Axi-Cel (Yescarta)-A CD19 Directed CAR-T Cell Product for Lymphoma

Oxygen. Cellulose cell or axis cell, is a car T cell therapy used to treat certain types of lymphoma. In this Know Your Therapy video, we'll explain how yes karta works who may be eligible. What the treatment process involves and the important side effects and monitoring patients and care partners should know about. What is to Gene silo Lucille axi cell, also known as. Yes, Gata. is Carta, which is also referred to as captain gene or axis cell. So you might hear either of these three terms interchangeably is a type of car T cell therapy car T stands for chimeric antigen receptor modified T cell. And essentially what that means is we can collect a patient's T cells, which are a type of white blood cell and then genetically modify them to attack lymphoma cells in the laboratory. These genetically modified Car-T cells are then grown up in the lab, and we infuse these T-cells back into patients the way this works is that these cells are genetically engineered to target Cd19, which is a protein that is found on the surface of most B-cell so once he has Carter, these T cells are infused into your body. The cells then rapidly multiply to produce even more Car-T cells, which are then looking for Cd19, And they bind to those cells and then kill the lymphoma. Which cancers are treated with? Yes. Carty and specifically yes, Carta are approved by the US, FDA for a few different types of B-cell lymphoma. In particular, you'll hear large B-cell lymphoma, the most common ones. are diffuse large B-cell lymphoma not otherwise specified. Primary mediastinum, large B-cell lymphoma, high grade B-cell lymphoma, and diffuse large B-cell lymphoma that is developed and or transformed from a low grade lymphoma, specifically follicular lymphoma. The other category that is a type of lymphoma for which it's approved is follicular lymphoma. These are different clinical scenarios, which I'll talk more about in a moment. And then thirdly, which will usually lump under the diffuse large B-cell lymphoma umbrella. Cada actually recently had a label change which does not exclude patients with central nervous system lymphoma, specifically primaries, CNS lymphomas. And so patients with both secondary and S lymphoma and primary Santos lymphoma are theoretically also potentially eligible for this therapy, At what point in a patient's treatment journey would Yasser to be considered? in terms of when we treat patients with. Yes. Specifically, there are a few different clinical scenarios for patients with large B-cell lymphoma or these central nervous system lymphomas. We'll think of it. Do you think of patients as anyone who really hasn't responded to front to first line treatment with chemo therapy? So your standard first line treatment for those lymphomas or lymphoma that has returned very quickly within those first 12 months of receiving first line chemo monotherapy. The other scenario that you'll see is in the later lines, if you've received two or more lines of treatment at any point, you're also eligible for T cells in that setting. If you have a large B-cell lymphoma, that's a little bit different follicular lymphoma, which is approved, which in which it's approved after two or more lines of prior treatments. Who is a good candidate for. Yes. Are there any patients who should not have card cell therapy? So some people worry that they may be too old, but actually age is just a number. And there's no age limit for Car T-cells. Similarly, there's no single medical problem that would necessarily prevent a patient from receiving Car-T cells. But my biggest concern is always whether or not they are healthy enough to safely receive the car T cells, But there's a lot we can do on that front. If someone is sick to either help them be better, because a lot of times it's driven by lymphoma. A lot of times we work with other specialists, especially cardiology, etc., to really optimize organ function so that they can safely receive Car-T cells. So I really tell people, listen, if you can get to a center, that's probably the single biggest barrier, because they does require a specialized center able to handle those complications. So otherwise leave the eligibility and the comorbidities to the person who's to the physician who's giving the car T cells. Because actually, I think more often than not we're saying, yes, you're potentially eligible. What responses have been seen with gesture to treatment. I divide responses by the type of lymphoma being treated. So for large B-cell lymphoma it depends upon if you're receiving the T cells second lines meaning as your second treatment or your third line treatment. we think that the vast majority of people have an initial response. the more important question is how durable are these responses and what do these responses look like one year or two years and so far? And can we be cured from this? The data suggests that within that first six months is the highest likelihood of relapsing after car T cells for the large B-cell lymphoma, and then one year is really that second milestone. In general, we see that about half of patients continue to have long term remission at that 1 to 2 year mark. And then probably the number of patients who long term have these very durable responses. We have five year data with that suggests probably around 40 to 45% of patients who receive the car to have long term durable remissions. And frankly, many of these patients may be cured. Actually, we just published ten year data from Penn that showed that there no relapses after five and a half years. And again, that was a small sample size. But I think the message is really that if you're out that long, really, we are thinking that some of these patients may be cured, which is really incredibly exciting given how challenging and how sick these patients can really be. And a really wonderful if it's third line or later, we think that there's probably between a 5% to 10% decrease in the number of patients who received durable remissions. We think that maybe just because, frankly, people's immune system is a little bit more beaten up, you've seen more therapy by definition. And so