Follicular and Mantle Cell Lymphoma — Sonali M Smith, MD

DR SMITH: It is always a pleasure to be a part of Year in Review, and I really appreciate being asked to participate. So I’m going to cover follicular lymphoma and mantle cell lymphoma and just say that there’s been a tremendous amount of very practice-changing and exciting data.

And I know this audience knows follicular lymphoma super well. Just by way of background to sort of ground set, a couple of points I wanted to make is that we know it’s indolent, we know it’s incurable and that most patients are older. However, a quarter of patients are under the age of 40, and I think that is something to remember when we think about long-term management.

We remain really, really stymied when we’re trying to provide individual prognosis at the time of diagnosis. We cannot use any of our current tools to really say what’s going to happen to somebody. So this lack of precision makes the front-line management pretty challenging.

We do, however, know that event-based outcomes will determine prognosis, and this POD24 has become an important part of how we evaluate trials and data in the relapsed/refractory setting. And then of course there is always that lurking risk of transformation.

So in the front-line setting for those patients who need therapy we divide into low and high tumor burden, and most of what we’re going to talk about has to do with the high tumor burden population, and the standard of care there remains chemoimmunotherapy or R². And for all of these I would say bendamustine and rituximab probably remains the most common option for people.

Once people are done with treatment maintenance rituximab and maintenance therapy was really very much in vogue, I would say at least for the last 15 years or so. And a couple of years ago we saw the 10-year data from PRIMA, which gave 1 dose of rituximab every 8 weeks for 2 years and then stopped and then followed patients out. And at the 10-year mark those patients who got the maintenance half of them still did not need another line of therapy. And so that favors doing some type of maintenance. But as I think most people know it also did not show an overall survival advantage, and so there remains this equipoise that’s there.

The other challenge is that PRIMA didn’t include bendamustine, and we already mentioned that bendamustine has become the go-to for front-line management. And they also did not use PET scan to look at an end of induction response, and so the value of maintenance in patients who had received either bendamustine or obinutuzumab remains a little bit in question.

So to address this the GALLIUM trial looked at chemoimmunotherapy induction, and then either paired it with rituximab or with obinutuzumab both as part of induction and as part of maintenance.

And just in late 2023 we saw the mature follow-up, now with about 5 years of follow-up, and what this shows is that those patients who had obinutuzumab as part of induction and as part of their maintenance have a superior progression-free survival, event-free survival, and time to next treatment, but again we come down to there is no difference in overall survival. There is also a little bit more toxicity in terms of infection for those patients who received the obinutuzumab, and so I think, again, we’re at a point of equipoise between the two.

I will say that in the COVID era the use of maintenance in my own practice has been a little bit more limited as I consider some of the infectious toxicity. And when I think about maintenance in general, do we use maintenance at all? What happens if you use bendamustine? There’s a couple of things.

The STiL trial, which was an older study where it was bendamustine and rituximab and no maintenance, R-CHOP was inferior to BR. In the BRIGHT trial, which again was BR versus R-CHOP, and about half the patients had maintenance, BR narrowly beat R-CHOP for progression-free survival.

And so maybe the maintenance is more important after R-CHOP, as we saw in PRIMA, but really not so much after bendamustine, and in the GALLIUM study there’s no difference. So I really take from this that maintenance, again, may help PFS but not overall survival, and its relative benefit after bendamustine is probably less.

DR LOVE: I was just flashing back when you mentioned the STiL trial because I remember I actually interviewed Dr Rummel. I was just thinking, it was kind of surprising that BR was better than R-CHOP. Any thoughts about why? Do you think there’s something different about bendamustine? I mean why do you think it was better than R-CHOP?

DR SMITH: Yeah. I mean when you go back to the study it was designed as a noninferiority trial, that bendamustine wouldn’t be inferior to R-CHOP, and it actually ended up being superior for progression-free but not necessarily overall survival. And I don’t know if it has to do with the fact that bendamustine is what we call a bifunctional alkylator, and it probably also has an element that is similar to fludarabine, almost like a purine analog, and perhaps it’s the mechanism that makes it superior.

And at the time, of course, the opportunity in an indolent lymphoma to not have somebody lose their hair or be exposed to an anthracycline that was a big deal, and I think many of us rushed to BR as our treatment of choice.

Today I will say I still think BR is the standard of care for the front-line management of indolent lymphomas like follicular, but I think we know a lot more about the immune suppressive effects of bendamustine today than we did back then. And this comes up again and again. When people try to build on BR it’s too toxic. Whether it’s in the front-line or relapsed setting there’s so many more infections. The T-cell dysfunction is profound, and a lot of people during the pandemic I think really suffered from that.

DR LOVE: What do you think you would see if a trial compared BR to mosunetuzumab alone?

DR SMITH: Yeah, yeah. Alone?

DR LOVE: Not even talking about combinations, just literally alone.

DR SMITH: Yeah. BR versus mosun.

It’s different patient populations. So mosun is being tested in your lower-tumor-burden patients as a monotherapy.

It’s being tested with lenalidomide in higher-tumor-burden patients, but mostly the mosun monotherapy has been in lower tumor, and BR is more in higher-tumor burden. So I don’t know.

We are going to have a study in SWOG, a head-to-head comparison of rituximab versus mosun, and I think mosun is going to win. That would be my bet.

DR LOVE: Wow. First-line rituximab versus mosun.

DR SMITH: Yup. Low-tumor-burden follicular lymphoma.

DR LOVE: What happens when you combine mosun and rituximab?

DR SMITH: Well, you would have a double dose of the anti-CD20, so I wonder if one would saturate the other. They would probably compete a little bit for the same target.

DR LOVE: I mean we’ll get into this when you go through that.

DR SMITH: Yeah.

DR LOVE: But in a way it’s like — so that’s really interesting though about it. I didn’t know that. that’s really interesting.

All right. Please continue.

DR SMITH: Yeah. So perfect segue as we move on from the front-line setting to relapsed/refractory follicular lymphoma. And again, we’re so conditioned that follicular lymphoma you’re going to take care of people for a long period of time, and of course that is true, but it’s important to remember that survival and progression-free survival does decrease by the line of therapy.

So in the curve on the left by the time you get to third-, fourth-, or fifth-line therapy the median progression-free survival is about a year, and this is with our pre-bispecific type of therapies, but it includes things like bendamustine and lenalidomide and rituximab. And when you look at overall survival, which is over on the right, by the time you get to third line and beyond the overall survival is also shortened. So this remains, I think, an area of need.

The other piece is something we alluded to at the very beginning, which is that early progression of disease, or POD24, is a concept that’s been really socialized over the last decade but has been validated in multiple settings, and that is that not all relapses are the same. If somebody relapses within 2 years of their initial chemoimmunotherapy, which is called POD24, it’s not just a poor prognostic marker for progression-free survival, it actually correlates with an inferior overall survival. And in the original LymphoCare trial the median survival was only 5 years for that 20% of patients who had early progression of disease. So I think that’s really an area of unmet need for that patient population.

The other tool we have is that getting a PET scan at the end of chemoimmunotherapy — if it is negative patients tend to do quite well, whereas if there is still activity, that’s another poor prognostic factor.

I do think what it tells us is that early progression is bad and PET positivity at the end of treatment is bad for overall outcome.

The other piece is that LymphoCare did not include anybody who had had bendamustine. So if you look after bendamustine there is a minority of patients who do have early progression of disease.

If they have early progression of disease the 2-year PFS is only 38%, and that’s pretty inferior.

The other important part is that many patients who had progression after BR had transformed disease, and people have always said is it the bendamustine that’s doing this. I don’t think so. I think this was a high tumor burden population. It’s a retrospective analysis for this particular study, and so I just think that there was probably transformation before they got the BR.

DR LOVE: Would you just clarify how you define POD24? Is that 2 years after the end of the rituximab?

DR SMITH: Yeah. So in the LymphoCare trial they did it from the end of the R-CHOP, and nobody got maintenance in that particular one. So in our current S1608, which is struggling a little bit, but it’s a clinical trial looking at this population. It’s actually rare. It’s only 20% of people who get chemoimmunotherapy. So we talk about it, it certainly comes up again and again, but it is a hard population to find, and in that trial we defined it from the end of chemotherapy. So…

DR LOVE: So it would be not that long after completing the rituximab then.

DR SMITH: That’s correct. That’s correct.

So when we’re thinking about the relapsed/refractory setting we now have a number of different options. And just over the next 15 minutes or so I’m going to cover both CAR T, as well as bispecifics. And I thought I would start with CAR T because it was approved before any of the bispecific agents, and there were some updates in 2023 that I thought were very encouraging.

And so as of today, early 2024, we have 2 products that are FDA approved. One is axi-cel based on the ZUMA-5 study, the other one is tisa-cel based on the ELARA trial, and they both now have mature follow-up that was presented. And I think just a couple of points is that both of these studies really looked for those patients with follicular lymphoma who had relapsed/refractory disease, a huge portion of patients who had early progression of disease who were refractory to their most recent line of therapy and were out of options in our toolbox.

So with that population in mind ZUMA-5 showed at ASH 2023, median follow-up of 52 months, that the overall response rate, which had previously been reported, is quite high, 90%. The CR rate is 75%. And I think what’s exciting is that for those patients who had a CR, 75%, the duration of response is around 5 years. Achieving CR seems really important. Those patients who had a PR have a duration of response of only 4.9 months, and the median overall survival is not reached. So I think if CAR T is done and a patient has a complete response, those patients do really, really well.

