Introduction

DR LOVE: Good evening, everyone. I’m Neil Love from Research To Practice and welcome to “What I Tell My Patients,” Part 4 of a 10-part series here at the ONS meeting. Tonight, we’re going to focus on the management of chronic lymphocytic leukemia and the use of bispecific antibodies in the management of non-Hodgkin lymphoma. We have a great faculty here on the stage, as always with our programs: 2 medical oncologists, Dr John Allan and Dr Brad Kahl, and 2 nurse practitioners, Ms Robin Klebig and Ms Mollie Moran. So we’re really looking forward to chatting with them tonight about these 2 very interesting topics where lots of things are happening.

As always, we will be talking about unapproved uses of agents, so check out the prescribing information for more details. For the people here in the room, all the slides are on your iPads. There’s also a survey for you to take, and you can use the iPad to ask questions. All the same functions are available for the people on Zoom. Hey to everybody up there. The slides are all in the chat room as well as the survey. We actually do a survey at the beginning and after the meeting. If you take this, you’ll get a lot more out of what we’re going to do here tonight. We are recording all these programs. We’ll let you know in a couple weeks when everything’s put together and ready to go for your colleagues who are unable to make it here.

Here are the 10 programs. This is actually the 4^th. We started out last night talking about breast cancer. We’ll be staying here in this same room, really making rounds here this week as we always do. We’re not focused on slides. We’re focused on discussing taking care of patients. And we are talking about these specific oncology situations, but in every one of these meetings we also are going to talk about just oncology in general and oncology nursing specifically. And as we’ve been talking about for this particular symposium, I interviewed 8 nurses that we’ve worked with over the years who weren’t able to join us here about some sort of common issues that come up in oncology, and we’re going to take a break every now and then during the meeting today, hear what they have to say, see what the faculty has to say. However, if you check out the link down there at the bottom, ResearchToPractice.com/ONS2024Clips, you’ll find 85 videos there that we produced, all less than 90 seconds, all going to be going up on social media. We’re curious to see what you think about this kind of content and what we can do with it. We are going to talk a lot about clinical research and try to as we go through and take a look at some of the research findings. We’ll also talk about some of these terminology issues that come up.

So we’re going to start out for the first half of this talking about CLL, and then we’ll talk about bispecifics. And I was going to show you this first video, but we always meet with the faculty ahead of time and I heard about this case. And I had heard a little bit about it. I was really going to bring it up last night because we were talking about how important it is to make sure — I don’t know if you were here last night, Dr Burstein was talking about how important it is to make sure you have really good pathology in your patients, that a good pathologist, has had a good pathologic examination. Here’s probably the most amazing story I’ve ever heard that makes that point. Robin, tell us about this patient.

MS KLEBIG: Oh yes, this is a story about how important it is to have accurate information before you talk to your patients. So this gentleman, 59 years old, and he had presented with some neuropathy. He had numbness and tingling, and he actually had foot drop on his right lower extremity. So he was seeing his primary care provider, and in the course of evaluating this they did an MRI, and the MRI had shown what sometimes the radiologist will read like an infiltrating marrow signal. And so the primary care provider saw this and the question was, well, is this metastatic bone cancer? Well, she contacted the patient, it was a Friday evening, and said, “Okay, I just didn’t want you to worry about these results. I wanted to make sure and tell you this. Are you by yourself?” “Yes, I’m by myself.” “Well, you might want to sit down and I have some not great news for you. I think it’s really important that you get your affairs in order because it looks like you have bone cancer. You’ve got metastatic bone cancer. And I’m going to send you for some more tests next week and we’ll see what those results are.” So this man was devastated on a Friday evening and all weekend. He got his family together and they talked about it. He was a business owner and had some sons. He was 59 at the time. I think his sons were in their 30s or so. And he decided, okay, if I’m dying, I’m going to turn my business over to you and I’ll just get my affairs in order like they advocated. So he goes through all the testing and it turns out, well, it looks like your white count’s high. In addition to all this other stuff, we’re going to send you to hematology. So it turns out, well, guess what? He’s got CLL. And in going through all of the testing they found he was really asymptomatic apart from the foot drop, which was deemed to be related to shingles. So that eventually got better with physical therapy and things. But in doing his CLL workup, he was found to have really pretty indolent disease and they said, “You really don’t need treatment. We’re just going to observe you.” And sometimes when people are given a cancer diagnosis or they’re told they have CLL, they’re pretty upset. This man was very ecstatic that he had CLL and did not need treatment, and he went for 10 years without needing treatment, so…

DR LOVE: People ask, “Why do you go into oncology?” And a part of it is just to see people like this. Can you imagine the human experience that this patient and his family had and kind of what it would be like to see them moving forward? It’s really incredible.

Also, John, it brings up the unique decisions that come up in CLL, and one of the most interesting ones is not to treat it at all, which is — how long did he go without treatment at all?

MS KLEBIG: He went 10 years.

DR LOVE: Ten years.

MS KLEBIG: Yeah.

DR LOVE: Unbelievable. John, any — we’re going to take a look at the video in a second. But any thoughts about trying to explain to patients why they have cancer but they don’t need to be treated?

DR ALLAN: Yeah, I mean, I think CLL is a unique disease in that aspect where fortunately we can provide some good news. They get this diagnosis, and what I always say is that this is life-changing, obviously. This is not something that’s going to go away. We have to watch it. We have to worry about it. But fortunately, this is a disease that is slow-growing, it’s indolent and the treatment advancements that we have nowadays really probably put you into a normal life expectancy, and I don’t want you to stress about this. And I kind of refer back to other leukemias where they may hear about their previous loved one or friend that had AML, that they just heard the term leukemia and have these poor outcomes. And I just always try to refocus the patient that this is a very different disease, really explain the biology and get into the genetics and the data and the history of how we got to this point. And then that really settles patients down and redirects them towards their future, which is bright, and the horizon is long.

DR LOVE: So Mollie, I’d like you to listen to what Jackie Broadway-Duren, who’s at MD Anderson, actually, in the CLL department, sees just CLL patients, has to say about one of the important themes we’ve been talking about. We’ve talked about this for years here at ONS but particularly this week, patient self-advocacy and allowing patients to be involved in the treatment decisions. Here’s Ms Broadway-Duren.

MS BROADWAY-DUREN: Patient involvement is key to their successful treatment with any regimen. We can present to them 2 or 3 options and we tell them what our strong recommendations are. But we — unless the patient buys in on it, generally they don’t do well over the long term with therapy. So we very much include the patient. Now, we may try to encourage them to use one treatment over another, such as time-limited treatments versus the treatment that they’ll be on for indeterminate amount of time. Most times the patients are going to go for that time-limited treatment. Patients tend to be more agreeable to treatments when they know that there’s an end in sight. So that happens in both populations, older and younger patients. The younger patients, of course, they absolutely want the time-limited therapy because they want to get on with life, so to speak. So I’ve seen it equally as popular among both. Nobody wants to be on treatment for a lifetime when they can take treatment for 12 months and be done, if, in fact, that’s applicable to their treatment.

DR LOVE: So Mollie, in fact, as we’re going to talk about, there are 2 therapies out there that’s, in terms of sort of long-term outcome and acute issues that’re pretty similar, either BTK inhibitor or venetoclax/obinutuzumab. As she was alluding to, one, the BTK, is indefinite, venetoclax/obinutuzumab is for 1 year and then stops, so so-called time-limited therapy. So one of the most interesting decisions in all of oncology — we have presented so many CLL patients the last few years, I never get tired of hearing it. It’s just so interesting to think about people trying to make these decisions, try to go through something that’s just going to be a year, but it’s going to be a bit more challenging, or just take another pill, you’re already taking 6, but it’s going to be for the rest of your life. How do you see patients processing this, Mollie? And how do you assess the patient in terms of how involved they’re going to be?

MS KLEBIG: It’s a great question. As Jackie said, I see both sides of the coin, and across all different ages with CLL patients. And some folks can’t conceive of the intensive blocks in the beginning whether it’s their work, or their family, or their commute or some of the risks that go along in the up-front with some of the time-limited therapies — the time-limited therapy — as opposed to starting on a twice a day dosing of a pill and just take that and come and see us every couple of weeks, or every couple of months, for the duration. And it’s a struggle for people. The appeal of a time-limited therapy is there. But if you can’t commit to that early part of the therapy, then that’s not really a great option for you. So if your job prevents you from taking that kind of time off, or your family obligations, if you’ve got a lot of little kids at home, maybe you can’t do that. Maybe you can’t be away for that long a time, and that sort of puts you into the category of not being on time-limited therapy. And so one of the things that we look at in our research in CLL is, can we figure out ways to make time-limited therapy accessible using different combinations of drugs, and sort of maybe making that an easier decision?

First-Line Therapy for Chronic Lymphocytic Leukemia (CLL)

DR LOVE: And we’re going to get into a lot of the ins and outs of what is actually involved in these 2 routes, and other routes as well. But, Brad, let’s talk a little bit about the initial assessment of the patient. We talk about the fact that some of these people don’t even need to be treated, others are high-risk. Can you talk about some of the key ways that we look, particularly at biomarkers, which has been a huge theme in oncology and what we’re talking about all week, to try to categorize what to expect from a specific case of CLL, Brad?

DR KAHL: Sure. So when we have a new patient, the first thing we try to determine is, are they symptomatic? Do they have symptoms? If they have symptoms from the disease, the decision making’s kind of easy. You definitely need to start on treatment because you can relieve those symptoms. Many patients don’t have symptoms, then you start looking at other clinical features. Are they starting to get marrow failure, a little bit anemic, or thrombocytopenic? Are they getting a big spleen, are the lymph nodes getting very sizeable? So you’re looking at all these features, and then we look at the biologic parameters. So when we have a newly diagnosed patient, we’ll send a CLL FISH panel. Particularly, we want to make sure or test for the deletion 17p, or a p53 mutation, which is a sequencing test. And then we want to check their IGHV mutational status. This is the 1 time where being mutated is good. In CLL world, IGHV mutated has some favorable implications and unmutated a little less favorable. And then you sort of factor all that in together when you try to make your treatment decisions.

DR LOVE: So John, we were talking about whether or not to actually treat the patients, and can you talk a little bit about what it is that will lead to treatment? We’re going to talk about the major treatments, but observation versus treatment, what kind of symptoms, what kind of situations? Can you have an asymptomatic patient and still treat?

DR ALLAN: Yeah, so it’s a great question, and it’s an active question of research, actually, right now. So fortunately, we do have a governing body in the CLL world, specifically for CLL, the iwCLL, which convenes every 2 years or so at the major meeting. And about every decade, they kind of re-examine all of the data out there on what are indications for therapy, what do you need to do when you start to treat patients and work them up, et cetera. And I always tell my patients, these guidelines put out there basically 5 big reasons for treatment. Because the first question that I get is, what am I going to feel? How do I know I’m going to need treatment? And basically, when you look at these 5 reasons, many times, and many of them, the patients actually don’t feel. And we are seeing them in labs, and/or on an exam, or in scans, and they actually still may feel well.

