Introduction: Overview of Bispecific Antibodies and Chimeric Antigen Receptor T-Cell Therapy for Non-Hodgkin Lymphoma

DR LOVE: Good evening, everyone. I'm Neil Love from Research To Practice, and welcome back to “Understanding the Current Paradigm and New Approaches in the Care of Patients with Cancer.” This is our 11^th and final program here at the ONS Congress. This is the 17^th year we're here, and we've had a fantastic week.

Tonight, we're going to close out with a topic of non-Hodgkin lymphoma. We have a great faculty this evening: Ms Robin Klebig from the Mayo Clinic in Rochester, Minnesota, Ms Caitlin Murphy from the Dana-Farber Cancer Institute in Boston, Dr Chris Flowers from The University of Texas, MD Anderson Cancer Center in Houston, and Dr Manali Kamdar from the University of Colorado Cancer Center in Aurora, and thanks for the great weather here, Manali.

As always, for all of our programs, we will be talking at points about the unapproved use of agents and regimens, so consult the package insert for more information.

We are recording all of these programs, and we'll let you know when they're ready for your colleagues who are not here tonight. And also we just recently launched a podcast, Oncology Nursing Update. We're going to put all 11 of the programs on this podcast feed over the next couple of weeks. Just go to podcast on your phone, hit search, type in Oncology Nursing Update, and follow us. We'll be putting a bunch of programs on this year, including Ms Amy Goodrich talking about bispecifics, something we're not going to talk about, but that was an hour just with Amy to talk about bispecific antibodies; CAR-T, another topic that we're talking about.

This is the 50^th anniversary of the Oncology Nursing Congress here, and when we arrived here, we had kind of a special welcome for them, and I thought just to close out tonight — I actually sent this to my daughter on her 50^th birthday. You can see what kind of father I am. So here's our 50^th welcome to the ONS.

MOLLY SHANNON: Ladies and gentlemen, my name is Sally O'Malley. I'm proud to say I'm 50 years old. I'm not one of those gals who's afraid to hide her age, unlike some other gals, and I like to kick, stretch, and kick. I'm 50, 50 years old, 50 years old, 50, 50.

DR LOVE: Like I said, we like to have a good time. This has been a great experience, going through these 11 programs. And we try to even go beyond the topic and try to get more into the general themes in oncology, nursing in general. We're really here to make rounds with our faculty. It's just such a pleasure and honor to have these 44 people come here to Denver and join us on the stage, and we're really looking forward to hearing what our faculty has to say tonight about non-Hodgkin lymphoma.

Here's where we're heading tonight. Usually when we do programs on NHL we spend most of our time, if not all of it, talking about bispecific antibodies and CAR-T therapy. That's the subject of our podcast that we just launched. But tonight we're just going to briefly talk about it and get into some other issues, and then we'll get into talking about mantle cell lymphoma, diffuse large B-cell lymphoma, and follicular lymphoma, the 3 major forms of non-Hodgkin lymphoma, and particularly what’s new and exciting.

Let's start out a little bit, just by way of background in terms of bispecific antibodies. So Manali, can you talk a little bit about what a bispecific is, particularly these CD3 bispecifics? What was it, Thursday morning, believe it or not, we did a program and the only thing we talked about was the use of a CD3 bispecific in small cell lung cancer, if you can imagine that. So anyhow, Manali, can you talk about what a bispecific is?

DR KAMDAR: Sure. So good evening, everyone. So the mechanism of bispecific antibodies rests on the fact that it's basically an antibody with 2 prongs. One prong sits on the antigen of interest. And lymphomas, right now we have CD20 bispecific antibody. So 1 prong sits on the CD20 antigen on the lymphoma, and the other prong basically brings the T cell, the patient's own innate T cell, close to the lymphoma cells and targets it for destruction. So it's an off-the-shelf antibody, doesn't need any manufacturing in vitro, which is a distinct difference from CD19 CAR T-cell therapies. These have definitely made huge advances in non-Hodgkin lymphoma so far.

DR LOVE: So Chris, we now have 3 approved in the United States, bispecifics approved, and 1 more, odronextamab, approved in Europe, and probably going to end up getting approved here. They're very similar in terms of their action, very active in terms of antitumor effect. We'll talk in a second about the side effect issue. Anything you want to say about sort of where these agents are used and their effectiveness?

DR FLOWERS: Yeah, thanks, Neil, for the question. But before I jump in I want to first make a comment about ONS in general, and I think it's so great to be here back at ONS again for the 50^th celebration, particularly great to celebrate with 2 nurses that first started off with me, Lisa Anderson and Lisa Jackson, who are here in the audience, and started with the start of my career.

To get to your question, Neil, when we really think about — thank you both. I probably wouldn't be here without you. So I think when we think about —one of them will at least say that for certain, that I wouldn't be here without her. When we think about the bispecific antibodies in this particular situation, these are antibodies that have been targeted against CD20 and CD3, as you just heard about, that are applicable really broadly across B-cell lymphomas, but most specifically in follicular lymphoma and diffuse large B-cell lymphoma. These seem to be a class effect, and if you look at the Phase II trials for these agents, which we really shouldn't cross-compare Phase II trials, but the response rates look to be fairly similar, and the progression-free survival looks to be fairly similar across these agents. And so I suspect that the outcomes that we will see for these agents differ really only in terms of the ways that they are administered, and in the ways that patients might experience side effects.

DR LOVE: So Caitlin, I'm curious what you observe in terms of response. Do most patients respond? When do they start responding? What have you observed?

MS MURPHY: No, I think this is a really exciting therapy because we do see a really great response, and we see it relatively early on in their therapy profile. So we're seeing responses within the first couple of weeks and months of their therapies. And I think that they're generally pretty well tolerated. There's some caveats around fatigue that I think we notice pretty significantly and from an infectious standpoint, but these are therapies that they can receive in the clinics, and I think that that is a huge game saver for them when they're thinking about their quality of life. But these therapies are quite exciting, and they respond quite well.

DR LOVE: So Robin, you were also on our podcast series talking about bispecifics as well. Anything you want to say about your experience with these agents, again, their efficacy and how patients tolerate them in general.

MS KLEBIG: It has been really exciting in people who have not responded to other therapies. And I think on the podcast I talk about somebody who was about to go into hospice, and we said, well, there's 1 more thing we can try. And now it's just so rewarding to see them actually respond and be able to live their life. And they are really well tolerated. As you mention, there're some caveats, especially with the first cycle. And when they get beyond cycle 2, the CRS and neurotoxicity is less of an issue. So it's just been really, really fun to see this as part of our treatment portfolio now.

DR LOVE: So Manali, actually preceding the bispecifics, and really similar kind of therapy, but of course, bispecifics are "off-the-shelf," whereas CAR-T that precedes it, particularly dramatic responses in diffuse large B-cell lymphoma, where you actually see people who seem to be cured. Can you talk about sort of what CAR-T is, and how it's done?

DR KAMDAR: Sure. So CD19 CAR T-cell therapy is currently FDA approved in diffuse large B-cell lymphoma in the third-line space, because there is about a 40% chance of cure. And in the second-line, high-risk relapsed, refractory diffuse large B-cell lymphoma, where it's really dethroned autotransplant, and now in that setting, we have a 55% chance of cure. So it's a curative treatment in a highly aggressive lymphoma.

The bane of CD19 CAR T-cell therapy really exists in the manufacturing, and the time it takes to get to CD19 CARs that are manufactured. Simply put, this is basically getting a patient on apheresis, which is collecting some blood from them, taking it to the lab, isolating the fighter cells, which are the T cells, and then genetically modifying them to making them super fighter cells. Think of it as a T cell with an antenna, which can now recognize lymphoma cell is a foreign entity, which otherwise they have forgotten to do when they were innately present in the human body.

Now this manufacturing could take anywhere from 17 days to about 22 days based on the product you choose. So currently in the third-line setting, we have axi-cel, tisa-cel and liso-cel. Clearly the cancer's not waiting while the CARs are being manufactured, and that is really what is, when I say bane, because we have to think of ways to stabilize the patient, basically their tumors, so that we can get them to CD19 CARs. After the CARs are manufactured, we typically give them low-dose chemo treatments consisting of fludarabine and cyclophosphamide. These are not necessarily meant to kill tumor. If they do, that's great, but they're primarily meant so that the CARs can home in the marrow and start doing the job that they're meant to do, which is attack the tumor.