Same thing for ELARA. We now have 3-year follow-up and again continues to show a high rate of durable responses. There were no new toxicities noted. And again, what you can see in the curve, both on the left and the right, is that if there is a complete response, which is the top-most curve, patients have a really, really great outcome, whereas the PR patients have relatively quick progression and don’t benefit nearly as much.

One criticism you could say for all of the CAR T-cell treatments is that we’re not clearly seeing a plateau on the curve, so I don’t know if this is a cure. But certainly considering some of those earlier slides I showed, where by the time people do get to their third, fourth, fifth line of treatment survival is significantly shortened, so I think this is very, very exciting.

And so then the third product that we are familiar with from the DLBCL world is liso-cel. And people may remember, this is a little bit of a different product. This one uses a specific ratio of CD4 and CD8-positive cells thinking that this may help both with peak CAR T expansion, as well as for persistence.

And what they did in their trial, which was presented, again, at Lugano last year and then again at ASH, is that they looked at doing CAR T for follicular lymphoma in both the second-line, as well as the third-line and beyond setting and just kind of wanted to compare if they did it a little bit earlier would the outcomes be a little bit better. What I’ll point out is that although they did it in the second-line setting those patients actually still had high-risk disease. About 48% of them were double refractory to an anti-CD20 and an alkylator, and 65% of them had POD24, so this is really a high-risk population even though they’re second line.

So they showed with very short follow-up, about a year and a half, that the CR rate is 96%. And again, it’s a small number of people, 23 patients in the second-line setting, many more in the third line.

Liso-cel is really well tolerated, and in fact out of all of the products this is the one that is most likely to go forward, I would think, as an outpatient option for people, because the CRS is lower, and the neurotoxicity is also lower.

So I would say one of the more exciting things happening in our field right now is that we are in the era of bispecific agents, and in follicular lymphoma and B-cell lymphomas in particular it’s been really exciting to see these compounds advance.

The ones that are the furthest along are listed on this slide right here, and they all share the property of being against both CD20 and CD3, so essentially trying to pull together B cells and T cells hopefully to get the T cells to work. The only one that’s FDA approved is the one that’s in the circle, mosunetuzumab, available both as an IV and a subQ formulation. And then there’s a couple of others.

Just to tell you a little bit about the differences between them, epcoritamab is available subQ. I think that’s something that could be kept in mind as the infusion burden for patients is relatively high for most cancers. And then glofitamab has a silent Fc that increase its half-life and may reduce the toxicity. So I think these are some interesting aspects.

And everybody always asks when you have bispecifics and CAR T how do you choose between them. They’re both T-cell engaging approaches. I would say that we can talk more about this, but for bispecifics the advantage is they are just off the shelf, there’s a lot lower cytokine release syndrome, very limited neurotoxicity. But for most of them, with the exception of mosunetuzumab, they continue indefinitely, or for much longer periods of time. Whereas CAR T the downside of course, it’s a much bigger process, requires manufacturing, higher toxicity, but it is one and done. So there may be some pros and cons for us to think about.

So what was presented just late 2023 at ASH is the epcoritamab data for follicular lymphoma. And so all of these agents, as I go through them, remember that they can all cause cytokine release syndrome because of the T-cell engaging aspect, and so all of them have adopted these stepped up dosing and other approaches to mitigate toxicity.

So in this particular trial for relapsed/refractory FL they looked at a high-risk population, 42% early progression, 70% refractory, 54% primary refractory, a very high-risk group, and they looked at the outcomes in each of these groups in terms of overall response rate and CR rate. So looking at the top half of this figure, in all of their groups, the entire group POD24, refractory to the last therapy, double refractory, whether it was second line or third line — I’m sorry, not second line, third line or fourth line and beyond, the response rates were all quite comparable. And so I think that’s exciting. It’s a novel mechanism I think.

And then in terms of cytokine release syndrome once they used their stepped-up optimization cohort they were able to reduce Grade 2 and 3 cytokine release syndrome to single digits, and it does resolve in all patients.

Mosunetuzumab, which is FDA approved, was also updated at ASH this year, and again high-risk population, stepped-up dosing. One unique aspect of mosunetuzumab is that it is limited-duration therapy, and it is response adapted. So everybody gets 8 cycles, and then if they have a CR you can stop. If they have a PR or stable disease you can continue up to 17 cycles. So I think there’s certainly an appeal to that strategy.

So the 3-year data is shown here, and very — again, high-risk population. The progression-free survival is about 2 years, the 2-year median progression-free survival. Then the median overall survival has not yet been reached, and the follow-up at this point is about 36 months.

And when you look at toxicity this is important, I think, from a practical perspective. At the bottom right you see a bar graph that shows the CRS rates and severity by cycle. And so it’s going to be within 5 hours for the first dose, cycle 1, day 1, which is the smallest dose. Then on the third week is when you have the big step up, and you get cytokine release syndrome at that point as well. And that can happen within 24 to 48 hours, so that’s kind of an important practical question. And then beyond that there really wasn’t much CRS.

Odronextamab is the next one that I just wanted to mention. This one is not FDA approved, and this one also has a stepped-up dosing. This is IV. This is given once every 3 weeks. It’s a very nice schedule. It is indefinite. You can go to every 4 weeks if somebody has a CR that is considered durable. And again in this high-risk population they have a very impressive overall response rate of 81%, CR rate of 73%, and a median progression-free survival of about 21 months.

Cytokine release syndrome was common at a low grade, Grade 1-2, but Grade 3 and 4 was very uncommon.

And so before I go on to the next section I just wanted to put in a few thoughts about bispecific agents in the community and expanding it. And one of the challenges we have is that most of the toxicity rating in all of these has been using CAR T criteria. What is cytokine release syndrome? And the approaches and the management have all been according to CAR T criteria.

So to address this a group from the Lymphoma Research Foundation, as well as a separate group, we came together, and this will be published soon in Blood, which is just guidelines for how to really get bispecifics to the community. And just the highlights of it are that I do think you need a dedicated team that’s going to be monitoring these patients. Patient education. Having them carry a card with some information about what to do with certain toxicities is important. For Grade 1 you can just let people take acetaminophen at home if they have a fever one time. If they have a persistent fever some of the experts thought you could give dexamethasone prescriptions, and people could just take it. Others wanted patients to come in to be evaluated. So I think that’s a point of controversy. But any fever that lasts beyond 24 to 48 hours is considered very life threatening, and those patients need to be admitted and monitored with tocilizumab available.

So I’ll move on to mantle cell lymphoma, and this, even though it’s an uncommon lymphoma it’s certainly one that’s received a lot of attention over the last 15 or 20 years, and I would say of all the lymphomas this is probably — this and CLL are probably the 2 where there’s been just like the most dramatic turnaround in terms of our understanding of the biology and moving away from chemo for at least some patients.

So with mantle cell lymphoma we divide people into fit or unfit. And for fit patients who are young the approach has been aggressive induction followed by an autotransplant and maintenance rituximab, and then for unfit or older it’s a less aggressive approach that has still relied on chemoimmunotherapy primarily, with BR probably being the most commonly used.

So at ASH this year we had a couple of twists on this schema or this algorithm if you will, and I just thought I would focus on a couple of them. Looking over for the fit patients chemotherapy is still part of the armamentarium here.

So ibrutinib/rituximab/venetoclax followed by a risk stratified approach to hyperCVAD was presented by the MD Anderson group. Then we have the Australian and Asian group looking at a BTK inhibitor (acalabrutinib)/rituximab induction followed by chemo and transplant. Then all the way on the right for the older, less fit patients there’s a BR/venetoclax study that I think is interesting to look at. And then finally we know that chemoimmunotherapy really is inadequate for those patients who have aberrations or deregulation of TP53, and so there’s some interesting data there for a BTK inhibitor with obinutuzumab and venetoclax.

So to go through those studies, this was presented by Michael Wang for young and fit patients with treatment-naïve mantle cell lymphoma. And this used an ibrutinib/rituximab induction for 4 cycles and then venetoclax is added in, and it’s added in later to avoid the tumor lysis syndrome and potential life-threatening hyperkalemia, et cetera. So it’s added in after the fourth round, and then patients are assessed and assigned whether or not they’re low risk, medium risk, or high risk based on their proliferation, their tumor burden, their MIPI score, their p53 status, and you can see some of the definitions here. And then based on that they either get no chemo, 2 cycles of hyperCVAD, or 4 cycles of hyperCVAD, and then they get the IRV maintenance for 2 years.

And what they found here. The median follow-up is now 41 months. The response to the ibrutinib, rituximab, and venetoclax is 100% CR rate, which I think is something that’s very intriguing. The progression-free survival overall is 85%, overall survival is 86%, and they found no difference between their risk groups or among patients who did or did not have the TP53 abnormalities.

Now this is pretty preliminary. It’s small. The number of patients per group I think is quite small. So I would just say this is very intriguing and exciting but certainly needs further validation in my mind.

The other approach was presented by Eliza Hawkes, and this was a really great presentation that Eliza did that looked at using acalabrutinib and rituximab as an induction strategy followed by chemotherapy that was cytarabine based with oxaliplatin and then optional BEAM transplant if they have had a CR or a PR and then acalabrutinib maintenance along with rituximab maintenance.