that's why, again, we emphasize that it is worth being referred as soon as possible. If there's potential for Car T-cells on the table. work very fast. And so even within the first month, typically on the clinical trials and at many centers will scan even people after a month to look at response assessment. And within that first month, we're seeing a majority of patients responding at that time. And general for follicular lymphoma, we see that those responses are much higher. Over 95% of those patients are initially responding at first response assessment. we do think that many of those are durable, although again, the data are a little bit less clear. And they think there's a high and there's a higher, there is a higher risk of relapsing from follicular lymphoma. But similarly we think that over half of these patients are getting long term remissions. So I'd say overall quite promising when you think about the really group of sick patients that we're treating. What factors influence response? what factors influence response for large B-cell lymphoma. And these are similar follicular lymphoma, but not quite as strong. We think that how patients how healthy patients are before the Car T-cells is very important. So specifically we've heard something as performance status. But that really means how functional you are. And so we know that healthier fitter patients tend to do better. So for example, if someone is walking, exercising, healthy enough to do household activities or even work, those patients on average tend to do much better than those patients who are bed bound, are much sicker. Other things that influence how well people respond are we know that elevated lactate hydrogenase, which can be a surrogate for tumor bulk. So essentially more disease going into Car-T cells may decrease the likelihood of response. In particular, we worry about patients with bulky disease. And so these are very large lymph nodes depending upon how they're defined. Somewhere between 7 and 10cm and maximum size of the lymph node. then the other prognostic feature that we know consistently associated with poor responses is lower platelet count. Actually, What are the steps involved in Car T-cell treatment? Car-T is not quick. the journey really starts from a patient being referred to me to consider our T-cells even feasible in the setting. And usually the answer is yes. Once we meet someone, then we send we send off for insurance approval. We may need baseline testing to show the insurance and prove that they are well enough to receive Car T-cells, so that process can typically take a couple of weeks from the time the insurance receives that submission. Once the insurance approves, we can then collect people white blood cells, specifically their T cells, to make the Car T-cell product. Then those cells are shipped off to company to manufacture the Car T-cells. So in parallel Our job is to keep people out of trouble from the standpoint of their lymphoma. so often people require bridging therapy or that's therapy given after collecting the T cells to make car T cells, but before the Car T-cells actually go back into the body. Once we know that there is a successful product successfully manufactured, and that also that the patient is doing well. then we can receive the product back and set up a time for patients to come in for chemotherapy that's given immediately prior to the car T cells. The chemotherapy given prior to Car-T re-infection is called lymphoid depleting chemotherapy. To learn more about lymphoid depleting chemotherapy, watch the health tree video on this topic in our car T treatment step by step course. What is lymphoid depleting chemotherapy? This is different than other types of chemotherapy we give. The intent is not to treat lymphoma, but the intent is to suppress the immune system a little bit, to create some space for the T cells that we infuse to grow. once the lymphoid depleting chemotherapy is given. patients come back the following week and then they receive their Car T-cell infusion. How long will you need to stay near the car t center for monitoring after the car T infusion? The FDA mandates at least that you're within your close, in close proximity of treatment center for the first two weeks after Car-T cells. Products may be given inpatient or outpatient. Learn what monitoring looks like in each setting in our car T treatment step by step course. What are the main side effects of? Yes. Karta. when I think about Car T-cells in general, I love the side effects into short term side effects and long term side effects. Short term, the two big ones are cytokine release syndrome and neurologic side effects. Long term, we worry about infection potentially the risk for low blood counts Please describe the cytokine release syndrome CRS associated with yes. Karta. Cytokine release syndrome, also called CRS for short, really common and expected, with the vast majority of patients who receive the car to 9,592% of patients get cytokine release syndrome. Cytokine release syndrome has a broad range of manifestations. By definition, it has to have a fever or you don't have cytokine release syndrome, and it can be as mild as just a fever or persistent fevers that lasts a few days. It can also be more severe. And described those bad flu like symptoms. So needing oxygen fluid in the lungs, needing to be in the hospital occasionally, low blood pressure and even needing blood pressure support with potentially other organ damage that's typically reversible. That's much less common. Less than 10% of patients have that very severe CRS, We know that in general, the median onset of time to CRS is somewhere around 2 to 3 days with. Yes, there's a big range. And that range is typically as early as, as really as the day, the same day or day after. And or that could be almost up to two weeks. And so that's really why there's that two week rule for being close to that treating facility On average, cytokine release syndrome can manifest as a single fever and be done that same day, but More commonly, it can last for at least a couple days or even a few weeks. Rarely, where there's persistent fevers, What is the treatment for cytokine release