But essentially, you see them listed here. So the first are B symptoms, fevers, night sweat, weight loss. This is a harbinger potentially of a transformation event and/or in patients with a lot of disease, and is not necessarily something that’s super common as an individual treatment indication. Fatigue, you say fatigue, all patients will say they have that. So you do have to be careful around that, because that is such a multifactorial symptom that you can’t always state that treatments will fix that. And so you have to make sure that the fatigue is truly due to CLL. I always kind of state that when it’s the only symptom, it’s a component of it.

Then we have our progressive symptomatic lymphadenopathy, our progressive bone marrow failure with worsening anemia, cytopenia, and typically you see this inverse relationship with the white blood cell count rising as those are decreasing. Rarely, in about 10% to 15% of patients will you see an autoimmune hemolytic anemia complication come out. It is something that needs to be cooled off. Steroids don’t typically cool it off. You may be on steroids for very a long period of time, and you need to eliminate the CLL cell. And then a progressive lymphocytosis. CLL does not double quickly, it overexpresses Bcl-2 which keeps the cell alive, and these cells accumulate over time. But when you see it take off, and it starts to double every 3 months, they’re coming in and it’s ratcheting up, you need to kind of put a stop to that because that’s the first domino that falls before all of these other things, these happen.

So those are the things that we look for. Now, the question about the asymptomatic patient that has high risk features, you might think that we want to start treatment early for these folks. And it makes us nervous sometimes to watch them because when patients transform, some of them actually transform during periods of observation. So you have to balance the risk feature of the patient with the activity of the disease. But right now, we have certain studies that have been done with ibrutinib and some that are going on with venetoclax/obinutuzumab, of treating high risk patients at diagnosis before they have actual treatment indications. And the current data, (1), being CLL12, which is now about followed 5, 6 years or so of ibrutinib at diagnosis versus placebo, have not shown an overall survival benefit by starting the ibrutinib early.

So this paradigm we are still kind of stuck in, and honestly, I don’t know if we will ever get out of it, even in high-risk patients. I do think that we will need treatment indications to actually impact an overall survival. But that is an active area of research. They’re looking at this with venetoclax/obinutuzumab in a SWOG study that’s ongoing. But right now, since the 80’s and 90’s, when we first established that treatment at diagnosis does not improve overall survival, we are still in this area where we watch and wait until you meet these iwCLL indications for therapy, no matter what those risk features are. And so that’s where you have to be smart and thoughtful about what’s going on, work the patient up appropriately, and then have these discussions and explain why we’re doing this, and explain that history of where we got to today.

The Impact of Comorbid Conditions on the Choice of First-Line Therapy for Newly Diagnosed CLL

DR LOVE: And Mollie, in a second, I’d like you to talk about your 73-year-old man who, interestingly, lives 2 and a half hours away from the clinic, which is a key issue. But he had, we were just talking about immune issues, and he had actually immune thrombocytopenia. And Brad, that was — in general before we hear about this case, can you elaborate a little bit more on what these “autoimmune complications” are, usually anemia, Mollie’s patients had thrombocytopenia, and how they’re managed?

DR KAHL: Yeah, so to have some immune dysregulation can happen in CLL, and it often, manifest is autoimmune thrombocytopenia, autoimmune hemolytic anemia, or I’ve seen autoimmune neutropenia as a complication to CLL. And it can happen when the CLL is very advanced, or it can happen when the CLL is very early stage. It’s quite unpredictable, actually. And you usually manage it initially like you would in someone who has ITP and no CLL, you just try to manage the ITP. But sometimes, you find that autoimmune complication keeps recurring, and then you say okay, now let’s treat your CLL and see if we can get it under control that way. So sometimes you end up on that kind of a pathway.

DR LOVE: So one other thing. John, you were talking about “transformation.” Can you explain what that is?

DR ALLAN: Yeah, so transformation, there’s a specific type of transformation called a Richter’s transformation, which is really restricted to CLL transforming into an aggressive, large B-cell lymphoma, like DLBCL. And this is a unique biology specific to CLL transformations. These are typically only about 10 percent of CLL patients will transform in their lifetime, thankfully, but those 10 percent are enriched in various high-risk genetic features that you can actually identify at diagnosis, know who is at potential risk for it, and think about those patients a little bit differently. Unfortunately, even in this day and age with these novel targeted agents that we have, these do not typically work very well or for very long if they do work for a true transformation event. And the standard of care today still is some form of aggressive immunochemotherapy, R-CHOP, R-EPOCH. And if the patient is young enough, which is difficult in CLL because the median age at diagnosis is 70, and able to get into a remission, which CR rates with chemotherapy are way less than what we see in de novo DLBCL, the standard of care would be that chemo and then taking that patient to an allogeneic transplant. And with that, you can actually have long-term remissions. But unfortunately, still in this day and age, the median survivals are measured about a year or so. It may be a little bit longer than that with some of the newer advancements and additions of new treatments, CAR T-cells and things like that. But it’s a devastating complication. We want to try to avoid it. And it is an active area of research and a true unmet need still in the CLL space.

DR LOVE: And, actually, it’s one of the more common causes of death in CLL. It may be more common than just dying of CLL or infections related to CLL.

So Mollie, we always talk about oncology in the real world. And I remember all the stories I would hear during the pandemic of trying to treat people with venetoclax and ramping people up but yet, you can’t get into clinic and people were secluded in nursing homes. It was pretty challenging and sort of still is to some extent. What happened with this man?

MS MORAN: This was a gentleman who had low-level disease and presented with a low platelet count. And so he was able to be treated with steroids, which was very effective at getting his platelet count back up. And then he was able to, we were able to watch him for a while. Steroids are not without their risks but this is just pulses of steroids, it’s not usually long-term steroids, and so you don’t get those sort of long-term steroid effects. And then he really didn’t need therapy for quite a few years after that. When he finally comes down around to getting therapy, again, he lives far away, he’s a farmer, he’s got infectious risks, he’s got a job that causes him to be stirring up muck, and all of that comes along. And one of the biggest risk factors in CLL and one of the biggest complications in having CLL is still infection, even with all of our great supportive care. We have growth factors, we have immunoglobulins, we have everything under the sun, great antibiotics, great stewardship. And still, you’re working against the odds because these are folks who have, can have profound long-term immunoglobulin deficiencies. And their immune system by nature of having CLL, isn’t generally intact. And so you’ve got this added onto that.

DR LOVE: Can you talk a little bit about what it was like to treat him? And did you try to use the resources at home? Did he have a doc at home who could do some of the work?

MS MORAN: Yeah, that’s a good — he did. Fortunately, he had a local oncologist who was helpful. But a lot of times, the local oncologists don’t want to do the ramping up of BCL2 inhibitors. They’re not familiar with the risk. And it’s not just that they’re, I mean, they’re familiar with it. You can read the data on it. But you have to have the resources. You have to have the lab that can turn around a blood order in minutes. You can’t send in a lab and then get a lab result back 8 hours later with a potassium of 6.5. You have to sort of think of the whole picture when you’re talking about managing patients who may have these risk factors. But this was a gentleman who was able to get someone to cover the farm and he could come down and spend his 2 nights and get his therapy and go back. I’m not familiar with farming. It’s not in my wheelhouse. But I think if you’re not doing it, you’re not, it’s like selling cars, if you’re not doing it, you’re not making money, right?

DR LOVE: Seems like it.

MS MORAN: Yeah, I don’t know. Any farmers?

DR LOVE: Most jobs work that way.

MS MORAN: Anyway. But he had a great support system. He had great people to help him and a local oncologist that was willing to keep an eye on the infections and all. That’s supportive care.

DR LOVE: That’s one of the themes we’re going to be talking about today and throughout this week, is the interaction between community-based clinics and tertiary centers. And that’s going to come up when we talk about a newer therapy, bispecifics. Actually, when venetoclax first started to come out, also even with AML, which is kind of a different story, the docs in the community did not want to be involved. They were kind of intimidated about it. Now, they do it like it’s water. But now, the new thing is going to be bispecifics.

Toxicities and Other Practical Considerations with Venetoclax-Based Treatment

DR LOVE: Let’s get back to venetoclax as a treatment, though, John. Can you talk a little bit about your vision of how the drug actually works? It’s a very interesting function related to so-called apoptosis. What is apoptosis? How does venetoclax work? And can you kind of get into a little bit about how it’s actually done when you combine it with an anti-CD20, particularly obinutuzumab, in some cases rituximab?

DR ALLAN: Yeah. So apoptosis is a controlled pathway for cell death. And so typically, it is activated upon DNA damage. And when the DNA damage is overwhelming to the cell, it will activate this apoptotic pathway of death. And this is kept in check by a delicate dance within the cytoplasm where there are what are called Bcl-2 family members of proteins counteracting proapoptotic proteins and they are binding these anti-apoptotic proteins. And so there is this pathway that is basically, the cell is always trying to die. And our anti-apoptotic proteins, of which BCL2 is one of those, is counteracting that and balancing it. And it’s this delicate dance that keeps the cell in homeostasis. CLL specifically overexpresses a protein, the protein called BCL2, and this is strongly overexpressed. And so when you have too much anti-apoptotic protein, you are sopping up all of those proteins that are trying to cause the cell death. And so CLL overexpresses this, other lymphomas can overexpress this.

And this is where the holy grail of cancer drug development has tried to find that perfect inhibitor for decades. And finally, we hit the homerun with a drug called venetoclax. And venetoclax is a very specific inhibitor to BCL2. Other ones had failed because they inhibited all of the anti-apoptotic proteins. And, therefore, they were getting bad toxicities, cytopenias and issues around other factors there. So venetoclax came around, very specific to BCL2. It binds up BCL2, freeing up these pro-apoptotic proteins that then can cause the cell to die, and can do that very effectively, very quickly and very potently. And that’s where the issues of tumor lysis and some of the toxicities that we deal with can come into play because it is such a powerful drug in the CLL space because it is so dependent on BCL2 keeping the cell alive that when you disrupt that homeostasis, one of the mechanisms of the cell is to overexpress the proapoptotic proteins. And so when you bind up BCL2, the cell is super primed to move forward to apoptosis. And, therefore, you can tip that balance and you can do that very quickly. And, therefore, it comes into how we use these agents and why we monitor them like we do.

Obinutuzumab has an added effect that the drug itself can cause toxicity to the cell when it binds the cell and the CD20 molecule, as well as it activates our immune system. So you’re getting multimodality forms of cell death, and that’s why these drugs work so well and so potently together.

DR LOVE: I was just looking at this slide again from Matt Davids from Dana-Farber. I’ve never really kind of appreciated the artwork there. The tumor cell, the happy little platelet. I like it.

Alright. Let’s go from theory to reality, Robin. What do you tell patients to expect when they’re going to get venetoclax, and particularly venetoclax with obinutuzumab?

MS KLEBIG: Well, when they’re going to get venetoclax, we do talk to them about the tumor lysis, the fact that we’ve got to ramp it up. Again, because it’s so effective, that’s a good thing but you have to be very careful about that. And so we make sure that they are drinking plenty of fluids. We know that we have to be checking their tumor lysis labs. And kind of talking to them about other side effects like GI toxicities, other cytopenias, fatigue, those kind of things. Taking the allopurinol, of course, is very important, starting that ahead of time. Let’s see. Some people do get a little bit of diarrhea. They can use loperamide as needed.