And I think maybe just as a plug, and maybe towards one of the conversation pieces we may have about how to get a trial done in a rare disease, right, I thought this was pretty interesting. So the Australian group looked at, and this is a cooperative group that includes a massive country where 25 million people live in the area the size of the US but they’re all so spread apart, and they did this hub and spoke approach that really facilitated accrual, and I thought this was a really nice model for how we could do trials in rare diseases. 

Anyway, going to the results, what they found with a median follow-up of 25 months is that there’s a 57% complete response rate after the acalabrutinib and rituximab induction. After the chemotherapy is added in it goes up to 88%, and the chemotherapy really did improve the MRD rate and that regardless of whether or not people had a transplant or not, but the majority of patients actually did have a transplant, the 2-year PFS was 73%, and the 2-year overall survival is 79%. So short follow-up, but I think the takeaway for me is just that using a BTK inhibitor with rituximab as an induction is something that is active and hopefully will be pursued.

And then the last treatment-naïve study — I’m sorry, not the last, but the next treatment-naïve study was in that p53-mutated group that we were talking about, where even transplant is just not good enough. This is chemoresistant disease. Patients have a shorter survival, worse outcome.

And so this was presented by Anita Kumar. 25 patients, looking at zanubrutinib and obinutuzumab induction, and then you add in the venetoclax. And they had a high-risk population, as you might imagine when you have p53. They had 20% of patients who had a blastoid or pleomorphic morphology. 62% had Ki-67 over 30%, a third of patients had a Ki-67 over 50%, high-risk MIPI, 86% p53 overexpression by immunohistochemistry, and then FISH abnormalities in 44%. And so, again, a very, very high-risk group. And again, a small study. Follow-up is 23 months, but what you see from the plot — the swimmers’ plot over on the right, is that the majority of patients responded, and many of them — the yellow shaded areas are those patients who stopped treatment and stayed in remission. So this is something that I think will be very interesting.

One piece will bring up is that there were 4 deaths. All were infectious. And again, this was all conducted during the pandemic, and I believe that at least 3 of those were related to COVID.

Older patients. Sorry, this is the last patient about treatment-naïve setting, but this is in the older patient setting. This was presented by Craig Portell at ASH and looked at BR with venetoclax added in. This group, 33 patients, median age was 71, and again high-risk features but really the highest risk from my perspective is that these were older patients going up to age 80, and the primary endpoint was CR rate. And what they showed is that there’s a really nice overall response rate, 97%. The CR by both PET and bone marrow is 85%, so again quite high. And their preliminary outcomes I think are very encouraging, with a PFS of 74% at 2 years and 2-year overall survival of 82%.

They did unfortunately have 8 deaths on study, including 4 from COVID and 1 from influenza. And we’ve been talking about how building on bendamustine can be kind of tough, and I do believe that during the pandemic some of that was even more obvious, and so that’s a — there is a lot of immune suppression associated with that, and venetoclax may add to it because there are more cytopenias when you add in venetoclax.

DR LOVE: So the thing that happened to me this past year in terms of mantle cell is last summer I spent a couple hours talking to Dr Wang, and one of the things that he was talking — that was of course a great experience, but one of the things that he mentioned was, I think it was presented at the lymphoma meeting last summer, acala/rituximab in older patients. Any thoughts about that, and I mean I almost wonder is that something you could offer to a patient now? I mean he does it, but I know — and he says I know people can’t necessarily access it. But theoretically, though, if you could, is that something that you would consider?

DR SMITH: Yes, absolutely. I mean I do think that in the front-line setting, especially for the older, unfit group, where BR is currently the standard of care, I don’t know why we have not pushed getting the BTK inhibitors into the front-line setting better than we have. I mean I think that’s kind of an unusual gap in our field.

And the acala/rituximab data is very interesting, very exciting. I know there are trials ongoing to see if that could become a new standard of care.

DR LOVE: I mean I should mention too, he’s like zanu is fine too. He just picked acala, I guess, for whatever reason.

DR SMITH: Yeah.

DR LOVE: But I don’t think it’s restricted to that.

The other thing I was kind of surprised at is using obinutuzumab versus rituximab in mantle cell.

DR SMITH: Mantle cell. Yeah. Most of the data has really focused on rituximab and not obinutuzumab. The way I think about obinutuzumab, it’s a glycoengineered antibody that has more persistence and also more toxicity, but it works better in CLL because CD20 is dim, and so you need that more potent antibody. I think in the other lymphomas, where CD20 density is so much higher on the cells, I don’t know that it matters as much.

DR LOVE: Yeah. That’s why I was surprised at that obinu/zanu/venetoclax —

DR SMITH: Yeah. The BOVen. Yeah.

DR LOVE: Yeah, the BOVen, because I assume it’s more toxic.

DR SMITH: All right. Well, I’m going to go on to relapsed/refractory mantle cell lymphoma. And what was presented at ASH this year was the long-term follow-up for SYMPATICO, which was a randomized Phase III trial of ibrutinib/venetoclax versus ibrutinib/placebo followed by 2 years of ibrutinib maintenance, and the primary endpoint here was the investigator initiated progression-free survival. And what you can see in the curves is that there is a significant advantage when ibrutinib is paired with venetoclax as opposed to ibrutinib alone, and this was statistically significant.

There’s no difference in overall survival just yet. There may be a slight trend towards that, but certainly the CR rate, the duration of response, and the progression-free survival all favor this combination.

The other part that I thought was really interesting is that there didn’t seem to be any unexpected toxicity, and the cytopenias were ones that really responded to supportive care and did not persist.

The other piece in relapsed/refractory mantle cell lymphoma is to look at BTK inhibitor monotherapy, and I think as this group knows this really changed the field when ibrutinib first came around. And one of the challenges with ibrutinib is that as we have gained more familiarity with it we know that there are some late side effects that are very difficult for patients to tolerate, and that includes the arthralgias, the myalgias, the AFib, hypertension, bleeding, bruising, infection.

And so with the new generation BTK inhibitors, such as acalabrutinib, is there an opportunity to maintain the activity without that toxicity. And this was just an update of acalabrutinib monotherapy looking, again, at the typical median age of 68, 21% with blastoid morphology, and a quarter of patients who had a high proliferation rate. And in this group I think it’s very respectable outcomes. The overall response rate is 81% with a CR of 47% and a 28% duration of response.

One thing that I thought about when I was looking at this study, again, is that it’s really the low-risk patients and the CR patients who do the best. And other patients — it just makes me think that if we’re going to use a monotherapy in the relapsed/refractory setting we should probably pick our patients a little bit more carefully, and low-risk patients may do really well for a long period of time, but others probably need to go more to the combination approach.

Now of course the newest thing in terms of BTK inhibitors is that we have a new class of agents, which is a reversible or noncovalent BTK inhibitor, with pirtobrutinib being the first to market. And this is the BRUIN Phase I/II trial. It looked at pirtobrutinib monotherapy mostly in people with relapsed/refractory mantle cell lymphoma, although they did have 14 patients who were naïve to prior BTK inhibitors. And the advantage to the reversible phenotype is that if there is new BTK that’s being generated it may be that pirtobrutinib can stabilize or maintain the BTK so that it doesn’t actually — it’s not able to do its activity in terms of B-cell receptor signaling.

So the results are shown here with relapsed/refractory mantle cell lymphoma that the overall response rate is 49%. And what you can see by the different shades of the bar is that it didn’t really matter if these patients had prior BTK exposure or not with the covalent inhibitors, and the median duration of response was 21 months.

DR LOVE: I’m trying to remember where, I guess it was CLL that I heard the idea that the actual duration of response is lower in people who’ve had prior BTK.

DR SMITH: Yeah. I think that is true.

DR LOVE: Is that the case with mantle cell too?

DR SMITH: I would say that in mantle cell we have very few numbers. I would guess that that’s going to be true, but I didn’t see it broken out by that. It’s only the overall response rate and not the duration of response that was broken out by prior BTK exposure.

DR LOVE: And then the other question, of course we can get into it when you talk about CAR T, is when — how are you utilizing pirtobrutinib right now and is it kind of like your third-line therapy or whatever, or is it a bridge to CAR T more likely?

DR SMITH: Yeah. So I’ve used pirtobrutinib in CLL for people who are intolerant to and/or have progressed on a standard covalent BTK inhibitor. In mantle cell lymphoma I haven’t used it just yet. I will say that if we need a bridge to CAR T we’ve used more venetoclax-based therapies than we have pirtobrutinib.

DR LOVE: And that works? Venetoclax as monotherapy is effective?

DR SMITH: In mantle cell lymphoma? Yes, it does work.

DR LOVE: I saw when they added it, but as monotherapy also. That’s interesting.

DR SMITH: Yes. Yeah.

DR LOVE: And so when you’ve used pirtobrutinib, I guess in CLL, have you used it enough to get a feel for kind of side effects and quality of life?

DR SMITH: I have. I mean I feel like it’s really well tolerated. I think pirtobrutinib is significantly better tolerated in my own experience but also when I look at some of the literature. And of course these are anecdotes for some of the patients I’ve treated. But yeah, there are people who had just very poor quality of life, and even on agents like zanubrutinib and acalabrutinib, which are generally better tolerated than ibrutinib. But they would switch to pirtobrutinib and really, really well tolerated. So…

DR LOVE: Any cardiac signals with pirtobrutinib?

DR SMITH: At least what’s been published so far it seems significantly less. I won’t say that it’s zero, but it’s significantly less compared to the covalent inhibitors.

DR LOVE: All right. Please continue.

