Introduction: Bispecific Antibodies in Community Practice

DR LOVE: Good afternoon, everyone. I’m Neil Love from Research To Practice, and welcome back to Year in Review, as today we talk about the management of non-Hodgkin lymphoma. We have a great faculty: Dr Stephen Ansell from the Mayo Clinic in Rochester, Minnesota, and Dr Brian Hill from the Cleveland Clinic Taussig Cancer Institute in Cleveland.

Today we’re here to talk about non-Hodgkin lymphoma, and as in all of our programs there will be mentions of the use of nonapproved agents and regimens, so check out the package inserts for more specific information.

So as we do in all of our Year in Review programs I meet with the faculty individually prior to this webinar, and I met with both of our faculty in the last week to record a presentation, and today we’re going to take some of the slides from the presentations and go into more depth about it. But this really is a Year in Review comprehensive review of many different papers. Right now they’re posted in the chat room, and we’ll send out a notice when this program is available. You can check it out there, as well, but this is really a comprehensive review of a lot of papers and presentations. What we’re going to try to do today is get into some of the clinical implications moving forward.

And here are some of the topics that we’re going to go through today. Particularly we’re going to focus on diffuse large B-cell, mantle cell and follicular and a few other relevant topics.

So before we kind of start talking about data, I’m curious — incidentally, we just got back from the Oncology Nursing Society meeting. We always go there. This is the 17^th year we’ve gone to ONS, and we did 11 programs there. But I just want to point out, we did an entire program at ONS on bispecifics in small cell lung cancer. So we’re going to talk about this in NHL, but this is a pretty interesting experience, and hearing about patients treated with a CD3 bispecific who have small cell, of course a very different patient population from non-Hodgkin lymphoma, and really interesting to see these agents starting to come into practice in the community.

So this is a question we actually asked to the audience as part of the premeeting survey, which is — and I’d like to know — I want you to kind of predict, Steve. We said here’s a situation. You’ve got a patient with follicular lymphoma, they’re getting BR, typical first-line treatment, then they get second-line R², and the decisions been made to use mosunetuzumab. And what I wanted to know from the audience is in their practice how would a patient typically get mosunetuzumab. Would they start the therapy themselves? Or would they send the patient to a tertiary center who would start it and send back to them? Or would the tertiary specialists keep it?

Steve, the reason I brought this up is I keep hearing investigators saying that mosunetuzumab is really well tolerated, it’s only given for a shorter period of time, and that it should, at some point, be something that could be given in community-based practice. Do you think that time is now, Steve, or we need to wait a little bit?

DR ANSELL: So I certainly would hope that the time was now, but I think, to be honest, I would predict that the answer might be number 3 here, where partnering up with a tertiary specialist to start in the ramp up and get the tolerability worked out, because subsequent doses would actually be well tolerated, and then the patient would be transferred back to a community practice. But if I was to cast my mind 6 to 12 months down the road that may be different, and I think there’ll be more and more familiarity with this treatment and more and more people likely to manage it in their practice.

DR LOVE: Brian, any thoughts? I guess one of the issues, even though this agent and the bispecifics in general seem to be very well tolerated, but you can see cytokine release syndrome, and I guess one of the issues is that most community-based general medical oncology practices don’t carry tocilizumab. Do you think that’s necessary in order to give these agents, Brian? Is it okay if there’s a tertiary center nearby with an ER that carries it? Any thoughts? And what is the likelihood that a patient on, for example mosunetuzumab, is going to have a serious problem with, for example CRS, or even ICANS?

DR HILL: Yes. These are great questions. I think that mosunetuzumab is well tolerated. It’s all outpatient therapy, there’s this prescribed ramp up, and there’s pretty good guidance about what to do in the event of fever or fever with hemodynamic or pulmonary instability. And what I think the key thing is that if you’re going to be starting this you kind of have to have a plan ahead of time of what are you going to do if there is a fever and it’s after hours, in particular. Even if the oncology clinic stocks the tocilizumab how are you going to get that to the patient on nights and weekends? If you have an emergency department that’s in your practice or referral network how are you going to communicate, especially after hours, if these things happen?

So to answer your question, the rates are low, and you can certainly temporize people with steroids before giving tocilizumab, and the likelihood of having really a high-grade CRS, I think, is not zero, but it is probably less than 5%. This is something that will probably evolve over time.

DR LOVE: So Steve, I know we’re going to talk later, but there are trials now actually looking at bispecifics up front, even combined with chemoimmunotherapy. What do you see in terms of, again, CRS and neurotoxicity when you add in chemotherapy, for example?

DR ANSELL: So that’s actually really interesting, and certainly if you use an antibody-drug conjugate or you use chemotherapy with a bispecific antibody some of those side effect profiles actually become less of a concern, particularly some of the CRS-type symptoms and the like. So actually when you are using additional, shall we say cytotoxic agents, that may actually make administration a little easier. I think one of the challenges is that other toxicities may become a little bit more of a challenge, including let’s say problems with infectious complications because of the fact that you are really effectively depleting B cells particularly.

DR LOVE: So we all predicted that everybody would say 3, but actually a lot of people are saying they would start therapy themselves, so I don’t know. Maybe our group is a little bit ahead of most other general medical oncologists, but that’s what they said. Interesting. We have to pursue that a little more and see whether that’s being reproduced.

Diffuse Large B-Cell Lymphoma

DR LOVE: Alright. So let’s go through some of the papers that you talked about. We’re going to begin with diffuse large B-cell lymphoma. And Steve, you talked about the update that we saw at ASH of the POLARIX study using pola/R-CHP and that the benefit now has continued to be maintained over 5 years. In your talk you go through all the discussion about cell of origin and the question of does everybody benefit. Do people benefit better who have ABC? There was some more data that came out that they included there from a global population.

