Dr. Rania Habib (Host): Lymphoma is a common cancer in the United States. The two main subtypes are Hodgkin's and non-Hodgkin's lymphoma. The American Cancer Society estimates that greater than 80,000 patients in the U.S. will be diagnosed with NHL in 2024, making it the 7th most common cancer in the U.S.; and greater than 85,000 cases of Hodgkin's, making it the 27th most common cancer.

B-cell lymphomas include Hodgkin's and most non-Hodgkin's lymphomas and cure rates are over 70%. What advances in treatment have produced these high cure rates in B-cell lymphomas?

Welcome to MD Cast by Tampa General Hospital, a go-to listening location for specialized physician-to-physician content, and a valuable learning tool for world-class healthcare. I'm your host, Dr. Rania Habib. Joining me today for a panel discussion are two malignant hematologists who focus on lymphoid malignancies. Dr. Nikesh Shah and Dr. Alan Kerr are both assistant members at Tampa General Cancer Institute. Our discussion will explain the overview of CAR T-cell therapy and bispecific antibodies in lymphoma, toxicities of treatment, and review challenges in access to care. Welcome to the podcast and thank you both for joining us today.

Dr. Alan Kerr: Thank you for having us.

Dr. Nikesh Shah: It's great to be here. Thanks.

Host: Dr. Kerr, let's begin with a refresher over the subtypes of B-cell lymphoid malignancies.

Dr. Alan Kerr: Thank you. So, in general, we classify kind of our B-cell malignancies into Hodgkins and non-Hodgkins. For the purpose of today, we're going to focus on the non-Hodgkins B-cell malignancies. In general, there are a lot of different subtypes of non-Hodgkin's B-cell lymphomas, but we're going to really simplify the classification to low-grade versus high-grade, right? So, your high grade B-cell lymphoma, the most common is going to be diffuse large B-cell lymphoma. The reason why we classify low-grade to high grade is not only how we treat, but also do we need to treat these. So, these high grade B-cell lymphomas absolutely need to be treated. These are not diseases that we can just monitor. They can be very aggressive. They are curable, but they do require treatment. The low-grade B-cell lymphomas, and there are a number of different subtypes, the most common being follicular lymphoma, which can also transform or be a higher grade lymphoma. Other subtypes include marginal zone lymphoma or a MALT lymphoma, which can involve the stomach lining. These low-grade lymphomas don't always require treatment.

When it comes to low-grade lymphomas, a lot of them we don't consider curable, but we kind of consider them an indolent disease that may or may not be causing any problems. When it comes to these low-grade lymphomas, it's important to note, is the patient having any symptoms or any complications from the lymphoma? So, we have a specific set of criteria we call GELF criteria that we use for a lot of these lymphomas to really determine does the patient require treatment? Do they have bulky lymphadenopathy, symptomatic organomegaly, particularly splenomegaly? Are they having any cytopenias from their lymphoma if they happen to have marrow involvement? Do they have B symptoms, the fevers, drenching night sweats, chills, unexplained weight loss, symptoms like that? Or even recurrent infections, sometimes we see in some of these lymphomas. So, really, the key about low-grade lymphomas is whether or not the patient is symptomatic. A lot of times, that dictates how or when we decide to treat these patients.

Host: Okay. Dr. Shah, Dr. Kerr just gave us a great overview of the different subtypes of B-cell lymphoid malignancies. What are the current treatment options for those patients that are diagnosed with relapsed or refractory large B-cell lymphoma?

Dr. Nikesh Shah: So, you mentioned in the beginning, you know, we cure about 70% of patients with large B-cell lymphoma with our initial treatment regimens. Unfortunately, for those 30% or so of patients who either don't respond to upfront therapy or who relapse at some point down the road, things are more difficult. You know, we still are able to cure a subgroup of those patients, but we're always trying to do better for our patients.

The last five or 10 years, we've seen a lot of new advances in therapy. Historically, our options were really limited to more intensive chemotherapy and what's called autologous stem cell transplant. And in the past five years or so, we've seen a lot of new FDA approvals for therapies, including antibody drug conjugates, immune therapies, which we'll talk about today, really focusing on CAR T therapy and bispecific antibodies. And there's some other targeted therapy options as well that we can use in these settings. But for the most part, we've had a lot of advancements in the last five years, but still a lot of room for improvement.

Host: Now, Dr. Kerr, Dr. Shah mentioned that we have these advances in therapy that are specifically immunotherapies. So, what are CAR T-cells and how are they different from bispecific antibodies?