And then the obinutuzumab, adding that, that’s another issue. I know at our institution and probably at many of yours, we start out just giving them just a small dose the first day of 100 mg. And most people will have a reaction to that, so we have to just prepare them for that. And then they get a larger dose the second day. They tend to do reasonably well then with the subsequent dosing. But it is a lot of visits for them, at least at the initial time until they get ramped up and onto that full dose of the venetoclax.

DR LOVE: And you can see here, it’s pretty complicated to determine how aggressive you’re going to be in preventing tumor lysis syndrome. Brad, part of it is, really, it makes sense. Actually, it’s a great thing that you see tumor lysis, right? The tumor is falling apart so fast, at least that’s the way I think about it, that that’s a great sign. But on the other hand, the more tumor you have, the more breakdown products are going to be circulating, potassium, et cetera, et cetera. So you can go anything from kind of hydration in the clinic to being admitted in the hospital, Brad. How do you sort of make that determination? You also have to factor in the renal function. As we were saying, these are older people. How does this all come together in terms of the way you, what you recommend, Brad?

DR KAHL: So I try to follow the package insert, and it’s spelled out in that slide there. So if someone does have high tumor burden, they should be admitted for observation during the first week of the ramp-up and the second week of the ramp-up. It’s usually 2 nights in the hospital when it’s all said and done. And it’s usually pretty uneventful. One of the nice things about the ven/obin regimen is it starts with the obinutuzumab. And so by the time you actually start the venetoclax, if you did have a patient who was in the high-risk category, a lot of them have moved into the intermediate or even the low-risk. So having to hospitalize someone getting the venetoclax/obinutuzumab regimen turns out to be pretty rare. If we have a patient who we’re trying to manage as an outpatient and their renal function is a little borderline, we’ll go out of our way to do extra hydration when they come to clinic on the ramp-up days. Because we’ve got to check their labs in the morning and we’ve got to check them again in the evening. So why don’t you just hang out with us the whole day and we’ll just hydrate you while you’re here. And so sometimes, we’ll add in a lot of IV fluids to help minimize the risk.

DR LOVE: So a lot of investment in terms of patient time and convenience, but I guess the patients in general feel pretty well during this. There’s a lot of hassles and blood drawing, et cetera. And, of course, the good news is it’s only going to be for a year. So once you get through all this stuff. But the other thing is, and maybe you can comment in general, John, about the concept of minimal residual disease. We’ve already been talking about it, even in breast cancer last night. It’s all over oncology and hematology. What about in CLL, John? It seems like more and more, we’re seeing this built into the trials and how people get managed. What is MRD in CLL and how do we use it, particularly in these venetoclax situations?

DR ALLAN: Yeah. So MRD or minimal residual disease is a concept that’s been around in CLL for a long time actually because we’ve been using chemoimmunotherapy, which is very potent and actually can achieve what’s called MRD, meaning you cannot find a CLL cell floating in the blood or in the bone marrow. And that typical definition is 1 CLL cell out of 10,000 nucleated cells evaluated. And if you’ve gotten below that threshold, whether it’s chemotherapy or now in this day and age with these targeted agents, those patients always do better than someone who doesn’t get there. Now it’s very relevant for any patient that stops treatment because the deeper remission you have, the longer time off of therapy typically you will have. And so it’s less relevant in our continuous therapy. So that’s why in the CLL space in the world that we live in now, it’s kind of controversial, the relevance of MRD. Because in an ibrutinib or a zanu or an acalabrutinib patient, typically these patients don’t get to MRD negativity. They can, about 15% after 6 or 7 years on drug can achieve this endpoint, but it’s not something that we use to guide our therapy.

But with venetoclax, a high, and particularly venetoclax/obinutuzumab, a high percentage of patients do achieve this endpoint, close to 60%, 70%. And in younger patients, close to 90% actually achieve an MRD negative state after a year of therapy with venetoclax/obinutuzumab. And we know the depth actually might start to matter. We have newer technologies now that we’ll probably get into later that can even measure lower, 1 in a million cells. And it looks like that those patients who get even deeper might actually do better than those patients who achieve that 1 in 10,000 endpoint, but not deeper than that.

And so our definition of what it means continues to evolve, but venetoclax/obinutuzumab can achieve it at high rates. And I do believe if you are thinking about a fixed-duration approach, it is likely important to try to strive to get a patient to that endpoint because we know once you stop, they are going to be in remission longer. It’s intuitive and we now have data to support that as well. And so I think that’s the concept of MRD in CLL.

The Selection and Sequencing of Therapies for Relapsed/Refractory CLL

DR LOVE: And also, if you think about it, you give a therapy for a year and you’re going to bump them out. They don’t need to be treated for a few years or a couple years. By the time they need to be treated, there may be a new drug coming along. And in fact, they’re coming along so fast, it’s almost likely that they’re going to get something new. But that also gets into the other sort of half of the equation, Brad, BTK inhibitors. And we’re also going to talk about the future of maybe even combining these 2 strategies together. Oncologists like to do that. But let’s just talk about BTK to start with, Brad. Can you talk about how it works? We have 3 available agents. And your perception of the difference between them. I guess you can add a fourth with the new one, pirtobrutinib with a different mechanism. But Brad, can you give us a little summary of BTK in CLL?

DR KAHL: Sure. So BTK or Bruton’s tyrosine kinase, it’s an enzyme that’s very important in B-cell physiology. It sort of transmits signals from the cell membrane down to the nucleus. And it turns out that in CLL cells, it’s a critical pathway for survival. So if you can block that enzyme and shut down that pathway, the CLL cells will die. So it turns out to be a pretty good target for CLL.

And we’ve had ibrutinib. Ibrutinib was the first one. We call it a first-generation BTK inhibitor. It’s been around for, gosh, 10 years now. And at the time, I thought this was the greatest drug I’d seen since rituximab. It worked so well and pretty well-tolerated although you did see nagging toxicities that would plague patients over time and then you had the risk for the atrial fibrillation and sometimes even more severe cardiac rhythm disturbances.

And so then along came the second-generation BTK inhibitors, acalabrutinib, zanubrutinib. And they’ve been compared head to head now against ibrutinib. And they’re clearly better tolerated based on the studies and, I’m sure, based on what we’ve all seen in clinic. They’re just better tolerated. And a head-to-head study of zanubrutinib and ibrutinib suggested zanubrutinib is even a little more active. So these second-generations are clearly preferable to ibrutinib, and that’s probably what most of us use nowadays. They’re super easy to initiate. It’s like the opposite of ven/obin which is a real pain in the butt for the first 2 months. It gets easy after that. But these, you basically say okay, here’s your bottle. See you in a month. It’s just easy to start someone on a BTK inhibitor. The downside, of course, is the indefinite nature, so there’s this big tradeoff. But by and large, acalabrutinib and zanubrutinib are very well-tolerated agents, they’re very effective.

And now, we have this third-generation, pirtobrutinib, which hits a totally different part of the molecule. So some of the mutations that give resistance to ibrutinib, acalabrutinib and zanubrutinib don’t give you resistance to pirtobrutinib. That’s why pirtobrutinib can work in a patient who has failed a prior BTK inhibitor.

DR LOVE: Whenever I think about BTK inhibitors, I always think about an education meeting I was doing with Brad. It wasn’t that long ago, maybe 7 or 8 years ago. And at that point, the front-line treatment for CLL was chemotherapy, usually with rituximab, so BR was a common one. And we were talking about that and I said well, Brad, if you had CLL, what would you want? And he said ibrutinib. And that was before it was even approved.

DR KAHL: Yeah.

DR LOVE: So we kind of knew what was going to happen. But, Brad, I see reports still of people getting chemo, like BR in the community. And it’s hard to figure out, is this because the docs aren’t aware? It’s hard to believe they couldn’t be aware of what’s going on. Every guideline talks about this. I wonder if there might be economic issues, copays or trying to access. But let me just, would you say that if you see a patient getting first-line treatment with BR or chemotherapy, it should raise a little bit of a red flag? Why is that happening?

DR KAHL: Yeah. Nowadays, there would need to be some extraordinary circumstance, some financial reason or literally, I’ve had patients with mental health issues who were totally unreliable taking pills. You just couldn’t count on them.

DR LOVE: But this is like 25% of people supposedly are getting this now.

DR KAHL: Yeah. But it shouldn’t happen often that you’re going back to old-timey chemo nowadays. These drugs are better tolerated and they’re more effective.

The Tolerability of Available Bruton Tyrosine Kinase (BTK) Inhibitors

DR LOVE: So maybe we can kind of move on and talk about, again, how this is really playing out in real life. And I think part of the issue is the tolerability issues, the toxicity issues. Mollie, can you talk a little bit? Brad alluded to, for example, atrial fibrillation. But again, when you sit down with a patient, and we’ll talk more about which BTK, but in general, what are the things that you’re going to be focused on in terms of educating them?

MS MORAN: Yeah. When I talk about the side effects when starting someone on a BTK inhibitor, the big 3 side effects that I always start with are the atrial fibrillation, hypertension and the risk of bleeding. And when I explain to a patient about what atrial fibrillation feels like, it’s that potentially you could feel like your heart is fluttering, you may feel like you get short of breath. And then a patient will say well, I already have that. Because this is a group of folks who are, we keep saying that this is an older population, and atrial fibrillation occurs in an older population as well. And so just trying to bring home to the patients that when you start to feel side effects, whether you think they’re not significant enough or not, you should reach out to us.

DR LOVE: There you go. You’re off. Okay, you’re good. We’ve got a solution for everything here.

MS MORAN: I think I’m back on.

DR LOVE: You’re back on? Alright, cool.

MS MORAN: Am I back on?

DR LOVE: Yeah.

MS MORAN: Am I coming in clearly? Sorry. If there’s a side effect, whether it’s significant or not, that they should reach out to us, and we can fix a lot of things over the phone. We actually work with a group of cardio-oncologists who are looking into reasons why atrial fibrillation may be, you know, how the BTK inhibitors play into that. They do cardiac MRIs at different points along their treatment. And maybe there’s a tell in there that can sort of view some predictability in the future for patients who develop atrial fibrillation.

The other thing I tell patients is just because you develop A-fib doesn’t necessarily mean you have to come off the drug. It’s that if it’s rate manageable, you can be on one of the, you know, something for anticoagulation. The one thing we can’t use is warfarin, but there are many of the other drugs we can use. And so that’s another thing that people get hesitant about. I always call it their would-be. They don’t want to let go of their drug and they don’t want to tell you what’s happening. So if you say that up-front that potentially you may not need to go off the drug or we can think about switching to another therapy. You’re not coming to a brick wall. You’re coming to a crossroad.

DR LOVE: So Robin, anything you want to add to that? What about quality-of-life issues with BTK inhibitors? Arthralgias, dermatologic issues?