So just to kind of take the temperature in terms of the 2 of you I’ll start with you, Brian. First of all, can a doc in practice who’s getting a cell of origin study through IHC depend upon it? And are you more likely to use pola/R-CHP in a patient who has nongerminal? Do you think it’s also effective in a patient with germinal cell and should be considered there? Do you think tolerability or toxicity is any different, Brian?

DR HILL: Yeah. Great questions. So the study was designed and prespecified for all comers, and that’s where the benefit was, small but significant in all comers. And in this study, and in a prior randomized trial in the relapsed setting, where pola was combined with BR, there’s a pretty strong signal that the benefit of polatuzumab vedotin is primarily in the activated B-cell subtype patients.

ABC or gene expression typing is something that is not routinely done in clinical practice. The tests are cumbersome and send-outs, but the best proxy we have is the Hans algorithm immunohistochemistry testing, which is pretty reliable and reasonably accurate, and I think there have — at this last ASH Meeting there was some real-world data suggesting that the Hans algorithm may adequate enough.

But to answer your question, in our practice we’re really kind of sticking with the labeled indication, which is for intermediate to high-risk, IPI score 2-5 diffuse large B-cell lymphoma, where you’re using polatuzumab with R-CHP because of the labeled indication, the approval are for that subset of patients.

And to answer your question about toxicity, the febrile neutropenia rate and myelosuppression looks pretty comparable. The neurotoxicity or peripheral neuropathy you see when you swap the vincristine out and insert polatuzumab is pretty similar. So that’s kind of where we’ve landed is sticking with the label.

DR LOVE: So Steve, what about older patients? In the past we’ve used R-mini-CHOP. Should pola/R-CHP be considered with mini-CHOP? Generally how do you approach patients, Steve, that you feel can’t really handle full-dose treatment?

DR ANSELL: Yeah, so I will just say that the original R-CHOP trials were actually done in those over 65. So where they showed that R-CHOP was superior to CHOP chemotherapy was actually in 2 elderly populations. Now clearly elderly is one thing, fragile is a different thing, so I think a lot of this is around not chronological age but biological age. So if you’re a fragile patient I think that does speak to whether you should be getting full-dose treatment.

I think R-mini-CHOP has been a go-to. There’s not been a lot of data around mini-pola/R-CHP, but I think there are some data that suggests that that’s feasible. I think the other thing that we’ve done in some patients is just do a pola/R-CHP but omit the doxorubicin as a way to utilize that regimen. However, I would say that whatever you do to modify the regimen you have to modify your expectations for outcome because clearly you’re leaving out key ingredients of the regimen that would help with good responses.

DR LOVE: Brian, any thoughts about whether in the next few years we’re going to see patients getting CAR-T in this situation maybe who wouldn’t be eligible for R-CHOP?

DR HILL: Yeah. I’m not sure about front-line CAR-T for the R-CHOP ineligible, but what I do think is going to be moving to the front line will be, again, anthracycline omitted regimens. Maybe we use rituximab with polatuzumab and for instance a bispecific. Even though those are so-called chemotherapy free, I think for the fragile elderly they still may pose some significant toxicity challenges.

So this group of patients is out there, the kind of 80- to 90-year-olds or the frail 70-year-olds, and they’re not really adequately met — their needs are not being adequately met by currently available approaches, so it is fertile ground.

DR LOVE: So this is a slide that Steve showed, which he goes through in his talk, but just focusing on the red circle there, second- and third-line therapy, which is increasingly numbers of options available.

And I want to get your take on some of the papers that Steve talked about first. We’ll get into CAR-T and bispecifics in a second. But Steve, of course we’ve had tafasitamab out there for diffuse large B-cell for a while, particularly with lenalidomide, very good outcomes. Also, you talked about loncastuximab tesirine, I call it lonca-T, I think everybody calls it lonca-T, another antibody-drug conjugate, very good results also. What have you observed, Steve, in terms of tolerability issues with lonca-T?

DR ANSELL: So in general the challenge is sometimes I hear is fluid retention, and sometimes additional steroid use can help to mitigate that. I think in general this agent, particularly if effective, you can administer it for multiple cycles. Not quite as well tolerated, I think, as for example agents such as tafasitamab, but certainly, as I say, an option.

I think one other comment to make is brentuximab vedotin in combination with chemotherapy was a bit of a surprise for its efficacy, but clearly antibody-drug conjugates in this space have actually been effective provided you can continue to administer it before toxicities make it limiting.

DR LOVE: And I know they’re looking at combinations with lonca-T as well. Brian, again, any clinical pearls about management of toxicity with lonca-T? What’s your experience?

DR HILL: Yeah. You really have to counsel patients on sun exposure, even something as simple as driving with your arm — with the window down and your left arm getting really exposed, so that’s one. Monitoring the liver function is important. And fluid accumulations can be mitigated by spironolactone, actually, has been used in the studies and is quite effective.

DR LOVE: So in a second I’m going to ask how you might sequence these 3 initial things that we’re talking about here. And Steve, this is a little bit of a surprise that happened at ASH. So B vedotin in diffuse large B-cell, the so-called ECHELON-3 study was presented. Interesting that the control arm was R², but you certainly saw a benefit, including, I believe, a survival benefit as well. Any thoughts about this? Were you expecting this, Steve, and what’s your take on it?