And then once day 0 hits, after LD chemo is given, which is exceptionally well tolerated after day 0, we then monitor the patient for about 14 days for unique CAR-T-related cytotoxicities, such as CRS, cytokine release syndrome usually in the first 7 days, and then ICANS or neurotoxicity in the second half, so day 7 through day 14. And based on the CAR T-cell therapy that you use, based on the expansion profiling, for example, CD28 CARs, which are the axi-cel CARs, we typically see a huge rush. As a result, there is a higher incidence of CRS and ICANS, and that's not typically seen with 4-1BB CARs, which are tisa-cel and liso-cel. But after the first 14 days, it's usually pretty good, because after that, patients are monitored in the outpatient setting.

DR LOVE: And Chris, of course this is sort of a one-and-done therapy, whereas bispecifics usually is longer term, although many of those are stopped as well. One of the themes that we've talked about all week and that you see throughout oncology is having multiple similar agents within the same class, but not having clinical trials comparing to, so we have to indirectly compare.

Here are the CAR-T therapies that are available, including brexucabtagene, very similar to axi but used in mantle cell. From your point of view, when you think about these, what are the differences indirectly? Which one would you pick for a younger, healthier patient? And these patients can receive these who maybe wouldn't even be eligible for an autologous transplant, older patients. What type of CAR would you use in that situation, Chris?

DR FLOWERS: Alright. Well, I think the first and the most important thing to think about with CARs, as Manali said, is that they add a new curative therapy for patients. And so for patients with diffuse large B-cell lymphoma, they can potentially be cured in the front-line, they can potentially be cured with autologous stem cell transplantation and they can now potentially be cured with CAR T-cells. Axicabtagene ciloleucel, or axi-cel, is the only 1 for which we have overall survival data to show that there's an overall survival advantage, and so for patients who are young enough and fit enough, that would be our preferred choice for giving of CAR T-cells. Now, young enough and fit enough is a little bit in the eye of the beholder, and so patients who are older and older, as we become more comfortable with managing these diseases and these CAR T-cells, are now more often getting axicabtagene ciloleucel.

As you heard from Dr Kamdar, is that those that are 4-1BB, so the tisagenlecleucel, or tisa-cel, and lisocabtagene maraleucel, or liso-cel, are the ones that are more easily tolerated in terms of the CRS. And so those are ones that we would think about in older individuals. And brexucabtagene is reserved for patients with mantle cell.

DR LOVE: So Caitlin, again, we spent a long time Thursday morning talking about both of these T-cell-directed therapies can cause cytokine release syndrome. A lot to talk about there. Can you just sort of summarize, because both of these strategies can cause this syndrome? Typically, CAR-T is given in a transplant center, then the patient returns to where they came from. Can you just comment on CRS, Caitlin?

MS MURPHY: Absolutely. So CRS, there's a very different profile between our CAR T-cell patients and our bispecific antibody patients. And I think that oftentimes we are very comfortable with managing fever, but as we get into hypotension and hypoxia, that gets a little bit more complicated. Patients need more intensive interventions. And so I think oftentimes that is a profile that's more often seen in our CAR T-cell patients. And they're seen in an ambulatory setting that's really used to this high acuity, or in the inpatient setting.

From a bispecific antibody setting, it's a little bit of a lower grade. They tend to have some fevers, but not necessarily needing kind of the intensive management strategies when we see those higher grades of CRS. And so fortunately, we're able to see these patients in the ambulatory setting, and very rarely need inpatient hospitalizations. And so I think that that's another keen conversation to have with a patient when you're thinking about these therapeutic options.

DR LOVE: And Robin, another issue, and particularly with CAR-T, maybe not quite as much with bispecific, but occasionally, are neurologic issues, so-called ICANS. Again, what do you see there?

MS KLEBIG: Since I'm in an outpatient setting, thankfully, I don't see any of it. But what you can see is certainly a lot of the neurological changes. I typically would refer people to looking at the grading to see what the symptoms are that they're having, and you look at the grade, and that way, you can kind of go down the algorithm to see what is the treatment that's going to be required for that.

So the other thing to keep in mind is, like if you look at some of the NCCN guidelines, it can be really scary going through this, but it'll kind of give you an idea of when you might expect this, kind of what's the usual timeline. And also the thing to remember is that these are typically temporary. So it can be really scary briefly, but it's temporary, so something to tell the patients and family.

DR FLOWERS: Neil, if I can jump in. I think ICANS is one of those situations where nursing care is absolutely critical. I think the vast majority of patients, particularly when it's something subtle, is something that's picked up by the nurse at the bedside.

DR LOVE: And also patients are either required or they're strongly encouraged to have family members around hopefully to pick up early changes neurologically, maybe some people have difficulty with their phones, et cetera.

Current and Future Use of Bruton Tyrosine Kinase Inhibitors for Mantle Cell Lymphoma

DR LOVE: Alright. Let's talk a little bit about mantle cell lymphoma and actually, we asked Manali to go through some of the clinical research and new therapies, particularly the use of bruton tyrosine kinase inhibitors. We had a program a couple nights ago on chronic lymphocytic leukemia, and as you can imagine, we spent a lot — this is one of the major forms of treatment, BTK inhibitors, but these are also very helpful in mantle cell. So Manali?

DR KAMDAR: Sure. So I'll start with the clinical case, 77-year-old male, good performance status, still working, with a past medical history significant for atrial fibrillation, controlled on metoprolol and apixaban. He was diagnosed with Stage IV bone marrow involvement with mantle cell lymphoma. The unique features of this mantle cell were that it was a blastoid variant, so a very aggressive subtype of mantle cell. It had a high Ki-67 of 70%. However, the FISH and NGS did not show any TP53 aberration. So the next steps in the management of high-risk mantle cell lymphoma patient in an older patient would be what, is the question?

So I'm going to take you through some of the key advances in mantle cell lymphoma, and one of the big splashes really happened way back in 2013 when ibrutinib got approved in patients with relapsed/refractory mantle cell lymphoma. Previously, patients just got chemo after chemo after chemo, and they really had a very poor dismal outcome, especially patients with high-risk mantle cell lymphoma, such as blastoid, pleomorphic, high Ki-67 and TP53 mutation. These were the three, especially the high-risk mantle cell, that were uniquely targeted very efficaciously with ibrutinib.

And then subsequently, later in 2017, 2019, second generation BTK inhibitors arrived, primarily acalabrutinib, zanubrutinib, as you can see. On the kinome profiling here, acalabrutinib and zanubrutinib have less off-target effects. As a result, they have less myalgia, less arthralgia, less atrial fibrillation, less bleeding compared to ibrutinib. And then the new kid on the block has been a noncovalent BTK inhibitor, meaning it actually sticks to the BTK socket, but it does not stick irreversibly, it does it reversibly. As a result, the chance of having a resistance is much lower. So noncovalent BTK inhibitors, now have made a foray, pirtobrutinib, now approved in 2023.

At this point in time, the FDA did withdraw ibrutinib in 2023. So most of the studies that I will show you that may include ibrutinib, we typically extrapolate to second-generation inhibitors with acal and zanubrutinib. So to keep it really quick and simple, young, fit, untreated, newly diagnosed mantle cell lymphoma historically used to be treated with chemo, intensive chemo, and if they achieved a complete response, used to get an autotransplant. Issues were that it's cytotoxic therapy, short-term, long-term side effects, but it was also not efficacious in the high-risk mantle cell lymphoma group, primarily TP53 aberration-derived mantle cell lymphoma.

And that's where, in my opinion, the WINDOW study that was an IIT designed by Dr Wang, made a huge splash in terms of figuring out if BTK inhibitors actually could be used in the front-line setting. So this was a study where BTK inhibitor ibrutinib plus rituximab was used, and then based on responses, they were consolidated with hyper-CVAD. The CR rate was stellar at 77%, with a progression-free survival at 5 years of 67%. What does this trial show? This trial showed us that incorporating BTK inhibitors are absolutely feasible, but still, you couldn't quite get away with chemotherapy, and the TP53 mutation patients didn't really have a huge, durable CR.

So come to 2023, at last year's ASH, we now have the TRIANGLE Phase III results. So what is the TRIANGLE study? In a nutshell, this is a study that randomizes in a 1 as to 1 as to 1 fashion into 3 arms. You have chemotherapy, followed by an autotransplant, followed by rituximab maintenance, versus you have chemo plus ibrutinib with the R-CHOP arm, followed by autotransplant, followed by autotransplant plus ibrutinib, or a completely transplant-free regimen where you have chemo with ibrutinib, followed by ibrutinib maintenance. The primary endpoint was failure-free survival. And you can see this was in 2022, made it to the plenary session of ASH, where Dr Dreyling presented these results of the TRIANGLE study. The failure-free survival superiority was established in the A + I versus A, which means having ibrutinib helps.