MS KLEBIG: Certainly, we do see arthralgias, myalgias, but they’re usually pretty self-limited. People are still able to do their important things. We just have them, you know, make sure you’re mobile, walking, doing some yoga. You can use acetaminophen if you need to. They can have rashes. It’s not typically, again, dose-limiting or a deal-breaker. We always, like you were saying with the bleeding risk, we always want to make sure that they let us know if they’re going to have a procedure because we’re going to want you to hold it for 3 to 7 days before and after depending on what that procedure is. And I think, yeah, those are — with the acalabrutinib, of course, there’s the headache that you can get. That seems to be most common with acalabrutinib. But we always tell them they might expect this and reassure them that it’s temporary and it’s usually pretty manageable as well. We have not really seen anybody want to come off or need to reduce their dose or anything because of that.

DR LOVE: People keep telling me that caffeine works for the headache.

MS KLEBIG: Caffeine if acetaminophen doesn’t work, or both. And make sure they’re drinking plenty of fluids.

DR LOVE: So John, anything else you want to add in terms of how an oncologist will select which one of these 3 BTK inhibitors to utilize? Again, this is an issue across oncology. Last night, we were talking about the 3 CDK inhibitors approved in breast cancer. And if you don’t compare one against the other in a trial and you’re comparing then indirectly, it’s very hard to figure out what’s going on. What do we know about the comparisons between these 3 agents, John? And how do you decide which one to use?

DR ALLAN: Yeah. Brad mentioned that we’ve kind of moved away from ibrutinib for the most part and are moving towards these more selective inhibitors. Not, you know, I always state that ibrutinib is a great drug. It changed the world. It’s still an extraordinarily effective drug. But when you can get similar outcomes with less toxicity, it kind of becomes this no-brainer when you are trying to manage a patient to move towards these less toxic drugs.

With that said, all of these agents can cause class effects of A-fib, bleeding, arthralgias, rash. So you cannot get away from any of these issues, you just have to watch for them. And with the more selective drugs, you do mitigate how many patients might experience them. And obviously, that’s a win.

Now to choose between these drugs, there is no head-to-head data outside of acala versus ibrutinib and zanu versus ibrutinib. There is no head-to-head data between acala and zanu. And so we don’t know if there is truly a best-in-class, and so we are left — there is still preference, physician comfort. Just with blood pressure medicines and anti-lipid medicines, we sometimes try new ones, obviously, to get some experience with some of these. And it really comes down to that. Now there are some subtleties and nuances. Maybe acalabrutinib might have less hypertension. Zanubrutinib has an advantage of being a once-a-day drug. And so these kinds of minor nuances could influence which drug you might want to use. Your patient wants, doesn’t have many other medications, they want to take their medicine and be done with it for the day. That might be a zanubrutinib person because you can use a once-a-day drug. Ibrutinib is a once-a-day drug. So all these things can come into play and that’s kind of how we choose. And you eventually just kind of get into your comfort level. And the nice thing is, is that there’s good data that if you have an issue or toxicity with one of the drugs, you can still switch within the class and typically, that issue that you’re experiencing does not seem to recur with another agent. And so just by having a more selective drug and having some issue with it doesn’t mean that the whole class is out of it. You can start to play around with it and see which one works for your patient.

DR LOVE: So Brad, I think you alluded to this but I’m just curious what your thoughts are about it. Because we always pay a lot of attention to potentially lethal toxicity, and there has been some suggestion, I think more with ibrutinib, of the possibility of ventricular arrythmias, which a lot of docs in the community get very uncomfortable about because they hear about their patients dying in their sleep. And oh yeah, that’s great, they live 10 years with their disease, but why do they die in their sleep? And I know at this point, I’m not sure how much ibrutinib is actually being used. I don’t know if this has been seen with the other BTKs. But what about ventricular arrythmias?

DR KAHL: It’s definitely reported with ibrutinib. It’s rare. It’s in the 1% range. And I’m not sure if I’ve seen any reports of it with acal or zanu. So the risk is even less with acal and zanu, for sure.

The Potential Role of Therapy Combining BTK Inhibitors and Venetoclax

DR LOVE: So I want to also get into this issue of combining. And, John, there have been so many different trials now doing this, either BTK plus venetoclax or anti-CD20 and BTK and venetoclax. Usually, this is, again, time-limited. So now you’re getting the BTK, but it’s only for a year as part of this time-limited therapy. It seems very, as a very attractive alternative. Of course, nobody wants to do anything until they have convincing data from a clinical trial. But any thoughts about this strategy, John? And do you think this is sort of where we’re heading over the next couple years?

DR ALLAN: Yeah. So preclinically, meaning in vitro and in a lab setting, where we were trying to find best partners for these agents, there was a lot of rationale and actual synergies observed when you used a BTK inhibitor plus a drug like venetoclax or a BCL2 inhibitor. And the BTK inhibitor can shift that BCL2 family member of proteins a little bit and shift reliance on BCL2, et cetera. Also, redistribute cells from lymph node niches where they’re a little bit more protected from venetoclax, et cetera, out into the blood and out from the bone marrow where these protective niches are no longer available and accessible to the CLL cell. And for all of these reasons, these synergies were seen and observed. And that was the major rationale to then combine these 2 oral agents, our 2 best drugs, put them together, and they work better together. And so now, we have clinical data to support that, that these 2 oral agents can work effectively together, can achieve pretty high rates of MRD negativity and allow for yet another fixed duration.

The nice advantage of an all-oral approach without the antibody is that you can debulk patients very quickly and easily and mitigate tumor lysis risk when you bring in the venetoclax. Because typically, how you use them together is you start about 3 months with the BTK inhibitor. That rapidly shrinks bulky disease and mitigates that tumor lysis risk 2 or 3 months later. Whereas when you start patients with a white count of 200,000 and a spleen that’s 20 cm and lymph nodes that might be 5 or 6 cm, tumor lysis risk is still very real when you start the antibody, of anywhere from 6 to 10% of patients might lyse. So that’s one advantage of an all-oral approach. The other advantage is eliminating the anti-CD20, which in the era of COVID became much more relevant with prolonged B-cell immunosuppression. And so you can eliminate that.

Now data will suggest that the antibody is very effective. And it actually does seem to add benefit and deepen responses, honestly. And so when I first started using the oral approach, I was like this is what we’re going to use for everybody. And as the data caught up, we started to realize that not everybody gets there and it actually may take some patients a little bit longer to achieve that MRD negative endpoint that we’re looking for. Whereas the antibody helps speed that up, basically, and seems to get about 15% more patients to that endpoint rather than the oral approach together. So we are left in this space right now where we don’t know where to exactly use a doublet, where to use that triplet. These studies are ongoing that will help, these head-to-head randomized Phase III studies are ongoing. We have not seen any data. And so I think this is yet more data to support that we can do this. And in fact, doublets are approved pretty much everywhere in the world expect in the US. It offers unique advantages and, again, we’re in this space though where you have to look at the patient in front of you, the physician comfort with it and really discuss these options, advantages, pros and cons because right now, data does not state this type of patient needs this type of treatment. And really, anything can go and you can use any of these therapies for any patient, frankly. And that’s the issue where we stand now and the problem and the conundrum that we’re in.

DR LOVE: So just a quick question. You had a 65-year-old woman who got zanubrutinib and venetoclax, that combination. What was it like to, you don’t have to go into the whole case, I’m just curious what it was like when she got treated? Was it easier than, say, doing ven/obin?

DR ALLAN: Yeah. So this was a patient who had a very high white blood cell count, maybe 180 or 190 when we were about to start. This was a patient who was in a school system on a daily basis with young children and were around constant infections and all these types of things who was really intrigued by not having prolonged immunosuppression from a B-cell depleting therapy like an antibody like obinutuzumab, and had high-risk disease. And so this was really the impetus to say hey, there’s a lot of disease around. You don’t want this long-term immunosuppression due to the work environment that she was in. And that’s why we went with this off-label approach of zanubrutinib and venetoclax, of which she tolerated great. The white count came down very quickly as expected once the venetoclax came on board. Still is doing phenomenally well. The lymph nodes are in nice deep remission. And we’re working on trying to deepen that response because the response wasn’t quite MRD at the end of that 1 year. So we’re now doing some response adaptive things. And this is all off-label, but in an informed manner. And ultimately, we are going to get her off therapy. And that was really the big emphasis because she’s still rather young and with this high-risk disease.

DR LOVE: So we’re going to move on in a minute and talk about bispecifics in non-Hodgkin lymphoma. But Brad, just a word about pirtobrutinib. In all these small molecules and TKIs, they’re not all exactly the same. We had the kinome up there. They’re slightly different. It really affects the toxicity issue. What do you see? This seems to be more specific. Do you see less toxicity than with the other BTK inhibitors? And I guess the other thing is, you see people who will respond who progressed on the other type of BTK. So any thoughts, Brad?

DR KAHL: Yeah. We definitely see patients who progress through acala, zanu or ibrutinib. And you give them pirtobrutinib and they get nice responses, so it can be active when those fail. Like I mentioned a few minutes ago, it binds to a different part of the BTK molecule, so the resistance mutations that affect those, the first 3 drugs, often don’t affect this drug. It’s very well-tolerated. I’ve seen easy bruising, maybe some edema in a patient or 2. But by and large, this is really well-tolerated. So it’s another great option to have for our CLL patients. And there are studies looking to see whether pirtobrutinib could leapfrog ahead of the other BTK inhibitors and be used before them, but we don’t know that yet.

DR LOVE: That’ll be very interesting. Also useful in mantle cell lymphoma. CAR T, we were talking about transformation and people dying from CLL, which does happen. CAR T has been used and is approved to be used in CLL. I just want to bring this up because we’re about to talk about bispecifics, John. And just to get into that because some of the issues with bispecifics are similar to issues with CAR T, particularly the cytokine release syndrome and the neurologic syndrome that you see with CAR T. So more than, you know, maybe you can comment a little bit about CAR T in CLL and if you’ve had patients go for CAR T and what you’ve seen, but also, again, a little bit more in terms of the tolerability issues. And then, we’ll sort of go into bispecifics and how that’s similar or different. But let’s start with CAR T, John.

DR ALLAN: Yeah. So you can see the mechanism of action here. So we take the T-cell from the patient, we modify it in vitro, ex vivo in a lab, grow these cells up, lymphodeplete the patient and then deliver them back in about 5 to 6 weeks later, 4 to 6 weeks later. This has revolutionized how we treat lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, other indolent lymphomas and now CLL. It is approved after 2 prior lines of therapy including a BTK inhibitor and venetoclax. This was approved maybe about a month ago in the CLL space. And it can be effective. Now when you look at the CR rates, they are way lower than what we might see in lymphoma where it’s about 20% or so. But these patients basically might be cured, honestly.

And I don’t know if you’re familiar, there was a New York Times article from some of the first patients that received CAR T for CLL at Penn. But they had been followed for 10-plus years with still detectable CAR T-cells, no CLL present. And while there’s a small number of patients that can achieve this very deep remission, what’s also unique and different than other histologies is that the partial remissions, actually, there’s a pretty good clinical benefit where the median PFS, even if the partial remission patients, can go 2 to 3 years or so. And so it may come down to some response criteria that’s used for CLL versus lymphoma. The iwCLL criteria for a CR is very stringent and you have to have all of your lymph nodes essentially disappear whereas in lymphoma, you don’t. You just need to have your PET scan clear.

