Current Role of Chimeric Antigen Receptor (CAR) T-Cell Therapy and Bispecific Antibodies in Various Non-Hodgkin Lymphoma (NHL) Subtypes — Brian T Hill, MD, PhD

DR HILL: I'm Dr Brian Hill. I'm the director of the Lymphoid Malignancies Program at the Cleveland Clinic Taussig Cancer Institute. And this is 2024 Year in Review for lymphoma. And we're going to talk about a range of topics in DLBCL - follicular, mantle cell and a little marginal zone. And really be focusing on the immunotherapies, which are CAR T-cell therapy and bispecific antibodies, which everyone is very interested in seeing all the emerging data for.

So I'm going to start by just reminding the audience that CAR-T is here to stay for diffuse large B-cell lymphoma.

We have axi-cel, liso-cel and tisa-cel. The data for liso-cel was updated at the most recent ASH meeting. This is from the Phase III TRANSFORM study. This is a large, global, randomized Phase III study, which compared standard of care, which was chemotherapy followed by planned autotransplant, compared to CAR T-cells with liso-cel. And this is a 3-year update that was presented at ASH. What we can see in terms of the best overall response rate to liso-cel, it was very high, 87% versus about half or 49% for chemotherapy. And complete remissions were actually the majority of those responses. We've been seeing a tendency for more and more duration of response curves at medians rather than PFS curves, which is okay if most people respond, but, if not, it's a little bit trickier to interpret. So what we see on this is a DOR curve, which is useful, because, again, the responses were relatively high, particularly in the liso-cel arm. And what you can see is the plateauing going out at 24 to 30 months with about half the patients still in remission. So this really has been thought of as curative intent treatment for second-line treatment of relapsed large B-cell lymphoma and is much better than the historical standard of chemotherapy with autotransplant. So there's the sort of not reached median DOR for the liso-cel arm.

One of the things that many people wonder about is whether persistence of the CAR-T product is important or not and also what the effects are on B-cells. And what was nice in the correlative studies from this presentation is that we had data on persistence of liso-cel by PCR. And what you can see is about a year out that 43% of patients still had detectable CAR-Ts. But if you go even out to 3 years, we do see droppage of the B-cell aplasia, which is a common and almost universal part of CAR T-cell therapy because the CAR T-cells eliminate CD19 B-cells. And so as we're using more and more CAR-T, we do see some late infections, but it's, I think, reassuring to see that the B-cell aplasia tends to fade with time as the CAR-T persistence drops.

Moving to bispecifics for DLBCL, this has been a very active area. We have approved agents with epcoritamab on top and glofitamab on bottom on this slide. What's common to both these bispecifics is that they engage CD20 on the target cell and CD3 or T-cell receptor on the T-cell target bringing them in proximity. The registrational trials of epcoritamab and glofitamab were a little different. In epco, the ramp-up of 4 weeks was followed by weekly dosing for 3 cycles, then every other week up until cycle 9 and then monthly with treatment until progression or intolerance. So really indefinite treatment. Whereas with glofitamab, there was again a ramp-up of 3 or 4 weeks and then the dosing is once every 3 weeks, so every 21 days, and then stoppage at 1 year. You probably could have designed the trials in the reverse order and seen similar outcomes but this is the way the studies were designed. And these are the way the drugs are approved for either indefinite treatment or stoppage. And so a question really is, do we really know? Do we need to keep treating patients? We think of large B-cell lymphoma as a curative entity and CAR T-cells seem to fade with time. You don't need to keep giving CAR T-cells. So do you or do you not need to keep giving bispecific antibodies?

So just to sort of focus a little bit on epco. Again, this is just a generic representation of what bispecific antibodies do. They're called T-cell engaging. Some people call them poor man's CAR T-cells. The data for epcoritamab was shown with a 3-year update for the NHL-1 study. This is the registrational trial that led to approval of epco for third-line plus relapsed refractory DLBCL.

This was a single-arm study. This is a heavily pretreated group of patients with a median of 3 prior lines of therapy. Many patients had prior CAR T-cell therapy, as you can see, about 40%. And if we look at again PFS long-term, this is sort of an elongated PFS curve. But it does show a pretty favorable 30-month PFS timepoint of about 70 to 80% for most populations. This is large B-cell lymphoma. These are again the complete responders. And so this is something that we think of as being very durable benefit, particularly for patients who had complete response. And so the question is, in this schematic that was presented at the meeting, on the right here we can see that of the patients who continued treatment beyond 12 months there was only 5 of the 47 who had relapsed between month 12 and 24. And then beyond 24 months, there were 29 patients and only 2 of them have had progressive disease. So this seems to speak to the potential for durable, ongoing remissions in the majority of patients. I will say that there is some concern about infections that can crop up with continued long-lasting B-cell depletion that accompanies bispecific antibody therapy and I think more data will be needed as we go forward to watch out for those.