And then looking at the second curve, which is failure-free survival of autologous bone marrow transplant versus ibrutinib, you can see that ibrutinib was just as good, if not better. And then most recently, at this year's ASH, we had the failure-free survival demonstrating absolutely no difference between A + I versus I, uniquely making autotransplant redundant in the first-line setting. Overall survival was no different between the ibrutinib-containing arms. You can see that there is probably a difference in the blue curve. The blue curve is the autotransplant curve.

So the key takeaways of the TRIANGLE study is that, based on the TRIANGLE regimen, we no longer offer autotransplant to our younger mantle cell lymphoma patients. What are the implications of it? It was done with ibrutinib. We have no longer ibrutinib available in the United States, in which case we typically extrapolate and use second-generation BTK inhibitors. What does it mean for patients who relapse? Could they be retreated with the BTK inhibitor strategy?

And then something really unique happened in the TP53 mutation mantle cell lymphoma patients where Anita Kumar from Memorial Sloan Kettering designed this absolutely fabulous study in a small cohort of patients, an N of 25, but only exclusively TP53 mutation patients with a completely chemo-free regimen. It consisted of zanubrutinib, followed by obinutuzumab, followed by venetoclax, and ZVO, called the BOVen regimen, was given for 24 months, and the key driver was MRD. If you achieved MRD negativity after 2 years, you could stop the regimen. It was absolutely well tolerated. Diarrhea was predominantly the side effect, but it is majority of the times Grade 1. Its complete response rate was 88% in a TP53 mutation mantle cell lymphoma. Eleven patients have completed treatment, and of the 10 patients where we have MRD data, 8 out of 10 have already achieved undetectable MRD, and they have subsequently stopped the regimen. The 2-year PFS is 72%. Practice implications, it's already on the NCCN guidelines. So for me, when somebody has TP53 mutation mantle cell lymphoma, I either offer the TRIANGLE regimen, or I offer the BOVen regimen, based on a lot of discussion that happens in the clinic room.

Again, this begs the question, what really happens when a patient relapses? Could we retreat with the same regimen? Could we retreat just with the BTK inhibitor? Potentially matters on the timing of the relapse, but that study probably has yet to be done. So in the young and fit patients, the ASCT era is over, and I do think now there is the chemo plus BTK era that we have landed into, eventually with a lot of attempts from different investigators going into a BTK alone, or a completely targeted regimen era.

Moving forward, the elderly and the unfit. Like Dr Flowers said, it's in the eyes of the beholder, but previously, uniquely, we only had chemo treatments to offer to our elderly folks, and then bendamustine rituximab made a foray and then kind of stuck with us for a very long time.

Again, Dr Michael Wang from MD Anderson made a huge splash with this study called the SHINE study. In a nutshell, this is a patient population that's older, newly diagnosed mantle cell, randomized to either getting bendamustine rituximab versus benda/ritux plus ibrutinib, no crossover permitted, followed by ibrutinib maintenance. The long and short of it is that the progression-free survival, which was a primary endpoint, was better in the triplet. However, it came at a cost of toxicity. So in terms of patients who lost their lives to treatment-emergent adverse events, there were more in the BRI versus the BR. As a result, this never really moved forward. But then Dr Wang subsequently presented the ECHO study with a second-generation inhibitor, acalabrutinib, very similar design, which is BRA versus BR, but here, crossover was permitted. There was a statistically significant higher complete response rate in the BTK-containing arm, and with regards to the primary endpoint, which was the progression-free survival, very different and much better in the BRA compared to BR, despite about 70% of patients having crossed over in the BR arm. So that is something that uniquely stands out about the ECHO study. The overall survival is not yet any different, potentially because we have many treatments that are available downstream. The toxicity profile was also absolutely manageable with no unique or new profile that was shown with the triplet combination. And thus, it's now FDA-approved for patients who are older, unfit, with newly diagnosed mantle cell lymphoma.

So to summarize, the treatment paradigm in the elderly and unfit previously used to be chemo, chemo, chemo, and I think now it's changing. It's changing based on the BOVen study that I showed as well as the ECHO study that's now approved, which will now entail chemo plus BTK inhibition.

So what did I do for my patient? So in January 2025, this regimen got approved. He got started on bendamustine/rituximab plus acalabrutinib. He complained of headaches. The third day after taking acalabrutinib, called our triage line, and we said, please start taking caffeinated beverages, and he couldn't believe it, why? But the minute he drank coffee, his headache was better. And then subsequently, the cycle 2 was complicated by nosebleeds that led to temporary interruption of acalabrutinib as well as his apixaban. And then subsequently, cycle 3 has gone really well so far. All his clinically palpable lymph nodes have resolved, and I'm actually awaiting his interim PET.

Of course, the question is, if he's in a CR at end of treatment, should I continue acalabrutinib until progression? Well, the trial tells me to. Or should I have an MRD-driven approach? Because now MRD is a test that we can get for patients who are older on Medicare, which patients over 65 do have.

So a lot is changing in management of mantle cell lymphoma in 2025. The key takeaway for everybody to know is that patients with mantle cell lymphoma deserve a TP53 check-in. And that happens on FISH as well as gene sequencing. FISH detects 17p deletion, and gene sequencing detects TP53 mutation. And it's absolutely important that we recognize before we offer these patients, especially chemo patients, chemo treatments if they have TP53 aberration.

DR LOVE: So Chris, Manali mentioned your colleague, Dr Michael Wang. And you know I love talking to him because he's usually about 5 years ahead of everybody else. And again, we were talking about CLL the other night, where the standard used to be very intensive chemotherapy, FCR for young patients. And then they compared it to a BTK inhibitor, and BTK inhibitor, much more effective, and of course much safer. But Dr Wang is already talking about not using chemo at all. He did the acala/BR study, but he's already doing studies now without chemotherapy, just like in CLL we don't use chemotherapy. But, for example, this study of acalabrutinib/ rituximab, you can see how effective, very few progressions in these patients. And then even the triplet of venetoclax/BTK, in this case acalabrutinib/rituximab, may be the wave of the future.

That TRIANGLE study really blew everybody — I don't think people were expecting it. They walked out of there going, really, we're going to stop doing transplant? Now we’re going from doing transplant to maybe not even doing chemo. Any thoughts, Chris?

DR FLOWERS: Yeah, this has really changed the landscape for patients with mantle cell lymphoma. So I was the introducer for Martin Dreyling at his plenary session at ASH. And I knew that there was going to be a big splash when that was presented. Ever since I came to MD Anderson in 2019, we've not really used chemotherapy for patients with mantle cell lymphoma. The standard of care for our patients with mantle cell lymphoma is going on a clinical trial. 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, 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: And again, in the CLL program, we were talking about the paper just presented. It's going to change the practice of CLL using acalabrutinib and venetoclax, 14 months, and they're done.

So one other thing, and in a second we're going to ask Robin to go through some of the nursing considerations with BTK inhibitors. But Manali, I noticed that your patient had atrial fibrillation and was on anticoagulation at the time he was treated. We know that BTK inhibitors can actually cause atrial fibrillation, although we were saying the other night, it's not unusual to use them in patients already in AFib. Any comments?

DR KAMDAR: Yeah, atrial fibrillation is not a contraindication to starting BTK inhibition, especially if the atrial fibrillation is like a CHADS2, risk is high, where they are on an anticoagulant. I'm usually getting them to a cardio-oncologist in parallel to make sure that they continue to be monitored through that lens. Typically if they have uncontrolled atrial fibrillation, I like to get that under control and then start a BTK inhibitor. But a second generation or a covalent BTK inhibitor is usually not considered a contraindication if a patient has AFib.

DR LOVE: And we were talking also the other night that, in terms of acalabrutinib versus zanubrutinib, very hard, they're very similar, both much more safe than ibrutinib.

Robin, let's talk a little bit about some of the nursing considerations in patients getting BTK inhibitors for mantle cell, including the acala/BR regimen.

MS KLEBIG: Okay. Thank you. Let's see. I'm going to advance that slide. Okay. So some of the things that we talk about, so number 1, again, very well tolerated, but there are some things worth discussing, and some of them Dr Kamdar has mentioned, but always the bleeding and bruising risk. That's going to be something you're going to want to be aware of and talk to the patients about. They may need to be told and reminded again that if they're going to have a procedure, whether it's a dental procedure or a knee replacement, they're going to have to hold their BTK inhibitor for a period of time, depending on what the risk is of the procedure.

Atrial fibrillation, we've been talking about. Likewise, any of the other cardiac events, hypertension, that is something that the patients — you've probably been seeing them for a while and maybe they haven't had high blood pressure, and then all of a sudden they start coming in and their blood pressure is creeping up and they're just passing, oh yeah, I got white coat syndrome. But if they haven't had it elevated in the past, it's something to keep in mind. And you might need to send them for a study to see how often are you having this, how long is it going on? And maybe send them — we also send ours to cardio or even their primary care provider if they're not around our area.