So little nuances there. But ultimately, you can get a lot of stable benefit, even in partial responders. And I think we welcome this treatment to our patients. There are patients that are going to fail our covalents, they’re going to fail venetoclax, they’re going to fail pirtobrutinib. And this is just another treatment that actually might rescue some of our sickest patients and offer them really long-term cures, or remissions.

DR LOVE: And in lymphomas, which we’re about to talk about, now CAR T has had a phenomenal effect. Diffuse large B-cell, maybe curing a significant fraction of patients with CAR T. Approved in follicular. Approved in mantle cell. So CAR T without coming behind it with a similar sort of T-cell principle or bispecifics, which is what we’re about to get into.

Just to sort of finish out on CLL, we’ve got some great questions from the audience. We won’t talk about it, but just to put it in your head. Current research studies, or if we have time later, on Richter’s transformation. DNA gum swab to try to figure out which BTK inhibitor will work best. I like that idea. How you know when to dose reduce people. And I really like this one. What role will AI technology have on CLL treatment? Compare your recommendation to ChatBTG. But in any event, so as we mentioned, CAR T is approved in CLL as well as in non-Hodgkin lymphoma. Several preparations, and we’re going to start to get into that.

I want to show you another video. This is from Amy Goodrich, another nurse who has worked with us over the years. She wasn’t able to make it here, but we wanted to get her input. Amy, it’s interesting, we’ve worked with her for many years. And Amy kind of filed under things happen in this world, things happen in this world. She sent me a picture of her view outside her window at Hopkins in Baltimore. Just kind of a reminder that sometimes, things happen you never would expect. Here’s some thoughts Amy has starting out with something we’ve already alluded to but we really want to get into a little bit, the interactions between community-based oncologists and tertiary centers, where that’s been and where that’s heading with regard to these types of therapies.

MS GOODRICH: Our perfect example is in CLL when venetoclax came out. We would commonly do the ramp-up and then send patients back to their local oncologist for the remainder of their therapy. We’re really not even doing that so much anymore because I think there’s more comfort in the community with venetoclax. But the bispecifics are really where I see this being our next frontier for that partnership, you know, getting patients through that ramped up, that stepped-up dosing, the dose escalation, getting that CRS and ICANS risk phase over with or the high-risk phase over with and then transitioning patients back to the community. I don’t think we’re there yet because I think we are still very much figuring out how to flow these patients through our own system. But I think that very quickly, we’re going to be ready to transition folks back to the community to get these drugs much closer to home after that initial acute period.

DR LOVE: So again, Mollie, any thoughts about this? Again, the idea — when venetoclax first came out in CLL, again, the docs in the community didn’t want to ramp these people up. But then, they saw you all do it, they learned how to do it and they were able to do that. We’re hoping the same thing is going to be happening with bispecifics. Any comments though? You’re in Ohio, a little bit more spaced out.

MS MORAN: Everything is a little spread out.

DR LOVE: Right. How you interact with community oncology.

MS MORAN: Yeah. I think the biggest, the most important when you deal with out — is communication, as I’m struggling with at the moment. Communication, it’s making sure that they know what we’ve done, what we plan to do, what’s the next step, how do you manage these patients. And that communication can’t be just with the referring physician. The whole practice has to buy into being able to do some of these more complex protocols. And that means include the nurses in the decisions. And how do we educate the nurses locally? And make sure that there’s an open line of communication, whether it’s 1 phone number to call or 1 person maybe even to come out and show you how things are done and walk through a single patient and basically hold hands as you go through. And that’s hard, sometimes you forget about that when you’re in an academic center because your volume and you’re moving things along. And so you have to sort of package these folks up very nicely with implicit directions on what’s the next step, what do you do when A happens, what do you do when B happens, when do you run up the flag, when do you get someone else involved. And so communication, I think, is going to be key on our end to make sure that people feel comfortable with these drugs and with these patients as they head back to the community.

Bispecific Antibodies as a Treatment Option for Non-Hodgkin Lymphoma

DR LOVE: So we’re going to kind of get into more in terms of how the drugs work and the tolerability issues. But again, Brad, just to pick back up on this issue of community interactions, et cetera. Because there’s just too many patients out there for you all to be able to treat everybody. But again, we’re talking about particularly cytokine release syndrome, a syndrome that really hasn’t been treated very much in the community setting. And incidentally, there’s a pretty hot-looking CD3 bispecific in small cell of the lung. So they’re going to have to figure it out as well. And that’s another theme, we were talking about this last night, when drugs come to specialties that haven’t used it before. Brad, how do you think through this in terms of when it's okay to start a patient on outpatient? When would it be okay to start the patient’s treatment in the community?

DR KAHL: Well, I think that’s, to answer the second question, that’s going to be up to the community doc and their comfort level. And I totally agree with Amy. I think, like with venetoclax, they will get there with the bispecifics. There’s always a little fear of the unknown. Once they treat a few patients and they get comfortable managing it, then I think the flood gates will open and they’ll be really comfortable. But for right now, we’re more than happy to take these patients that need bispecifics and get them started and get through the high-risk period. Right now, we’re just following the package inserts. So mosunetuzumab, no inpatient stay is required. Glofitamab and epcoritamab each have 1 brief hospital stay required, the day 8 dose for glofitamab and the day 15 dose for epcoritamab. Who can remember all this stuff? So we just do it that way for now. I wouldn’t be surprised though if we get to the point where we don’t feel like the hospitalization is really required. But these are very new drugs. They’re even, you know, they’re new to us, so we’re taking it cautious at the beginning and just following the package insert.

Cytokine Release Syndrome and Neurotoxicity with Bispecific Antibodies

DR LOVE: John, what about cytokine release in the community setting? Do you need to have tocilizumab available? And what’s the spectrum of what you see? I’ve heard stories where investigators have managed cytokine release as an outpatient and given people, with mosunetuzumab, a prescription of steroids. They say call me if you get a fever, and treat over the phone. Everything from that to having to bring somebody in. Can you talk about that whole dynamic of CRS? And that’s why I brought up CAR T, because that’s really where we first saw it.

DR ALLAN: Yeah. So with bispecifics, CRS can occur. The nice thing about bispecifics is that the rates of high-grade serous are much less than what we saw with CAR T. Same with ICANS whereas ICANS with CAR T can be anywhere from 15% to 30% Grade 3 or 4 or greater. Typically, any grade with a bispecific, less than 5% and typically in the single-digit percentage of high-grade — I’m sorry, any grade ICANS. So ICANS is much less of an issue with bispecifics, fortunately. CRS is seen. Typically it is low grade, Grade 1 or 2.

And to your point, Dr Love, Grade 1 CRS is typically a fever. We usually see these in the first week or 2 depending on the agent that you’re using. And each agent specifically might have a little bit of a different percentage of these. But in general, Grade 1 CRS can be managed with conservative measures, acetaminophen, having educated patients to say be measuring your temperature, getting a blood pressure cuff, having an O2 sat oximeter at home. These are the things to watch for.

And obviously, Grade 2 or greater, that’s where we want to know about it and where we would be bringing patients in. But I’ve had patients that have had a persistent fever, and it was just a fever that persisted for a day or 2 to where finally, the acetaminophen wasn’t working, where they had the script at home and we finally said, yeah, take the dexamethasone. And sure enough, I was like if it persists the next day or you wake up and the fever has come back, that’s when you’re coming into the hospital. No questions about it. And sure enough, it mitigated it. The patient stayed out of the hospital. But that’s still a rare thing. Most patients are doing pretty well. It might be a Grade 1 a day, take some acetaminophen, it goes away. You don’t have to do these more advanced treatments.

But in general, we do send them home with steroids because even though toci is the mainstay treatment for CRS and higher-grade CRS, steroids can help mitigate that. And when you’re in a pinch and at home, you want your patient to have that so they can take it and they might be on the way to the ER or whatever, but at least they get something on board and start to control and decrease that inflammation that can start to escalate on you.

DR LOVE: Brad, you had a comment. And also, Brad, I was curious about your thoughts about the neurologic syndrome. With CAR T, they would say you need to have family members there because sometimes it’s delayed and only the family is going to notice they’re different. So what were you about to say with response to John? And maybe you can comment a little bit on the neurologic syndrome.

DR KAHL: Yeah. Just to echo John’s points, the toxicities with bispecifics are just very different than CAR, much milder, much easier to deal with. The neurologic toxicity almost never happens. It’s really rare. It’s mostly CRS and it’s frankly pretty easy to manage. I actually don’t want my patients going to the ER and getting the million-dollar workup when they get the fever the day after their bispecific. We send them home with dex and I’m like yeah, if your fever, if you feel like you have the flu, I say take the dex. Because I know what’s happening. We gave them the drug yesterday and the next day, they have this fever. You just know what it is. And that almost always takes care of it. There’ll be rare instances where they’re going to have to come in and get toci, but not often.

DR LOVE: We’re going to talk about BRAF therapy tomorrow night. Same thing, they see fevers there and they don’t work them up. They just give them steroids and tell them to take it.

Other Tolerability and Toxicity Issues with Bispecific Antibody Therapy

DR LOVE: I want to get into the issue of bispecifics. Frankly, I’m hoping you can straighten this out for me. Not just about the infections, infectious risk, not just with the relationship to bispecifics. But I kind of held off on getting into it in depth with the CLL, but I want to talk about that too. So vaccinations, infections, how you manage that. But here’s Amy’s initial thoughts about it.

MS GOODRICH: The bispecifics are getting moved up sooner and sooner in therapy for many patients. So somebody on second or third-line therapy is not going to have the immune system incompetency that somebody who is on their tenth line of therapy is going to have.

The other thing with infections with bispecifics is really looking at that prescriber’s information in the package inserts. So mild infections, for most bispecifics, you keep treating because if you hold a bispecific for X amount of time, you have to start the escalation over again. You start it at the lower dose again. And I think that is something that’s very different than many of the newer agents that have come to market, the fact that if you have a gap in the administration, you start over again. And I think that just awareness of that is a really critical point. But using your prophylaxis and watching those IgG levels is important to try to prevent infections.

DR LOVE: So John, maybe you can start and talk about what we know about the risk for infection, how people respond also to immunization with CLL and people who are on bispecifics, for example.

DR ALLAN: Yeah. So CLL is an immunosuppressive disease state like most indolent lymphomas and all lymphomas. But CLL is seemingly different a little bit more so in its ability to cause a disruption between the T-cell and the B-cell synapse. And so CLL patients are unique in that as disease advances, they get more and more immunosuppressed and, therefore, can be at risk for developing kind of like AIDS-defining type of infections like PCP pneumonias, PJP pneumonias and CMV viral infections and other things like that that can come out, shingles, and have very difficult times sometimes with COVID and organizing pneumonias and these inflammatory things that occur afterward. So it’s something that we need to be aggressive with, to stay up with guidelines on vaccinations, pneumonia vaccines, shingles vaccines, which are inactivated nowadays, and COVID vaccinations, et cetera. So we stay aggressive with them.