Dr. Alan Kerr: That's an excellent question. Really, an analogy I like to use for my patients, and I think it works pretty well, is to think of it as a race car. And no pun intended, because these are CAR T-cells. But what you're really doing for CAR T, you're taking someone's own T-cells, that's part of their endogenous immune system, and you're re-engineering, so they're putting a viral vector in there that encodes for a gene that will create a receptor that binds to typically CD-19 for most of our B-cell malignancies. But they can bind to other receptors however it's designed. But when it binds to that, instead of binding to an antigen from a virus or some other infection, it's binding to the lymphoma cell. And when it does, it triggers a rapid immune response and rapid proliferation of these T-cells, right? So, these are re-engineered T-cells that we take from the patient, re engineer them, and give them back. So, we give them supercharged T-cells. So if you're thinking about a race car, you're basically rebuilding the car. You're putting a different engine in it. It's a completely different car. It's much more productive, much faster on the track, right?

The difference between that and bispecifics, in bispecifics, you're not changing the car, you're changing the driver. So, you're putting a better driver in the car so that you can get better results, but you're still using your endogenous T-cells. So, you're not changing the biology necessarily of these cells that make up the immune system, but those bispecific antibodies can activate those T-cells in a better way. So, what they're doing is they have one epitope that binds to the lymphoma cell, typically CD20 from our lymphoma bispecifics, and then another epitope that binds to CD3 on the T-cell, basically bridging the gap. You're bringing the T-cell into the tumor microenvironment, and you're activating the T-cell. So then, it starts to release granules, toxic granules, that can help to destroy the lymphoma cells. So, that's really the analogy I use, is that both of these are really about causing a T-cell response against the cancer. It's just which way do you do that? Do you just change the driver so you're just getting a better response from your normal T-cells, or do you re-engineer the entire T-cell and then reintroduce that into the patient?

Host: Now, this sounds like very specific therapy. So Dr. Shah, what are the possible side effects and how do they differ between CAR T-cell therapy and bispecific antibody therapy?

Dr. Nikesh Shah: So, there's a lot of overlap between the two in terms of side effects and toxicity. But first, let me talk about some of the unique things with CAR T therapy. With CAR T therapy, like Dr. Kerr mentioned, you know, we're genetically engineering these T-cells, manufacturing them in a lab, and then giving them back to the patient through an IV infusion. And in order to do that, before we give the cells back to the patient, give these enhanced CAR T-cells back, we do kind of, for lack of a better term, have to make a little bit of space, but we also have to deplete or reduce the patient's own immune system. So, we have to reduce the patient's native T-cells be to make room to allow these CAR T-cells to grow and expand in the body once we give them back. And so to do that, we have to give what's called lymphodepleting chemotherapy. That's a higher intensity chemotherapy that we have to give over the course of kind of three to five days. That does come with some side effects on its own that are really temporary and short-lived, but they do lower the blood counts. Someone may need transfusions of blood products. They can weaken the immune system, so infection is a risk. Typically, depending on the center, that can be done either as an inpatient admitted to the hospital or, at certain centers that have a lot of outpatient infrastructure, can be done in the outpatient setting as well, but definitely needs close monitoring.

Now, kind of some of the overlap between side effects, the really two unique things that we think about for both CAR T-cells and bispecific antibodies is one group of side effects called cytokine release syndrome, or CRS. And the other is called neurotoxicity or what we call ICANS, which is immune cell effector-associated neurotoxicity syndrome. We just call it neurotoxicity to make life easy. And so, both of those can happen for patients with either of these therapies, and they're really both a side effect of overactivating the immune system, right? And so, cytokine release syndrome or CRS is really what I tell patients, it's really something similar to what happens when you get the flu or when you get COVID. Your immune system is ramped up and trying to fight something. And so, at its very lowest, at its very mildest, that could just be fevers, right? When you have the flu, when you have one of these infections, you get fevers. And we see that very commonly in our patients that get one of these therapies, right? They have some low-grade fevers, and we monitor them closely. That can obviously get more severe. And that could be something like fevers, low blood pressure, high heart rate, some need for some low-dose oxygen, but rarely that can be more severe and rarely patients may need to be in the intensive care unit for closer monitoring or for support as we support them through these side effects.