If we shift and look at glofitamab, again similar mechanism of action, slightly different structure as I showed earlier, the long-term follow-up was also presented recently. This is 3-year data from the registrational trial of glofitamab and this is just showing the schematic with the ramp-up. There is a day 1 dose of obinutuzumab to deplete B-cells and then step-up dosing over the next 3 weeks before reaching target dose. And what you can see here on the PFS and overall survival curves for the glofitamab is that we again have, if you look at sort of a landmark here at 1 year, this is when the treatment stopped. So you have about 80% of patients who have not progressed at 1 year. And then if you look sort of at what happens over the next year, we have a little bit of a drop off, 20% roughly. Again, excellent overall survival for the patients who get into complete remission. But, I think, we don't quite know yet whether this is a significant difference between the 2 trials and whether or not continuous treatment is needed or if maybe we should do some sort of response adapted continuation or treatment based on response or MRD, for instance.

One of the benefits of discontinuing B-cell depleting therapy is that you recover your B-cells. So, as you can see, starting right around 12 months, which is the timepoint when the glofitamab was discontinued, you have recovery of B-cells and your immunoglobulin levels sort of dipped and recovered. Although those are not highly significant differences, I think that probably discontinuing treatment is going to lead to better immune reconstitution over time.

So because of the recent approvals of these, there's a lot of interest in combining bispecifics with traditional cytotoxic chemotherapy, particularly because for a highly aggressive disease like relapsed large B-cell lymphoma, many patients have early progression during the ramp-up phase, which takes about a month, and during that time patients are really getting somewhat suboptimally dosed with the active agent.

And so this was the so-called STARGLO trial, which was recently published in Lancet. This is a large, global, randomized Phase III trial of chemotherapy with GemOx with or without glofitamab. And the red curve here shows the PFS on the left and overall survival on the right greatly favoring the addition of glofitamab to GemOx. And this is done largely in countries that didn't have CAR T-cells. So very few patients went on to get CAR T-cell therapy. And so this sort of suggests that a strategy when using bispecifics with chemotherapy, may kind of get the best of both worlds for immediate disease control followed by long-term immune effector cell engagement, which may, you know, with longer timepoints we may see whether or not these plateaus in the curve hold up. And maybe we can sort of cure patients with a chemotherapy bispecific approach rather than relying on CAR-T, which is, of course, cumbersome and not available at all centers.

So we were quite interested in this topic of the different bispecifics and we put together with 20 US academic medical centers something we call REALBiTE, which is real-world outcomes of bispecific T-cell engaging therapies. And we were able to collect data on over 200 patients treated at multiple centers. And without belaboring the details too much what we did see is not surprisingly the progression-free survival of patients who would've been likely eligible for the clinical trials was much better than these patients in the real world who did not fulfill eligibility. And this is something we've seen time and time again with real-world data is that clinical trial eligible patients tend to do better than those who are not due to comorbidities or other factors.

But another story, which I think is really important to highlight, is that the studies that led to approval required CD20 expression. And as we know in lymphomas as you get treated with rituximab containing chemotherapy, CD20 loss is a pretty well-described phenomenon. We identified a number of patients who at the pretreatment biopsy with bispecific actually had already lost CD20. And what we can see is a major difference in the outcomes based on CD20 status. So I think this does need to be on the radar screen for clinicians as they're thinking about using bispecifics to make sure that the antigen is still present.

And then we did have a number of patients who had a known TP53 mutation and when we compared those with wild-type or unknown TP53, there was really overlapping curves, which seems to suggest that unlike chemotherapy, the bispecifics can work very well in those with TP53 mutations. And there's the CD20.