syndrome CRS. you may just actually be observed. So you may not need any of these things and maybe just a little bit of Tylenol. But if it's deemed to be necessary to intervene further, we give a drug called tocilizumab, The other common medication we typically will use is a corticosteroid called dexamethasone. So we use those either a single or in combination. And that's standard first line treatment for cytokine release syndrome. Can you describe the neurological side effects, also known as immune effector cell associated neurologic syndrome? ICANN's seen with yesterday. in terms of neurologic side effects. The the medical term we'll use is I cans or immune effector cell associated neurologic syndrome, that incurs in the majority of patients around three quarters of patients who receive. Yes. And somewhere between about I'd say 1 in 5 to 1 in 4 patients can get severe I can and neurologic toxicity These neurologic side effects can manifest very subtly. And that can be as as subtle as maybe some fine motor issues. So we actually follow handwriting samples, leave it or not, and look for changes in handwriting samples or a little bit of difficulty with attention where people are just a little less attentive or a little bit of trouble coordinating. So, for example, one patient who had some tropical tea like spooning feeding involves it's hard to get into my mouth correctly. The those are typically more mild, more severe, can be really sleepy and less alert. And then more rarely that can be seizures and in severe instances, swelling of the brain, which can be life threatening. symptoms that I that patients and their caregivers should look for are any sort of I tell people like your baseline is what you went in as the way you were when you received your car T cells. And if someone's not acting right. The answer is we need to assess for neurologic toxicity. Or if someone's having some new some new weakness or some new or some new warm finding difficulty, any of that, we have a very low threshold to act because we know, again, just like CRS, the intervening early for neurologic toxicity or icons really does improve those outcomes. In general. We think that this occurs a little later after the cytokine release syndrome. So most commonly the textbook description is people get cytokine release syndrome and then afterwards they get the neurologic toxicity. But on average this is around 4 to 6 days after the Car T-cells, although again it can happen later to even in that second or third week after the Car T-cells. How has ICANN's managed? terms of how we manage this. People will be hospitalized for further observation because we don't know how severe that's going to be already. And typically corticosteroids, meaning dexamethasone is the first line treatment. Anakin Rose and common drug that we will also use if needed. For someone who is having seizures, for sure we would treat with anti-seizure medications as well. And if someone has thought to be at higher risk for seizures going in often, we will often even give them preventative medications for seizures. Why does Escada increase infection risk? the issue with infections and Car-T cells is a real and frankly, the biggest cause of, mortality after car T cells, that's not related to lymphoma. the challenge with car T cells is Car T-cells because they get Cd19. That protein is not only expressed on lymphoma cells, but it's also expressed on other white blood cells that make antibodies. And so you and because the car T cells can hang around, especially if you're in a remission, we also see that antibody levels can remain quite low after car T cells majority of patients. We think after a couple of years about 50% of patients have their have antibody recovery. But again that's half. And so there is a significant portion who remain long term immunosuppressed to some degree. As a result, it's really common that both that we see people get infections. And so these infections most commonly tend to be upper respiratory viral infections. That's far and away the most common thing that's reported in terms of late side effects. But we more rarely see opportunistic infections. So infections that we don't wouldn't see unless someone is immune to suppress it. And those can be bacterial and fungal infections as well. How is infection risk after his car to managed. patients often will stay on additional antibiotic or antifungal medication if their blood counts remain low If the antibody levels are low, we will we typically will monitor that. And often people can receive a drug called IVIg or intravenous immunoglobulin, which is basically pooled donor antibodies. And we know that if you're not making your own, sometimes we can replace those with donor antibodies to help prevent infection, as long with low antibodies in some patients we can see low blood counts persist as well. And so that's not just the white blood cells that can also be red blood cells or platelets that persist as well. So we sometimes do see that people need periodic blood transfusions. And this may not be constant. 1st May be used to chemo where blood counts drop low and they remain low, and then they come back up and everything is done with car T cells. We can see these transient dips in the blood counts. so I'll just tell people that have a low threshold that if something doesn't feel right, you really need to reach out to your oncologist and not just assume that it's far enough away that it's no longer related to the car T cells. Low antibody levels are known as gamma globular anemia, while persistent low blood counts after Car-T therapy are called immune effector cell associated hematoma toxicity IHC. To learn more about these potential side effects, watch the dedicated videos on. Globulin and iChat in Health Tree University's Car-T treatment step by step course. What is the role of vaccination after Car-T treatment? we know that right after the Car T-cells, we think that vaccines are a little bit less effective. So the easy answer is actually for vaccines, if you're not up to date, you get vaccinated before your Car T-cell treatment, ideally before lymphoid depleting chemotherapy starts, so immune system has some time to