DR ANSELL: So I think the surprise was not necessarily that it was more effective, it was the overall survival advantage. I think that was more surprising than anything, because one thought that you would have other agents that would impact things in general. I think it does speak to the fact that this is a sick population of people where sometimes if disease progresses there’s not all that many options subsequently, and that might impact things. But I think we may not have been quite so surprised, because brentuximab vedotin as a single agent in this space was actually tested many years ago and showed about a 40% response rate, and interestingly that was regardless as to whether there was expression of CD30 or not. So again, exactly how this is delivered to the cancer cell or whether it’s just delivered to cells in the microenvironment I think is somewhat unknown at this point.

DR LOVE: So Brian, any comments on toxicity that is observed or that you would expect with this combination? It kind of seems like it’s — R² has its own issues, and B vedotin has its own issues that we know from Hodgkin’s, et cetera, but they seem kind of like they’re not the same toxicity, but any thoughts about how these 2 are going to play out clinically, Brian?

DR HILL: Yeah. My concern with this is because it’s a little late to the game, and many patients are getting a different vedotin, you’re going to see people getting exposed to the same monomethyl auristatin E payload with polatuzumab vedotin, are they then going to respond to this vedotin ADC? We really don’t know that because the patients in here I think few if any had prior polatuzumab vedotin exposure.

DR LOVE: Yeah. So all the ADC people always argue about why do people become resistant. Is it the target? Is it the payload? I guess it’s kind of hard to determine that, but people usually like to switch things up a little bit.

So Steve, when you look at these 3 options, at least that we’re talking about right now, maybe this may be a patient who’s already had a bispecific, maybe even CAR-T. How would you think about sequencing them? And what kind of patient for which agent, Steve?

DR ANSELL: So I think it’s nice that we have lots of options, and I think if I think about my practice, for me it’s very much about what is the goal and where are we trying to go. So if we’re trying to bridge to something, where we’re trying to get some degree of response, in other words a shorter course of treatment would be reasonable, I think the antibody-drug conjugate or containing regimens are something that I would look to more.

If, on the other hand, I’m hoping to get something I can give for a much longer period of time, I think tafasitamab and lenalidomide is a little better for a longer-duration treatment, and that would be my preference and where I would look.

DR LOVE: Brian?

DR HILL: Yeah. I agree with that. I think you can’t really go beyond 4-6 cycles of lonca-T and also brentuximab, eventually likely to get some peripheral neuropathy. So the challenge with the tafasitamab/lenalidomide combo is for the really refractory patients it doesn’t seem to work as well. So if it’s a later relapse in an elder patient who you think this is their destination therapy, it is a second-line approval and is on guidelines to use in second line, so if you think they can tolerate the lenalidomide I think it’s a reasonable option.

DR LOVE: So let’s talk a little bit about bispecifics. Of course there are 3 that are approved, 2 in diffuse large B-cell, epcoritamab and glofitamab. And Brian, this is a slide that you showed during your talk.

It’s kind of tough for us out there in the real world to figure out when new classes of agents come in how to differentiate them because usually they haven’t been directly compared so you have to indirectly compare them. But of course the thing that really jumps out here, at least in the way they were tested, and I’m not sure exactly why, but Brian, is the question of duration of treatment. So you have glofitamab with a fixed duration of treatment for a year, whereas epco is indefinitely.

Any thoughts about how that factors into your decision about choosing treatment, Brian? And why were these agents studied that way?

DR HILL: Yeah. I don’t know why, and I don’t think it’s anything magical about the drugs. I think it was just the way the studies were written many years ago. And the issue, I think, with bispecifics in the kind of real-world practice, you’re looking at pretty heavily pretreated patients, they’ve often had CAR-T or can’t get the CAR-T, you’re in kind of third or fourth line, it’s an aggressive disease. So to be honest, I’m not really worried about what’s happening a year from now, I’m really worried about can I get this patient into remission now and then a year from now if they happen to still be in remission then we’ll have a good problem to address.

But that being said, we are starting to see patients who’ve gotten into complete remissions, and they’ve been on treatment for a year, and we don’t know yet if it’s safe to stop or not, and I think as we learn more about how these agents perform these will be important questions.

DR LOVE: Steve, how do you decide between these 2 agents?

DR ANSELL: So I think a lot of this comes down to familiarity with an agent at an institution. I think sometimes you kind of just begin to pick your favorite that you like. I think there is a benefit, potentially, for some for a subcutaneous approach versus the intravenous, there may be merit for that.

But I think to the point about duration of treatment there may be some merit to stopping from a perspective of allowing your immune system to recover a little bit, and endless treatment may make more in the way of risk for infections. And I think also when you get to a year, to what Brian was saying, patients — it’s a good problem to have, but they’re getting a little antsy, where they sometimes start to say, “How about could I stop? I’d love to take a break.” So I do think you’re going to see the indefinite therapy molecules be tested, and they are already, in a defined period of time instead of indefinite.

DR LOVE: So in his talk Brian goes through some of the more recent data with epcoritamab, as well as for glofitamab. I think everybody’s familiar with how these agents work.

Anything you want to say, Brian, in terms of response at the end of treatment that you see with glofitamab? And also, you were talking about recovery, but immune recovery after seeing glofitamab stopped.

DR HILL: Yeah. So I think it was on the previous slide we showed at the 12-month mark, when the treatment stops, there is some drop-off in that first between 12 and 24 months after stopping glofitamab. And even those in CR seem to be — there’s some decay of remission, so that suggests that you’re not cured at that point, at least not all patients.