So let's kind of move on from large B-cell lymphoma to follicular lymphoma. Again, it's a similar theme here that we have cellular therapy and immune-engaging T-cell bispecific antibodies. So we'll start with CAR-T for follicular lymphoma. This is a crowded space. There's 3 agents that are used but I'll start with liso-cel. This is the TRANSCEND FL study, which was presented in updated form with 2-year follow-up. And the outcomes or the study design was patients with high-risk relapsed refectory follicular lymphoma. Most of the patients were in the third-line setting, as you can see on the right, 114 of the 139. But there were a small number of patients who had high-risk follicular lymphoma in second-line including those with POD24. So that's early progression within 24 months of front-line therapy.

And here are the outcomes. So we have, on the left, duration of response, PFS in the middle, overall survival on the right. And you can see very favorable outcomes. I mean, the overall survival is really phenomenal. If you really focus on the middle at PFS what I would say is that not surprisingly the third-line patients tended to have slightly worse outcomes, as you can see in this orange curve, compared to those who had second-line treatment. And so there is an ongoing expansion, cohort of this study targeting the POD24 patients to see if this may be the solution for these patients, which historically have had very poor survival and outcomes.

Tisa-cel is, you know, the maybe less spoken about CAR-T product, but it does have an approval in follicular lymphoma. I'll just show kind of briefly the ELARA trial. Again, single-arm, Phase II trial, as most of these CAR-T studies are. And we do have pretty long follow-up shown here. Again, maybe focus on the middle, which is the purple curve. This is the progression-free survival. And if you kind of look out at 24 months or so, the plateau on the curve looks pretty good. But if you look at about 30 months out, 60% of patients, maybe a little bit lower than with liso-cel, but relatively low rates of cytokine release syndrome and low rates of neurotoxicity with tisa-cel.

And then the third CAR-T product, that is used probably much more for large B-cell lymphoma but does have an approval for follicular, is axi-cel. Again this is targeting CD19 as all the other CAR T-cells are. And what we can see is that the PFS with follicular lymphoma and some marginal zone lymphoma patients plateauing right around 50%. This is independent of the high-risk features including POD24.

So I think that it's a crowded space right now and we have a few different agents. The toxicity profile of axi-cel tends to be a little more on the CRS and neurotoxicity arm. So if you have older, frailer patients many would prefer one of the other products liso-cel or tisa-cel. But in the case of really aggressive follicular lymphoma that's sort of behaving like a transformed disease, and you have a young patient, axi-cel may be a good option.

And then staying within the follicular lymphoma space, we'll jump back to the bispecifics. Again, mosunetuzumab is the third bispecific that's approved for lymphoma, but it was actually, the third one we've talked about, but it actually came before the others in terms of their approval. It's currently approved for third-line treatment of follicular lymphoma. And what we can see in sort of some long-term data for follicular lymphoma is in this single-arm study plateaus on the curve right around 50% including pretty high-risk patients. So I think that mosunetuzumab is a good option, but we do have a lot of other things that we can do for patients in the relapsed space for third-line plus follicular lymphoma.

Not to belabor the point but we do now have another approval of a bispecific for third-line plus follicular lymphoma. This is epcoritamab. This one should sound familiar from earlier because its first approval was for large B-cell lymphoma, but it does now have an approval for follicular lymphoma.

What we can see in the EPCORE NHL-1 study is that for patients with relapsed refractory follicular lymphoma, again PFS on the left plateauing around 50%. And that's again a huge difference with the durations of response with those who had got a CR being very favorable, you know, at 2 years you're looking at upwards of 60 or 70% of those who got a CR and people who did not respond or obviously or had a partial respond tend to have a rapid drop off. The nice thing here was that the EPCORE study did include MRD status and in this case we do have a pretty big difference between those who did or did not achieve MRD undetectable state. So this is suggesting that end of treatment MRD is probably very prognostic of long-term PFS.