You can have ventricular arrhythmias and heart failure, fortunately not as common. The arthralgias, as you mentioned, more common in Ibrutinib. Headaches, mentioned in acalabrutinib. Some GI issues, maybe a little diarrhea, rarely is it dose limiting. Low blood counts, that's just almost common in anything that we do. And of course the common things that can happen. If they do get neutropenia, of course they're going to be at risk for infections. Thrombocytopenia can add to the bleeding risk. They may have a little bit of fatigue. Again, it's usually not dose limiting. Rash and also nail changes, again, with ibrutinib. But I have not really seen that with any of the other BTK inhibitors.

So this is a slide that kind of gives some guidance on how to coach your patients through some of the things that we just talked about. As you mentioned with the headaches, the acetaminophen and caffeine, hydrating. Let's see, one thing I want to point out is like for the fatigue, you can have fatigue with just about anything that you're on and even just having cancer. But one of the things that I always encourage my patients is try to maintain activity because you want to maintain your conditioning. And I often tell them, you're not going to feel like getting up and taking a walk. You're not just going to be sitting on the couch and all of a sudden, hey, I'm going to get up and do something. It's like you have to just make yourself do it and kind of create your own energy, if you will.

So I am going to present my patient that — so you asked me to find an older patient and older, what is that, older than me I guess? But he's a delightful patient. He gave me a picture of his family because that was one of the driving things for him. One of the things he wanted me to point out is that, when patients are given this diagnosis, they are Googling it. And they're looking up that, oh my gosh, mantle cell lymphoma, that is not a good prognosis. I am not going to be living for very long. So that really plays into when they're a part of the decision of what they want to do for their treatment.

So he was a relatively healthy guy, had gout, again married, had a couple kids, very active, enjoyed golfing, fishing and all that, lived an hour and a half from Mayo. So initially, he actually presented in 2020. He had had this lymph node that he palpated actually for a couple of years before he presented. So that kind of tells you a little bit about what mantle cell is like. It can present in an indolent fashion, like this guy did, or it can present aggressively, and it can change over time. So he had this diagnosis, mantle cell lymphoma with biopsy. He had bone marrow involvement, so really Stage IV at diagnosis. So that was pretty scary for him. But because he was asymptomatic, he had obviously had it for a while, and it was COVID, it was elected to watch him for a while. And he was actually observed for about a year and a half. So in September of ‘21 he actually progressed, really with symptoms that he wasn't expecting. Significant left upper quadrant pain, radiating to the left shoulder. Went in, had a CT that showed a huge spleen and a splenic infarct really causing some pain. Bone marrow at that time showed 60% involvement by mantle cell. It was not blastoid or pleomorphic, but it was time to start some treatment. So to make a long story short, he enrolled on a clinical trial, as we put most of our patients on, if possible at Mayo. And he was randomized to rituximab, bendamustine and acalabrutinib.

So there's his baseline scan on the left. You can see that huge spleen. Holy cow. That was just filling his abdomen. And you can see a little bit of the infarct. You can maybe make out a little bit of the axillary adenopathy there under the arms. And so he went ahead and completed 6 cycles of treatment. He responded really well, had a complete response on his PET scan. And he also had a negative bone marrow, so completely in remission. In fact, also MRD-negative.

So what do we do now? Well, this is where — it's interesting when the patients are brought into the decision-making process. So at that time, his physician said, well, 1 option would be we could observe you, might not be the recommendation but it's an option. Another would be to go to auto stem cell transplant, that was standard of care at the time. Another would be to go to maintenance rituximab. Or we have a clinical trial, the EA4151, that would randomize you if you're MRD-negative to either rituxi maintenance or auto stem cell followed by maintenance.

Well, as I showed you on the first picture, his family was very important to him, and he came from this background of thinking he's going to be gone in a couple years. He wants to enjoy time with his family. They had started building their dream house on a lake. And here it was, about to be summer, and he's presented with this option of going to auto stem cell. And he's like, I don't want to spend the summer in the hospital. And that was a driving factor of him saying, no, I don't want to do transplant. I don't even want to do the clinical trial because what if I'm randomized to that arm? But I'll do the rituxi maintenance. He didn't want to not do anything. So that's what he did and he is just about to finish next month. And he shared with me a picture of he and his wife when they were traveling. And these are his little grandchildren that were born really just — this is a recent picture. So it's been so cool to see him through this and to go through life with him and see all these milestones. So you can see, as soon as he's done with his maintenance, they're going for their 40^th anniversary to Italy. The whole family is coming, even the babies. So it's cool. It's a good day.

DR LOVE: So one of the things we've talked about over the years is how often people come up to us and go, isn't oncology depressing? And not always, I guess.

So Caitlin, any comments on what you've observed on patients getting this regimen that's only recently been used? This patient actually is a little bit ahead of the schedule, acala/BR. What do you typically observe? And also from a quality-of-life point of view, Robin was mentioning fatigue. Any other issues that come up?

MS MURPHY: Yeah, I will say we've approached our mantle cell patients with a very similar dynamic of treatment and they really, truly enjoy their life. And I think the hardest part might be that acalabrutinib is a twice a day dosing regimen that they may forget or have to be a little bit more diligent about things. But it is really something that they manage quite well.

You kind of coach them through those initial headaches, those resolve really quickly. And I think they do. I think the AFib, the hypertension, you monitor. I hear the questions too. Oh, it's just my white coat. But oftentimes it's very much a manageable, long-term chronic side effect. And if we can stop that BTK based on MRD testing, I think that also leverages a lot of good conversation around quality of life and long-term therapy for these patients.

First-Line Therapy for Diffuse Large B-Cell Lymphoma (DLBCL)

DR LOVE: So we're going to move on and talk about another form of non-Hodgkin lymphoma, diffuse large B-cell lymphoma. Again, Chris is going to go through some of the clinical research data. This is kind of a different model of therapy. Mantle cell you can't cure, but you just heard the examples of being able to relieve symptoms for long periods of time. And maybe we are going to be seeing cure moving in the future. But Chris, for a long time now we've known that diffuse large B-cell can be cured with chemotherapy and rituximab up front. And you're going to also talk about a newer sort of twist to this, adding an antibody-drug conjugate, polatuzumab vedotin.

For those of you who weren't here when we got started Wednesday afternoon, we did an entire program just on antibody-drug conjugates. If you didn't see it, check it out on the podcast. There's a lot to talk about there. So Chris, can you talk about our approach to the up front treatment of diffuse large B-cell?

DR FLOWERS: I will. Thanks, Neil. And I'll start off with the cases. Well, my patient is also a 63-year-old patient, but mine's a young 63-year-old patient. At least in our setting old is judged by being older than the oldest clinician in their practitioner group, and now that's in the mid-80s for our practice group.

So this is a 63-year-old woman who was playing tennis and actually was having a bad time with her tennis game and was noticing that she was having some back pain and ultimately went to be evaluated for that and was found to have an epidural mass with compression and a compression fracture there as well. She ultimately had a biopsy that showed what probably should be better characterized as a nongerminal center B-cell lymphoma typed by the Hans algorithm, and had a PET CT scan that showed that she had Stage IV disease also with bone marrow involvement. She had an elevated lactate dehydrogenase, which is another poor prognostic factor, but had a lumbar puncture that was negative and had no evidence of CNS disease.

And so as we think about diffuse large B-cell lymphoma, I think one of the most important things to consider is what's shown here in this graph. This is the most common of the subtypes of the lymphomas, and what you see to the left of diffuse large B-cell lymphoma in the gray triangle of the pie chart is PCN, or plasma cell neoplasm. So that's all of multiple myeloma. So this 1 subtype of lymphoma is essentially equivalent or more than all of myeloma that you see. And this was the first time that we worked together with the American Cancer Society and the National Cancer Institute to be able to define the non-Hodgkin lymphoma subtypes by World Health Organization classification across the United States. And the other thing that we found is that there also are differences in survival for various groups within the United States, which is something that we also need to be able to address in the ways that we provide therapy to patients.

The other component though, for patients with diffuse large B-cell lymphoma, is for the patients who you define as being older. And you'll hear in my talk later on some of those definitions of being older. But for those patients, the approach is to be able to dose reduce the CHOP regimen in a regimen that was developed by the French group called mini-CHOP, where that has the potential for curative therapy, but the progression-free survival is markedly less than what you see with R-CHOP as the standard regimen.

And so as Neil alluded to, that there is a new kid on the block in terms of therapies for diffuse large B-cell lymphoma. It was first approved in the relapsed setting based upon these data, the combination of polatuzumab plus bendamustine/rituximab, which was compared in a randomized Phase II setting to bendamustine/rituximab alone, and showed an overall survival advantage.