But what is nice, as Steve points out, is that you do see pretty — within 6 to 12 — 24 months you get B-cell recovery, and that’s a concern with ongoing bispecific antibody therapy, is the B-cell aplasia that comes with it, and the infection risk.

DR LOVE: So Steve, Brian also talked about the idea of, as we were alluding to, of combining bispecifics with chemotherapy. And he talked about this paper looking at glofitamab with GEMOX. Any comments on this? I guess one of the issues is it kind of gives you a little bit of an antitumor boost as you’re ramping up the dose. But what are your thoughts about this, Steve?

DR ANSELL: So I think these are really encouraging results. People have always been very concerned about is it a good idea to do something in the way of chemotherapy at the same time as using a treatment that’s trying to get an immunological effect, and I think this, again, just very clearly shows that it’s beneficial to use the 2 together. And I think we’re learning that T-cells are actually quite quick in replenishing themselves and actually may not be a bad thing to have targeted the cancer, which is poisoning the patient’s immune system, to allow some fresh T-cells to show up, which may be immunologically more active.

DR LOVE: So Steve, you also — I mean Brian, you also talked about your own work. I like the title of this thing, the REALBiTE study. We see so many real-world outcomes — datasets coming out in oncology, so helpful to see this. Can you comment on what you saw? The thing that really struck me was this issue of CD20 status, which I’m not sure people have been focused on. Can you go through that, Brian?

DR HILL: Yeah. So this is a large center — 20 centers. We had over 200 patients, and we really just asked the question what happens when patients get bispecifics in the real world. And one of the first things you can see on the left is that if they were known to be ineligible for the registrational clinical trials based on the published inclusion/exclusion criteria for the registrational trials they did worse, but both of the trials for epco and glofit did require CD20 expression. And on this study we did find that a number of patients had biopsies immediately prior to bispecific antibody therapy that did not demonstrate CD20 expression. And as you can see, their PFS and their overall survival actually was much worse.

So I think that this does need to be on the radar screen of clinicians. We are familiar with CD20 loss due to the ubiquitous use of rituximab often in multiple lines of therapy. It’s recycled, and we know that the incidence of CD20 downregulation is somewhere around 15 or 20% of cases. So I think this is important.

And then just one final datapoint. We were able to ask the centers that did next-generation sequencing for those who had a TP53 mutation the outcomes looked pretty good for this treatment that hadn’t been reported before. So it’s encouraging to think that a mutation that we think of as conferring resistance to chemotherapy may not matter as much for immunotherapy.

DR LOVE: Yeah. The TP53 data is really interesting. Steve, do you check CD20 levels? Do you think people should do that as a standard?

DR ANSELL: Well, to be honest, I think our pathologists very commonly have that in their biopsy analysis, and IHC panel, when they do an analysis of patients. So I think we get that report, but I do think based on this data and some other data that I think looks similar, I think it is important if you’re going to pick a target and then not have the target present I think you might consider other options.

DR LOVE: A question from the chat room, Brian, from Kamal. Relapsed lymphoma with leptomeningeal disease. Any preference for epco versus glofitamab? And in general how do you manage that situation, Brian?

DR HILL: Yeah. I mean CNS relapse is always hard. I think if the patient can go through high-dose methotrexate or cytarabine or other blood-brain barrier-penetrating therapies or an autotransplant that’s kind of the preferred road to go down. In this study we had I think 5 or 6 patients with CNS involvement and none of them responded. So that’s small numbers, but it think more to come on whether or not bispecifics can help patients in that situation.

DR LOVE: So there wasn’t a whole lot new, at least at ASH, in CAR-T, Steve, but one thing that was interesting was a new, unapproved CAR-T product, rapcabtagene autoleucel that was presented at ASH. And the thing that was really interesting there is apparently this is prepared in 2 days.

So I’m just kind of curious, Steve, and we’re just — this is just a Phase II study, 88% response rate, very encouraging. Typical profiles in terms of ICANS and CRS from what I can see. I guess this platform, I don’t know how they do it, a 2-day T-Charge platform. How much of a problem is the delay, Steve, in terms of — particularly in terms of progression of disease? And any thoughts about this? And I guess there are other attempts to try to shorten this time.

DR ANSELL: Yeah. So I think there are 2 reasons to shorten the time. The one is obviously the delay to actually treating a patient, and if you have very aggressive disease relapse, the longer it takes, obviously, the patient requires bridging treatment. And some of the bridging treatments are not always that favorable for the patient's outcome subsequently, and to be frank, the fact that you needed to give the bridging therapy is already a challenge.

But the other thing that I think is interesting here is long time of stimulating the cell and making the CAR T-cells actually induces more immune exhaustion. So one of the potential things here is that the short duration of developing a CAR-T may actually allow that CAR-T to be more immunologically younger or more healthy, if you like, which potentially could result in better results. And I think the results from this trial were actually quite good. Whether it’s better than a standard CAR-T I think we still need to see.

DR LOVE: Brian, anything you want to add to that?

DR HILL: Yeah. I agree that the manufacturing time is still a problem, and sometimes you don’t find out for 2 weeks that actually there was a manufacturing failure. So if you have a manufacturing time of 2 days you’ll have your answer quickly, and you can move on if you need to make arrangements for repeat leukapheresis, for instance.

CD19, CD20 or Both? AZD0486 Bispecific Antibody

DR LOVE: So I was actually — I didn’t tell you this, Brian, but when you were presenting this next paper I was thinking of When Harry Met Sally, the scene when somebody else goes “I’ll have some of that.”

DR HILL: Oh, yeah.

DR LOVE: When I heard you say this, I’m like “I’ll have some of this.”