The neurotoxicity piece is a little less well-studied. And it can be something as very subtle as somebody's handwriting is a little bit off. And that's actually one of the things we check when we give these therapies, is we ask them to write sentences over and over again through the course of their treatment to see if we're picking up on any early signs of neurotoxicity. It can also kind of evolve into some confusion where they're a little slower than usual, or it can be profound confusion in very rare severe cases where patients don't know where they are. They don't know what's going on around them. They may not recognize family members. And severely, this can even look like stroke like symptoms, difficulty talking, slurred speech, trouble moving one arm or one leg. And so, obviously, these side effects, we need close monitoring. These products need to be given in a center where the physician, the nurses, all of the providers are well-versed in recognizing these and picking up on them early and knowing how to manage them. And that's one of the things we'll talk about potentially down the road, is these therapies need to be given in a place where providers are well-versed and have experience in managing these side effects.

The side effects tend to be temporary, so the cytokine release syndrome and the neurotoxicity tend to be short-lived. As patients get through treatment, a few months down the road, we're not experiencing these side effects anymore. Some of the long-term side effects with CAR T therapy, you can see long-term drop and reduction in blood counts that can sometimes take months or up to a year to recover, but that's the minority of patients.

Host: Will patients also see the common side effects that we think of with chemotherapies such as nausea, vomiting, hair loss, or do we not see that in the specific immunotherapy?

Dr. Nikesh Shah: Good question. We don't see that with the bispecific antibodies. Those really are activating the immune system, and so we're not seeing those side effects of chemotherapy. With CAR T, because we are giving the lymphodepleting chemotherapy before infusing the CAR T-cells, we do see a little bit of that, but it tends not to be very significant. It tends to be mild and we can support our patients through that pretty well.

Host: Dr. Kerr, how do we treat these unique side effects from these therapies?

Dr. Alan Kerr: So, as Dr. Shah was saying, you know, the main side effects with this cytokine release and this ICAN, this neurotoxicity, the side effects are from significant immune response, right? We've ramped up inflammation, cytokine release, cytokine storm. So, the way we treat this really is by suppressing the immune system. The mainstay of treatment for most of our patients is going to be steroids. We prefer dexamethasone. I think that's important to note as well. Sometimes you can treat these in the outpatient setting. So if you're going to send them an oral treatment, if they have low-grade disease, you can consider oral therapy, but you want to make sure you use dexamethasone. We do prefer that over prednisone for most of our patients.

The other main drug that we will use is a monoclonal antibody called tocilizumab, which is an interleukin inhibitor, so it can actually help decrease some of that cytokine release, right? So, if you have low-grade adverse reaction, like a grade 1, for example, cytokine release, we would start with steroids. Certainly, you're going to want to rule out an infection, because I think the important thing to note is that cytokine release syndrome can mimic infection, because they're going to have fevers, they might start to develop hypotension, hypoxia, some of those things that Dr. Shah was mentioning. So, you want to rule out infection. And if someone shows up in the ER, giving them broad-spectrum antibiotics is not a bad idea. Treat them as if they are septic upfront. But if you don't see any obvious source of infection right away and you have these symptoms that are suggestive of cytokine release, you want to start steroids early. So, really, you know, if you have a fever, and you're not significantly hypotensive, not significantly hypoxic, the dexamethasone by itself might be enough. If you start to get more significant cytokine release, like grade 2 or higher, then you want to consider using that monoclonal antibody, tocilizumab.

Host: Okay.

Dr. Alan Kerr: This drug is actually pretty widely available. It became more available during COVID, because a lot of hospitals were using this, because you get a similar CRS type of picture with COVID infections. So, a lot of community hospitals are carrying this drug now, which is good, at least from our standpoint, because we know they have the capabilities. But it is important to think about this in the setting of treatment, right? If you don't think they're infected and you think this is cytokine release and the patient is not responding to steroids, or they're becoming more hypotensive, not responding to fluids, you want to think about using the tocilizumab, that monoclonal antibody.

As far as the neurotoxicity is concerned, really steroids are the mainstay because, unless you have concomitant cytokine release, the toci really doesn't help too much with the neurotoxicity, so we'd focus more on using steroids as well as additional supportive care. Anti-seizure medications, sometimes we get neurology on board if they are developing seizures or worsening mental status, close neuro checks. A lot of these patients may need to be moved to the ICU just for neuro checks. Just like Dr. Shah said, it is reversible. And most patients do recover, but it certainly can be quite frightening when they're having those symptoms upfront. So, that's why we want to be aggressive in those settings by using steroids, giving other supportive measures. And of course, in any setting, you want to rule out infection with these patients because, just like Dr. Shah mentioned, they're always at high risk for infection, so you want to make sure you're not missing that while you're managing. But as far as medications are concerned, you really have two main medications, dexamethasone and tocilizumab. Those are going to be your two main medicines that we use primarily for these side effects.

