← The Fellow on Call: The Heme/Onc Podcast
The Fellow on Call: The Heme/Onc Podcast
Episode 139: Follicular Lymphoma Series, Pt 4 - Relapsed/Refractory Management (Cellular therapy options)
Ronak Mistry, Vivek Patel, Dan Hausrath
Loading summary
Transcript30 lines
- [00:00]
A
Hey, friends. This episode of the Fellow on Call is not meant to be used for medical advice and is intended for educational purposes only. Patient information has been modified to ensure privacy. The views expressed in this episode do not necessarily reflect the views of our employers. Enjoy. Welcome to another episode of the Fellow on Call, the Hemong Podcast. We're coming at you from Rollo University Medical Center. I'm Ronuk.
- [00:23]
B
I'm Vivek.
- [00:24]
A
And Dan's not here today. Dan's out on vacation.
- [00:28]
B
Dan's lazy. I don't even know where he is. He might be on vacation.
- [00:32]
A
I could have sworn he said he was leaving for vacation. But you're right. Who knows? You never really know with Dan. But nonetheless, Vivek, I'm excited to be on another episode today. And today we're continuing our conversation focusing on our relapse refractory patients with follicular lymphoma, specifically talking about car T& Bite therapy for these patients. So certainly a hot topic. This is all always talked about at big conferences, ash, asco, et cetera. So I'm excited to talk through the data and to also hear how you approach patients when you're considering these therapies.
- [01:05]
B
Cellular therapies are really important in hemelignancies, particularly CAR T cell therapy and bispecific antibody therapy. So excited to get into this one.
- [01:13]
A
All right, guys, without further ado, let's roll that show. So, Vivek, we're back to our final episode in our follicular lymphoma series. I'm excited to be talking about bispecific agents and CAR T today and, you know, really picking your brain about how you think about these cellular therapies and how you use them for your patients. The look on your face, I wish our listeners could see it. I mean, you are grinning from ear.
- [01:40]
B
To ear here at Rouleaux. You know, one of my specialties is getting these agents. So really excited to get into this one. Let's just get into it. Ronak. I'm going to kick us off with a case. So recall this is a similar case that you heard from our last episode. We have a seven year old female with a history of relapsed follicular lymphoma, originally diagnosed about 10 years ago, was treated with bendamustine rituximab for six cycles followed by rituximab maintenance. She relapsed five years later and was treated with lenolidomide rituximab that R squared regimen that we've referred to achieving a complete response. She now presents four years later she had done well. Four years later though, she has progressive adenopathy, drenching night sweats and a 15 pound unintentional weight loss concerning for relapse disease. We then got a PET CT which shows avid adenopathy above and below the diaphragm with a maximum SUV of 13 and a right axillary node. So before we get into cellular therapies, what are the next steps in her management? Roanoke, what have we been talking about over the last couple of episodes?
- [02:39]
A
Just to remind our listeners the things that we had talked about is number one, it's always important to repeat the biopsy, especially of that most avid lesion for follicular and that's because you are really wanting to ensure that this isn't a transformation to a large B cell lymph. Ideally you want to try to get an excisional biopsy, but in cases where the most avid node is in the abdomen, it's reasonable to obtain a core of the lymph node if there's a significant discrepancy in SUV uptake. A bone marrow biopsy is not necessary unless there are significant cytopenias. And we're trying to rule out things like myeloid malignancies that can occur especially from prior treatments. And in this case, because of how you describe this patient, I would recommend an axillary excisional biopsy, especially because that was a very avid node.
- [03:27]
B
So she undergoes her excisional biopsy which is consistent with classic follicular lymphoma. So no evidence of large cell transformation. After doing her own research, she asks you about immunotherapy options which have recently been approved for follicular lymphoma. So we're planning to start bispecific antibody therapy with a fixed duration mosinetuzumab in a third line setting for her. So before we get into that, we've discussed CAR T cell therapy and bispecific antibody therapies in our DLBCL series. So feel free to check episode rotation guides. If you're interested, go to our website, click through that, you can easily get to those episodes and see our show notes. We have lots of graphics for it, but I really think we should take a moment to discuss the mechanisms and really the stark differences between these therapies. We always talk about cellular therapies, but these two things are very different. So Rona, can you go through the foundational principle behind these therapies?