DR HILL: Yeah. “I’ll have what she’s having” or something.

DR LOVE: So wow. Yeah, “I’ll have what she’s having.”

DR HILL: Yeah.

DR LOVE: So tell me about AZD0486, pretty interesting.

DR HILL: Yeah. I mean, again, it just shows the number of ways you can put together targets and mechanisms. So if CD19-directed CARs work, and if CD20-directed bispecifics work, why not make a CD19-directed bispecific? And that’s what this is.

So the step-up dosing should look familiar by now. This study was a Phase I with multiple different cohorts and different step-up doses. But what we saw. This was the — I think this is the follicular lymphoma cases that really the waterfall plot was pretty remarkable, overall response rate of 95%, CRs of 85%, so that’s really eye popping. And sometimes you don’t know if that’s going to hold up in future trials, but I’m aware that this is going to be further developed hopefully very quickly.

DR LOVE: So again, Steve, any thoughts? And also the issue of, again, sequencing, mechanisms of resistance. First of all, that’s a great waterfall plot, but it seems logical that it would be great to have a different target that you could switch to. Any thoughts about these data and where you think it might lead, Steve?

DR ANSELL: So I do think it’s great to have another molecule. This one also, if I remember correctly, is interesting because it has a low affinity binding to CD3, which may actually decrease the CRS issue that we spoke about before. So that may also give it — and maintaining the merit and the benefit of it. So I think that’s an additional potential plus.

To your point about sequencing, though, it’s going to be a little challenging sometimes if someone’s had a CAR-T, where they’re going right onto CD19 immediately post-CAR-T, particularly if it’s a CD19 CAR-T, is going to be your best strategy. But alternatively, if you’ve gone after a different target, this may be a very viable and very important thing to consider subsequently. And then also, as we’re learning in follicular and other diseases, we may hold CAR-T cells a little more in reserve so then this may be a good option earlier in the disease course.

DR LOVE: So to be continued, but it seems quite interesting.

Mantle Cell Lymphoma

DR LOVE: Let’s move on to one of my favorite topics in oncology, mantle cell lymphoma, particularly up-front treatment. And Steve, you went through the recent history of this. It seems like it’s been years, but actually a lot of this is in the past year, beginning with the famous, or infamous, TRIANGLE study. Steve, I think everybody in general has heard about this and the fact that it really raised the question of whether transplant or even intensive chemotherapy is indicated, something that’s been for a long time in younger patients. Anything you want to say about this study and some of the talk you’ve heard about this study and what the impact has been from what you’ve been able to observe in your own practice and in your colleagues, Steve?

DR ANSELL: So I would say that this study has turned out we manage mantle cell lymphoma on its head. I think in the past we always did the young patient gets an intensive treatment and then intensify it further with an autologous transplant and then use rituximab maintenance. Now I think we’re looking at a BTK inhibitor in the induction and consolidation, or maintenance phase, and most people are moving away from doing an autologous transplant. And that was further confirmed by the ECOG study, which showed that if you were MRD-negative there was no merit to doing an autologous transplant. So I think most transplanters are actually seeing the number of patients with mantle cell lymphoma considered for a transplant drop off substantially, and in our practice I think we’ve almost gone to next to nobody getting a transplant.

DR LOVE: Brian, anything you want to add to that? And also, this issue of MRD, could you see intensification of therapy in patients who are MRD-positive? In general, maybe not just in mantle cell, but in NHL in general, as we’re talking about it today, do you see MRD coming into clinical community-based practice in the near future?

DR HILL: Yeah. What was interesting in the ECOG trial was that so many patients with standard — whatever they got as their induction the MRD rates were high, 70 to 80%, which is really nice to see, and the test was reliable. In terms of the outcomes there were some patients who did get autotransplants for MRD positivity at the end of induction, and a subset of those people did convert to MRD. But again, it doesn’t really ask the question whether they would have been just better of going on a BTK inhibitor, which has become our practice. So I love the technology of MRD. I think in a practical sense we don’t really need to know what the results are because really everyone should just get a BTK inhibitor in lieu of transplant, in my view, based on these data.

DR LOVE: So speaking of trials that change practice, I guess in this case it changed it by cutting out something we’re doing. But this trial presented at last year’s EHA meeting by Dr Michael Wang from MD Anderson of acala and BR seems to have changed practice in general. Steve, can you talk a little bit about the design of this study, what they saw, and what you think it means?

DR ANSELL: So I think this was an elderly patient study. Patients got bendamustine/rituximab either with a placebo or with acalabrutinib and then received acalabrutinib, and you could add maintenance rituximab to that for the long term afterwards. The outcomes showed that there was a progression-free survival advantage for receiving acalabrutinib plus bendamustine and rituximab. And to what Brian was saying, that actually has become now, even though this study was specific for elderly patients, many of us are adopting this for younger patients because BR results were pretty good already in the past, and now with acalabrutinib even better, and then using a BTK inhibitor with rituximab as maintenance and no transplant is actually becoming the go-to regimen, certainly, in my practice.

DR LOVE: So of course here is the data in terms of PFS. But also, Steve, you talked about subsets and what they saw there. Can you comment on that?

DR ANSELL: Yeah. So this was really just to what Brian was saying about MRD positivity versus negativity, and if you just look at the little purple group in the second column in each of the circumstances, these are the people that kind of remained MRD-positive at the end of 24 weeks. And you can see that’s a very small minority in the patients that got acalabrutinib plus bendamustine/rituximab compared to the placebo/BR, which is more. But to what he said is that’s still in the 70-something-percent range, the patients are MRD-negative. So it’s an effective therapy, bendamustine plus rituximab, made even more effective then with the addition of acalabrutinib. And the acalabrutinib maintenance, I think, really helps for that to be sustained.