And then in the kind of last bit of the section here we'll focus on mantle cell lymphoma. Continuing with the theme, we have both CAR-T and bispecifics now emerging as an option. We'll start with liso-cel for mantle cell lymphoma. This was the TRANSCEND NHL 001 study, final results of the registrational trial for liso-cel. This was presented at the ASTCT Tandem Meeting this winter of 2025. So the study again was a single-arm Phase II with about almost 90 patients. But you can see here, heavily pretreated patients; 30% had 5 or more prior lines of therapy, almost everyone had a prior BTK inhibitor, the majority of those were refractory to the BTK inhibitor, and about a quarter were TP53 mutated. So lots of high-risk features in this group. And what you can see is incredible. Overall response rate of 83%, 72% CRs. And again the famous DOR curve on the right showing patients who respond tend to have pretty durable response, maybe not quite as good in mantle cell as what we see in diffuse large B-cell lymphoma. Anecdotally, I think we do sometimes see later relapse off of CAR-T for mantle cell and that might be what you're seeing here with a little bit more suggestion of a droppage even for those who achieve complete remission. One of the unique things about liso-cel compared to let's say brexu-cel, which is the first approval CAR-T product for mantle cell, is that the rates of cytokine release syndrome are only 1% Grade 3 or greater and the neurotoxicity, although about a third of patients have some neurotoxicity, it's only about less than 10% of high-grade. So you still have the potential for infections and hematologic toxicities and so forth. So CAR-T is still I don't think for the faint of heart, but for reasonably fit patients in their 60s and 70s, I think that liso-cel is a welcome addition to what we have currently.

And if we kind of look a little bit towards the future, which is almost here for mantle cell, going back to the bispecific era. And so we have a registrational trial that we don't have an approval yet for but likely will or I would imagine will be considered in the near future, which is glofitamab for relapsed refractory mantle cell lymphoma. Again in a heavily pretreated patient population, you're getting some reasonable disease control around 40% for heavily pretreated patients. So I think that the introduction or eventual approval of bispecifics for mantle cell will be a welcome addition. Because other than chemotherapy and BTK inhibitors, really the only thing we have is CAR-T in that kind of third-line space and patients often exhaust all of those treatment options.

So looking to the future it's always a little tricky to cover things that are not yet approved but may be on the horizon. When we talk about marginal zone lymphoma, it seems like even though it's a rare entity, there's always drugs that are chasing this diagnosis. We don't have public results but there has been a press release from topline results of liso-cel in adult patients with relapsed-refractory marginal zone lymphoma. These patients can burn through treatments and particularly for young patients who've had things like R-CHOP and BTK inhibitors. Right now there is no approved CAR T-cell therapy for marginal zone lymphoma. So having something maybe later this year that could be approved would be welcome. So I would anticipate that this will be something that will be presented at a summer meeting near you.

And then in the last couple of minutes, maybe sort of looking further down into the future. These are not approved, but I think it's worth highlighting, which is still in the same sort of class of agents that we've been talking about, which is immunotherapies. So this is called AZD0486. This is again a bispecific T-cell engaging bispecific antibody that targets CD19, which is different from all of the approved bispecific agents that we've been talking about today, which are all targeting CD20. And as I showed, if you don't have CD20, your bispecific targeting CD20 probably won't work.

So this is a First-in-Human study with step-up dosing, which has been done to mitigate cytokine release syndrome. And what you can see in this single-arm is that they have to start at low doses, 2.4, 7.2 then 15 mg. And in a patient population with heavily pretreated diffuse large B-cell lymphoma with half the patients having 4 or more prior lines of therapy and about 60% having prior CD19-directed CAR T-cell therapy, we actually see very promising clinical activity. If you look overall at all the patients, the response rate across different dose levels was up to 50% at the highest dose level with most of those being complete remissions. And there was also an arm for follicular lymphoma. Again heavily pretreated follicular lymphoma in this cohort, 20% bulky disease, a third of them with POD24, 60% with 3 or more prior lines of therapy. Many of them had prior CAR-T or some of them, I should say, had prior CAR-T or CD20 T-cell engaging therapy. And what you can see in the waterfall plot is pretty remarkable. So really just dropping off some of the product of the tumor diameter. Overall response rate 95% with a CR rate of 85%. So pretty impressive. And the rates of adverse events and neurotoxicity were pretty minimal, pretty manageable with step-up dosing.

And so, I think, looking to the future, this type of approach, where you have different CARs and different bispecifics targeting different antigens, is going to be really exciting to see what happens with this agent in the future.

Other Available and Emerging Novel Therapies for NHL — Stephen M Ansell, MD, PhD

DR ANSELL: Well, hi. I’m Steve Ansell, and I’m from Mayo Clinic. I’m one of the lymphoma physicians at Mayo, and it’s my privilege to be talking about available and novel and emerging therapies that are specific for non-Hodgkin lymphoma.

Firstly, I’d just like to say that we will do this in 3 groups. We’re going to talk about diffuse large B-cell lymphoma, then about follicular lymphoma, and subsequently about new updates in mantle cell lymphoma, a very exciting time in each of these particular diseases.