DR SMITH: Yup. So the other treatment option we have for mantle cell lymphoma is CAR T. And we already have a couple of products, like brexu-cel has already been approved, and I’ll show you some of that data, but what was new this year was liso-cel. So this looked at 104 patients, and the overall feasibility is 88 of the 104 were able to receive their product. And remember, again, with liso-cel it’s that 1:1 very specific ratio for the CD4 and CD8 cells.

Sometimes we use what’s called out of spec products, meaning it doesn’t have the exact ratio that we want, but it’s still an active drug. So I think in this particular trial they mostly stuck with patients who had the right ratio, but I think the feasibility in the real world may be a little bit better. It’s just my bias.

But anyway, the patient characteristics here is that they looked at kind of your typical older patient population, 20% over the age of 74, a third had blastoid morphology, 23% with TP53 mutation, and a median 3 prior regimens. And in mantle cell, very different than follicular. By the time you are third line, in general, you’re sick, the disease is pretty aggressive, and to that point 70% had refractory disease.

So in this population the overall response rate and the CR rate was quite high, 74% CR, and at least with the follow-up that’s been presented, which I believe is about 28 months, the duration of response was about 16 months, PFS 15 months, and overall survival 18 months. And there’s a suggestion on that overall survival curve and the duration of response curve maybe, maybe there won’t be any late relapses.

Looking at some of the toxicities, cytokine release syndrome was common for Grade 1 and 2, but almost no Grade 3. And I think that’s a consistent theme we have seen with liso-cel across all of the disease states is that CRS appears to be much less, and the same thing with neurotoxicity seems to be much less. So that was for the liso-cel.

Now the one that actually is FDA approved is brexu-cel, and this is based on the ZUMA-2 study, and we saw 4-year follow-up at ASH this year. And then they also had an expanded access study that they called ZUMA-18 that increased the number of patients who have been treated with this. And so again, older population, 4 prior therapies, so this is a really beat up group of patients. 91% had prior BTK inhibitor before they went on to receive CAR T. And you can see the breakdown of the types of BTK inhibitors that are there. And 26% had relapsed after a prior auto.

So to look at the expanded access study first, this is 23 patients. Early going, but the overall response rate 87%, the CR rate 57%. The cytokine release syndrome Grade 3 was in only 1 patient. Otherwise this was really well tolerated, and I think this is very, very encouraging preliminary data.

The 4-year results that they showed of their original cohort with 68 patients I think is also really great to see just in the sense that with a median follow-up of 47 months the overall survival was 5 years. I mean it’s 58.7 months for those patients who had a CR. And out of — after almost 4 years of median follow-up 30 patients were still alive, the majority of whom had had a CR.

So I think, again, CR seems to matter, so if we can find who’s going to get that I think CAR T is really great.

So I think I shared a ton of data today. I hopefully put in a few just personal thoughts and interpretations of the data, but I would just say that our toolbox has continued to grow, and the real question today is we’ve got all of these buckets — bispecifics, CAR T, targeted agents — and how to use these best as we go forward I think is going to be just really exciting to be a part of.

Diffuse Large B-Cell Lymphoma and Hodgkin Lymphoma — Andrew M Evens, DO, MBA, MSc

DR EVENS: Hi. My name is Dr Andy Evens at the Rutgers Cancer Institute of New Jersey and the RWJBarnabas Oncology Service Line. And I’m really happy to be here with Dr Love in the 2023 Year in Review and where I will talk about updates in the management of diffuse large B-cell lymphoma and Hodgkin lymphoma. It’s been really a robust year with a lot of good data that has come out.

So we’ll start with diffuse large B-cell lymphoma. I think everyone knows within the rubric of non-Hodgkin lymphoma, there are more than 90 subtypes, clinical, molecular or clinical pathologic, but this is the most common. And we know there’s different subtypes. Diffuse large B-cell lymphoma constitute about one-third of all non-Hodgkin lymphomas.

And so what did we see in 2023? Well, this is really one of the pivotal studies. And the reason I say that is there have not been many FDA approvals in front-line, untreated, advanced-stage diffuse large B-cell lymphoma in the past 2 decades. Obviously, rituximab has been around about 20 years now. And that’s not for lack of trying, by the way. There have been a multitude of Phase III clinical trials, smart, good clinical trials. Just nothing has broken through.

So what was the POLARIX study? This was taking the R-CHOP backbone and this was a placebo double-blind randomized control study of substituting polatuzumab vedotin, the antibody drug conjugate, in lieu or in place of vincristine so to avoid that double cross reactivity. It was a smart trial design. And then all patients after 6 cycles of each went on for 2 more doses of rituximab. And you can see just about 900 patients were randomized. And one critical point is patients had to have a classic IPI score. The reason I say classic, there’s been iterations of it. The original of 2 or more. So this was high-risk diffuse large B-cell lymphoma, so IPI 2 or more.

And it garnered topline results on average when looking at all patients, about a 5% absolute improvement in progression-free survival. And that garnered FDA approval for the indication. So what have we seen since that time? And especially data from ASH as this has shown here is we saw data from Dr Morschhauser showing by cell of origin. So we’ve long classified, at least for the last 10 if not 15 years, cell of origin known as GCB there in the middle, germinal center. B-cell or activated B-cell type, some call it nongerminal center. And then a third smaller, you can look at the absolute numbers, of unclassified. And what’s shown here is what they did on the study by gene expression. And so that’s a very important point that I’ll come back to. But as the obvious summary you can see on this slide is when looking back at patients who were activated B-cell type, ABC, it looked to be they garnered the yeoman’s benefit from adding polatuzumab/R-CHOP as you can see in orange whereas germinal center did not. Unclassified interestingly had somewhat of a benefit, not as much as ABC type.

DR LOVE: Just out of curiosity, maybe it’s more of a technical thing, but is this type of analysis sort of legitimate? Was this prospectively randomized? I don’t know how you define it. But is this considered a legitimate way to break this out? Or is this sort of a post-design look at the data?

DR EVENS: Yeah, I would call it a double-edged sword, Neil. So a yes and a no. So scientifically, yes, of course it’s legitimate. It was gene expression. We know that is pretty good conduct. But I think to your point is, does this impact care at the bedside? And the reason I say not yet is, as I highlighted, this was gene expression. We don’t do gene, or most centers, the vast majority, do not have access to clinical gene expression. We do immunohistochemistry which is good. But as you probably know, there’s about, A, a 10 to 15% discordance from IHC to that, number 1. Number 2, this was not done on all patients. And in the small subset where it wasn’t done, it still looked like there was a benefit. Number 3, yes, this was done ad hoc. It was preplanned, but it was ad hoc. And patients were not randomized to germinal center subtype. And number 4, Neil, is this gene expression is even, as we’re going to show in a minute, kind of just 1 layer. Now by sequencing, this is breaking out into 3 categories. It’s now 6 to 8 different categories. And there are even some sequenced type, as we’ll show in a minute, under germinal center that may benefit. So I think it’s very interesting. There’s scientific rationale. But to me, we don’t use this at the bedside. In other words, we cannot pick or choose. As long as it fits the FDA qualification, we’re considering this our standard.

DR LOVE: You could imagine how many people I’ve asked that question to, and you are the first person, to me, who brought up this issue of IHC. So you’re saying that you can’t really, the community-based doc cannot really trust necessarily the IHC assay they’re sending. And if they’re doing that and determining it, they may be missing patients who could benefit.

DR EVENS: That’s the problem. And is it the majority? No, it’s not. But of course we don’t want to hold critically effective and potentially life-saving treatment for a patient based on a test that has an error rate or a non-discordant rate. Yes, that is true. And not even all community docs, and they’re all fantastic and hardworking and smart, not all of them even have access. Their pathology labs, when we get referrals, they aren’t even all doing cell of origin by IHC. But even if they are, yeah, it just doesn’t, it’s not quite there yet to this cell of origin much less it certainly doesn’t correlate with deeper sequencing of data that’s available. So I think it’s just very, what I would say, strongly hypothesis-generating, but we need more data. And when I say more data, data that’s going to help clinicians and patients in the community and at the bedside.

DR LOVE: So it sounds like you’re saying that if you do have a reliable source to really test the cell of origin, I guess what is it, NGS or you’re looking at the DNA or something?

DR EVENS: It is.

DR LOVE: If you have that then you feel much more comfortable about maybe avoiding this in GCB. But if you’re out in the community and you’re not sure, you can’t get it or whatever, maybe that’s a different message. And incidentally, that’s what I’m saying, of all the people I’ve asked that question, they always focus on the question. Nobody has ever brought up the assay.

DR EVENS: And I think that’s important because, yes, the science, as you can see here, looks pretty strong. But we know from other data that we’re going to show here in a minute that even within the germinal center rubric, there are some molecular patients that likely benefit, some certain categories. So I think it’s very strong data, but at least with what we have now at the bedside which is really for most practices is immunohistochemistry which is imperfect, it’s good but imperfect, is I think we just do not want to miss patients who could benefit. So yeah, the good news is there are a number of assays that are being looked at. Hopefully, one of those will be commercialized and will be a little more specific that we can do and truly guide precision therapy. Not just for polatuzumab vedotin, but really for most of the treatments we give in lymphoma.

DR LOVE: It’s amazing how often really important trials, it takes a couple years for stuff to come out sometimes just talking to people over and over. Anyhow, please continue.

