for adult patients with large B-cell lymphoma who received standard frontline treatment, who achieved a complete metabolic response or a partial response suitable for observation at the end of frontline treatment by PET-CT scan and a positive MRD test. We can have this kind of trial ratio one-to-one, observation versus this allogeneic CAR T to really understand if it's possible to increase the response with the conversion from PR to CR and also to prolong the duration of the response. And the primary endpoint is event-free survival.

Ongoing Healthcare Professionals’ Challenges Regarding Novel ADC Therapies

We can skip this because, as you know very well, there are ongoing healthcare professional challenges regarding the novel ADC therapies. And I think it's important, in particular, how to combine with bispecifics or other drugs and also at the end of the day, one of the important points is the financial concerns for facility and availability of patient resources.

Pearls for the Multidisciplinary Team

Perils for the multidisciplinary teams: older patients are less likely to tolerate higher doses of steroids. Close monitoring of patients for infusion-related reactions, management of infections, and peripheral neuropathy is key. Educating patients on when to report to the emergency department is essential to assess for development of emerging known toxicity and to avoid organ injury. And finally, preparing patients for less common photosensitivity reactions and cutaneous adverse effects is key for achieving success.

[01:18:10]

Conclusions

In conclusion, integrating targeted therapies into community workflows is important. And clinical trial enrollment should be discussed with patients and their caregivers at initial diagnosis and at the time of relapse. Common misconceptions about clinical trials should be addressed with patients and, of course, with the caregiver. And finally, patients and their caregivers need to be directed to and enabled with trial findings resource.

Now, Let’s Revisit Our Question

And I come back to the polling questions.

Posttest 4

Which of the following investigational agents is an allogeneic CD19-directed CAR T-cell therapy? A, B, C, and D.

Please vote.

Now it's very easy.

Okay.

Interactive Panel Discussion

Deciding Between Available ADCs, Bispecific Antibodies, and CAR T-Cells for R/R DLBCL

Dr. Salles: We will take time for discussion. I think there are many questions that will come. Before that, if I can have the next slide. That's probably the topics for discussion. And before we open to the panel, if I can have the next slide. Eventually, yeah.

EHA 2026: Key Studies in DLBCL

Just to outline to the audience a couple of key studies that will be presented during this meeting. In the plenary, Dr. Lenz and colleagues will present the FRONTMIND study on anti-CD19 plus lenalidomide in the first-line. CELMoD plus pola-R-CHP. EPCORE DLBCL-1: Dr. Falchi will present the first results of this randomized single-agent epcoritamab versus immunochemotherapy. An analysis of bridging CAR T-cell in large B-cell lymphoma. And in the next slide, please.

EHA 2026: Key Studies in DLBCL

I think we have Dr. Budde and colleagues presenting an update of the mosunetuzumab-polatuzumab versus GemOx in the SUNMO study with very interesting results. Sustained remissions beyond four years with epcoritamab and five years with glofitamab. So an update of bispecific antibodies suggesting the possibility of cure.

A Final Survey

Poll 6

So I open – we have a final survey, we'll open the Q&A. But maybe we can keep the discussion going for the last five minutes before going to this final polling question.

Question and Answer Session

Maybe I ask another question to both Dr. Budde and Dr. Zinzani. We have seen in the last two years many studies beating GemOx. Do you think GemOx is definitely dead?

Dr. Budde: I would think so. Now maybe it could be used as a bridge, but for very brief use. But as a control arm, it's no longer valid.

Dr. Zinzani: I think it's dead.

Dr. Salles: Okay, I hope that everybody can have access to one of the drugs to be combined with GemOx, which include, as you know, many agents from antibody-drug conjugates to bispecific therapy. You mentioned the question of age in terms of CAR T-cell therapy, which again will be depending on the place where you work and the access to different CAR Ts. I understand that you are maybe frustrated for your older patients not having access in DLBCL to CAR T. Do you think there is an age limit? And the same question for Dr. Budde in this area.