- [04:22]
A
So before you go through the foundational principles, the way that we talked about this last time, that I think is a good way to start this is let's talk about what's norma. So as our listeners know, you have B cells and their job is that they secrete antibodies and these antibodies have really high affinity for specific target antigens that may be present against tumor specific antigens if they have a barren expression of non self proteins. So recall that there are two main types of T cells. There's your CD4 helper T cells that coordinate the immune system by activating killer T cells and memory B cells. Then you have your CD8 positive killer t cells that have direct cytotoxic activity against cancer cells. So in order to function, the CD8 positive T cells need to both recognize the cancer cell and they also need a CO stimulatory signal. The T cell receptor is what can recognize these foreign antigens but does not have the same sort of high affinity targeting as the antibody. And so it requires binding to MHC I complexes on the tumor cell and often presentation from antigen presenting cells. So these T cells are developed in the thymus and they undergo a process known as negative selection. And only T cells that have very low affinity for self antigens survive. You can see how this can be an issue because tumor cells will definitely have self antigens. As a result, T cells have a difficult time finding and binding to the tumor cells and they need a CO stimulation as well. And, and so that requires other antigen presenting cells in order to identify tumor cells. So once T cells are activated, though, they can expand, they create an army. And that's how they kill tumors in the real world. Super fascinating. Although some of you may be getting flashbacks to immunology, maybe from college, but really, really, really fascinating stuff.
- [06:18]
B
That was a great summary and a great segue to talk about CAR T cells. What exactly is that? And I'll kind of take it from here. So what is CAR T cell? And this is a gene cell therapy where we actually take that T cell receptor and remember that that T cell receptor is the thing that will end up finding an antigen to bind to. And once it binds, it requires a CO stimulation to kill the target. So what's done here is that T cell receptor is modified in a lab so that whenever it binds to something there will be an immediate cytotoxic response. You don't need CO stimulation. The second thing it does is that we modify these T cell receptors to search for a very specific target. We choose a target and lucky for us, in B Cell malignancies. All B cells universally express CD19. So we say, hey, go find CD19, have the homing missile capability of that antibody that B cells make. Because normally the B cells are secreting these antibodies directly to a specific antigen. In this case we say whatever, let's wipe out all the B cells, both good and bad, anything with CD19. Because we know the cancer B cells have CD19 and the good ones have CD19. And so it's basically searching for CD19. We'll hit it and we'll kill it. So how is that done? So the first thing that happens is as a physician, we say this patient needs CAR T cell therapy. Once that happens, we then have to go through insurance approval process. That's not short, that takes a lot of time. After insurance approval process goes in, then we got to collect those T cells, we bring in the patient, we put a big line in them and then we apherese out their T cells. So now we've got their native T cells. So that's another time point. Then we have to ship those T cells to the manufacturing company. They do the gene cell therapy and modify those T cells. So they have this homing missile capability and automatic kill capability. That takes time, that manufacturing process takes some time. Then they ship it back. Now we've got the product in hand and then we bring the patient back to us in clinic, give them a little bit of lymphodepleting chemotherapy for a couple of days so that we wipe out their native white blood cells. So that way their native lymphocytes aren't messing with our Car T products. And then we infuse those Car T cells back in 2 million all at once. And then they self expand inside. As Ronick had mentioned, these T cells expand themselves when they find their target. So they self expand like a living drug and then they go and they kill the tumor cells causing lots of inflammation. And then after that we deal with the fallout. It's a one time infusion, deal with the fallout. And then at that 30 day mark, we get a PET scan. We say are the patient in remission or not? And that's the basis of CAR T cell therapy. So Ronak, what about bispecific antibody therapy? How does that work?
- [09:01]
A
In contrast to CAR T therapy which is individualized for the patient utilizing their cells that are engineered and reinfused back into them. You may often hear bispecific antibody therapy as being referred to as off the shelf medication and that' it doesn't require specific manufacturing for that specific patient, it's like a molecular matchmaker. There are two arms of the Y shaped antibodies and what they do is they bind to different targets. One arm binds to CD3 on the T cell and the other arm binds to CD20 on the B cell. This sort of binding helps bring these cells closer together. And so this will trigger the cytotoxic T cell activity, resulting in cell death of the CD20 expressing B cell. So instead of a one and done treatment like Car T therapy, this is given initially at low doses, then increase over the first few weeks to prevent side effects. The treatment is then continued either as fixed duration, every three weeks or continuously until progression, depending on the product that's used. So a little bit different than CAR T. But, you know, I think sometimes you know this better than I. There seems to be a lot of misconception and confusion about CAR T versus bispecific agents. And I think a lot of that really stems from the similar cytotoxicity and the toxicity profile that we see. So could you sort of speak to that a little bit?