So firstly to focus on diffuse large B-cell lymphoma. Many would know that the POLARIX study specifically has explored the use of polatuzumab vedotin, an antibody-drug conjugate, in combination with R-CHP chemotherapy, omitting vincristine, and comparing that in a head-to-head comparison to R-CHOP chemotherapy. The study initially showed that there was a significant benefit to the use of polatuzumab vedotin plus R-CHP as regards to progression-free survival, and recent data now has looked at the ongoing benefit with now 5 years of follow-up.

So shown in this Kaplan-Meier curve one can see that patients receiving polatuzumab/R-CHP, at the 5-year mark, approximately 65% of patients remain in remission compared to patients receiving R-CHOP chemotherapy, where that is 59%. So the benefit of the use of polatuzumab vedotin plus R-CHP chemotherapy that was initially seen at the 2-year mark has been updated and shown to be still true at 5 years.

Additionally, subgroup analysis has shown that the benefit for the addition of polatuzumab vedotin appears predominantly in the ABC subtype. So if one casts your eye down to far at the bottom of this table you can see the nanostring cell of origin, and you can see that the ABC subtype benefitted substantially in this analysis. Now I have to stress that this analysis was ad hoc. It was not a primary endpoint of the study, but I do think that’s informative as we think about where this agent is probably best utilized.

Additional data that was recently presented was to see if the outcomes are still maintained with additional patients added. So a further cohort of 130 patients, a Chinese cohort, was added to the analysis. This obviously allowed for a more global perspective and furthermore enriched the cohort for more patients with the ABC subtype.

Again you can see the maintained benefit for patients by progression-free survival analysis. However, not quite yet a statistical significance as far as overall survival is concerned. You can see though that as longer time is passing there is a suggestion that possibly a benefit for polatuzumab/R-CHP may be seen later on as far as overall survival is concerned. This is challenging to show, particularly in Europe and the US, because of subsequent therapies with CAR T-cells and other treatments, but potentially in China and other countries where those agents and combinations are not as easily and readily available that might be where the bigger difference for overall survival could be seen.

The second thing to talk about in diffuse large B-cell lymphoma is now moving from first-line therapy, where polatuzumab has made a difference, now right down to what do to after patients have failed second-line treatment. So as shown in this algorithm, many patients who fail front-line treatment are considered for CAR T-cells, if they fail early, or potentially even for an autologous stem cell transplant. But shown in the circle there is a sizeable group of patients where either they are not eligible for that therapy, or they received that therapy and subsequently progressed. So data to share now is those investigational and novel agents used post CAR and post-transplant and to see how effective they are with longer-term follow-up.

So the first agent to mention here is tafasitamab. Tafasitamab, as you would remember, is a CD19 antibody and is utilized in combination with lenalidomide. Again, promising initial data now showing 5-year efficacy, and I think the encouraging takeaway here is that the overall response rate in this patient population was 57% with a CR rate of 41%, data showing that the progression-free survival was almost a year.

But I think what is interesting for me, when one looks at this Kaplan-Meier curve, is that you can see if you received this agent as the first line of subsequent therapy, compared to second or subsequent lines, you can see a significant increase in benefit the earlier in the disease course the patient receives the agent. Also really interesting to me is to see that there is a degree of plateau to these curves. Now looking out to 5 years one can see that approximately a third of patients continue to benefit, and all of these patients actually have remained on the drug until progression, showing that you can administer this drug over time and a subset of patients continue to benefit.

A second agent in the same space to discuss is loncastuximab tesirine. This is an antibody-drug conjugate targeting CD19 with a PBD dimer attached to it delivering a cytotoxic agent in a targeted way to the tumor cells. And in this study, again, long-term efficacy being confirmed. 145 patients were treated, and almost half of the patients having an objective response, approximately a quarter of them achieving a complete remission. But as we have longer-term follow-up now you can see that the progression-free survival, while the median is only around 5 months, you can see that a subset of patients continue to have very durable long-term remissions, particularly if you had a complete response to treatment, the blue line at the top shows a real benefit for those patients, and the benefit appears to be very durable.

A second antibody-drug conjugate, brentuximab vedotin, is well known to many. It’s been used predominantly in T-cell lymphomas and Hodgkin lymphoma. But here it was utilized in combination with lenalidomide and rituximab, the R² regimen, and it was compared to the R² regimen with placebo. So in the study in patients with relapsed and refractory diffuse large B-cell lymphoma, 230 patients were randomized to those 2 arms.