As you see in the cartoon to the left, polatuzumab vedotin is an antibody-drug conjugate that binds to CD79b. When we first made naked antibodies to CD79b, those were not effective because when the antibody binds to CD79b, it gets internalized into the cell, and so it cannot stimulate other T cells the same way that you saw in some of the cartoons earlier. But this is perfect for an antibody-drug conjugate, because when it brings that antibody-drug conjugate inside of the cells, it brings in the cell poison to the cell and kills the lymphoma cells.

And so that was then compared, after the first trial, into a second randomized controlled trial that was eventually published in The New England Journal of Medicine that we participated in as one of the US leads comparing polatuzumab, substituting vincristine in the R-CHOP regimen with an R-CHOP placebo in that arm, to R-CHOP with a polatuzumab placebo.

One of the things that is a little bit unique about this regimen is that 2 additional doses of rituximab were given at the end of that. That was really owing to the compromise between the US group and the French group, where the French typically gives 8 total cycles of therapy versus 6 cycles of therapy. With polatuzumab in the earlier phase trials, we saw that toxicity occurred after 6 cycles of therapy, so only 6 cycles of the polatuzumab were given. And what you see here is that there was an improvement in progression-free survival, which was the primary endpoint for the study, showing that polatuzumab plus vedotin in the R-CHP regimen showed improvements over R-CHOP.

When you look at the safety profile of these two regimens, they look essentially identical. There is a little bit more neutropenia seen in the group that received polatuzumab/R-CHP compared to R-CHOP, but that did not translate into a greater rate of infectious or infectious-related deaths.

And so as we think about moving forward in the management of patients with diffuse large B-cell lymphoma and moving into the modern era, we're now moving into an era where we're using gene expression profiling subtyping and now even other forms of NGS subtyping to be able to define lymphoma subgroups, both in terms of their gene expression, their mutations and the lymphoma microenvironment.

But one prominent way that has been looked at within the context of this clinical trial is shown in the forest plot to the right, which is a complicated forest plot but defines various different subgroups. We have seen, as seen to the far left, in an article that came out after the original New England Journal of Medicine article, that the ABC subtype, when defined by gene expression profiling, has better outcomes with pola-R-CHP than R-CHOP, and perhaps limited or no benefits to the group that has GCB as their gene expression. I think one thing that we need to be cautious about here is that this was defined by gene expression, and in routine clinical practice we use immunohistochemistry, and using immunohistochemistry, there's about a 20% misclassification of patients, and so that should not be used to define who should get therapy. The other thing that you can see in the complicated forest plot to the right is that there are multiple different subgroups in addition to the ABC subgroup that also benefit more with pola-R-CHP, and so identifying which of those subgroups a patient falls into might be overlapping with their cell of origin subtype.

So in terms of kind of the key take-home points, we do now know that pola-R-CHP provides a novel first-line therapy. There's now been a 5-year follow-up that was presented this year by Gilles Salles at ASH that confirmed that benefit, and maybe even starts to suggest that there might be an overall survival benefit that could occur in the future, and so that trial is now being followed for that. That is not significant yet. And I think as we look in the future, we'll be looking for molecularly targeted therapies for diffuse large B-cell lymphoma, but many more factors need to be involved before we start to do that.

DR LOVE: So we're going to talk a little bit also about nursing issues and sort of helping patients get through this therapy. Again, a very different model of therapy than we just talked about with mantle cell, kind of more similar to what you see with Hodgkin lymphoma, where you're trying to cure the patient and then get them off therapy indefinitely. Caitlin, we asked you to talk a little bit about some of the things you think about in patients getting up-front treatment but also specifically patients getting polatuzumab.

MS MURPHY: Absolutely. So I think it's been tried and true. Everyone knows R-CHOP. I think no matter how long or how short your career in oncology has been, it's been kind of our backbone for diffuse large B-cell. So I think it's really exciting to have something that's a little bit different in the front-line setting. And as you can see, side to side, looking at these regimens, you can understand, there's going to be a lot of parallels and similarities when we're thinking about common side effects from GI upset, mucositis, nausea, or anthracyclines, where we think about our cardio-oncology considerations. So I'm going to focus, really, on where it's a little bit different in the polatuzumab component.

So similar to rituximab, because of it being a monoclonal antibody, it's going to have a notable HSR hypersensitivity reaction potential. So that's something that you're going to coach your patients. You're going to tell them, when they're in the infusion chair, that they're going to potentially have that reaction. And I think when we have both rituximab and polatuzumab that you're administering, you have to be really keen to be able to monitor and see very similar in terms of the presentation.

As Dr Flowers mentioned, peripheral neuropathy and febrile neutropenia, these are very classic symptoms that we coach our patients to report. I think that's the other thing that nursing has really been critical around neuropathy, where they're going to kind of be a little guarded with our clinicians and not tell us exactly. Some things that I start to notice, they may not wear earrings anymore, they may not wear bracelets, they may change what they wear to clinic, they may fumble a signature. We don't necessarily check that as often, but those are things that you can definitely monitor for neuropathy, which can be a little bit more subtle than what they're going to admit to when you ask them.

When we think about infections, we're thinking about upper respiratory infections, and then classic hematologic AEs, that lymphopenia with the B cell depletion of the therapies, it's very intentional, but then opens up a little bit of a different plethora of infectious concerns. GI rates, when we think about vincristine, we always think about constipation. This is a little bit of a different profile when we think about polatuzumab. There's a fair amount of diarrhea, but it's still pretty favorable in terms of that. And then fatigue is pretty classic with this patient population, and so I think encouraging them to exercise, like Robin said, it's very, very hard, and so it's maintaining that, and I think that that's a great nursing intervention that you can do.

So related to the hypersensitivity reaction, we're thinking about the classic premedications. From an infectious standpoint, we're thinking about prophylaxis, we're using those G-CSFs, whether it's the long acting or shorter acting, because we're moderating some of these concerns around bone pain that they may experience. We think about these opportunistic infections, herpes simplex virus that can reactivate, so we're thinking about the consideration of prophylaxis for the duration of their therapy.

In some cases, tumor lysis syndrome can occur for these patients. They may have really bulky nodes that we need to consider when we start to cytoreduce them with these therapies that are so effective that we need to be monitoring their labs for tumor lysis and then drug-drug interactions because of the mechanisms in that MMAE payload that is delivered with the polatuzumab.

Classic 21-day cycle, 6 cycles, is what we've talked about. And in terms of the infusion, these are lengthy infusions, they're spending lots of time in your chair, but the nice thing is is that if they tolerate that first infusion, and they may need some breakthrough support with additional reaction medication management, but oftentimes they can get into that shorter infusion, which I think is also favorable.

So this is a gentleman that I took care of. He actually presented to his primary care with right hip pain that was really bothersome. He actually presented with a cane. He started to really notice it was inhibiting all of his quality of life and all of his activities. And so subsequently had imaging, then went on to have an additional scan after his MRI, and this is his PET scan. So you can see all of these avid areas. So pretty diffuse in terms of spread, so Stage IV diffuse large B-cell, that non-GCB subtype that we alluded to that has a little bit of a different response rate. LDH was elevated. He had preserved renal function, which I think is helpful when we think about these therapies.

DR FLOWERS: So Caitlin, was that an old or a young 64-year-old?

MS MURPHY: I think he was young, but…

DR FLOWERS: You're the tiebreaker.

MS MURPHY: Yes, I'll be the tiebreaker.

So this is his interim PET. I think the things that he experienced was notable fatigue. He was taking off a little bit more work, but he was still able to work during this regimen, which I thought was really impressive. He had some mild nausea. We had a pretty robust anti-emetic regimen. But he did have neuropathy, and that was something that he wasn't quite sure if it was maybe related to his arthritis. Some of this had kind of paralleled his presentation with some of these symptoms, but it was having more of that numbness, more of that tingling, trouble with texting, things like that. But I will say a pretty impressive response.

And then he went on to have 3 additional cycles, and this is his end of treatment. And when he came back, he's like, I'm glad that I stayed as active as I was, because that was something that he mentioned improved his fatigue. And then the neuropathy did improve after stopping therapy and finishing his regimen. So I think that that's also something when we're talking to our patients, it's cumulative and it can build and build and build, but unfortunately there comes to a point where it doesn't recede. And so I think being really transparent with your care team, but also that it can get better.

DR LOVE: So fortunately, it looks like this man may be well on his way towards cure. Curious, Robin, when you kind of take a step back and look at what patients go through, what they went through before with R-CHOP and now these patients getting pola-R-CHP. The difference in terms of efficacy wasn't that great, but we talked about hazard rates the other day. Chris was saying hazard rate of 0.73. What that means is at any given point in time, 73 minus 100, 27% less chance that he would progress or that anyone would progress. So not a 100% better, but significantly better. Does it come at a cost? Globally, Robin, how do you see these patients tolerating treatment?