- [10:28]
B
Yeah, it's a great question. And it's very important to understand that although both of these therapies we're going to talk about have cytokine release syndrome or CRS or this neurotoxicity syndrome called icans, they're very, very different. Both of them utilize a T cell receptor. CD3 is on the T cell receptor. As Ronick mentioned at the beginning of the episode, the the T cell receptor binds to a target and then it'll kill the target self, expand, cause a lot of inflammatory cascade to happen. So in general, when we think about CAR T cell therapy, there's more inflammation, it's a sprint, it's all happening at once. Whereas in bispecific antibody therapy, it's a slower churn. So what is CRS or cytokine release syndrome? This is essentially inflammation that starts with fever and can progress to a severe SIRS reaction with hypotension, potentially progressing to hypoxia and for higher grade cytokine release syndrome. So more severe cytokine release syndrome, maybe the patient requires pressure support in the intensive care unit. This side effect is expected early on in therapy due to more T cell activation because you have more tumor bulk and this results in more inflammation. Crs, like I said, occurs at much higher frequencies in CAR T cell therapies. Unlike bispecifics for CAR T, the patient may experience that fever and this will commonly cascade into hypotension. Maybe some hypoxia. If the patient doesn't receive antidote therapy with an anti IL6 agent, often tocilizumab and steroids. And the reason for this is because these patients are having significant expansion of their T cells. So these CAR T cells are expanding rapidly, they're causing lots of inflammation, and a lot of that is directed through IL6. And so what that does is it causes higher grade reactions requiring inpatient tocilizumab and dexamethasone, some steroids, unlike CAR T, for bispecific antibody therapy, you're just binding one edge of that Y shape to the CD3 receptor and then the other edge to its target. In this case, it's CD20 on the B cells. That's what it's targeting. Instead of 19, it's targeting CD20. So when those two things come together, you're getting a little bit of inflammation, so you might get a little bit of a fever. And these are things that can be safely managed. In the outpatient sett, we'll have a future episode dedicated to how do you manage bispecific antibodies? But this is very manageable in the outpatient setting. Patients can have pill in the pocket, steroid, they call in, they take their steroid, maybe just some Tylenol, and they do fine. So it's way different. These are managed in the outpatient setting. You could treat a patient who's older, more frail, because these toxicities aren't leading to this massive inflammatory cascade that's requiring intensive care unit stay. So, Rhona, can you explain to us what this neurotoxicity syndrome, this ICANS thing.
- [13:15]
A
When we talk about icans, this is the neurologic manifestations that can occur with these cellular therapies. And we use a scoring system called the ICE score, and that was developed so that we can grade, we can objectively measure how patients are doing with regards to this concern. For icans, it's not something that you need to memorize, but no, it's kind of like that MMSC that you may have done when you were, for instance, on a geriatric rotation. So what are some things to look out for? Number one, it can be more delayed than crs, although many times it can occur concurrently. So remember that CRS may be earlier and these neurologic manifestations may happen later. For many patients, this is managed with steroids exclusively. So Vivek just mentioned a drug called tocilizumab for the treatment of crs. But for icans, you're managing this with steroids, it's extremely uncommon with bispecific antibody therapy. And it really is estimated to occur only in about less than 5% of patients. So definitely something we worry more about with CAR T. ICANs can occur at higher rates in severity with CAR T therapy, as I just mentioned. So, again, things to really, really look out for. We just wanted to explicitly state them here. The other thing that I wanted to mention, in addition to icans and also CRS is the other sort of toxicities that we need to look out for in our patients. And essentially, like Vivek said, what we're doing to our patients is we're sort of wiping out their functional, healthy in addition to their unhealthy B cells. And so we mentioned that the job of the B cell is to make antibodies in the body. So you can imagine that this can also lead to an acquired hypogammaglobulin anemia in patients. And so it is important to measure this. It's important to make sure that you're keeping an eye on their IgG levels, for instance. And if those levels are low, giving something like IVIG supplementation is really, really important. That also means that our patients are going to be predisposed to infections, right? Because we're getting rid of these B cells, it's important to be cognizant of infections as well. The final thing to keep in mind is that CAR T therapy actually also increases risk of infection, but can actually be more severe. And by that I mean many of our patients, in fact, most of our patients, may require repeat immunization with, for instance, childhood vaccinations, just because we are essentially wiping out their immune system.