Dr. Zinzani: I mean, the real problem in our center in Italy is, as I said before, the really no good interaction between some referral centers and the CAR T center. I think it's very important for the patients potentially eligible for CAR T to move to CAR T, in particular in second-line for sure. And the age, the age – I mean, Italy is the only country in Europe with this kind of situation in terms of age because in the other countries like the United States, there is no limitation. But our drug agency decided to put this cutoff at 75 years and I think could be quite correct because at the end of the day, it's so difficult to – I mean, this is my opinion, to use CAR T in a patient with an age more than 75 years old.

Dr. Budde: Yeah, I think age is probably a relative number based on patient performance status, which is also very important. As far as organ function, I think we are fortunate we're able to give CAR T for patients even in their 80s. We have seen that data looking at elderly patients receiving CAR T, the side effect profiles and responses are quite similar to patients who are younger, but I definitely think there is a selection bias. But with the newer CAR Ts, it's a better safety profile and without sacrificing efficacy, I think CAR T should be more and more available for patients who are older.

Dr. Salles: And given this race that you mentioned between cellular therapies brought to the patient and the improved tolerability and safety profile, but also the impressive results that we see with combinations of bispecifics with other agents or new generations of bispecifics, do you think there is a possibility that in the future we will have a choice? During the last five years, we used to say the best curative option is CAR T. You already touched upon the fact that bispecifics are potentially curative in this setting. How do you think this race is developing?

Dr. Budde: Yeah, I think that it's actually really great for patients, it's not either-or, both are available. In some patients, if they prefer to stay in the community, bispecifics are really entering into the community. We need the community to be more comfortable, just as Professor Zinzani mentioned, with the community readiness, how to manage the side effect toxicities. So I think there's probably a higher penetration use of bispecific combos in a community setting. But for those patients who want to have a one-time fixed-duration treatment, CAR T definitely has the advantage. But you can also do a hybrid, which will be, I think, the focus of future clinical trials.

Dr. Zinzani: I think there is a problem in – there are several Phase II studies with fantastic results, chemo-free regimens, bispecific plus. But at the end of the day, if you conclude the trial, Phase II, the next step is a Phase III randomized trial for the potential registration. How to do? Because the problem is, in this case, you have to do a trial against CAR T. It could be really difficult to do this kind of trial, for several reasons, I mean.

Dr. Salles: Yeah, I think it's – so, we have a large number of questions online. We won't be able to answer them all. I know there are a few clinical cases, individual cases. Some of us may be able to answer that. Maybe there is one question that comes on the top to me from the different ones that were asked. And I would like to thank the more than 120 people online who are attending this symposium. In the relapse post-CAR T setting, while the patient maintains CD19 and CD20 expression, what bispecific agent will you choose? I think at this time, it's probably only those that are available, except in clinical trials. But do you see there is a role for bispecifics? You presented the LYSA study. How do you treat this patient now in real life when you see post-CAR T relapse?

Dr. Zinzani: I mean, if it's CD19/CD20-positive, with glofitamab in my hands, and I mean, the results are quite good, 30-35% complete metabolic response. The next step is, the question is, to do a consolidation with allogeneic transplant or not.

Dr. Salles: Is that something you use in your practice?

Dr. Zinzani: No. Okay.

Dr. Salles: Dr. Budde?

Dr. Budde: Yeah, I concur. I think that post-CAR T relapse, if you look at third-line, outside of clinical trials, bispecifics will be the choice.

Dr. Salles: And do you consolidate your patient with an allogeneic transplant?

Dr. Budde: I will not. I will probably consider allo-transplant for those patients who fail CAR T and fail bispecifics.

Dr. Salles: Yeah, I think this is an interesting debate because I think two years ago, with the early results, any patients that were in CR were eventually discussing allogeneic transplant. I think we still have this discussion for a few patients, but I think, again, the emerging data clearly showing that patients who achieve a CR with these T-cell engaging bispecific antibodies appear to maintain the CR in a prolonged way, make it challenging to discuss that.