I think this was a very surprising and encouraging result. The first you can see is that the progression-free survival was substantially better for patients receiving brentuximab vedotin plus lenalidomide and rituximab, at 4.2 months compared to 2.6 months for just lenalidomide and rituximab. But even more interesting, as shown on the right, is that there was an impact seen on overall survival, with a 14-month overall survival when brentuximab was added to the combination, compared to 8.5 months. And this has resulted in this agent being approved in this indication.

What was further interesting was that expression of CD30 was not really correlated with benefit. Benefit was seen where the CD30 could easily be detected or not. So again, I think this is a very encouraging and interesting result seen in the ECHELON-3 trial.

I want to move now to follicular lymphoma. So again, just to level set and remind ourselves as to how we typically manage follicular lymphoma. New patients diagnosed with follicular lymphoma we would utilize FLIPI scores, stage of disease, the symptoms and whether or not the patient was symptomatic, as well as patient preferences to stratify patients really into 3 groups of patients: those who have very low burden and low risk who can be observed, patients with really mild symptoms who would be treated with an antibody therapy such as rituximab, and then the group of patients which we will focus on in the next few slides, which are the high tumor burden patients, many of whom will receive bendamustine plus rituximab or even R-CHOP chemotherapy. Furthermore, data is showing that lenalidomide plus rituximab — R² — is also effective in these patients.

So in relapsed patients who now progress after that strategy a Phase III study was presented in the past year. This was a comparison of taking lenalidomide plus rituximab and building on it by adding the CD19 antibody we discussed earlier, tafasitamab, in a combination approach. And that was compared to the R², which was really the standard arm. And in this study the main points were progression-free survival and long-term outcome.

Initially just looking at response rates you can see the overall response rate increased when tafasitamab was added. It was 84% compared to 72% when it was just rituximab and lenalidomide, and that was significantly different. But when one looks also at the progression-free survival you can see that it had significantly increased. Lenalidomide plus rituximab resulted in a median progression-free survival of just over a year, at 14 months. Patients receiving tafasitamab plus lenalidomide and rituximab, that was almost 2 years at 22.4 months, a significant improvement. Again, encouraging to see that patients could remain on these therapies over a significant period of time with ongoing durable benefit.

The second agent to discuss in these relapsed and refractory patients with follicular lymphoma, again, is the loncastuximab tesirine, reminding you that that’s the CD19 antibody-drug conjugate. And in this study, small study but with very promising results, 39 patients were treated. Important to see that the response rate after 12 weeks was around 67%, but at longer follow-up that response rate increased all the way to 97%, and many of the patients retaining a complete response when treated.

And that resulted in progression-free survival and overall survival curves that looked extremely encouraging. You can see here that although the follow-up is fairly short at only 12 months you can see progression-free survival here of 95%. Obviously, overall survival was also high, but that for follicular lymphoma is not very surprising, as patients can remain in remission or remain in reasonable health despite progression for an extended period of time.

So the third group where probably the greatest changes and findings have occurred is mantle cell lymphoma. So again just wanted to level set and remind us as to what had been in many respects the standard approach for mantle cell lymphoma and then share some data that has really kind of challenged our thinking and is moving the field in a very different direction.

So pretty much 5 years ago one would have considered a mantle cell lymphoma patient really in 2 categories, a young patient, less than 65, and an older patient, greater than 65. And then you would always factor in fitness as to whether the patient was fit or unfit, so that would obviously impact both groups.

But the patients that were young, the strategy was in general to use a dose-intense regimen, many people using R-CHOP alternating with R-DHAP or high-dose cytarabine-containing regimens, as an intense initial therapy, and then consolidate that with an autologous stem cell transplant followed typically thereafter with maintenance rituximab.

In an elderly patient for whom a high-dose therapy approach may be challenging, a more moderate chemotherapy approach, such as R-CHOP chemotherapy or bendamustine plus rituximab, would typically be used, and then rituximab maintenance administered thereafter. For patients who were significantly compromised one would try a lower-dose type of approach of bendamustine plus rituximab or even just simply a rituximab/best supportive care kind of approach, and then thereafter novel agents would be potentially considered.

A number of clinical trials have been reported in the past year that have substantially challenged how we need to think about mantle cell lymphoma.