DR EVENS: Yeah, it does. And with that said, you start somewhere and you move along. And just to that point, so this was one point I was just highlighting of if you look at that data, you would say well no germinal center patients benefit from polatuzumab vedotin. Well this was another extension taking a little bit of a deeper dive. This is called the so-called dark zone signature. The Vancouver group published an excellent paper, David Scott, Christian Steidl, and others. There was a prior signature, if you recall, called a double-hit signature that really was aligned mostly with high-grade B-cell lymphoma. So this is a little bit of an evolution of that, this so-called double-zone signature. Again, this is not available at the bedside, but it’s still very interesting science. And what you can see when looking at this data when looking at all dark zone signature which, by the way, is under germinal center, so this is germinal center B-cell. And you can see in the text there what further sub-delineations, subgroups that it’s associated with. As you see, EZH2, B6 — BCL6, and NOTCH2 in there. But what we’re seeing again is within this dark zone signature which is within germinal center, pola/R-CHOP appeared to improve 2-year progression-free survival.

But this just, again, highlights the point that it’s not even as simple as gene expression cell of origin. There’s even deeper layers and levels to that. So really great data in front of us. And the hope is we will sometime in the near future, not months, probably hopefully a few years, have a commercial test available that’s not just immunohistochemistry. And importantly, number 2 is we start designing clinical trials and truly, truly having more personalized therapy based on a patient’s individual signature in their tumor. So much more to come on that with clinical trials.

But one other aspect we could look at is, what about the elderly or much older patients? We know that, especially as we get north of 80 years, 85 years, or even patients in their 70s with a multitude of comorbidities who maybe aren’t performing instrumental activities of daily living. And so many of us I think in current state have grafted onto the mini-R-CHOP regimen which is basically almost a 50% dose reduction. The cyclophosphamide is not quite 50%, but the doxorubicin, the vincristine are reduced. And amazingly, Neil, it makes a world of difference. And the effectiveness looks pretty good in these older patients. And so what about including polatuzumab vedotin? That’s what this POLAR BEAR study was. And we had an initial output at EHA last year looking mainly at safety data. We haven’t seen a report out on the efficacy. And this is just a straight study, so it’s not a randomized study but at least — I’m sorry, it is randomized, but it’s not as large as the original POLARIX, but still an important study. And I think what you can see from the safety chart here is it looks fairly comparable. Maybe a little bit more GI tract on the righthand side for pola/R-mini-CHP versus R-mini-CHOP. So I think this will be a really important output once we see the efficacy data for our older patients.

Well, that’s newly diagnosed. And certainly, we’re happy with those results with polatuzumab vedotin but there are a multitude of not just scientific, but other agents that are looking to make it to the front-line. So this is one agent that, as you can see here, they used the acronym L-MIND, tafasitamab in combination with lenalidomide. So this is a targeted agent that is now, in this combination, FDA approved for patients with relapsed/refractory diffuse large B-cell lymphoma, 1 to 3 prior regimens or not eligible for a transplant. And this is how the dosing comes along. And really, it’s an incredibly well tolerated regimen as we go along and as I’ll show you here in a minute.

And these were the topline results that you can see published in Haematologica. And so this was an updated extended data. It was already FDA approved before last year. This was updated data where you see overall response rates are around the up close to 60% range with CR rates of 40%. And importantly, as you see, median progression-free survival, not that’s all patients, at 5 years is 2 years which is really impressive. And the median duration of response is not even reached yet. So if you’re a responder which is a little more than half of the patients, they look to be durable. And I’ve had a multitude of patients even patients, frankly a couple patients, who had failed CAR T who have garnered a response to this regimen.

And so that’s great. Can we move it to the front line? And the quick answer is it’s being looked at in this so-called First-MIND trial. Randomized Phase III study looking first at — or this was a randomized Phase II study first looking at the feasibility of adding tafasitamab/lenalidomide to one arm and just tafasitamab to the other arm, so looking really a little bit at the contribution of lenalidomide.

And this was a small randomized Phase II study, but you see some of the outputs look mostly similar, maybe a little bit more on the lenalidomide side. Obviously, we need to consider tolerability. Lenalidomide oral medication is pretty well tolerated. Yes, it will add, we know, some GI symptoms and also some cytopenias that we have to be aware of. But I would say generally speaking, at least looking between these 2, fairly similar except for definitely a little more cytopenias but mostly were manageable on that. So more to come in terms of a larger Phase III study.

What other agents? This is another antibody drug conjugate, loncastuximab tesirine. And one that is certainly interesting, a targeted agent that’s approved now in the clinic for relapsed/refractory diffuse large B-cell more than 2, 2 or more prior therapies. Maybe not quite as robust of a response rate. But for patients achieving response, especially patients who achieve a CR as you can see on the righthand side, it tends to be durable. Maybe a unique side effect or toxicity we see with this is sometimes pleural effusions you have to be mindful of with this agent. It’s in the minority of patients but in that minority, sometimes can be significant, so is one additional tolerability component to be mindful of.

We participated in some of the initial clinical trials.

And I think it is like many things in life, you need to use it a few times and get comfortable with it. It is a little more toxic. And I think anytime anything is, A, a little more toxic and, B, anytime you get an unusual side effect that we’re not used to. Not that effusions, pleural effusions are something we’ve never seen before, it’s just not a typical toxicity that we’re used to. So I think you just have to be aware going in of its unique tolerability, and then it’s manageable. It’s just with available agents with, we’ve already talked about CAR T, bispecifics, we’ve talked about tafasitamab. I don’t think we’re going to talk about polatuzumab vedotin in the relapsed setting. Where it comes up as fifth-line or sixth-line, often patients are having a tough time at that point in terms of relapse.

DR LOVE: Do you know what the deal was with the trial that had to be stopped or anything about that?

DR EVENS: Yeah, I think not all of it was made public. And that, I hope we do see more details on that. But there were some severe adverse events that warranted its early closure, is my understanding. So obviously, that’s another yellow, if not a red, flag. We need to see those results. Because even in older patients, you want to make sure that agent is tolerable because that’s the real world. Patients who have relapsed diffuse large B-cell lymphoma more often than not are older patients with comorbidities.

Well, we all know the true big game changer in our field of non-Hodgkin lymphoma is CAR T-cell therapy, in particular CD19-based CAR T therapy. And in the relapsed/refractory diffuse large B-cell space, we have 3 different products approved. And now not just in the relapsed/refractory. After transplant or unable to receive a transplant, I will show data where it is in first relapse as well. But this was one of the initial, the ZUMA-1. They are numbered 1, 2, 3, 4, 5. This was the first pivotal study. Fred Locke from the Moffitt Cancer Center was the first author here when it was presented at ASCO. You can see it’s a one-time treatment. Patients are screened. With this particular agent, axicabtagene-ciloleucel, this is one that is pretty good turnaround, 3 weeks, at most 4 weeks from the time you leukapherese and it’s returned to you for reinfusion. There’s a 3-day conditioning. We usually will do it on a Wednesday, Thursday, Friday. Patients will come back Monday for the infusion of the axi-cel. It says hospitalization there. We’re doing more and more patients outpatient for at least that first 5, if not 7, days. If there is cytokine release or neuro encephalopathy type symptoms, it tends to be beyond the 5-day mark. So it’s maybe a little harder with axi-cel to be able to do that. The 2 other agents, tisa-cel and liso-cel, it’s manageable in the outpatient setting.

But when we look at the ZUMA-1 5year efficacy update, so this is longer follow-up, this is what we’re seeing. So good response, initial response rate as you see, 84% with 59% complete remission rate. And in terms of ongoing response is right around the 30% range. If we want to say at the end of the day, 100 unselected patients, how many is that truly durable? And when we say durable at 5 years, Neil, this is probably cure at this point. Which frankly, before CAR T-cell therapy, that bar was not at the 30 or 35% barometer. It was lower, so it’s definitely been brought up with this.

And so where has this evolved is, well let’s not wait for 2 or more relapses or relapse after a transplant. What about at first relapse? Well of course, what’s been the standard of care for the last 30, if not 40, years in this space is an autologous stem cell transplant. So to really prove the benefit as well as the safety, it had to go head-to-head versus an autologous stem cell transplant which was unheard of, but it was done in this study and others. The TRANSFORM study that we’ll show in a minute. So it was older — patients over age 18. You can see in patients intended to receive to an autologous stem cell transplant. And these were patients who relapsed within 12 months of front-line therapy. Jason Westin from MD Anderson presented this at ASCO last year in this randomized study.

And topline results in terms of progression-free and overall survival, you see here. And there’s no other way, and Jason was the first author in the New England Journal, to say this was a gamechanger. There have been few and far between studies in diffuse large B-cell lymphoma that we can say improved overall survival, that patients are living longer. They’re not just cured, but living longer than the standard of care, in this case, autologous stem cell transplant. So you see the top curve in this space. This is, again, first relapse. Right leveling out right in the 40 to 45% range. And you see the standard of care which, again, was transplant where it levels out for PFS. But if you look at the bottom at overall survival, yes, that’s a 25 — I’m sorry, a 27% improvement in overall survival with axi-cel therapy in this space. So just a really big breakthrough in our field.

Well, where is this agent in particular going? So ZUMA-12 now is saying, all right, we have it approved in second or more relapse. Now, it’s approved in first relapse. What about earlier? What about front-line therapy? So this is looking at high-risk large B-cell lymphoma. So how is that defined? You see in the bullet in the upper left. So it’s the so-called double-hit, meaning it is MYC and BCL2 and/or BCL6 translocation, so that’s molecular definition, and high-grade B-cell lymphoma with a molecular double or triple-hit, or large B-cell lymphoma with an IPI score of 3 or more. And there’s going to be looking at different assessments as they go through and as I’ll work through here.