MS KLEBIG: Actually, I would say I see them tolerating it a little bit better symptomatically as far as what they're feeling. I think the most notable thing I've noticed, because you have patients with constipation, with vincristine, I mean, even bowel obstruction risk, and that really impacts their day for about a whole week or so. And I have not seen the constipation. I haven't even really seen that much diarrhea, but you'd almost rather have a little loose stool rather than being constipated and having all that. And then the other ways that neuropathy can present, like sometimes with R-CHOP, with the vincristine, we would even see other things like bladder dysfunction, having a little bit more frequency, even enuresis, bedwetting, sometime rarely, the voice, the effect that it has on the vocal cords, I haven't seen a lot of that. So I would say in general, we see better tolerance with the polatuzumab.

DR LOVE: Chris?

DR FLOWERS: Yeah, I think one of the things that is meaningful about this regimen compared to R-CHOP is that, while there's not that dramatic a difference of a progression-free survival and no overall survival difference, that's in part because there are many other ways that patients with diffuse large B-cell can be cured. And when you look at particularly the 5-year follow-up, there were fewer patients on the pola-R-CHP arm who needed to have an autologous transplant, fewer patients who needed to have CAR T-cell. So they were actually cured in the first-line without needing those additional therapies to be cured, which obviously is a great benefit for patients and their families.

DR LOVE: So a few words about those patients who do relapse after this primary therapy, whether it's R-CHOP or pola-R-CHP. And of course, bispecifics and CAR-T are a very big part of therapy. Typically, that's what we'd be talking about now, but we wanted to focus on other approaches because there are many others and there are many patients not eligible for CAR-T. A lot of patients, they may be in their 80s or have comorbidities, even bispecifics. And so there are many other agents that can be used that can be effective from a palliative point of view.

Role of Loncastuximab Tesirine for Patients with Relapsed/Refractory (R/R) DLBCL

DR LOVE: We're going to talk a little bit about an antibody-drug conjugate, another one, loncastuximab tesirine, that's used as one of the therapies. We'll talk about others as well. But Manali, can you talk a little bit about Lonca-T and some of the other treatments used for patients beyond CAR-T and bispecifics?

DR KAMDAR: Sure. So let's start with a clinical case, 65-year-old male, good performance status, past medical history significant for coronary artery disease, stent in 2009, on aspirin. He was diagnosed in 2023 with Stage III diffuse large B-cell lymphoma. It was GC subtype and he subsequently got treated with R-CHOP and achieved a complete response. His complete response was documented in August of 2023.

Unfortunately, within a year, so that's June of 2024, he was diagnosed with a biopsy-proven relapse, Stage III diffused large B-cell lymphoma. And because he was a high-risk second-line relapse, he underwent apheresis per standard of care. He got bridging chemo with R-Gem-Ox and then received CAR T-cell therapy with liso-cel in August of 2023. His course was complicated by Grade 2 CRS from which he fully recovered. At day 90, his PET was a complete response. This was in November, 2023.

Now 6 months later, he now has a relapse in February of 2025 and it is biopsy proven. And it's very important to check the biopsy for CD19 and CD20, CD20 because we have CD20 bispecific T-cell engages that we can offer these patients that have an excellent response rate. But in his case, the tumor biopsy was negative for CD20. It remained positive for CD19. He was completely fine with regards to functional status, counts were normal, so how would we now move forward with next steps?

So with that, I'll first start with this treatment algorithm for patients with relapsed/refractory diffused large B-cell lymphoma in 2025. If patients have relapsed after 1 line of treatment, we no longer ask what's their performance state. We basically say, when do they relapse? If they relapse within 1 year, then the answer is CAR T-cell therapy. However, if they relapse more than a year out, then we look at transplant eligibility, and if they remain transplant eligible, then offer an auto-transplant. If patients relapse with diffused large B-cell lymphoma and are in the third-line setting, then we typically see if they have been exposed to CAR-T, in which case we go to CD20 bispecific T-cell antibodies, but there is a new problem that we are dealing with in 2025, which is there are patients who are CAR T-cell therapy and bispecific antibody exposed or ineligible are not able to get it. So what about those patients? How do we manage those patients? What are the treatment options for those patients?

And with that in mind, this is loncastuximab tesirine. For simplicity, let's call it Lonca-T. This is an antibody-drug conjugate. You have had a whole session on ADCs, so you know that this is a targeted chemo. Basically, the linker attaches to a chemotherapy. Here, the chemotherapy is a chemo called PBD that causes cell destruction and tumor lysis. The target is CD19, so this antibody binds to CD19 and then releases chemo just to the tumor cells.

This is the LOTIS-2 study. This is the pivotal Phase II study that got Lonca-T approved. The primary endpoint was overall response rate by an independent review body and a total of 145 patients got enrolled if they had received 2 or more prior lines of treatment. I would like you to look at the median age. The median age is 66 with a range of 23 to 94. So we are not ages. If patients have a good performance status, we give them treatment if they want treatment. Median line of treatment, 3, with a range of 2 to 7, about 20% primary refractory, and 10% of patients had been exposed to prior CD19 CARs.

Now, all of these patients had to have CD19 expression in order to get enrolled on this clinical study. Lonca is given as an IV infusion. Remember, steroids are your friend when you talk about Lonca-T, as well as for side effects that may happen because of Lonca-T. So there is a steroid premedication that we give, and these cycles are repeated every 21 days for up to 1 year. This is the final efficacy result at a median follow-up of about 8 months. You can see in a heavily pretreated population, the overall response rate was 50% with a complete response rate of 24%. And the median time to this response was actually 41 days. So it's very quick.

And then you're beginning to see all of these curves, not only in the general population, but in lymphoma you will see a lot of us investigators look at what happens to patients if they achieve a CR. Do they maintain the CR? Is the CR durable? And the answer is yes. For the whole population, the 2-year progression-free survival was only 30%, but if they achieved a CR, the 2-year progression-free survival was 73%. And with regards to median duration of remission, it was about 13.4 in the whole population, but if they achieved a complete response, it had not been reached. So it's a really uniquely efficacious drug.

However, when it comes to safety, I have pointed out on some of the key unique toxicities that you can see with Lonca-T, particularly increased GGT. In my opinion, it's just a number. I look at it and I move forward, but the things that are actionable are the peripheral edema. This is absolutely something that can happen. We interrupt the drug, we give diuretics, give steroids, and it's complete resolution. The same goes for pleural effusion. The most important, I live in Colorado, lots of patients with photosensitivity. So not just sun protectants, but have to wear hats, even if it means it's the winter. So these are some of the management pearls around loncastuximab.

A big question in the field is, what does lonca do if you have received prior CARs, and is lonca something that I can do before I can give a patient CARs as subsequent treatment? So in terms of data that says, what if somebody has received liso-cel or axi-cel like our patient has, and has now relapsed, and from that setting we have 2 studies, 1 from the LOTIS-2 study, which basically says that the response rate does not matter. And then there is the multicenter retrospective study that was led by Naren Epperla, who also showed that the responses are preserved. So if somebody receives CD19 CAR-T, and they continue to express CD19, I would give them Lonca-T. And then what of the reverse? What if somebody doesn't have a caregiver, and they are not able to finagle a 400-km trip to Denver? In that case, could I use Lonca-T until they finagle a social caregiving plan for CD19 CAR? And the long and short of it is based on retrospective analysis, as well as a CIBMTR study, we can say that we are able to offer them, provided they continue to express CD19.

So what did we do for our clinical case? Like we discussed, the tumor biopsy post-CD19 CAR was CD20-negative. So I could not offer this patient a CD20 bispecific T-cell engager. Just in February, he started single-agent Lonca-T. And in March, his isolated adenopathy was much clinically smaller. So what are the questions for me? If he does have a complete response, which I typically check prior to the fourth cycle, then he's 65, he's still very fit, working, should I offer him an allotransplant, which is potentially the only known curative entity still in diffuse large B-cell lymphoma that has relapsed? Or could I continue Lonca-T, hoping that that median duration of response that was not reached in complete responder would be this patient?

DR LOVE: Curious how he's tolerated therapy, and is he outside a lot? Has he been able to avoid the sun exposure? Is he using sunscreen and hats?

DR KAMDAR: Now, that's a great question. This patient is actually, triathlon, because in Colorado, even an 80-year-old, they're fitter than I am. So despite me telling him that, please be very aware, he's like, I chap like the sunscreen all over, and I'm fine, I'm just going for it. And he's gone for it.

DR LOVE: I'm sure he's very happy to be in such a great remission.

Alright, Robin, let's talk about some of the nursing considerations in this situation.