- [15:47]
B
And that's important to know, right, that we're redirecting the T cells. So now our army is redirected to kill our own army, our B cells. And so you're left with that increased risk of infection. And these CAR T cell patients have to get their childhood vaccinations. And again, so it's a big deal. Let's go through a broad overview of patient selection for these two different strategies. Who can get a bispecific? Who can get CAR T cell therapy? Bispecific antibodies have several advantages, particularly in maybe an indolent lymphoma like follicular lymphoma, which can be a slow churn and burn. They're off the shelf products and they can be given quickly without that lengthy approval process that we talked about. Patients don't need to go through rigorous clearance with Cardiac testing, pulmonary function testing, things like that. Because we don't expect those high grades of inflammation. We expect very low rates, low grade inflammation. The toxicities are very manageable. And we can do this really in the outpatient setting. And we encourage everybody who's listening to the show to understand this can be safely done in the community. You do not need a specialized academic center. And we hope that this goes more to the communities than we think it will. CAR T has some limitations but offers some advantages. More stringent patient selection criteria. These patients go to specialized CAR T centers, go through a pretty rigorous evaluation. Pulmonary function testing, cardiac testing, they caregiver support, things like that are very, very important. The patient has to be fit enough. Not quite like an autologous stem cell transplant, but still they go through a rigorous evaluation. There's a big time gap because of the insurance approval, the apheresis, the manufacturing, all the things we talked about. So they often need disease holding therapy. And for patients who are chemo refractory, that becomes quite a challenge to keep their disease under control until we get that product back. The CRS and ICANS are higher grade and there is truly more of an infection risk and more of a late cytopenia risk even after CAR T for a year or more after CAR T cell therapy. So even though it's a one time infusion, so we think about it as one and done, other than bispecific antibodies have to be given more on a more continuous schedule, it leads to a lot of fallout that lasts a year and often more than a year when it comes to infection risk, maybe late cytopenias. The big advantage though of CAR T is that if you have rapidly progressive disease, it might be a more effective therapy. It can lead to that big punch for disease control if you have more aggressive disease. Same thing. And lastly there is some data and we'll go through that in this episode, that it may lead to durable cures. We need even longer term follow up. That 10, 15 year follow up to say that. But the five year follow up looks really, really good. So there's this thought, maybe we can cure some people with the CAR T cell therapy. We also think we might be able to do that with bispecific antibodies will tell.
- [18:28]
A
That sounds great. And so, you know, I'm sort of curious if we go back to our case, right? You had presented this 70 year old female, she came in now needing third line treatment. Let's first start with bispecific antibody options. How do you sort of think about what's currently FDA approved and how do you sort of think through the data and then obviously, how do you present that to your patients?
- [18:52]
B
Yeah, that's a great question. And right now in the United States, there are two FDA approved products as single agents in the third line setting for follicular lymphoma. This landscape will soon change and we'll get to that. There's very likely to be approval in the second line, but currently at the time of this recording, we only have it approved in the third line setting. Two products we have are mostanutuzumab. It's an IV formulation as a fixed duration therapy given every three weeks for either eight cycles if a patient's in a complete remission, or potentially up to 14 cycles if the patient has not achieved a complete remission. And so what we're looking at for eight cycles, every three weeks, six months, total of therapy and you're done. So that's pretty appealing. Epcoritamab is subcutaneous, so another very appealing option, right, no iv. It is a shot. Patient comes in, I'm going to give you a shot and you're good to go. So easy peasy, right? And this is until disease progression and it's on a schedule similar to daratumumab. Many people are familiar with that schedule that we'll go through outside of the US and European countries. There's another product approved called Odranextamab, that's an IV formulation. We'll talk about the schedule for that because it's a little bit different and that's given until disease progression. So we have that fixed duration mosinutuzumab and these more sort of indefinite until disease progression therapies. So first let's go through the approval of mosinutuzumab. So what led to that approval? There's a phase two multicenter study for follicular lymphoma patients, third line or higher. And I'm going to go through the inclusion criteria for this trial, but it applies to all the trials really that we're going to be talking about today. These patients must have received an alkyllator and an anti CD20 agent. Like I said, mosinutuzumab is given every three weeks for a total of eight cycles. But in cycle one, it's given weekly in step up doses. So each dose is increased until a full dose. So day one, day eight and day 15 you have escalating doses and at day 15 you have the highest dose. A total of 90 patients were enrolled. About 80 patients had received prior anthracycline, a third had prior auto transplant and over 50% were progression of disease within 24 months and were refractory to