What are we seeing? Impressive results thus far. So more to come on this as well as we start to compare this to the standard of care.

And, of course, as I alluded to, there are other products in this space, this one in particular, lisocabtagene maraleucel or liso-cel. And this was not the initial pivotal approval for relapsed/refractory. This was also a second-line treatment for relapsed/refractory large B-cell lymphoma. Similar cadence to the treatment where there’s leukapheresis. This product is a little longer. And sometimes, that’s how I’ll choose. If I have a patient who really needs it in 3 weeks, I’ll think about axi-cel. Liso-cel tends to be a little better tolerated, but you need to wait usually 4 to 5 weeks for the return of the product. This is one that is one to consider. And, of course, there’s always the concept of bridging therapy, Neil.

And if I even step back another second, I was just in clinic yesterday where we had a patient relapsing with really big tumor burden 6 months after receiving R-CHOP therapy. And it’s one that he was a Stage II patient, so he only received R-CHOP therapy. But he’s really progressing quite rampantly. And we’re probably going to need to think of pre-bridging therapy. But you have to be cautious in that space. And there’s been a lot of data about trying to get collection without injuring the T-cells. So you want as vial of T-cells. You want that T-cell fidelity. So there have been a little bit of different publications to this end. Bendamustine is one to be cautious of. The majority of publications have said to be cautious of bendamustine, especially in that pre-bridge. Try to keep them steady, leukapherese them, then even think about bridging therapy in a smart fashion. In other words, don’t burn bridges before the ultimate CAR T-cells come back.

So let’s look at the results to the TRANSFORM study. Dr Nastoupil, as you can see here from the MD Anderson as well, presented this data at ASCO. And just really striking benefits to liso-cel in terms of event-free survival and progression-free survival. And again, when we say standard of care, standard of care was an autologous stem cell transplant.

DR LOVE: So one question in terms of kind of general tolerability, sort of an indirect comparison. But if you put CAR T on one end, and I’m going to say axi-cel, and you put bispecifics on the other end, pick whatever one you want, and you think about the kind of patient that would be eligible for each one and whether there might be some people who would be eligible for bispecifics you wouldn’t want to give axi-cel to. Where in between does liso-cel fit? Is it closer to axi-cel or closer to bispecifics in terms of general tolerability and kind of what you need to see in a patient?

DR EVENS: Yeah. We talk a lot about this within our internal, our weekly multi-D lymphoma group and other forums. Generally speaking, I would say we think of liso-cel tracking more close to axi-cel in terms of it’s a CAR T agent. And when we’re thinking of is it CAR T, to your point, versus bispecific, we lump it closer over to axi-cel, but it is better tolerated. There’s just less especially early toxicity. So it tends to be one that we think about more often than not as long as you know there might be a 4 or 5-week lag from the time that you leukapherese it. But to your point, it’s a great discussion about CAR T versus bispecific in general, especially for a patient relapsing after a transplant or after 2 prior therapies. And to me, I think it’s one that generally speaking I tend to lean towards the one with the better track record, the longer rack record. But bispecific antibodies are obviously incredibly active. Now what’s the converse to that is obviously CAR T is a one-time treatment where bispecifics, there is a time-limited one for 1 year and another that’s indefinite, so that’s a factor.

The upside, the flipside to CAR T, as we know, it’s a one-time treatment. To us, patients in first relapse or second relapse who are naïve to both CAR T-cell therapy and bispecific, for diffuse large B-cell lymphoma, we’ll generally lean towards CAR T. Generally, unless there is a patient, and you see some, I saw a patient recently, an 84-year-old, kind of a brittle diabetic, some other comorbidities. We weren’t quite sure if CAR T was really going to be tolerable, so we leaned more towards bispecific in that patient.

DR LOVE: Yeah, that’s exactly the situation I’m thinking about. And I would guess that one of the big issues here would be the intensity and duration of CRS. Which it’s hard to kind of get a feel for that in terms of, let’s say, a patient like that. Do you think that the level of CRS that you see with liso-cel is such that you would not want to be giving it to a patient like that and would be okay giving a bispecific? Or bispecific might be a big problem too?

DR EVENS: No, I think generally speaking, and there’s always individual cases and 1 in 1,000s and things like that. But generally speaking, the bispecifics have less CRS than CAR T including liso-cel. And that’s not to say liso-cel has a significant amount of CRS. It doesn’t happen in everyone, number . And even in the patients it happens, it tends not to be severe. The problem is, and albeit single digits, it can be severe. Now is it usually self-limiting in a way and we give the appropriate tocilizumab or sometimes steroids? Yes. But sometimes, it can be severe. But generally speaking, bispecifics will have less CRS that we have seen.

DR LOVE: That’s very helpful.

DR EVENS: So with all of that great data generally speaking with CAR T-cell therapy, of course with any new agent, in particular biologic agent, excuse me, there needs to be continual surveillance for not just ongoing efficacy, but sometimes with any agents that are approved in medicine, sometimes down the road it takes years for an adverse signal to pop up. So this is one that popped up. And it actually popped up right around the ASH meeting. There wasn’t a lot at ASH. There was actually a single case report that was not accepted. But this really broke through right around December and certainly into January as I’m going to call it a yellow flag because I’m not convinced it’s a full red flag. It’s a full issue that needs to be teased out.

So you can see this was a press release that the FDA put out at the end of November that it’s investigating the risk of T-cell malignancy, in particular T-cell lymphoma, following BCMA-directed or CD19 autologous CAR T-cell therapy. And so there have been a handful and it is a small amount of cases identified after CAR T. So where there needs to be introspect and analysis is, of course, T-cell lymphomas are second malignancies after an initial malignancy have been part of our field as long as we’ve had treatment agents and just the cancer in general. In other words, there can be second malignancies. So that’s one critical point.

Is what’s being seen different or increased than the baseline expectation for T-cell lymphoma or any second malignancy to happen? That’s number 1. We need to do that analysis. And number 2, obviously, there should be some scientific delineation as well. And there was a question of a case where they found the construct question, I think it still needs to be validated, of the CAR T construct within the T-cell malignancy itself. In other words, was it truly part of the etiology or pathogenesis? My read on that is still TBD, to be determined on that.

There was a really important paper put out in Nature Journals by the UPenn group where they at least looked back at their experience in a careful and thoughtful way. And they found a couple cases, not surprisingly, of second malignancy including a couple T-cell lymphomas. But they did not find any issues, at least of the biologic construct within the malignancy, in their data analysis. And obviously, they’re one of the leaders in this field. And really, their rates looked to be lower than the expectation in terms of second malignancy. So this is not to minimize this in any way. I think it just really, again as I said, is something, it’s there. We need to really think about it carefully.

DR LOVE: So you mentioned ASH. I don’t know if you know about the informal consensus conference that was done at ASH on this issue. Just kidding. We did 4 CME programs with 21 investigators on Friday of ASH, and I asked every single one of them about this. And some of it got into the meetings we did and others were just for my information. And their response was very similar to kind of what you said, particularly their immediate reaction kind of reminded me of myeloma with the lenalidomide maintenance was risk/benefit which is kind of obvious. But the other thing though that came out a little bit was the issue of the psychologic impact that you can’t really measure right now on a patient. And in fact, one of those 21 investigators said he actually had a patient who was considering CAR T for follicular lymphoma who decided to hold off for a while because it wasn’t really urgent, it wasn’t diffuse large B-cell. So that was kind of one situation I hadn’t thought about. But in any event, obviously, more to be done on this. It’s one thing to look at the risk/benefit. It’s another, again, the — you saw this with lenalidomide, you know?

DR EVENS: We did. And that’s where I think it’s not going to — however the data falls out is, like you said, it’s going to be at that patient, risk/benefit not just of the disease they have, but the individual patient, what treatments they’ve received and so on.

DR LOVE: This is really different in a way though. I don’t recall any — because you think about, as we were talking about, myeloma. Actually, we were talking about tamoxifen in endometrial cancer as another example. Obviously, anthracycline is in AML. But this is kind of a little different in the T-cell nature. T-cell therapy causing a very rare cancer. I’m not sure T-cell malignancy is a typical second cancer in these other things.

DR EVENS: It’s not, but we do see it sometimes, Neil. Whether it’s a secondary cancer or it was just like a natural evolution that a patient may have. We’ve seen it but yeah, it’s not certainly the thing that tops out most in our mind. We think of the general B-cell lymphoma or an MDS type of entity. But yeah, I think it was acutely in a little bit of a way maybe a little, like the media can do, blown out of proportion. But at the end of the day, it’s something. It’s there. It's a signal. Let’s understand it fully, not just in its epidemiologic scope but especially biologically.

DR LOVE: Yeah. The cool thing was 5 of those 21 people were myeloma people and it was the same issue with them really, theoretically.

DR EVENS: Yeah. And that’s one, yes, you’re absolutely right. Well and to your point is well maybe in early myeloma when there is a predicted life-long span and a multitude of therapies, God forbid smoldering myeloma, this might not be the agent right now until this is further delineated and flushed out.

DR LOVE: Yeah, we’ll see where that heads. Because myeloma doesn’t have, you know, CAR T in myeloma is not the same as CAR T in diffuse large B-cell too in terms of long term.