Dr. Nikesh Shah: The only thing I actually wanted to add to what Dr. Kerr mentioned about managing side effects is that, while some of these can sound scary when they get severe both for patients and families and for providers who are not used to seeing them, the severe side effects, the rates are not very high. Depending on which product we're talking about, we might be talking about 5% or 6% of patients getting these high-risk side effects

Host: That's fantastic. Dr. Shah, what are the success rates of treatment with CAR T-cell versus bispecific antibody treatment?

Dr. Nikesh Shah: This is a really important question. And the short answer is that we don't have any head to head comparisons just yet. There are no trials that have been done prospectively randomizing patients to either get CAR T therapy or one of the bispecific antibodies. And so, we don't have an answer to say, in a perfectly randomized environment without any biases, which therapy is better for patients. Unfortunately, we probably won't have that data just because of how these drugs are approved by the FDA and how these trials are designed. So, I don't think we'll ever have a perfect answer for that. But more practically, these therapies tend to work well for a group of patients. Our overall response rates, depending on which product we're talking about for CAR T therapy, can be anywhere from kind of 50-80%. And similarly for bispecifics, we see kind of a 50-60%, 70% response rate, depending on the product.

Now, one important thing to think about in that setting is obviously, well, the response rates are good for patients that have not responded or relapsed after prior therapies, but how long do patients kind of stay in remission or how long do patients respond for? And I think that's a really important point for patients and people deciding to go through these therapies that come with side effects. And really, with CAR T therapy, we've kind of have long-term followup depending on which study you look at. You know, sometimes five years or a little bit more longer followup that says we think we cure about 40% of patients with relapsed or refractory large B-cell lymphoma with most of the CAR T therapy products. We start to see that relapse rate level off around 40%.

Host: Okay.

Dr. Nikesh Shah: With bispecific antibodies, we're starting to see something similar for the two FDA-approved bispecific antibodies and some of the other ones that are currently on clinical trials, but we don't have as long of a followup period because these are newer therapies than CAR T. And so, we'll see what the five-year kind of followup shows from these studies, but we think that they may be similar.

Host: Dr. Kerr, we mentioned that these medications can have up to a 70% cure rate, but what factors limit widespread use and availability of these therapies?

Dr. Alan Kerr: So, that's an excellent question. And actually, moving forward, it's definitely going to guide which of these therapies we pick for a lot of our patients. So, you know, CAR T therapy is something that's, in general, only given at larger tertiary centers, right? It requires processing of the T-cells, that process can take a few weeks. It's not an off-the-shelf product. You have to harvest the T-cells from the patient. You have to process them, give them back, make sure that you have quality product before you give them back to the patient. A lot of times when these patients relapse with high grade B-cell lymphoma, you can't always wait a month or so to get the T-cells ready. So, a lot of these patients will require bridging therapy. And there are a lot of different regimens that we will use to bridge. We have a few good ones that have been pretty effective that you can put someone on to at least stabilize the disease or maybe reduce the disease a little bit before they get to CAR. So, those steps are required to get someone on CAR. And they have to be near a tertiary or be able to get to a tertiary cancer center. So, I think the lack of availability, the vast majority of our patients are treated in the community. And a lot of these patients are not necessarily in a city or close enough to a city where they can get to the tertiary center. So, that logistic right there really does limit a lot of patients.

Another limitation would be processing, right? If they've had a lot of prior treatment, sometimes we beat up the T-cells as well when we give them these lymphoma treatments, right? Because they're lymphodepleting regimens. So, sometimes we can't harvest enough healthy T-cells from the patient to be able to create the CAR. So, that is also another limitation. Physical fitness or performance status is a limitation, not so much as other treatments. You know, we compare it sometimes to autologous transplant, which we're not using as much for lymphoma anymore because of CAR T. In the clinical trials, they've given patients in their 80s and 90s CAR T before. So, age is not necessarily a limiting factor depending on how fit the patient is. But, that being said, it does, just like Dr. Shah mentioned earlier, you require some lymphodepleting chemotherapy before you get the CAR. It is a more intense treatment. The side effect profile, while you have similar types of toxicities, the rate of severe toxicity is definitely much higher with CAR compared to bispecific. So, it is still an intense therapy, even though we have more availability compared to transplant, for example, but it is a pretty intense therapy. So, those are a number of limitations.