The first of these is the TRIANGLE study. So this was a study done in Europe, which as you can see in Arm A, took exactly that standard we just discussed, R-CHOP with R-DHAP, 3 cycles of each. Patients then went to an autologous stem cell transplant and were thereafter observed, and depending on the country could receive rituximab maintenance. That was then compared to the use of adding a BTK inhibitor. So ibrutinib was the BTK inhibitor utilized in the study. Ibrutinib was added to each of the cycles of R-CHOP, patients went to a transplant, but then received ibrutinib maintenance with or without rituximab, and that was in the second arm.

The third arm took it to even a further step, where the transplant was entirely omitted. So patients received ibrutinib along with R-CHOP and then — alternating with R-DHAP as the induction, simply went straight to maintenance with ibrutinib with or without rituximab. Again, just reminding you that patients were younger. They had to be 65 and younger.

So the data from this trial were extremely interesting. Group A, or the standard folks receiving standard chemotherapy and autologous transplant followed by observation with rituximab, and you can see that is the red line in the first of the curves on the left-hand side. Group A plus I are the patients for whom ibrutinib was added to the regimen but who still received an autologous transplant. And you can see that patients had a significantly better outcome when ibrutinib, the BTK inhibitor, was added to this therapy.

On the right was an even more interesting result, and that is when one compares the group that did not receive an autologous stem cell transplant, the blue line, you can see that a very similar benefit was seen, suggesting that the role of autologous transplant as consolidation in patients with mantle cell lymphoma, if a BTK inhibitor is part of the induction and subsequently as consolidation and maintenance, whether a transplant is needed.

The second study that was interesting was then addressing the elderly patients. So these are the patients over 65 years of age, and as I pointed out on the previous slide, these are patients for whom bendamustine plus rituximab would be a standard of care.

And you can see in the blue box in this figure that bendamustine plus rituximab plus a placebo, that was the control arm, was compared to bendamustine plus rituximab plus acalabrutinib, the BTK inhibitor. Patients received 6 cycles of treatment over a 28-day cycle period, and then thereafter either received acalabrutinib maintenance for 2 years with rituximab or placebo with rituximab.

And again, very interesting results showing that acalabrutinib plus bendamustine plus rituximab showed a significant improvement over the patients receiving bendamustine plus rituximab without acalabrutinib. And you can see that the median progression-free survival was 49 months for the control arm and 66 months for the patients receiving the BTK inhibitor.

This is additional follow-up subsequently. Two questions were asked, and that is over time at the end of 2 years are patients still remaining in remission, and number 2, what about the high-risk patients, particularly those with high Ki-67 indexes or p53 mutations. And the follow-up data presented at ASH last year showed that the progression-free survival benefit was consistent across all of the different groups, including those with TP53 mutations, blastoid morphology or a high index of proliferation.

And as shown in the image, you can see that the acalabrutinib plus bendamustine/rituximab arm, if you look at the purple at the top, the number of patients for whom MRD became positive was a very small group, in contrast to the patients who received bendamustine plus rituximab plus placebo, where there was actually a much more sizeable group that were positive for MRD at the end of therapy. Again, all this to say that the progression-free survival was improved across all groups, and the depth of the response was greater and more durable.

So as one looks then to see further steps and where one can take treatment next, the obvious next question addressed by the ENRICH trial was do you need the chemotherapy. Could you get away with utilizing a BTK inhibitor plus rituximab in comparison to chemotherapy plus rituximab? So in this trial institutions chose the initial chemotherapy that they wished, either R-bendamustine or R-CHOP. Once they had decided they were then randomized to either receive that regimen over 6 cycles of time and then rituximab maintenance, as shown on the left of the image, or alternatively randomized to receive ibrutinib plus rituximab.

And the interesting result from this study, with a median follow-up of around 4 years, showed that patients receiving ibrutinib/rituximab had a superior progression-free survival of 65 months compared to the patients receiving standard R-chemotherapy, where it was 42 months.

Additional follow-up looked at the actual chemotherapy side of things and showed that the advantage was predominantly seen in comparison to the patients receiving R-CHOP. So you can see on the left, the green line, or the R-CHOP-treated patients, and they did significantly poorer than the patients receiving ibrutinib plus rituximab. In contrast, patients receiving bendamustine plus rituximab had a lot more similar difference in progression-free survival to those receiving ibrutinib/rituximab. So I think clearly the benefit for the ibrutinib/rituximab was over those receiving R-CHOP. This does not mean that ibrutinib/rituximab doesn’t have advantages over bendamustine/rituximab, as the results still show a similar outcome, and obviously that is not a chemotherapy regimen and is better potentially tolerated.