DR LOVE: So I guess another question is do you need the bendamustine. And Steve reviewed a paper looking at BTK/rituximab, in this case ibrutinib, in the so-called ENRICH study. Very encouraging results.

But we’ve also seen data with acalabrutinib and rituximab. Again, this is from the ASH Meeting, Dr Jain. Pretty good-looking Phase II study, but you can see there on the right the PFS, a pretty straight line there.

Brian, any thoughts about whether or not we can just go with a BTK? I mean, theoretically I know I’ve talked to Dr Wang. He thinks zanubrutinib might be also equally effective, although I think they’ve looked more at acala at MD Anderson. But what about this strategy, Brian? Is it ready for prime time now or maybe in a little bit?

DR HILL: I think it’s ready for prime time now in patients with TP53 mutation, where we know that the cytotoxic chemotherapy is adding basically toxicity without benefit. And so we have different combinations. You can use BTK with rituximab. I think there’s the BOVen regimen, which maybe we’re talking about later, which is to use zanubrutinib with venetoclax and obinutuzumab, a triplet for that group. But for the garden-variety non-TP53 mutated, right now in 2025 our practice is still to use bendamustine as long as patients can tolerate it. But for the frail, elderly or the TP53 mutated going straight to a BTK inhibitor, I think, is perfectly reasonable.

DR LOVE: So Steve, what about bringing in venetoclax? This is another study from Dr Wang looking at acala/ven and rituximab. Of course, we just saw the big AMPLIFY study in CLL, time-limited acala/ven that maybe is going to become first-line therapy. And also Brian mentioned the BOVen study out of Memorial. There they’re using zanu/obin, interestingly, and venetoclax in high-risk p53-positive. Very encouraging results.

Again, Steve, any thoughts? We also saw a paper in relapsed mantle cell looking at BTK plus venetoclax, in this case ibrutinib. So Steve, again, is venetoclax ready for prime time up front outside a trial or maybe in a while?

DR ANSELL: So I’m not sure that it’s ready for prime time up front, but I think certainly in second line that’s a very reasonable — or third line, very reasonable option to consider. I do think that clearly the combination of another agent, be it a CD20 antibody or be it venetoclax, with a BTK inhibitor increases the response rates and the durability of those responses. So I think we’re learning a lot from CLL because a lot of these trends are following what we’ve done in CLL, and I think we’re probably going to be even doing more time-limited kind of therapies in this space as we kind of move forward. But certainly these results make a strong case for the fact that the chemotherapy component is kind of dropping out of necessity.

DR LOVE: So I just report what people say to me, but sometimes I hear some pretty interesting things, Brian. And I mentioned the fact I always love talking to — this is Dr Michael Wang that we just talked about from MD Anderson. I always love talking to him. He’s of course the maven of mantle cell, but usually a couple years ahead of the rest of us.

But I mentioned that we were just at the ONS meeting, and we did a program on lymphoma, and we had Chris Flowers there. I just want to show you a very brief interchange we had related to Dr Wang and up-front treatment of mantle cell.

DR FLOWERS: This has really changed the landscape for patients with mantle cell lymphomas. Ever since I came to MD Anderson in 2019, we've not really used chemotherapy for patients with mantle cell lymphoma. About 60% of our patients go on a clinical trial, so they're on studies like this that Michael has led, looking at here, the combination of acalabrutinib and venetoclax and rituximab.

Now we've moved on to pirtobrutinib, venetoclax and obinutuzumab as combination trials that we're doing for high-risk patients. And then other trials like the one that you saw from Preetesh Jain, his colleague at MD Anderson who led the work looking at acalabrutinib/rituximab, which has really become our standard of care for older patients with mantle cell lymphoma.

DR LOVE: So Steve, he says at MD Anderson they’re not using chemo. Any thoughts?

DR ANSELL: So I think, again, Michael has kind of led the field, and I’ll give him kudos to say that because of that we’ve kind of learned a lot from him over time. And I would say that if we look at what we’ve learned so far in the front line this intensive chemotherapy is clearly not necessary. We just discussed whether we really need bendamustine in front line. I guess there’s some questions, and if you just see the data we spoke about in second and subsequent lines there’s not a chemo agent in that combination. So is chemo really necessary? I think you could make the case that it’s not clear.

DR LOVE: So one final question back to you, Brian, in terms of mantle cell. We hear about TP53, high Ki-67, blastoid histology, other adverse predictive factors, how adverse are they with the typical therapies? And nowadays how are you managing these patients?

DR HILL: Yeah. Definitely blastoid is still bad no matter what you do. I don’t know that the novel agents have solved that problem. TP53, if it’s a normal histologic appearance, I think we are kind of able to overcome that high-risk feature by using the targeted agents. And then of course in the relapsed setting if they don’t get — if they’re not chemotherapy candidates because of TP53 you still have CAR-T as a subsequent line of therapy, which probably overcomes some of those high-risk features.

DR LOVE: And that does lead to the question of patients with relapsed disease, Steve. So of course bispecifics, right now there’s nothing approved, but we do have some data looking at it. It looks like it responds. I mean, if you give acala/BR first line, Steve, for eligible patients, is CAR-T next? And how do you get them there? How toxic is CAR-T? Do you see bispecifics coming along and maybe nudging CAR-T away the way it has, from my point of view, from what I’ve seen, in follicular lymphoma?