Regarding bispecific, it’s also a very B-cell depleting treatment. You can become hypogammaglobulinemic. In the studies, they have reported CMV reactivations, PJP pneumonias, other infections. And so over time, you have to watch for this. And these hypogammaglobulinemic patients, if you’re starting to see recurrent infections, these are people who you need to strongly start to think about repletion with intravenous immunoglobulin or IVIG.

DR LOVE: So Robin, can you kind of add on to that in terms of your clinical experience, again, in terms of preventive and prophylaxis, treatment, vaccinations?

MS KLEBIG: Definitely, I would echo the importance of the vaccinations. And in this day and age, too there’s a lot of people who they don’t want to get the COVID vaccine. But it’s so important to give them that education. And in the end, it’s their decision, but we definitely recommend that.

I think we definitely base a lot of our prophylaxis on what their counts are. So if they’re lymphocytopenic or if they have low CD4, we’ll have them on prophylactic antimicrobials with acyclovir and a PJP prophylaxis, and typically not routinely, antibacterial prophylaxis like with levofloxacin unless they’re really neutropenic, especially if they’ve had previous therapy. But also, the education too as far as teaching them basic things like good handwashing, common sense things like stay away from people who are sick, try to stay out of crowds, and really making sure they have a thermometer so that they’re monitoring for any symptoms and getting seen if they have symptoms. Because that’s the sad thing about CLL and lymphoma, is sometimes their disease, their cancer might be doing well but they may end up getting really sick or dying from infection.

DR LOVE: So let’s get more into more detail about the bispecifics, what they are, how they’re different and what they’re used in various tumors. So, Brad, maybe you can start out and talk about your vision for what a bispecific is. We’re seeing so many throughout oncology. Not just immune based, but also attacking 2 parts of the tumors like we were talking about bispecifics with HER2, et cetera. What is a bispecific, Brad?

DR KAHL: Yeah. It’s pretty easy to explain, actually, because we’ve been explaining rituximab for 25 years. And so I would explain rituximab to a patient, we’re going to give you this antibody, it’s infused in your blood. It’ll go stick to your cancer cells and it’s going to trick your immune system into fighting the cancer. Well that’s exactly what the bispecifics are doing as well. The only difference is the rituximab was kind of inviting the immune system, the bispecifics are insisting the immune system come in and fight. So the bispecifics are more potent. And for patients, it’s kind of appealing. There’s no chemo. You’re working through the immune system. But that’s how I try to explain it to patients.

DR LOVE: So John, here’s a list of the 4 that we’ve seen the most data on. Can you kind of provide an overview of what the difference is, where they’re being utilized and sort of where you see things heading with these agents?

DR ALLAN: Yeah. So there are 3 currently FDA approved, as you can see there. They do have different histologies that they are approved for. So mosunetuzumab is the only one approved for follicular lymphoma, as of right now, though others may enter that space like epcoritamab or even odronextamab potentially. Glofitamab and epcoritamab are the only approved after, for DLBCL, both after 3 lines of prior therapy. And again, these drugs all seem similarly active. The use of them is a little bit different in terms of the administration. Epco is the only subcutaneous one. And the dosing schedule is slightly different whereas glofitamab, you actually have to add in an initial dose of obinutuzumab. And so each is a little bit unique.

In the lymphoma space, they all target CD20. Though in myeloma, they target other proteins like BCMA and other things like that. Blinatumomab was one of the original BiTEs or bispecific T-cell engaging antibodies, which targeted CD19. But it didn’t have the Fc fragment and it had short half-life and all these types of things that we, as technology advanced, developed these more advanced antibodies, as you can see here listed.

Bispecific Antibodies for the Management of Follicular Lymphoma

DR LOVE: So I want to hear about, Robin, your case in a second of your 82-year-old lady who got mosunetuzumab, actually, sub-Q on a clinical trial. But before we get into that, we’re going to focus particularly in follicular lymphoma and diffuse large B-cell lymphoma. Brad, can you kind of provide a little bit of an overview of where we are right now with the sequencing of therapy with follicular lymphoma? What are the bispecifics that seem to be relevant there? And where are they fitting in now? And where do you see them fitting in in the future?

DR KAHL: So in follicular lymphoma, 2024, probably if you have a high tumor burden patient, they’re probably still getting bendamustine/rituximab or some folks like R-CHOP or obinutuzumab/CHOP or something like that in the front line. Probably the most common second-line regimen would be R-squared, lenalidomide/rituximab. It can be used in second-line according to its label.

Now when you get into third line, then lots of things open up. And that’s where I see mosunetuzumab fitting in right now. It’s very active. The overall response rate and the complete response rates are high and the durability is very good. Most patients are still holding the remission at 2 years. And it’s pretty well-tolerated. Obviously, you have the CRS risk at the beginning. You’ve got to work through that. But once you’re past that, then that’s behind you. Once people are just getting their every-3-week infusion, it usually goes very smooth. I’ve seen a little bit of neutropenia with it. You have to watch for that. And, of course, there is the B-cell depletion, so you have to be on high alert for infections just like with any treatment we give. But I see right now, mosunetuzumab solidly is the third-line therapy of choice in follicular lymphoma and it could move up into earlier lines with further study.

DR LOVE: So let’s see how this plays out. And what happened with this 82-year-old lady who got mosunetuzumab?

MS KLEBIG: So this was an interesting situation. It is a clinical trial using subcutaneous mosunetuzumab in an untreated person. And this was not your typical 82-year-old lady. She’s not like a little old grandmother sitting at home knitting and looking at pictures of her grandchildren. She and her husband were very active. They owned a business. They owned also a golf course, so she golfed every day. And she actually lived about 3 and a half hours from our center, but she wanted to come to our center and see what we had for treatment. Decided to go on this trial, which meant that she had to be in town staying at site for 3 days each week while she was being ramped up. So we felt a little bit lucky that she took the time out of her busy schedule to come up and stay with us. But she actually did very well. She was, again, a very intelligent lady. Every time I saw her, I knew I would be, it would be a prolonged visit, let’s just say. She had a lot of questions. I always wondered if she was a librarian because she would just take such intricate notes and she would refer back to, okay, when I saw you 2 weeks ago, you told me this. And so I always want to make sure I mind my P’s and Q’s. But she ended up doing really well. I don’t know if you want me to tell you the story about her PJP prophylaxis.

DR LOVE: Sure.

MS KLEBIG: Yeah. She had very specific ideas. She had no healthcare background, but she did a lot of reading. And so being, taking the antimicrobial, she was on sulfa for PJP prophylaxis in addition to the others. And when she went in for one of her ramp-up sessions, the hospital team noted that she had a rash. So they determined that well the rash must be due to the sulfa. So they stopped that, put her on pentamidine. And she didn’t like that because she had to go in and it was off schedule and she had symptoms. Subsequently, it was determined that maybe the rash was due to the mosunetuzumab, which was a fair thing to think about. But yet, if somebody has listed now, it’s on their chart that they’ve got this allergy, nobody wants to put them back on it, right? Well, she came to see me. And she was just very persistent and demanded basically. I don’t want to take this pentamidine anymore. It makes me cough. I get short of breath. I said, are they giving you the albuterol with it? Yeah, they’re doing all the things. And I verified it. I just know that that rash was not related to the antibiotic, I want to go back on that. So I said okay, I will give you this prescription. You need to be very mindful. If you have any hint of a rash again, you stop it immediately, take some diphenhydramine, let us know what’s going on. If you get really sick, obviously, go to the ED. But fortunately, she did well. She got her wish. She went back on the sulfa. And she knew what was best for her, I guess.

DR LOVE: I guess. So we’ve been talking about these agents. I really like this graphic. Brad, maybe you can talk a little bit more about specifically the way these agents actually work, starting out here with mosunetuzumab.

DR KAHL: Yeah. They’re call T-cell redirecting agents. So the antibody will bind to CD20 on the B-cell and then it’ll bind to CD3 on the T-cell, so it brings the T-cell in proximity to the B-cell. And when that happens, that’ll trigger the T-cell to release its contents. They’re called granzymes and perforins. They literally will punch holes in the cell membrane of the B-cell and cause the B-cell to die.

The Role of Bispecific Antibody Therapy in the Treatment of Diffuse Large B-Cell Lymphoma

DR LOVE: So we want to talk also about bispecific antibodies in diffuse large B-cell. And before we get into that, John, can you just talk about where we are right now in general with diffuse large B-cell up-front therapy and then therapy of the relapsed patient? And then, we’ll start to look at how these bispecifics, particularly these particular two, glofitamab and epcoritamab, fit in.

DR ALLAN: Yeah. So diffuse large B-cell lymphoma is a highly curable disease for the vast majority of patients, even with really high-risk features and a lot of risk factors against you. Only about 20% to 30% of patients may relapse after front-line chemoimmunotherapy. So that bar is pretty high to overcome. And over the past 30-plus years, R-CHOP has remained kind of the standard of care until very recently when a new antibody drug conjugate called polatuzumab was introduce to an R-CHOP backbone and actually, for the first time in a long time, showed a true progression-free survival benefit at the 2-year mark. And it was modest, but it was the only study that has technically met that primary endpoint. And so the standard of care in the front-line setting has started to shift. Because there’s no overall survival benefit and because there was subgroup analyses showing certain patients may be doing best with the polatuzumab and the majority of that effect being in these higher-risk subgroups, some are favoring just polatuzumab/R-CHOP for those types of patients versus R-CHOP. So it’s not the standard of care despite the fact that it did beat R-CHOP. But now, we have kind of 2 approaches that we use in that front-line setting.

Subsequent, it all comes down to the time of your relapse and is it within the first year or not. And if it’s within the first year, CAR T-cells are standard of care as now second-line treatment. Bispecifics currently remain in third-line or later settings, and so it can be potentially a question of which to use. Let’s say a patient relapsed at 3 years, the standard of care there is to get a stem cell transplant after chemo. And so if they relapse beyond that, you have both CAR T-cells and bispecifics currently available. And so we don’t know the best approach and which is most effective in a specific sequence. And that comes down to the patient factors and things like that. CAR T-cells seem to be potentially maybe a little bit more effective when you look at the numeric outcomes. But with that said, bispecifics are so well-tolerated and so effective, even post-CAR T-cells and in these high-risk third-line and later settings, that this agent is now moving up. And we have pivotal registrational Phase III clinical trials that are ongoing in the front-line setting in combination with R-CHOP-based treatments. And so it’s not going to sit in a third-line and later salvage setting for long probably if what we see from the early Phase I and II studies continues to show because high-risk patients respond really beautifully and the toxicity seems very manageable.

And it’s very possible that bispecifics may actually be able to move into a first-line setting in combination with chemo. And even in our older patients, we might even get to a chemo-free approach where they can’t tolerate R-CHOP, and these drugs might actually be able to offer cure to some of these older patients that aren’t able to address the — tolerate these aggressive approaches. So that’s where bispecifics currently are, but it’s a fast moving, quick evolving, exciting area of research that every 6 months to a year, each congress that comes out, more data. You have to sit down for hours to wrap your head around this stuff and really stay up to date.