both anti CD20 and alkylator therapy. So a very high risk patient cohort. We had long term three year follow up published in blood in February of 2025 that showed an overall response rate of 80% and the CR rate was of 60%. This is significantly higher than historical norms. I mean this is a heavily pretreated patient population and 60% of them, over half of them are achieving a remission, which is crazy. The median time to first response, which is true really for most bispecific antibody therapies is about one and a half months. This also comes to be when do we scan these patients? That's the first scan time point. So it's no surprise that it's going to take a little bit of time and it's about three months to the first CR, usually that first PET scan at the three month mark to get that first CR. The three year progression free survival rate was close to 50%. So about half these patients have no progression at three years, which is pretty incredible. For those who do achieve a CR, 72% of these patients remained in CR at 3 year follow up. That's crazy. So if you get your cr, you're good to go, you're going to remain in cross. What about those who achieved a partial response? They had a much shorter median duration of response, only four months. So achieving that CR is highly prognostic for these patients. These results were outstanding and it really gave us a good option, fixed duration therapy in the third line setting that you can treat older patients on. The important thing that there's a subgroup analysis in that study. The median time to B cell recovery in an exploratory analysis was 18 months with this fixed duration approach. So we have recovery of the normal B cells in a year and which is pretty impressive when you think about a therapy for a follicular lymphoma patient who's been through like a stem cell transplant, anthracycline based R CHOP therapy, lots of, lots of pretreatment. It's pretty incredible to get these astonishing results at three year follow up.
- [22:52]
A
That sounds awesome, especially like you said for a patient population that's so heavily pre treated. But I feel like there's a catch here. Vivek, this sounds almost too good to be true. So what are we talking about with regards to side effect profile?
- [23:07]
B
So CRS occurred in about 40% of patients. And these were really predictable. A majority of these events were fever, maybe a little bit of low blood pressure requiring a tinge of fluids. And nowadays we can treat many of these patients at home. There's no mandatory hospitalization, so this is an outpatient therapy, which is huge. Very few patients require tocilizumab. Again, fluids, steroids, pretty manageable and easy to treat. Icans only occurred in five patients. All of these were mild confusion and they all resolved. So very, very low rates of neurotoxicity syndrome. Again, these are things that can resolve easily with steroid therapy. Neutropenia occurs in about a fourth of patients. And a low phosphorus is common with this therapy, so that also occurs in about a fourth of patients. And neutropenia occurring in a fourth of patients is common across bispecific antibody products. In follicular lymphoma, itching and rash occur in maybe 1 in 5 patients, about 20%. And serious infections requiring hospitalization occurred in about 1 in 5 patients. So 20% of patients are still getting very serious infections, may be admitted to the hospital. So there is real immune suppression. These patients are on PJP prophylaxis, they're on Valtrex. Again, like I said, we'll talk about more of these intricacies in a later episode. What's amazing is only four patients developed COVID 19 infection, and these patients were enrolled from 2019 to 2020. So it's very impressive that there are very few COVID 19 infections. So overall it was very well tolerated. Ronak, what about epcoritamab? What's the deal with eparitamab?
- [24:36]
A
There's also promising data here as well. So this was approved based on the EPCOR NHL 1 trial that was published in Lancet Hematology in 2024. And so as Vivek said, the difference here is that epcritamab is a subcutaneous injection, so it doesn't require an infusion, which is a huge positive for some patients. In cycle one, the doses increase weekly until the full dose at week four. It's given similar to daratumumab, which many of our listeners may be familiar with from myeloma. And so essentially we give it weekly for three months and then every other week for six months and then monthly until disease progression or if there's unacceptable toxicity, unlike mosinetuzumab, which Vivek just mentioned, as you may note here, this is indefinite therapy, so it's not fixed duration. So there were 128 patients who were enrolled who were similar to the mosinutuzumab study in the third line or higher setting, the overall response rate was 82% and the CR rate was 63%. With regards to patients that developed CRS, that was about 60% of patients. ICANS was pretty uncommon. In fact, only 6% of patients had ICANS. That was noted. And again, just minor confusion. Without that progression to aphasia, coma, seizures, which is what we think about with CAR T. Once they optimized the step up dosing and they tested this in over 80 patients, the CRS rates dropped to about 50% and in fact there were no ICANS events. So that's even better. Now. Neutropenia occurred in about a quarter of patients. Generalized fatigue occurred in about a quarter of patients. There were some patients that had minor injection site reactions and this was seen in roughly half of patients in the study. There was a higher incidence of COVID 19 that occurred in just under 50%, roughly 40% of patients. Though we should not compare this number to the mosinutuzumab trial which had a much lower incidence. And we are still awaiting the long term follow up data for this, but things are looking pretty promising.