DR ANSELL: So I think it’s certainly a consideration. I think, to be frank, we’re more likely to use a CAR-T in a third-line area unless the patient has very aggressive disease, rapid relapse, and particularly, as Brian was just saying, if they have blastoid morphology or one of those, I think those are patients where would consider it.

And to your question about toxicity, high numbers of circulating cells are always challenging because those patients do have more toxicity. They actually have more toxicity from bispecifics, as well, so that remains a challenging circumstance. If there are ways to decrease the bulk of disease I think that does also make it a little easier to administer the therapy.

DR LOVE: Brian, what about pirtobrutinib? How long are the responses you see from this agent? Can they maintain patients for a couple years?

DR HILL: Yeah. Pirtobrutinib, for those who aren’t familiar, is a noncovalent BTK inhibitor that is very well tolerated and very active in CLL. Patients who’ve failed to have a durable response to covalent BTK inhibitor, so there’s a classic mutation in cysteine 481, which confers resistance to the covalent BTK inhibitors like acala and zanu, and pirtobrutinib works very well for those.

Mantle cell is a little more complicated. The resistance mechanisms are not as perhaps straightforward, where they’re typically in BTK or PI3 kinase in CLL, you see different patterns in mantle cell. And although pirtobrutinib is well tolerated and has reasonably good response rates in mantle cell lymphoma, the durability is not overwhelming, and it seems that I view it more of a bridge therapy that we’re using as we’re lining up hopefully CAR-T or a clinical trial or something else.

DR LOVE: So Steve, Ibuka in the chat room is asking about skin rashes on acalabrutinib. Do you switch to zanu? But do you see skin rashes with acala, Steve?

DR ANSELL: So again, I would say I haven’t seen that to be a substantial challenge. I’m sure there are some patients that get that. I’ll be honest and say that zanubrutinib is the agent that I would use more, and I have limited experience with acalabrutinib. I’m not sure that automatically switching to a different BTK inhibitor, I think it’s worth a try, I don’t know that it’s necessarily going to mean that those issues are resolved if it was in any way BTK associated.

Brian, I don’t know if you’ve had experience with a lot of rashes.

DR HILL: Yeah. Actually, between the 2 I think that the rash is more common with zanu. Certainly any drug can cause rash, but it’s not a common toxicity that we see with acalabrutinib. We’re more familiar with the headache that’s fairly common but manageable. So overall I think they’re both pretty well tolerated, and when I have had rashes with one, and if I think the patient’s responding, then I will often switch just empirically and often do see resolution of the toxicity, including rash.

Follicular Lymphoma

DR LOVE: So let’s talk a little bit about follicular lymphoma. I was just mentioning we did this 2-hour program just on relapsed follicular lymphoma, if you can imagine we can talk about that for 2 hours, but we did, and it was all really interesting, including a couple studies that you talked about, Steve, that I don’t know, I was kind of surprised. We mentioned tafa in diffuse large B-cell, and then boom, all of a sudden it pops up with follicular being added to R². And they had pretty impressive results, as you go through in your talk.

The other surprise to me is, again, I always associated lonca-T with diffuse large B-cell, but here we saw data with follicular that also looks pretty encouraging.

Steve, any thoughts about these 2 agents in follicular?

DR ANSELL: So I think one of the things that’s always encouraging about follicular lymphoma is that it’s very typical that patients will benefit and respond to many agents. And I think, again, these are 2 agents where we see either on their own or in combinations we see really high response rates.

I think what’s also encouraging is that the responses here look quite durable, and I think the point being with loncastuximab tesirine that it’s how well tolerated it is — how well tolerated is it if you keep going for a long period of time. I think that’s a bit of a challenge sometimes. I think the tafasitamab with R² the results actually are good because R² is a very standard approach, and tafasitamab added to that, I think, is a logical combination and again with pretty good efficacy.

DR LOVE: So let’s talk about — I’m sorry. Go ahead, Brian.

DR HILL: I was just going to say that it really shows that, again, you’re talking about 2 agents targeting 19, CD19, in lonca-T and tafa, and really revealing that the data with lonca-T and rituximab are pretty spectacular. And then the data of adding tafasitamab to R² really shows additive benefit. So multiple targets and in both cases not really excessive toxicity.

DR LOVE: Steve, also, we didn’t talk about it, but there was a paper at ASH looking at zanubrutinib with obinutuzumab, again a little bit of a surprise. I kind of have never really figured out whether BTK fits into lymphoma, but then all of a sudden — I don’t how much of it was the obinutuzumab. Any thoughts about that combination, Steve?

DR ANSELL: Yeah. So I think that, again, was really encouraging data and a little bit different to what we had seen with BTK inhibitors in follicular lymphoma in general. I would, however, say that initially when the studies with BTK inhibitors were done, I think the expectation was that it was going to be highly effective in follicular lymphoma, and I think many of us were surprised when it was a little less effective. But clearly when you modulate the environment within the tumor using an antibody targeting CD20 you may well change things and allow for BTK inhibition then to actually have additional benefit. So I think all of this is just to say that that is really encouraging progress in follicular lymphoma and hopefully will actually result in something that we can continue to build on.

DR LOVE: So Brian, back to bispecifics. I was just flashing. This morning I was working with Dr Harrison for the myelofibrosis program next week, and she told me about a CD30 bispecific to CALR in myelofibrosis.

DR HILL: Wow.

DR LOVE: There’s also an antibody to CALR. I don’t think there’s any data on any of these things.

DR HILL: Yeah.