DR LOVE: So Brad, maybe you can talk a little bit about these 2 bispecifics that seem to have so much activity. But before you get into that, I guess one of the issues here that John just alluded to is what comes first in a patient with diffuse large B-cell, bispecifics that maybe is going to be better tolerated or CAR T where maybe you can see the patient cured? How does this decision get made, Brad? And as the patient gets older and with more comorbidities, how does that affect it?

DR KAHL: Right now, most of the time, CAR is going to come first. And the reason is we have more experience, longer follow-up and we feel fairly confident that the CARs are curing a proportion of patients. We don’t know that yet about the bispecifics. They’re too new. And so my answer might change in a few years once we have longer follow-up from bispecifics. But right now, CARs are generally going to come before bispecifics. Now there will be exceptions, of course. You can have patients that, because of age or comorbidities, are just not appropriate for CAR T-cell therapy. And by and large, bispecifics are much easier to administer, safer than CARs. And so there will be times where you will move a bispecific ahead of a CAR depending upon the patient.

DR LOVE: So epco with a familiar mechanism there. Can you talk a little bit about what we know about it specifically?

DR KAHL: Right. So a bispecific works like we just described a few minutes ago. The unique things about epco, it’s given subcutaneously, which is nice, it’s a shorter chair time for the patient. The CRS, over half the patients get some CRS but it’s usually Grade 1 or Grade 2. The ICANS is really rare, like we said before. It almost never happens. The epcoritamab schedule is a little intense. It’s given weekly in the beginning and then every-other-week for many months, so there’s a lot of trips to the doctor to get the epcoritamab. And unlike the other bispecifics, it’s not a fixed duration therapy. This one was designed to be given indefinitely.

DR LOVE: So you had a 60-year-old woman who got glofitamab, Brad. What happened with her?

DR KAHL: Yeah. So this is sort of the exception that proves the rule. So she was only 60. She had follicular. It transformed. And so now, we had to manage her diffuse large B-cell lymphoma. She had very severe emphysema, really heavy smoker. So she’s like an 80-year-old 60-year-old. And we got her in remission from the large cell, but then it came back. We took her through another round of chemo, it came back. I knew she was not appropriate for stem cell transplant or CAR but just to do my due diligence, I sent her to the cellular therapy team. And they couldn’t send her back to me fast enough. They said absolutely not. So anyway, her most recent treatment, we started her on glofitamab. And I was a little nervous about it because her lungs are so bad. We admitted her for the mandatory hospitalization stay. But it’s really gone remarkably smooth. She hasn’t had any CRS, knock on wood, or infections. And her PET scan after 3 cycles shows she’s in a CR already. And we’re just finishing out the planned 12 cycles of glofitamab right now, but it’s going remarkably smooth.

DR LOVE: So John, do you want to talk a little bit more? This is, again, another visual to try to explain the way these drugs work. Your comments on glofitamab.

DR ALLAN: Yeah. So glofitamab has a unique structure. It actually has 2 CD20 binding sites compared to just 1 on all of the other agents. And this translated to actually improved efficacy. So when this drug was in development, compared to an agent like glofitamab, because they are actually being developed within the same company, this agent actually killed more cells. And so there was a benefit to having this extra CD20. You can bind more CD20, you can activate more T-cells, et cetera. And so that kind of went forward in more aggressive histologies, et cetera. But with that came seemingly more CRS and more activation, more immune activation. And glofitamab had kind of some of the higher rates of CRS and even ICANS in some of the studies. Now it’s still rare and much less than CAR T-cells, but this unique mechanism was probably partially a cause of that. Now glofit, in order to help mitigate that, actually requires a pre-dose of obinutuzumab which is an anti-CD20 antibody. So in a way, it kind of sops up some of those free CD20 antigens. And kind of in doing that, blocks some of that activation. And once that came onto play and became a standard for using this agent, mitigated a lot of that higher CRS and did not seem to affect an outcome or a long-term remission or CR rate or anything along those lines. So that’s another unique aspect of glofit comparatively to the other agents that we’re using.

DR LOVE: Robin, can you talk a little bit about how you explain to patients what bispecifics are and what you’ve observed in terms of how patients do on them?

MS KLEBIG: So basically, the first thing I tell them is it’s not chemotherapy, it’s immunotherapy. And it’s targeted therapy, as we’ve kind of talked about. These patients have B-cell lymphomas. And so the bispecifics, so these are 2 antibodies. So the one targets the B-cell just like rituximab would, targets the CD20, and the other one, the other part of the Y as when I draw the picture, it targets the CD3 on the T-cell. So it kind of brings those cells together. You get the cell kill with the CD20 antibody, but then you get also kind of introducing the T-cell to, hey, this is what you want to go after. And so as I usually tell people when they’re going on immunotherapy, your immune system is designed to really protect you. So your immune system is going to get really excited. It’s going to probably overreact, and that’s why we expect some of these symptoms like cytokine release syndrome, the neurotoxicity and that sort of thing. And so those are the kinds of main things that I talk about.

Now if people have heard about the CRS or CAR T-cell therapy, they might get a bit nervous about it because they can sound extreme. And I think sometimes as nurses and healthcare professionals, we get nervous too. But we always want to make sure that we reassure them. So we’re teaching them how exciting and how effective these new therapies are, but we also want to make sure that we instill confidence in them. We tell them, okay, we know how to manage. We know to expect this. It might happen, it might not. But we’re going to expect it and we’re going to have everything ready in case it does happen. So we know that there are guidelines that we can go to, there are ways that we grade these symptoms, these toxicities if we have them. And it’ll, you know, we can actually look at the algorithms. So we point to things like NCCN guidelines and just make sure that they’re comfortable and they feel confident in their care team.

DR LOVE: I see you actually had a 38-year-old man, a young man who got mosunetuzumab. Can you talk about what happened to him? I see he also had a couple of young children. That’s something we’ve talked a lot about in the ONS meeting over the years, patients with serious illnesses with minor children and minor grandchildren. What happened with him when he got the mosunetuzumab? And what’s going on in his family?

MS KLEBIG: I’m so glad that you asked me because this is probably my favorite story. So yeah, 38, that’s pretty young to have follicular lymphoma and need treatment, but he was on the same clinical trial getting the subcutaneous mosunetuzumab. So 38 years old, you know, that’s like right in the primetime of your life. Was married. So he worked as a, like owned or managed an auto parts store and he was also a firefighter. His wife also worked a very stressful job. They had 2 children in elementary school. He was also a coach for the teams for his kids. And then in the meantime, he comes up with cancer, and has to come for treatment. And as we talked about, this is like weekly treatment. He’s got to be at our site for 3 days out of each week, and he lives like 3 hours away. So he’s having to arrange childcare because he was an involved dad. It wasn’t just I’m going to leave that up to my wife. No, he was involved in all this. So we were talking about things to look for, the CRS and the potential neurotoxicity. And as Brad said, it’s not very common but we still let them know about it. So after he was coming in a few weeks, one thing he told me is, well, you know, his busy life, we decided to get a puppy. And I wanted to say, are you crazy? You’ve got all this going on in your life, and you want a puppy. Okay, whatever.

So then, a couple weeks more go by, and he comes in. And his wife, they’re very concerned because he now has developed, he’s forgetful and he can’t think of the words sometimes. He’s coaching and he can’t remember some of the names of the players on his team. So this is, of course, very concerning to all of us. Well especially when you’re on a clinical trial, you’ve got to really be careful about what symptoms and side effects. So we held treatment that day. We said we’ve got to get him to see neurology, just make sure nothing is going on. And in the back of my mind, I’m still thinking, okay, he’s got a lot going on. But sure enough, went to neurology, had the complete workup including an MRI of the brain. And the bottom line was, the neurologist says, you’re stressed. You’re stressed and you’re sleep deprived, but there’s nothing neurologically wrong with you. So he was able to resume treatment. Side effects, you can expect but it might not all be related to the drug.

DR LOVE: What a great story. What’s going on with his 6- and 7-year-old children? What do they know about what’s going on?

MS KLEBIG: They came actually, they brought them one time to the visit. And they, I think they’ve taught them that, yes, Dad’s got an illness but he’s getting treated. And despite all of the stuff going on in their life, they’re not super-anxious people, actually. So they’re very good. And on the days that he does come down or that he did come down, he’s through that phase now, but they were able to stay with grandma and grandpa, so they thought that was pretty cool.

DR LOVE: So another bispecific, John, odronextamab. And you actually had a patient who received the drug. What’s the difference between this and the others? Again, in oncology, we see multiple agents within similar classes and we’re always trying to figure out what the difference is. What is it here?

DR ALLAN: Yeah. So I was involved with this agent for many years, actually, as part of their first-in-human Phase I study. And so this drug actually really made me a believer of, wow, this is going to change how we treat patients. There’s no doubt. Because I had a young patient, he was maybe 47 when I first met him. Post-auto, post-CAR T, and came to me refractory. And also, with several children. And this is somebody without some of these drugs, you know, if the next thing doesn’t work, you’re running out of time. And so enrolled on this Phase I study with odronextamab specifically. And I can proudly say he’s still on this drug and he’s now almost 5 years later in remission.

DR LOVE: Wow.

Other Practical Considerations with the Use of Bispecific Antibodies

DR ALLAN: And this is a drug that is to progression like epcoritamab. Remains on it and isn’t really having major infectious issues. He was so immunosuppressed from all the other things he’s had. He is getting IVIG. He gets these recurrent URIs and things like that, but we manage it with IVIG. And he’s out there and living life and working. And I don’t see it stopping. So this case specifically really made me a believer, like this is changing the game. And now, it has.

Now odro, unfortunately, has not achieved an FDA approval. It had a PDUFA date a month or so ago. And it has lagged in its development, even though it was one of the first drugs being dosed in patients. Because of some issues around the trial enrollments and things like that, the FDA has kind of put a pause on the accelerated approval. It’s an active drug. It’s probably going to cross the finish line. But it is unique in that it is a little bit more cumbersome in terms of dosing, at least in the trials. How will it be dosed when it’s FDA approved? Could they modify that? It’s possible, I suppose. But this drug requires 4 interim doses before you get to full dose whereas all the others are about 3, so it cuts 1 week off. And in addition to that, it actually, in the studies, requires a split dose. So patients are being admitted where they get half of the dose on day 1 and then the other half on the following day where all other agents get the full dose of that week on that 1 setting.

And so there’s some logistical issues, and it’s maybe a little bit more cumbersome and that’s a unique aspect of this drug. But nonetheless, very effective, very effective in follicular lymphoma, very effective in all of these disease histologies post-CAR T. It looks very similar to all of the currently FDA approved agents. And so it is out there, keep an eye on it, watch that space because this would be a potential fourth agent that we might have to treat our patients.