So the next steps thereafter have really been to see can we further build on this chemo-free regimen. So I will show you 2 studies that were presented in the previous year that have really looked at bringing venetoclax, a further agent that could target the tumor cells in mantle cell lymphoma. So venetoclax, as most will know, targets Bcl-2. So here was a regimen of acalabrutinib, venetoclax and rituximab. It’s a small study of only 21 patients.

I’ll draw your attention to the bar graphs in yellow, in the middle, but the finding here that was very encouraging was that the overall response rate using these 3 agents was 100%. And you can see on the right-hand side at the Kaplan-Meier curves, if your eye goes to the blue curve, you can see that actually the progression-free survival for patients when deaths from infection were censored, was outstanding.

However, this study was done right in the middle of the pandemic, and they did have a number of deaths from COVID-19, and obviously that then made the progression-free survival, as shown in the purple, drop down particularly at around the 18-month mark.

I think the takeaway here is that this is a very effective therapy. However, this may make one a little more susceptible to infections, and in the middle of a pandemic that obviously had significant risks.

Additional data that informs that combination is the clinical trial of a regimen called BOVen, and what this is is zanubrutinib plus obinutuzumab plus venetoclax, so a very similar principle of a BTK inhibitor, a CD20 antibody and a BCL2 inhibitor, but this specifically focused on the high-risk patients that are TP53 mutated. Most will know that TP53 mutations are problematic when one gives chemotherapy because patients are not particularly sensitive to that. This regimen was very encouraging in that the study showed a very high response rate.

If you look at the top on the right, the overall response rate was 96%, with a complete response of 88%. Toxicities were manageable. And the 2-year progression-free survival in a high-risk patient that notoriously does very poorly was 72%, which was very encouraging. So while this was a relatively small study, this, I think, is a regimen that has a lot of promise, particularly in this population of patients.

And finally can we utilize a BTK inhibitor and a BCL2 inhibitor in the relapsed circumstance. So this is after patients have received front-line therapy and have had disease progression. This was a randomized comparison of 134 patients who received ibrutinib alone compared to 134 patients who received ibrutinib plus venetoclax. And the ibrutinib/venetoclax, shown in blue, showed a higher overall response rate and a higher complete response rate when compared to the ibrutinib plus placebo. So those were 82% compared to 74%, 54% compared to 32%.

And encouragingly, as shown on the bottom, you can see that the median progression-free survival for the combination was 32 months compared to 22 months for patients receiving ibrutinib. So I think, again, the encouraging result here was that in the relapsed and refractory setting this combination is highly effective.

So what do I think over the last year we’ve learned and the takeaway messages that have really informed practice? Well, firstly I think in diffuse large B-cell lymphoma the addition of polatuzumab vedotin to the R-CHP regimen as front-line therapy has established that as a front-line combination. It improves the progression-free survival over R-CHOP chemotherapy, and it appears to be particularly active in the ABC subtype.

Tafasitamab, the CD19 antibody, in combination with lenalidomide or loncastuximab tesirine, the CD19 antibody-drug conjugate, both have been tested in diffuse large B-cell lymphoma and follicular lymphoma. Both show real promise, particularly in the relapsed/refractory setting.

Brentuximab vedotin, the CD30 antibody-drug conjugate, in combination with lenalidomide and rituximab has shown to be effective in relapsed diffuse large B-cell lymphoma, and that combination has an overall survival advantage over lenalidomide/rituximab alone.

And then in mantle cell lymphoma a number of findings that have been very interesting. The addition of a BTK inhibitor to chemotherapy or immunotherapy in newly diagnosed patients substantially improves outcome, and this has called into question whether intensive chemotherapy and particularly an autologous stem cell transplant are really needed when a BTK inhibitor is added.

The use of the BCL2 inhibitor venetoclax added to a BTK inhibitor and a CD20 antibody has been shown in 2 studies to be effective therapy for mantle cell lymphoma, and I think is particularly valuable in patients that have p53-mutated disease.

And then thinking a little about the patients who have relapsed and refractory mantle cell lymphoma, similarly, venetoclax plus ibrutinib has been shown to be beneficial and superior over using ibrutinib alone.

So with that I’ll end. And thank you very much for your time and attention. And I’m pleased to have presented to you some really interesting data from the past year.