MS KLEBIG: Alright, let's see. So a lot of this, I'm just going to kind of hit the high points because I think Dr Kamdar mentioned it quite a bit. But of course, this is for patients with relapsed or refractory that have had at least 2 regimens of other systemic therapy. The response rate, sometimes I hit on that if they're interested in talking about that. Again, going over the antibody-drug conjugate, that this targets the cell and releases the drug into the cell, and then the chemotherapy component causes DNA damage to lead to that cancer cell death.

We talk about what the regimen looks like. So it's given every 3 weeks. It's an outpatient infusion over 30 minutes. In the first 2 cycles, you get a certain dose, and then subsequent cycles the dose actually drops. And generally, we tell them, well, this will continue either until disease progression or unacceptable toxicity. So we don't really have an end in sight. Like when they get R-CHOP or pola-R-CHP, they know, okay, I'm going to get this many cycles. But with this, with these relapsed, it's hard to know. You just kind of take it a step at a time, sometimes a scan at a time.

So again, some of the side effects we talked about is nausea, fatigue, again the low blood counts. A lot of these things are very common in many regimens. Again, the GGT, I will mention, in the patient that we gave it to. So I think the patient that I am going to present, it was one of the first patients that we had, and we saw that the GGT went up and got a little bit excited. But when you look at the grading, really only if it gets to be like 5 times the upper limit of normal is that when you would actually hold it. So I was much more relaxed as well, when it was like, yep, it's elevated, but it’s not bad.

So the notable things about these, as you mentioned, are the edema and the effusions, like pericardial effusions or pleural effusions. We don't normally expect that with other regimens. So this is something really to be mindful of watching for symptomatically. And then as you mentioned, the severe cutaneous reactions. So I can't say enough about making sure that the patients understand that they should be taking the dexamethasone, typically starting a day before and continuing it for 3 days, and then of course wearing the sunscreen and sun protection. So this again, as far as the nursing, always we're monitoring labs, whether it's CBC values, chemistry values, the symptoms related to the effusions or fluid retention, and some other things.

So I'm going to go into my patient who, this was a number of years ago. He was 74, he was older than me. And he was very sick. You look at his past medical history, chronic ischemic heart disease, had a LAD stent, an ICD, unstable angina, factor V Leiden, on all kinds of anticoagulants, warfarin, clopidogrel, et cetera, diabetes, COPD, Parkinson's. And oh, by the way, he had low-grade lymphoma in the past. So he had had rituximab 15 months prior.

So his social history is really important in talking about his case, because he was widowed. He had 2 children, but unfortunately they were somewhat estranged from him. He did not have a strong social support. He was one of these people — he wasn't a triathlon or anything, but he loved to be out in the sun fishing. And he also lived one and a half hours from Mayo, similar to my other patient, but for him it was a struggle to get him to our center, and there wasn't really another good option for him. So with his DLBCL presentation, he presented with abdominal pain, shortness of breath. This was at an outside facility. Physical exam had showed a huge spleen. He was pancytopenic. CT scan showed a splenic infarct, again just like my other patient. But those are about the only things that they had in common, splenic infarct and they lived an hour and a half from Mayo.

So when he was in his local facility, they knew they had to transfer him up to us. He had a really rough hospital course. This guy, he really was kind of one of these, had an outer crust to him, if you know what I mean. He was kind of cantankerous. If you read through the hospital chart, people were always describing him as being angry. And so the initial thought was, well, they would take him for a splenectomy, but then he just deteriorated. They were not able to take him for this, ended up in respiratory failure in ICU. And he was just not at all happy once he was able to realize he didn't get that. So his PET scan that was performed fortunately showed another area to biopsy. So the biopsy was of the right axilla. It did show the diffuse large B-cell and actually it gave a hint that it was a transformation from his previous low-grade lymphoma. It was a non-GCB double expressor and FISH was negative. It was not a high-grade Bcl. So what did we do? So as he was very sick, a lot of it because of the lymphoma. So after he had the biopsy, while waiting for that, they had to start him on something while we're waiting for pathology. And he was given rituximab and methylprednisolone. And then once that result came back that it was indeed DLBCL, wanted to give him like standard treatment. But, you saw his cardiac history. He was not a good candidate for R-CHOP. He couldn't have an anthracycline. So he received R-CEOP, which substitutes the etoposide for doxorubicin. It's got cyclophosphamide, vincristine, and prednisone.

So he generally responded well. You can see his baseline scan. And I will say that, if you can see a Foley catheter on your baseline PET scan, that's a poor prognostic. But look at that huge spleen, the axillary adenopathy. And after 6 cycles, again, he had a really nice response. So what I didn't tell you, he had 60% involvement of his bone marrow at presentation. And it was a mixed picture. It was like part of it was the low-grade small cells, and a part of it was the large cells. So after 6 cycles, his scan looked good, but his marrow still showed a minimal, but it was still there. It's like being a little pregnant. You still have a little bit of lymphoma that you got to deal with. Had it been just low-grade, maybe we would have observed. But because there was still a large cell component, we knew that we couldn't stop. We had to do more.

So again, with his social history, this was a great conversation to have because we have so many options. This was not a candidate for CAR T-cell therapy or bispecific. I don't think we had bispecifics back at this time. But we did have all these other options. So we talked about what about polatuzumab and BR? We had been using that with some success, but shoot, that would have made him come 2 days to clinic, which was not going to make his daughter, who had come back into the picture to help him out — she was present, but she wasn't very supportive. Let's just say that.

Tafasitamab/lenalidomide, well, pretty soon we'll talk about what that schedule is. That was not going to work for him. Loncastuximab, as I mentioned, that's something given every 3 weeks. Selinexor, potentially, but in the long run we ended up choosing loncastuximab mostly because that was a schedule that suited him. So he did tolerate it well. So you can imagine with his cardiac history, we were kind of like, okay, how's this going to go with fluid overload and that kind of thing? But he actually tolerated it well. I will say, as I was talking about the dexamethasone, so this guy has difficulty finding a ride. His daughter drives him here. She's not very happy sitting over in the side of the room like this. So the first time he comes in for like day 1 of cycle 1 and the nurses have done their education with him. He comes in on a Monday. Did you take your dexamethasone yesterday? Oh, no, I forgot all about it. Oh, no, we all just about panicked because he's here. We're going to have to reschedule him. His daughter's going to have a fit, you know? This was new, we hadn't given a lot of loncastuximab, and thankfully in pouring over things, then we saw that, oh, you can actually give it as long as you give it 2 hours before. So thankfully that saved it. He was able to receive it. And we said, you know what, from now on why don't we have him come in on a Tuesday and you can call him on Monday afternoon to remind him to take his dex? So that worked out for the rest of it.

So as far as in the loncastuximab, between that, we got him on the dex. We had to really coach him on using the sunscreen. He was out there fishing. I don't think he ever used sunscreen in his life, but he did, didn't have any skin toxicities. Tolerated that part well, but he had that whole list of comorbidities and he just didn't have a lot of support, not a lot of good medical care where he was. And his INR — he's on warfarin, right? It would just be randomly crazy. It would be like 10 or 15 or something. He would end up with GI bleeds in and out of the hospital, COPD exacerbation and cardiac issues.

So after 6 cycles, we didn't have to repeat a PET because it was negative basically. We repeated his bone marrow. It was negative and we said this is it. You're in remission. Let's just see what happens. And unfortunately, as you see at the bottom, he did expire about 6 months later, but he didn't die of lymphoma. He died of COPD, heart failure, and so…

DR LOVE: That's life, but what an amazing story.

Role of Tafasitamab for Patients with R/R DLBCL and Follicular Lymphoma

DR LOVE: Alright, we're going to finish out. You mentioned tafasitamab, which has been used a lot for diffuse large B-cell lymphoma in relapsed setting. Now, more recently in the last few months, there've been reports of benefits in follicular lymphoma. So Chris, can you talk a little bit about the use of tafasitamab in diffuse large B cell as well as follicular?

DR FLOWERS: Sure. And I'll maybe go fairly quickly through this case. So this is a 72-year-old gentleman who initially got started on a clinical trial in one of the R-CHOP plus X trials. I think at the time that he was treated, we didn't know what X was, but it ultimately turned out to be bortezomib from the trial that he was in a randomized trial to. But unfortunately, he relapsed about 28 months after that. He received an autologous stem cell transplant at that time and then relapsed again and received CAR T-cell therapy in the third line.