DR LOVE: So Brad, you’ve been so involved with clinical research, particularly in the cooperative groups. I’m curious, you hear all these new agents, all different strategies, how you as researchers sit down and try to figure out what’s the next trial, what’s the next strategy. There’s so many different potential ways to go. How do you all figure this out? How does industry become involved? They’re also funding tons and tons of research. Can you give us a little bit of insight of how you sort of figure out what the next step is going to be?

DR KAHL: Well, it’s a good problem to have. And, I mean, yeah, we’re literally just sitting in a room sitting around a table trying to think, okay, what questions make the most sense, what advance would make the biggest leap forward in the field. And we’re trying to design studies using those principles. I can tell you that we’re very excited about bispecifics as a class. Just to give you a couple of examples. The cooperative groups within the next month or 2 will be opening a trial in low tumor burden follicular lymphoma, like a resort population, of rituximab versus mosunetuzumab in the front-line. So just antibody versus antibody. And I just had a call with Genentech this week, and they want us to try to design something in high tumor burden follicular lymphoma using mosunetuzumab. Now it’ll probably be in combination because in high tumor burden follicular, single agent mosun may not be enough, so we have to decide what’s the best combination partner. And that would be compared against a standard approach like bendamustine/rituximab. So we’re taking mosunetuzumab and we’re moving it right to front-line in follicular lymphoma, and we’re going to test it there.

DR LOVE: Should be really exciting. John, anything you want to add to that? What do you see in terms of the future of these strategies? Particularly, as Brad was just talking about, in both follicular lymphoma, diffuse large B-cell, also mantle cell lymphoma. We haven’t talked about that as well. But that certainly responds to CAR-T therapy. Where do you see this heading, John?

DR ALLAN: Yeah. I think with most new drugs, the sooner you move them up, and particularly in drugs that harness the immune system, the earlier you use them, the stronger that immune system is, the more functional that it is, the more effective the agent is. And so I think it’s an exciting space to see these outcomes improve as we use them earlier and earlier, and really start to move the needle. And I think it is something that we’re lucky to practice in this day and age to be able to offer these to our patients.

DR LOVE: So I want to move to another section here. We may come back and pick up on some of the questions we’re getting from the faculty. But one of the topics we’ve had over the years in ONS has been avoiding burnout. And we mentioned last night that we were going to show one of the nurses that we talked to. If we can bring up, yeah, there we go. Ms Glennie, who actually focuses her work on AML, told a pretty interesting story. And I’m just kind of curious what your all thoughts are, both on the panel and also the audience. She graduated nursing school at the age of 22, decided kind of naively to go to work in a bone marrow transplant inpatient unit. She told me quite a few interesting stories of, of course, younger patients and a lot of trauma that she experienced. And it was just too much for her. Yet here she is. So we’re going to talk about how she got from point A to point B. Here’s Ms Glennie.

MS GLENNIE: I was 22, 23. To be honest with you, I don’t think I realized I was burned out until I had quit. I thought that I just wanted to take some time off to travel. But it turns out, once I got a little space between me and that particular job, I realized how burned out I was.

I was not sleeping well. I was not eating well. I look back on kind of how rocky some of my relationships, friendships and intimate relationships, were. I’m married to Henry, who I was with during that time period, and it’s kind of a miracle that we survived. But I was not myself. And again, it took that space for me to be able to realize that I needed some time away.

As I think most health systems do, we had an employee assistance program, the EAP, and I remember calling because one day I woke after like 3 hours of sleep from night shift and was pacing around my house. And I remember calling the EAP, and she went through, I think it would have been the PHQ-9, right? And it took somebody asking me those questions verbally for something to kind of go off in my head and say oh, oh, this is — there is something going on here. This is not my normal state. It was very helpful to talk to somebody just about the sort of symptoms and the feelings that I was going through.

I remember one of the questions she asked me, she said, “Sonia, do you feel like you have trouble accessing your emotions?” And I was like, accessing my emotions? What does that even mean?

DR LOVE: So Mollie, any thoughts? I’ll say myself, I had a great experience a long time ago with an employee systems person as well. Any thoughts here in the beginning of this story?

MS MORAN: I think the hardest part as a nurse is to recognize that maybe you do need to take a step back and reach out to someone for help. And I think as times have — if you ask any nurse how much actual nursing they get to do, they probably say not as much as they would like to, right? And that’s just the change in how complicated these patients are and complicated these therapies are. And so that reward part of nursing that you found at the core of you and why you went into it are sort of being, you’re being robbed of those kind of things. So being able to recognize in yourself that you may need to reach out to an employee program. We have a great one at our institution as well. But you don’t want to admit that, that’s hard, that failure, to say I’m not good at this, I’m not good at my job. And that’s not what you’re saying. That’s not what it is at all. And being able to move forward with grace and say I’m going to do something about this. That’s hard.

DR LOVE: A little bit more from Ms Glennie.

I can imagine you at the age of 22 in the situation you described. I guess the question is, if at the age of 22, somehow you found yourself at the ONS Congress, talk to them. Talk to yourself.

MS GLENNIE: Talk to myself. What would I tell myself at 22? I don’t think that everyone who reaches that degree of burnout would be necessarily ready to go back to that work. And I think that that is okay. There is no shame in switching fields. There is no shame in going back to school to take some space. Those years were formative for me as a person, also as a professional, and I’m very appreciative of those experiences, generally, now. I think that they have helped me to be more compassionate and to be a better clinician. For me, it was affecting my relationships, my sleep, my eating, my exercise. There’s simply no shame in taking some time away.

DR LOVE: Why was it that you went back?

MS GLENNIE: Do you want the honest answer? The honest answer is that it was where I got a job. I had applied to a couple labor and delivery jobs, which were very hard to get into. I wound up loving it enough that I’ll be 10 years at Swedish in September. So went back to school, I’m a nurse practitioner now, and I would say that I like working in oncology more than ever at this time.

DR LOVE: Things sometimes happen for a reason, and that was the only job available. That sort of falls into that category in my book. So, Robin, any thoughts?

MS KLEBIG: I think all of us, as nurses especially, but I think anyone in healthcare, we’re so good at taking care of other people, but we have to give ourselves permission to take care of ourselves. Self-care, whether it means taking time off, just taking a break and allowing ourselves to admit I’m struggling. And you’ll often find that you’re not alone. You’re not the only one. And sometimes, that helps just to get that out. Because sometimes when things are in our head, it just seems so much bigger. But if you can share with other people and then if you can’t bring yourself to care for yourself, they’ll be there to help you.

DR LOVE: Brad, any thoughts? One of the things I’ve thought about, and particularly when we come to ONS, is these sessions are more than education, to me. There’s a fellowship issue here and there’s a teamwork issue here. And sitting together just for the 3 or 4 days and learning, it’s more about, it’s more than just taking in the data. There’s a process that goes on here. Sometimes, it reminds me of being in a temple, et cetera. But, Brad, any thoughts about the challenges of being in oncology? You see some patients going through very, very difficult times. Any thoughts about what you see in your colleagues?

DR KAHL: Yeah. I guess I have 2 thoughts. One is just the self-care thought is I think it’s, you know, I really like what I do and I like the work, but it does drain you some. So you have to figure out a way to recharge yourself. So whatever that is, like if I can get a round of golf in over the weekend, I am recharged. Or my wife and I, we just always try to have a show we’re watching together on the weeknights. Just little things like that just help get me recharged for the next day so you’re not constantly getting depleted.

And then I have an awesome work team. It’s like the second family. And I bet a lot of people here do too. Hi, Laura, my nurse sitting out there. And so we take care of each other. And with your work family, you see the highs and lows that they’re all going through, sick parent, sick child, some life event turning their world upside down. So try to get your work family as good as your home family, and take care of that too.

DR LOVE: So John, I remember during the pandemic, we were doing so many videos with nurses. And one year, I asked, I don’t know, 25 nurses on video individually, they all gave the same answer to this question which is, do people come up and ask you why you’re in oncology, isn’t it depressing? Does that happen to you, John? And what do you think at that point?

DR ALLAN: Yeah. I think it’s something that does take a unique personality. You have to really understand the reasons why you’re going into this field specifically. And obviously, we’re all here to help people. We’re here to participate in advancements and betterment of the world. And oncology is a field where almost all other medicine kind of follows us in terms of our trials and innovation and things along those lines. And so those are the exciting things, and you always just have to center yourself back on why this field specifically. And obviously, yes, it can be difficult work, difficult conversations. But you can also have these wonderful outcomes, and you really see people’s lives change for the better. And so I think you do have to balance it, for sure. There can be hard days, and you do need to find ways to get away and be with your friends, family. Not even be thinking about work or the notes.

And one thing that has helped me is that while oncology is so data-driven and there’s always a right answer, in reality, all you have to do is make the decision that is best, that you believe is best based on the data that you have at the time that you have. And as long as there’s communication between you and that patient, that decision will always be the right one essentially. And so I stop agonizing about, did I do the right thing? Yes, there can be very difficult things. And sometimes, something can tip. But as long as you utilize that data, you are thoughtful about it and you communicate your thought process and the preferences of that patient, you’ll always be steered in the right direction, I’ve found.

DR LOVE: Yeah. It’s interesting, Robin. We’ve talked for — we used to do these meetings, we would start out by having everybody show pictures of what they did to kind of get away from their job. Because we’ve always talked about avoiding burnout. But this is the first time I talked to somebody who actually had a history of having that happen. And that was the point at which I said, you know what, we’re posting all this stuff. Because originally, we were only going to show all the — we’re putting it all up. If people want to hear about it, I want them to hear about it. But I was thinking too, Robin, it’s not just about avoiding burnout, it’s optimizing your own level of happiness. And there are ways to do that. I was thinking about the fact, I think it was the last time we were here in Washington, which I think was 2018. And the day before the last meeting, I went to a Chinese restaurant next door to the hotel. It wasn’t this hotel. It was some other not-as-good hotel. And this was the fortune cookie thing that I got.

MS MORAN: You saved it?

DR LOVE: Yeah. And I showed it the next day at the meeting. And it kind of was like something is talking to me a little bit about what we, what you go through and whether it’s worth it. What do you feel you’ve learned as a human being, Robin? How have you changed as a person over the years because of your job?

MS KLEBIG: I think I’ve learned a lot from my patients. And I think that’s one of the things that I think — it’s kind of the way you think about things. When I’m struggling with something, struggling with burnout or whatever, I go back to, why did I go into this anyway? Because I want to help people. I want to make a difference. One of the first ONS Congresses I came to when I was a young nurse, it was in Orlando, and it was the magic of making a difference, and that’s what we do. And sometimes, that means reframing our thinking. I can say, oh my gosh, I had such a stressful day. Why am I doing this? It’s such an emotionally taxing job. But then I can think, that’s what I want to do. I went to school, I went to graduate school so that I could do these things. I can make a difference. We can’t always tell everybody that they’re cured, but we can make a difference in what they’re doing. And I can say instead of I had a stressful day, I had a really productive day. I made a difference. And it’s good, I’m doing what I’m supposed to.

DR LOVE: So thank you for those thoughts. Thank you for attending. Thank you. Come on back tomorrow morning, 6:00 am, head and neck cancer.

MS MORAN: Thank you.