DR LOVE: Bispecifics are popping up all over the place where you wouldn’t expect it. But let’s talk about in follicular lymphoma starting out with mosunetuzumab that we talked about earlier in terms of who or how it can be given. Anything you want to say about what patients go through with these 2, and epcoritamab also?

And also, we didn’t say too much about odronextamab, which is not approved in the United States, although it is approved in Europe, Brian, and whether you see that also coming onboard in the United States. The data kind of looks pretty similar.

DR HILL: Yeah.

DR LOVE: So any general thoughts about that, Brian?

DR HILL: I mean, the general thoughts for follicular lymphoma is that we do now have 2 approved agents with mosunetuzumab and epcoritamab. Both look like they give very high response rates, high CRs and pretty durable responses.

As far as odronextamab goes, it’s not yet FDA approved in the United States. It’s probably coming. It’s not clear that it’s superior in any way, but it’s something that’s probably going to continue to crowd the landscape in the not too distant future. I think this data is really interesting, to see those MRD-negative patients have really spectacular results on the far right.

DR LOVE: So we’re going to get into CAR-T in a second, but Steve, anything else you want to say about bispecifics and what patients typically go through and for the mosunetuzumab how long their on treatment?

DR ANSELL: Yeah. So I think in general once you’ve managed the initial kind of few weeks I think patients actually will tolerate it pretty well. I think in general the challenge is just that when you get out many months patients find it a little frustrating, especially in our practice where they often are coming from a substantial distance to receive treatment. And that’s, again, to the point we made right in the beginning, partnering with practices closer to home is kind of one of the things that’s really important.

And then I think, obviously, monitoring for infectious complications over time because I do think that’s one of the things that impacts patients a lot. And I think that’s really relevant in follicular lymphoma. If you look at patients that do well for a 2-year period, the POD24-achieved patients, the people that don’t progress, those people have a similar outcome to the national average. So you want to be a little careful not to hurt them with a lot of infectious problems, which may shorten their lives, when the outcome was actually going to be very good.

DR LOVE: So Brian, what kind of infections do you see specifically in this situation? And what about response to vaccines?

DR HILL: Yeah. So the most common types of infections we see in the kind of B-cell-depleted patients after CAR-T or bispecific would be prolonged sinus — sinonasal kind of infections that just linger and linger and require multiple rounds of antibiotics. But we’ve also seen CMV reactivation and other viral reactivations. So it’s not a trivial consideration, and of course we are talking about often patients who are elderly, maybe in their 60s, 70s, have comorbidities and often have had prior exposure to chemotherapies, so it had the cumulative effect of really sometimes years of immunosuppression, which can really have a negative impact on patients’ quality of life.

DR LOVE: So let’s talk a little bit about CAR-T in follicular lymphoma. Steve, again, we’re talking about follicular, not transformed disease here. And Brian went through the data with liso-cel, where you see the TRANSCEND 2-year follow-up data, pretty encouraging. Also with tisa-cel, again, the ALARA study, again seeing good effects in terms of progression-free survival.

Steve, can you talk a little bit about first of all how often you use it, how many times in the last year you’ve sent a patient with FL for CAR-T, and what your preference is in terms of the specific type of CAR-T?

DR ANSELL: So I do think these CAR-Ts, particularly the 2 you highlight here, have a slow activation because of the 4-1BB activation motif, so I think that’s a good thing because I think the very rapid progression — or activation obviously puts patients at a risk for more toxicity, so that’s actually something that’s well tolerated, or reasonably tolerated in this circumstance.

I will say though that if I look at who we are considering for CAR-T for follicular lymphoma, I think it’s those patients that we really struggle to get into a good remission, and we’re seeing progressing kind of right off the bat with therapy. Patients that have a very good response to the first line and then a very good response to a subsequent line, as you pointed out, it’s a crowded space with lots of active agents. We tend to be a little less likely to reach for CAR-T in the responding and durably responding patients. So it’s really those patients with aggressive-behaving CAR-T — aggressive-behaving follicular lymphomas that we would give CAR-T to.

CAR T-Cell Therapy for Marginal Zone Lymphoma

DR LOVE: So one final point, and this is about marginal zone lymphoma that Brian brought up in his talk. It sounds like there was a press that came out in February looking at liso-cel in marginal zone lymphoma that looks positive. I don’t know. Maybe at next year’s Year in Review we’ll be reviewing the data from that one, Brian. But any thoughts about where this is going to fit in in terms of marginal zone lymphoma, Brian?

DR HILL: Yeah. Similar to Steve’s point about FL, I think marginal zone tends to be indolent, tends to do well, but when it doesn’t it can go south quickly. And we do see patients, they are behaving as if they’ve got a transformed aggressive large B-cell lymphoma, and you get biopsies, and you can’t really prove it, but it just feels that way; short remissions, inadequate response to therapy. And right now, actually, despite all of the things we’ve been talking about, there is no approved CAR-T available for marginal zone lymphoma.

So I think we’ll probably see this sometime this summer, and when we see the data, if it’s good enough to get an approval, that would be a really welcome thing for patients with this disease.

DR LOVE: Steve, anything you want to add to that?

DR ANSELL: No. I think it’s exactly right. We’d love to see an additional tool in the toolbox for marginal zone lymphoma, and this would be a very valuable asset, particularly for those rapidly early-progressing kind of patients.

DR LOVE: So Steve and Brian, thank you so much for working with us today. We all learned a lot. Thanks to everyone for attending. Be safe, stay well and have a great night. Thanks so much, Steve. Thanks so much, Brian. Have a good one.

DR HILL: Alright. Thanks so much. Take care.

DR ANSELL: Thank you.