I think, from my experience, I've worked in a community clinic with a lot of older patients who live quite a distance from Tampa, for example. Sometimes they just can't make it to Tampa General or Moffitt to be able to get the CAR for various reasons. So, for this reason, bispecifics are actually a really exciting option, I do believe, for community oncologists. This is a product that's off-the-shelf, does not require central line, it's a peripheral IV, or even a subcutaneous injectable. We do a dose ramp-up with the bispecifics, so you don't start at the max dose, you start with the low dose and step up, which does reduce the side effect profile, especially the cytokine release. The neurotoxicity, we really don't see much, at least in the lymphoma bispecific space, we really don't see a lot of neurotoxicity at all. It's very minimal, which is good. And the cytokine release, as Dr. Shah mentioned, is lower. So, that makes them more available for the community, I think, and it's something you can start right away. So, if someone's having symptoms, you don't have to, you know, process cells. You have the product that's ready to go, so you can get them started right away, which can help a lot of our patients. The limitation right now, at least with the high-grade lymphoma bispecifics, is that based on how they did it in the clinical trial, we do require one inpatient stay, at least one inpatient stay, as they do the dose ramp-up. So, they have to be at a hospital, they can give it inpatient, monitor them overnight. And then if they do well, they can continue treatment outpatient after that. But that first ramp-up cycle can be difficult if they're out in the community, because you would have to get them to a tertiary center at least to get them through that first cycle. And then, perhaps, they can come back to the community for continued treatment.

So, that currently is a limitation. We do have one lymphoma bispecific that's for follicular, mosunetuzumab. That is an all outpatient ramp-up. So as long as they don't have grade 3 or higher CRS, they will continue their treatment outpatient. And that is already something that can be readily available for the community, but we're not quite there yet with the high-grade lymphoma bispecifics.

One major reason is with the high-grade lymphomas, you're going to expect more toxicities, which is what we saw in the trial. So, a little bit more CRS, a little bit of a higher grade CRS than we saw with the follicular lymphoma, so that's why they're doing the inpatient ramp-up. There are already trials underway looking at all outpatient ramp-up for high-grade lymphoma, so I do think probably within the next year or so, we'll be able to do outpatient ramp-ups. But for now, according to the current FDA label of these two drugs, they do need to get at least one dose during that first cycle in the hospital. So, that is a limitation with the bispecifics as far as getting them to the community.

I will say another limitation for giving bispecifics in the community is really just understanding CRS, right? The oncologist might know. But if you're out in the community hospital and you develop a fever and you end up in an emergency room, does the ER physician know to think about CRS as a potential side effect? A lot of times, the ER will hear the word cancer, they'll hear the word chemotherapy. And they'll think, "Oh, they're on chemo, they're septic, let's treat them for an infection." They may not be neutropenic, because they're on a bispecific, they're not on chemotherapy. So, the ER doctor may not even think to call the oncologist because they're thinking, "Oh, they're not neutropenic. It's an infection. We can manage this." And then, the patient continues to decline despite aggressive antibiotics, because they're not getting steroids. So, I think recognizing that that's a possibility and at least contacting the primary oncologist, I think, will be helpful. Now, a lot of the bispecifics that are coming out, they're giving patients wallet cards that have a little QR code on it, so if they do end up in an emergency room, and that's crucial. I think patient education is crucial, and caregiver education is crucial, because they're the ones who are going to tell the ER physician, "Hey, they're on this drug. There's this thing called CRS." You know, "Scan this QR code. Call the oncologist." And really, that's all they need to do. The ER physician does not need to know how to treat CRS. They just need to know that it's a thing and to call us.

Host: That it exists. Right.

Dr. Alan Kerr: Exactly. So, I think really managing those toxicities, that's a barrier now. But to be honest, education, same thing we saw with checkpoint inhibitors, we were using Keytruda, Opdivo, these other drugs with a whole new set of toxicities. Now, community hospitals, hospitalists, and infectious disease, and ER physicians, they're all learning these toxicities from some of these other drugs. So, it's a learning curve that we'll eventually get there with the bispecifics as well. But in general, I think they're definitely going to move to the community much more quickly, and they should. I'm excited about bispecifics, because I really think they're going to provide a much better opportunity for a lot of patients who can't get the CAR.

Host: Well, thank you so much for joining us today. You guys provided some very insightful information about the treatment of B-cell lymphoma. Thank you, Dr. Shah and Dr. Kerr.

Dr. Alan Kerr: Thank you so much for having us.

Dr. Nikesh Shah: Thanks for having us.

Host: Thank you for listening to MD Cast by Tampa General Hospital, which is available on all major streaming services for free. To collect your CME, please click on the link in the description. I'm your host, Dr. Rania Habib, wishing you well. For other CME opportunities, including live webinars, on-demand videos, and local events offered to you by Tampa General Hospital, please visit cme.tgh.org. Thank you.