- [26:45]
B
That was a great recap. And now I want to provide our listeners with a thought of. You might be wondering, okay, we've got epcoritamab, convenient subcutaneous, we've got that mosinutuzumab, fixed duration. Which one do you choose? Which one's better? Which one do you go for? The truth is we have no idea. But what might you think about? We know that epcoritamab works well in DLBCL as a single agent. As we talked about in our prior series, while mosinutuzumab had less efficacy in this setting, there is newer data that a combination of mosinutuzumab plus polatuzumab vedotin might be a good promising strategy in large B cell lymphoma. But as a single agent, it just didn't meet that mark. So if you have a patient where you're clinically concerned for possible large cell transformation, maybe they had more rapid disease progression. Very high SUV uptakes would be like an SUV uptake of like 19, 20, 18. And you just really suspect that the patient had large cell transformation. Maybe you couldn't get a good excisional biopsy, you could only get a core and showed follicular. But you still in your head are saying, I really think this patient has large B cell lymphoma somewhere Hidden in there. That might be where you might think about that epcoritamab option, those more aggressive patients. Because epcoritamab works for both. Offering a fixed duration approach is also very appealing. So if you don't have that situation, then you offer it to the patient. You say, this is an IV formulation, it's fixed duration, we've got some good long term follow up for it. And if you achieve a cr, it's only six months of treatment. And so that's really appealing for some patients. I do want to mention a couple of things. The field is evolving. We also know that these therapies are going to be moved in the frontline setting. There's multiple ASH abstracts, ASCO abstracts, looking at mosinutuzumab as a subcutaneous formulation in the frontline setting in combination with things like lenalidomide. There are epcoritamab in the frontline setting studies. They're happening all the time. There has recently been a press release for what will likely become a standard of care option. And the first bispecific and the second line setting, and that's epcoritamab plus lenalidomide and rituximab for a fixed duration of two years. That R squared regimen plus epcoritamab bispecific antibody therapy. Remember, this is different than tafecitumab plus lenalimidomide rituximab that we talked in our prior episode because it's just more effective. And we'll see that data at ASH of this year, I'm sure. And I suspect that this will become an approved therapy in the second line setting.
- [29:06]
A
That sounds great. As we've said many, many times on our show, if things work really effectively in later lines, why not try to really push the bar there and bring it higher up in our treatment algorithm? So I'm glad to see that we're moving in that direction. Just really briefly, Vic, you had mentioned another bispecific that they use in Europe. Could you just remind us of what this drug is and a little bit about it?
- [29:30]
B
So this is odranextamab. It's an IV formulation of a bispecific antibody. And the major downside to this bispecific antibodies is schedule. It's split dosing weekly for the step ups, meaning it's given on day one and day two, day eight and day nine, day 15 and day 16, then weekly for two months and then every other week until disease progression. If the patients have achieved a sustained CR for nine months. It can go to monthly, but that's a lot of visits. In addition, it requires. In the trial, it mandated hospitalizations after each step up dosing to monitor for CRS and icans. This is a very effective drug. It is effective in large B cell lymphoma. The data in follicular lymphoma mirrors the other two studies that we've discussed. We'll link it to our show notes. Again, just always check out our show notes. It'll have all this data in there. And I think the big thing is it's not FDA approved now. It likely will be soon and then we'll have three products. Which one do you choose? I'm hard pressed to choose this one because of the schedule. And I think that's really important. We think about time toxicity for the patient.
- [30:31]
A
That sounds great. Yeah. And we talk about that too. Right? Especially coming to and from clinic appointments is nothing that we should minimize. That's a big burden on our patients. So I think. Moving on. Why don't we talk a little bit about CAR T? I know we spoke a lot about CAR T in our DLBCL series. We also had a whole episode dedicated to CAR T, talking about the nuts and bolts of it. But what is the data behind the use of axis cel and lysacel in the follicular space?