DR EVENS: No, it’s different. It’s different in efficacy as well as tolerability. Absolutely right.

DR LOVE: All right, please continue.

DR EVENS: So speaking of bispecific antibodies. And, again, when we say bispecific, it is a dual CD20/CD3. So instead of like CAR T-cell where we’re taking out the native T-cell, sending it to a company, manufacturing it, super charging it, transfecting an antibody, and reinserting it and hopefully hyper expanding in a controlled fashion, this is taking those native T-cells and hopefully they attach to this by construct and it’s delivering the patient’s own immune system hopefully to the lymphoma in a targeted fashion.

So there are a couple on the market. This is one of them called glofitamab. And this is Dr Martin Hutchings has been one of the leaders with this agent as he presented an update on this to ASH. So these are more similar than different. There are a couple differences between the approved agent. So one difference with glofitamab is you can see, which I think is an upside, is the fixed duration treatment. One of the things that we and patients for that matter certainly in the lymphoma space would rather not to be on a treatment that’s indefinite and long-term. So this was, as you can see, up to 12 cycles. And 12 cycles is actually 8.3 months the way it’s constructed. One difference versus another agent that we’ll talk about in terms of mitigating CRS was there is a one-time dose of the CD20 second generation antibody, obinutuzumab. And so that is given initially. And there’s a little bit of a ramp-up as you can see, this day 1, 8, 15 on the dosing. And this agent is given intravenously, by the way, the glofitamab. And then it’s given, as you can see, in 21-day cycles through those 12 cycles once you get up to 30 mg for cycle 2 through cycle 12.

And what type of results do we see? We see very active results. And this was looking at relapsed/refractory diffuse large B-cell lymphoma or transformed large cell lymphoma in 132 patients as well as patients who had failed, in the third column, prior CD19 CAR T-cell therapy. So in the larger patient group, we see CR rates, as you can see there, around — or an overall response rate, I should say, of 56% with the majority of those being complete remission. And, again, this is a very sick patient population. To see a median duration of response of more than 2 years is impressive. And you can see the percentage is north of 50%. Even in CAR T failure, there was a response rate of 50%. Maybe not quite as robust of a CR rate, but still 37%.

I just saw a patient yesterday, Neil, in clinic, of a gentleman who actually was in an early relapse of diffuse large B-cell lymphoma. It was his first relapse, but he had comorbidities. He had Marie-Charcot-Tooth disease where he had braces. You lose your perineal muscle. He couldn’t walk so really wasn’t a transplant candidate. He received CAR T, and despite being a later relapser, did not respond. Within 4 months, was progressing. And progressing in a significant way, interestingly. Biopsy-proven progression, large 12 cm mass. He started on glofitamab. And the reason he’s resonating in my mind is he just had a PET scan and after cycle number 4 is in a complete remission through metabolic PET. So that’s an N of 1, of course, so I don’t want to amplify that too much, but it was an impressive case nonetheless. And you can see the duration of response curve there on the right.

So what is another agent that is FDA approved in this space is epcoritamab. And a couple differences I’d like to call out is I would call it an upside of subQ dosing, so a little bit faster you could say, not need for intravenous access. That is an upside. Other side of the coin with this agent, it is not time-limited. It is indefinite. But nonetheless, when you look at the data, it is pretty comparable. And so when I say similar, I think effectiveness is pretty similar, more similar than not between these. They also looked at, you can see in the bottom right, in terms of response rate, around 60%, around a 40% CR rate. So both very active agents. We don’t know, as we were speaking to earlier, what about bispecifics versus CAR T? Hopefully, there will be a trial done at some point that makes sense in the right patients at the right time. But impressive data nonetheless. And yes, there is CRS. You can see 51% with this agent. But importantly, the vast majority were Grade 1/2. And I don’t know if it was just the patient population. And, again, this my personal observation that CRS is not that high.

In ours, I’d say maybe one-quarter of patients, one-third. And still most of those are low-grade. Not to say there can’t be severe. Yes, there can. And so, Neil, what we’re, I would say grappling with would be a strong word, but working on is we’re a large service line health system. We have 15 hospitals, 12 adult, 3 pediatric. Obviously, anchored around an academic medical center. And how do we export this to our community providers where some of them are larger practices, 10, 12 oncologists. Others are 1 or 2, jack of all trades, great oncologists. But do they have the support systems? And I don’t mean the local docs, but educating the emergency room what to expect. Do you have tocilizumab on supply? So we’re actively working carefully, but in a forward-leaning fashion to make sure this can be delivered whether you’re at the academic medical center or a community center as well.

So this is another player on the market, odronextamab, as you can see. We actually were one of the worldwide leaders in accrual. Rajat Bannerji who went back to industry was the first author on many of these. And this is another active bispecific antibody. And you can see the cartoon as we had described, the CD20 and the CD3 construct binding to the cancer cell and bringing hopefully the T-cells along with it. So I would say similarly active. I think it’s been a little delayed for unclear reasons. I don’t know how much of it is priority within company. There’s maybe a little bit more, I think, in terms of toxicity. Again, this is my personal opinion, a little more CRS, maybe a little more infectious issues. And I’m just thinking of some of the 30 or so patients we accrued on the initial clinical trials. But I think one that likely will make it to market and will be another one to choose between the others for diffuse large B-cell. And, of course, we’re not talking about follicular lymphoma. I’m sure, Dr Sonali Smith, that these bispecific antibodies as well as CAR T are being used there as well.

So this is, you can see, study design to this study called ELM-1. And this was specifically looking at post-CAR T. And this is where I — this was a few years ago when we were enrolling on the initial study. This is Jennifer Crombie from the Dana-Farber presenting this update. But, again, in post-CAR T failures seeing pretty consistent as the other bispecifics right around an overall response of 50% and a CR rate of 30%. And you can see those CR curves are quite impressive, to say the least. Obviously, we need longer follow-up to measure the durability.

So I’m really happy to talk about a topic near and dear to my heart, Hodgkin lymphoma. And it’ll be a little bit less. We’ll run through a couple pivotal updates that happened in the year 2023.

So we know vis-à-vis ECHELON-1 that brentuximab vedotin used in place or in lieu of bleomycin, so-called BV-AVD, versus ABVD garnered FDA approval several years ago. What we saw last year was, to me, a landmark publication showing an overall survival improvement. And why I say that was landmark is there had never been a study in the history of Hodgkin lymphoma showing an overall survival advantage to classic ABVD. So that was an important breakthrough. And that’s great. So where do we build beyond that? And this is one such study that is looking at untreated Hodgkin lymphoma. You can see in the BREACH study and really showing quite similar robust results in this randomized Phase II study.

But as great of a breakthrough as that was, as with any malignancy, how can we do better? Where can we go to the next step? So this was an important study and a plenary presentation at ASCO last year by my friend and colleague, Alex Herrera, at the City of Hope. A senior author, Jonathan Friedberg. I was the ECOG champion for this study. And it was an intergroup study that not only included, Neil, the adult groups but importantly, one of the first collaborations that also included the Children’s Oncology group. Before this study, we were really on different islands in how we treated it. So after a lot of careful consideration, thought, even negotiation with the COG leader in lymphoma at that time, Kara Kelly, really congealed together to do this study for patients ages 12 years old and above. And the reason I say above, no upper age limit, Neil, is you see with the BV-AVD and nivo/AVD since BEACOPP was not one of the agents, you cannot treat anyone with BEACOPP over age 60. Since that wasn’t part of the equation here, there was no upper age limit. And I’ll mention that specifically because about 10% of patients were over age 60. But it was, as you can see, about 1,000-patient study to BV-AVD. And this study started 5 years ago. So we kind of bought in, as ECHELON-1 as the standard arm, with the new arm being nivo, nivolumab/AVD for 6 cycles for advanced-stage newly diagnosed Hodgkin lymphoma.

And what did we see in the topline results when looking at all patients on the upper left? Now it was only at 1 year. And part of the reason why obviously that’s an early timepoint, but part of the reason this was shown is it was recommended by the SWOG Data Safety Monitoring Board to not stop the study because the study had already essentially finished accrual, was really the surprising results at 1 year. In most studies, at 1 year in Hodgkin, it usually takes 2 years to see a breakthrough difference, but it was already seen at 1 year when looking at all patients, as you can see here, absolute 1-year progression-free survival, 94% with nivo/AVD, 86% with BV-AVD. And with that hazard ratio, another way to say that is a 52% improvement in PFS at 1 year. Of course, we need longer follow-up. That should hopefully be happening any day. And soon thereafter, hopefully being published in a high-impact journal.

Looking to the right of tolerability, that was why in a way it was a double win, at least at 1 year. Not only progression-free survival, and maybe not surprisingly, but generally better tolerated to the point of much less neuropathy, whether motor or sensory neuropathy, less in terms of cytopenias. Although actually, I step back a second. Growth factor was mandated in all BV-AVD patients. So it was different cytopenias. It was only given to half of nivo/AVD since it was physician discretion. And there was a little bit increase in thyroid, TSH levels, et cetera. But interestingly, all the other autoimmune, whether pulmonary, LFTs, or GI, were not different between the 2 arms. So that was important to see.

Well, you could say great, can we start to look at patient subgroups? So Dr Sarah Rutherford who is at Cornell in New York City was the lead author on this study where I had alluded to that about 100 patients were over age 60, so it is a smaller snapshot. But when we look at these 100 patients, so 49 and 48 on the 2 arms, you can see yeah, not only was nivo/AVD the winner at 1 year, it was a pretty big winner in this older patient population. And I think part of it was not just the efficacy, but probably the tolerability of BV/AVD in this older patient population.