Had a very long remission to his CAR T-cell therapy, which is a little bit unusual to be in remission as long as he was, and then still relapsed, but returned 3 years later at the time that he was 72 and had a new lymph node biopsy that was performed in his inguinal region that showed evidence of relapsed diffuse large B-cell lymphoma with ABC subtype. And I think we've talked a little bit about who are old, you heard my definition, but here are definitions that are used in the literature from the American Society of Clinical Oncology and the International Society of Geriatric Oncology. But I think, as you've heard throughout these presentations, what's most important is the assessment of functional status as opposed to chronologic age, either doing things like formal geriatric assessments, although those have not been fully standardized, or things that are more simple like a walk test. But leveraging that, I think it's really important to use some form of functional status to decide whether somebody's fit enough to have an aggressive regimen.

I think the other thing that you've heard is that not everybody will benefit from CAR-T, and this just shows an example of a number of factors that we've seen, those patients who have more than 2 extranodal sites, those who have a high tumor metabolic volume on PET, or have an elevated lactate dehydrogenase. And when you have more than one of these factors, and in particular when you have 2 factors, those are patients who would not expect to benefit from CAR-T. And the other thing that you heard from Dr Kamdar's talk is that not everybody who's eligible for CAR-T can actually get to CAR-T, and it's only really about 20% of those patients who we see that are eligible for CAR-T who can get to CAR-T. So that's why we need to think about all of these other regimens.

And so you've heard about loncastuximab tesirine, selinexor, I won't spend much time talking about. That's a regimen that has had some response rate, and is approved based on a CR rate of 10% in a large single-arm clinical trial, but has a relatively short progression-free survival. For those patients who do respond, the duration of response can be meaningful. And I mentioned at the beginning, in the talk about polatuzumab, the role of the pola/BR regimen.

So I'll spend a little bit of time talking about tafasitamab and lenalidomide, which is a combination regimen that is approved. So you heard about the role of CD19 antibody-drug conjugates in Lonca-T. Tafasitamab is, like, a CD19 antibody that binds to the surface of the tumor cells, and in doing so is externalized, and can then bind natural killer cells or bind macrophages, which in turn then kill the cell directly. It also can have a direct cell kill on the tumor.

And these are the outcomes for the clinical trial of tafasitamab and lenalidomide, compared to lenalidomide alone, that showed a median progression-free survival of that combination, and a median overall survival of 33 months. So quite a meaningful benefit for those patients who receive therapy and stay on therapy, albeit one that is more commonly used, at least in this trial, in earlier lines of therapy in patients that had much less heavily been treated.

When you look at the terms of the safety of this regimen, tafasitamab/lenalidomide looks fairly similar to lenalidomide alone. And so when you look at the majority of the toxicities, they occurred during the combination when both drugs were given for up to 12 cycles, with neutropenia, anemia, and thrombocytopenia. After the completion of the 12 cycles of therapy, when tafasitamab is given alone as a monotherapy from cycle 13 and onward, you can see that the toxicities are markedly less in that particular time period.

And then the data that Neil alluded to that are really new and hot off the press is this study that was presented by Laurie Sehn as a late-breaking abstract at this year's ASH meeting, of the inMIND study that looked at the combination of tafasitamab, lenalidomide and rituximab, versus lenalidomide and rituximab, or the R² regimen in follicular lymphoma. And what that showed is that there was a progression-free survival benefit for those patients who received tafa/R² versus R², and the toxicities looked quite similar to R² alone. And so this is yet another new regimen on the horizon now for follicular lymphoma in this particular patient population.

DR LOVE: So it seems like every year at ONS it's around the same time as Coachella. I always visualize this as the oncology version of Coachella. And Caitlin, you get the opportunity to do the last song in the oncology version of Coachella. Let's talk a little bit about nursing considerations with tafasitamab.

MS MURPHY: Well, I hope I can make tafa look as fun as Coachella. So tafasitamab and lenalidomide, like Chris said, in terms of the relapsed or refractory diffuse large B-cell setting, but also in the low-grade or diffuse large B-cell arising from that low-grade who aren't eligible for an auto stem cell transplant. Robin took away the thunder of this very complex dosing schedule. It's pretty arduous for this first cycle where they're coming in at least twice a week for that first one and then going to weekly. And then it kind of lightens up as you get further along.

But I will still say that as you get to cycle 4 you're still coming in every 2 weeks. And so in combination with the lenalidomide, which is an oral therapy, and that is also a little bit of a different schedule where it's daily, days 1 to 21 of the 28-day cycle. So you're kind of buoying your patient between 2 dosing schedules, and when are you off and when are you on? I guess the nicest thing is that they're in the infusion chair and you can keep asking them. Have you taken it today? Have you missed any doses? And then you can continue with the tafa monotherapy until disease progression or unacceptable toxicity, so in terms of the same conversation with our patients in terms of how long they're on this therapy.

So when we're thinking about adverse effects and common toxicities, the infusion-related reaction is pretty robust in this patient population. Thirty minutes prior, you're going to do your standard premedications, our hematologic AEs, neutropenia, anemia, thrombocytopenia. With our immune modulators, many of us are very familiar with lenalidomide from our experience with the myeloma population. And so we're really quite diligent about checking our CBCs and monitoring that. And then in tandem, because of the neutropenia, we are seeing a fair amount of infection. So these are respiratory infections, urinary tract infection, bronchitis, things like that.

Notable diarrhea, about a third of our patients are experiencing diarrhea, so a lot of coaching around management, dietary changes and then peripheral neuropathy, and can't get away from that fatigue unfortunately. So as I mentioned, the infusion-related reaction is pretty notable. About 80% of patients will have it. The nice thing often happens in the earlier cycles. So you can really kind of staff appropriately so you know that these are going to be patients that are going to need a little bit more TLC and intervention and close monitoring. But then often it becomes much more manageable.

You're monitoring their CBC because of those cytopenias that you're concerned about. And definitely this is when the education around neutropenia and signs of infection, where you're constantly saying, if you have a new cough, burning with urination, new skin lesions, anything like that, that they may kind of downplay or discredit, this is something that you're going to be asking about, and then additionally some of the support with the G-CSF.

Lenalidomide, just as a reminder of the REMS program, obviously, when we're talking about contraception, we can't be ageist. This could be a consideration for our entire adult patient population that we utilize these therapies for. And then we also want to take into consideration the risk of DVT and pulmonary embolism. So you're thinking about an antithrombotic. In our older adult population, they may be on anticoagulation for a multitude of other cardiovascular reasons, but just making sure that they're on a baby aspirin if they're not already on something in tandem. And then again, with the cytopenias, when we're thinking about prophylaxis for this patient population, where they're going to run into these more commonly, herpes simplex, shingles in that way.

So I'm going to present a case of a woman who's 72. She had a notable history of IBS, hypertension, hyperlipidemia, arthritis. She presented with weight loss and bloating. She underwent a CT, which had a pretty notable 5 by 5 cm retroperitoneal mass and an SUV of 12 and some scattered pulmonary nodules. So we went forward, got that biopsy, was consistent with the diffuse large B-cell. She received 6 cycles of R-CHOP. End of treatment, PET still had some of those lung nodules, which we can sometimes see and kind of continue to follow as we bring patients into surveillance. Then we're in this midst of surveillance and unfortunately with intermittent — she had some of these waxing and waning cervical nodes on presentation, but they went away, they came back and oftentimes we can see that in some of our patients, especially if it's something that may have been indolent and a transformation. So subsequently in 2024, she really had these cervical nodes and we kind of said, let's see if we can get a biopsy and that's when that biopsy was consistent with diffuse large B-cell.

So when we thought about her treatment considerations, hers was more about location of care, and so she really didn't want to go to a larger medical center. She was at our regional campuses and really enjoyed having a 5-minute drive to clinic and not dealing with parking at the main campus. And also for caregiver support, you saw that complex regimen. You knew how many times she was coming into clinic for those visits and so it was something that she was able to rotate between family members and neighbors. It was only a 5-minute drive. It wasn't a big ask for her to be able to get that kind of support. And then goals of care and intensity of treatment, I think is always a consideration when we think about our older adult population, not that this woman, I would say, is in that older, older adult population, but those are things that you really need to be thoughtful and mindful about the intensity of treatment. They may want something a little bit more palatable in terms of how they can manage this.

So as I mentioned, that community-based setting, not a change in location of care. Sometimes that can happen, where they really grow fond of the team that's been caring for them over many years and so I think that that's another component of this. So she had a hypersensitivity reaction as we anticipated and coached it. She did have, unfortunately, cytopenias. We dose reduced the lenalidomide, which I think at 25 mg is a pretty hefty dose. She was able to maintain with a dose reduction. Her interim restaging PET showed a PR and she went on to continue with the 12 cycles. And still those pulmonary nodes just kind of hung around.

DR LOVE: So what a pleasure and honor it's been to work with you this week. It was so great to work with you all tonight. What a great job. All I have to say is: San Antonio, 2026. Have a great night. Thank you so much.