- [31:00]
B
Yeah, I think this is an important question. And as before, we recorded this episode. One of the things that came up when Ronick and I were talking, why are Car Ts CD19 directed and these bispecific antibodies, CD20 directed? And there's a couple of reasons for that. One of the main reasons why bispecific antibodies are a CD3 CD20 as opposed to CD3 CD19 interaction is because the epitope for the CD20 was taken from our known CD20 antibodies. It was convenient. We had these epitopes created. What those were were, let's say we had obinutuzumab. Let's use that same epitope to make a bispecific antibody product. We had rituximab. Let's use that same epitope that rituximab has to bind to CD20 to make a bispecific antibody product. So it's just that we used our existing things and just kind of modified them to make these bispecific antibodies. That's one reason why we had that. Another reason was we already had CD19 directed car T cells that were. That were created well, why don't we take another antigen to target in case the patient does relapses after CD19 car T cell therapy. So that's why you commonly will see this. CAR T cell therapy was started in all where you don't always have CD20, but you certainly have CD19. And that's why CD19 took off and went to other diseases other than all and started going into B cell lymphomas. And so that's why you have that discrepancy. So we're talking about CD19 Car T products, two pivotal studies. One was for AXI CEL, the other one was for a product called Lysacel. We have the Zuma 5 Phase 2 trial and the Transcend FL for Lysacel. Bottom line for both of these products, pretty outstanding CR rates for the Axi cell trial. Probably a higher risk population than the Transcend FL trial which includes some second line patients. The AXI cell trial included third line or higher setting. The CR rate in that study was about 80%. The five year follow up of that Axi cell study showed that 50% of patients who achieved a CR remained in CR. And that's where we have this hint of maybe a potential cure for the Lysa Cel trial. It was ridiculous. The CR rate was 94%. Pretty insane, insane CR rates. We don't have durability of response for long term follow up yet for the Lysisl study. Very promising, very different patient population. So you can see these products lead to higher CR rates than the bispecific antibody products. They do come with more toxicity and so it's really important to factor that in. So you might be wondering, when do you choose CAR T cell therapy? When do you choose bispecific antibody therapy? In 2025? The truth is we have no earthly idea when we look at it. If you've looked at the five year follow up, the long term follow up for the Axi Cel study, because we don't have that in the Lysocell study. Really. And you compare that to the Mosin Netuzumab long term follow up that we discussed earlier, the results are pretty identical. They're very, very similar. So it's hard for a lot of us who treat this frequently to not recommend one of these less toxic bispecific antibody products. Particularly because many of our follicular lymphoma patients are older. Some patients prefer that fixed duration approach, some patients are younger and you want to give them that shot at cure or if you're really concerned about a large cell transformation, you might be pushing for that CAR T product where we know enlarged B cell lymphoma. We have seen long term durable cures.
- [34:17]
A
That was fantastic. And such promising data listeners definitely check out our show notes. We will put links to all of these studies that we mentioned in the show notes for you to review. But again, what's amazing is that we have such great options, therapeutic options for our patients in this day and age. It's important to understand the data. It's also really, really important to understand the very unique side effect profile with cellular therapy. That's something that you definitely need to know as a fellow, as anybody taking care of these patients. It will come up on your board exams. So be familiar with the concept of CRS icans, how to treat them and now specifically, which sort of therapies are associated with what sorts of side effect profiles. Super, super helpful, Vivek. Thank you for going through all of that. Any final thoughts that you have?
- [35:06]
B
We're wrapping up our follicular lymphoma series with this. It's been a great series. Please listen to our episodes. We've really spent a long time crafting how you break down this very complicated disease. The last thing that I'll say, bispecific antibody therapies are very manageable. At Rouleaux, I've treated a patient who's 90 years old with a bispecific antibody therapy who went into remission and is playing bridge in their bridge group now. And that's how amazing these products are. Therapies that were not approved were able to give to an older, more frail population and potentially get that durable remission and, and have very little time toxicity and very little adverse events associated with these therapies. So it's an amazing time to be in hematologic malignancies and just really excited to see where the field goes.
- [35:51]
A
That's awesome. It's a great way to wrap up. So guys, I think that wraps up another fantastic episode of the fellow on call. Until next time, we'll see you all later.
- [36:00]
B
See you later.