DR LOVE: So I’m just kind of curious. I was always curious about why this study with nivo came out so late after we saw the data with BV/AVD and the ECHELON study. Did it take longer to do this study than the ECHELON study? Or it just got started earlier?

DR EVENS: Yeah, ECHELON was started earlier. So E-1, you know, when we were the S1826 means we started discussing this in 2018, Neil. I think the study opened officially not until ’19 or ’20. So in fact, Neil, when we were discussing this study in 2018 and 2019, and that discussion was led by Dr Friedberg and Dr Herrera, the initial 2-year E-1 just came out. And it was very controversial at that time and took a lot of discussion, especially with our pediatric colleagues, to use BV-AVD as a standard arm. There was a lot of discussion, as there should have been, talking about RATHL or just ABVD. So in a way, it was a little controversial because we had just seen the E-1 data at that time. So yeah, this was almost kind of quickly building upon E-1.

DR LOVE: Yeah, I remember that. And it was actually, I think that, even the trial itself being done, kind of encouraged people to do BV-AVD in the clinical practice. But what I was wondering about is, can industry get a Phase III study done faster than a cooperative group?

DR EVENS: Boy, that’s a loaded question. So what I’m going to say is I think it’s similar, honestly. Is it possible due partly to resources and financial constraints where maybe it’s a little more challenging through the cooperative groups? What I can say, Neil, and I’m speaking really for the last probably 6 to 8 years, it is much improved than it was. And this is specifically for lymphoma. We have some great advocates at CTEP and at the NCI. And so, of course, you still have to go through the approval processes. But what I would say is once a proposal is approved by CTEP and NCI, it moves pretty well in the current space. Could it get better? Of course, it can. But I would say in today’s world, once a concept is approved, now that can take a while for a concept to get approved. Don’t get me wrong. That could take a year or longer. But once a concept is approved, it moves in a pretty expeditious fashion. And I think 1826 is a testament to that. The fact that we didn’t start really enrolling in 19 or 20 and we’re already having a plenary presentation at ASCO in 2023 I think in a way is a testament to that.

DR LOVE: For sure. We could talk a lot about this but maybe we will in the webinar. But just one other general question about that. Globally, what would you say right now the fraction of, I don’t know, research or Phase III trials, whatever you want to look at it, being done by cooperative groups as opposed to industry?

DR EVENS: Yeah, I think, and it’s interesting you said that because Hodgkin lymphoma is really unique and I think you know about this global consortium HoLISTIC we have, Hodgkin Lymphoma International Study for Individual Care. The reason we’ve had such success, and by the way, we’re close to 20,000 patients in the consortium and soon to be over 30,000. The reason we’ve been able to do that is the vast majority of front-line studies early stage and not have not been industry. It’s been through cooperative groups whether in the US or England or France or Australia. I don’t know why I think industry had not been interested in Hodgkin lymphoma probably over the years. ECHELON-1 was really one of the first to really breakthrough on that so that’s why we’ve been able to work with these groups. And so with that said, I’m hopeful industry becomes more interested in Hodgkin lymphoma as even though, yes, these cure rates are high, it’s still young patients, there’s subacute and late effects that we see, and we want to continue to replace chemotherapy or radiation with novel targeted agents.

DR LOVE: So yeah, I think Hodgkin probably is a little bit different. I mean, my impression, for example, if I were to ask the same question about Phase III trials in non-small cell lung cancer, I’d say like 90, 95% of the ones I see are through industry as opposed to cooperative groups so maybe that’s different depending upon which cancer you look at.

DR EVENS: Yeah, I think the lymphoma groups it’s just been an awesome collaboration and when I say not just within the US or North America but globally of just really pushing each other to do these studies. If you look at diffuse large B cell, is it 50/50, maybe 60/40 industry to academia? But thankfully, academia still has a thankful big presence whether in the initial diagnosed or relapsed space and hopefully it’ll stay that way obviously in continued collaboration with our industry partners.

DR LOVE: All right, let’s finish out here with your other slides.

DR EVENS: So, more to come on older patients. At ASH as well, there was also a presentation on adolescent young adult patients and so we’ll see more as time moves on. These were the conclusions from the older patient that just like the global patient population, nivo/AVD was better tolerated and we look forward to longer follow-up.

Well, that’s advanced-stage disease. To wrap up, what about early-stage disease and targeted agents? Because right now in the clinic, even in our clinic and most clinics, off of a clinical trial, the standard of care is ABVD and the discussion points are, how many cycles and do I consider consolidative radio therapy? And so we’re very interested to integrate novel targeted agents for early-stage disease. And depending on how you break it down, I’m more of a splitter than a lumper. I’ll think about early favorable Hodgkin like with 1 or 2 sites versus early unfavorable where it might be above the diaphragm but it’s in 6 sites and you treat it similar to an advanced stage patient. This is one such, it’s more of a sequential Phase II studies that have integrated brentuximab vedotin +/- nivolumab. And not surprisingly, as in many Phase II studies in Hodgkin lymphoma, the results look fantastic in terms of overall response and CR rate and the durability looks good as well. And when we look at the nivolumab arm, and again, I think we always have to be careful when looking at a Phase II study in Hodgkin lymphoma, looks really good. And at the end of the day, how are we going to approve this of course is through a Phase III randomized study. And the good news is, we have tackled that within the cooperative groups.

So this is an important study I want to call out to all community partners and really just everybody, Neil, nationally. Please look at this study. It just opened a few months ago called AHOD 2131. And so, adult oncologists do not be scared away by the AHOD acronym. Yes, it’s being led by COG just like they joined S1826, but this is involving as you can see by the pictures here all of the adult cooperative groups as well. And we are looking at favorable early-stage Hodgkin’s, so more limited sites, low SED rate, not bulky mediastinum, or unfavorable. It’s all early stage and, by the way, this is ages 5 to 60 and you’ll see why we had to cap it at 60 in a minute. But what’s great about this study is all patients regardless of study randomization, everybody receives 2 cycles of ABVD, classic dose dense ABVD as you can see. Then a second PET scan is done and then the terminology we’re using here, Neil, is either rapid early response or slow early, rapid meaning a Deauville 3, 2 or 1. A slow early response is like still a positive PET scan. Then there’s a randomization. And just to call out for rapid in favorable, it’s 2 more cycles of ABVD, no radiation, or no more classic chemo, brentuximab/nivo. For slow early responders, it’s 2 cycles of escalated BEOCOPP or 4 of BV/nivo. And the reason you can see here, Neil, this is treating by the best results by the EORTC age 10 showed these results and that is the standard arm versus BV/nivo regardless of slow or rapid response. What about unfavorable? It really is a RATHL type design, so RATHL meaning PET-2 negative for unfavorable, you drop the bleomycin, give 4 more of AVD. And what about slow early response? 2 cycles of BEACOPP or 4 BV/nivo. So what you really see is some nice symmetry is really it’s trying to look at it in a really 50,000-foot level, Neil, is, can we treat all early- stage Hodgkin with only 2 cycles of ABVD regardless of PET response? And then in the experimental arms, all patients received BV/nivo +/- radiation if you’re a slow early responder.

And so we’re really excited about this. You can see it’s a robust enrollment and a kudos to CTEP because, yes, progression-free survival is a critical endpoint but we’re also looking at 12-year overall survival and that takes resources for the NCI to commit to because we’re not — yes, we’re critically going to look at the early progression-free survival but we want to look at those post-acute and late effects that evolve over time.

So just quickly to summarize this study, large study, the primary endpoint I just mentioned is 3-year progression-free survival. We will look at 12-year overall survival. Only very few patients due to randomization and PET scores will actually receive the 2 cycles of BEACOPP, should be around 5% of all patients and hopefully it’ll be an important study. And of course we have a bunch of correlative studies that are embedded, not just metabolic PET, but ctDNA, of course quality of life, and other analyses on survivorship.

DR LOVE: So you maybe have, I’m sure have heard the thought of what’s the best management of this patient or a patient, you know, be in a clinical trial? But this is a situation where really for real, particularly in the community, if I’m a patient, I want to be on this study, not just about what it’s looking at but just to make sure I’m getting managed in state-of-the-art way. I mean, the actual flow that you have here I think would be very reassuring to a general medical oncologists who then deal with this every day that the patient’s going into kind of a platform that hopefully will manage them optimally. I mean, not just for the future but even currently.

DR EVENS: I completely agree. And we have — I think it’s one that — I think there’s just a lot of symmetry to this study, not only because of as I mentioned that the way to explain it to patients is, well, number 1, everyone receives 2 ABVD so there’s that initial symmetry, then you have the downstream randomization, and it’s really looking at continued chemotherapy +/- radiation or novel targeted therapy and trying to be able to do this. So I think it’s one — now someone could say, well gosh, what about escalated BEACOPP? I have no doubt our community oncologists can do it. Number 1, is it harder therapy? Yes, it is. But number 2, it’s only 2 cycles, and number 3, our previous advanced-stage trial under the cooperative groups was 1806 where we gave 6 cycles and they were able to do it. So it’s one that we needed a standard-of-care arm that you don’t want to finish your study and be doubted: “Well, if you didn’t do this, it wouldn’t have beaten this.” So we had to pick the “best outcomes” published in the literature and so we chose, as you can see, what we have here for the standard arm. So it’s a great study.