to make those work. moving forward, typically I typically tell my patients that I like to look for a little bit the cell recovery, meaning evidence that some of their immune system is starting to reconstitute prior to giving vaccines. That's not the same as the annual vaccine. So for flu and or Covid, if you're receiving those vaccines, those are very seasonally timed vaccines. And so typically I will tell patients I think there's little downside to getting those vaccines. I don't think it's likely to hurt you, but the risk is that you may not have the same degree of the response, and thus protection that you would have if you were healthier had not recently received Car-T cells, Other vaccines such as, for example, maybe they're due for a pneumococcal, pneumococcal or they haven't received shingles vaccines, something like that. for me personally, at least I wait at least a few months afterwards. The recommendation is at least three months. Some of us will wait longer, even like a year afterwards. I usually personally tend that ten to time that based on when I see evidence that the B cells and T cells are recovering. But that's a little bit of a personalized discussion with you and your local a junior oncologist. What extra precautions should be taken after Car-T treatment to reduce infection risk? Patients always ask me what kind of extra precautions they should take to reduce in risk of infection. It's a really common question and an important one. I say that honestly, the single most important time is actually before the car T cells, because what we know is if you have an active infection and receive car T cells, that can be life threatening So it's really important not to get an infection right before you get car T cells. So I actually tell people really be cautious right around the week or two before you're going to get your car. T cells is a single most important time after the car T cells. The degree of precaution, I think in part may depend upon how sick you are, as well as your own personal preferences. know. One's trapped in a bubble. It's not that degree of immunosuppression where you're forced to isolate. That being said, you definitely are a little bit more suppressed. So I think it's being cognizant that if you're going to say a party that's indoors or if you're going, say, through a crowded airport, that you are more likely if you pick to pick to be the one who picks up that respiratory, viral and illness and more likely to take a little longer to kick it. so for some people they say that's okay. And I don't they don't mind dealing with that. And so for some people, that does result in folks being a little bit more cautious about masking and about masking and perhaps a little bit more distance from folks who are sick. I tell people that in general, I would prefer if within that first month after the Car T-cells, there's a lot of other issues going on, and so it's preferable not to get an infection to be specifically cautious that first month especially. Are there any other side effects you want to mention? It's common for people to tell me that for the first three months after the car T cells, they really feel fatigued and just not quite back to their normal energy level. But usually that starts to come back after about three months after the car T cells. Some people bounce back as quickly as within a month. then in terms of other late toxicities, if you're reading about rare but serious things, we'll see risks secondary cancers. So we think that maybe the suppression resulting from the Car T-cells, because there is a significant amount of may decrease your immune surveillance and predispose towards secondary cancers in general. Not so much any different ones, but really the higher risk for the same one. So it really is important to stay on top of standard cancer screening, skin cancer, skin cancer screening and other recommended preventative training, substance and that sort of thing. What does recovery after yesterday look like? I think it all depends on two things, which is what's the status of women and what kind of side effects did you have after the T cells. like we talked about earlier, there's that need to remain close to the treating facility for those first two weeks after the Car T-cell infusion. So for sure, life is not back to normal. After those first two weeks. We will typically return someone to their treating physician as early as that first month after car T cells, to occasionally three months, depending upon the the comfort of their physician with managing acute Car T-cell toxicities. But I'd say somewhere between 1 to 3 months they return to their their referring physician and to their home. The monitoring right after the car T cells is typically several times a week. For the first week, the Car T-cells go in if you're outpatient and typically at least 1 to 2 times a week for those first three weeks afterwards. So for that first month, I say that the visits are fairly intense again, to monitor for toxicity and intervene appropriately early after that first month. Usually those visits can be spaced out. think, frankly, a lot of that will depend upon blood counts and blood work, as well as if there's any lingering toxicity essentially, once people are ready to go back to their referring physician, coordinate with them to and tell their referring physician what to look for. Typically that's the issues with infection. And then obviously, if there are if there's any concern for neurologic toxicity or other toxicity, slow bed counts, that sort of thing, that's not improving to let us know. But often the local physicians can manage infections. And low antibody levels are also called globule anemia much closer to home. And everyone's happier, frankly, to return home to their own homes. People typically feel better somewhere between a month or three months after the Car. T-cells. For me, if someone's still not returning to their baseline after three months after the solid, I start scratching my head a bit and looking for other causes of that, as well as for sure assessing the status of lymphoma. What is the role of a caregiver during Car-T treatment? first and foremost, very, very important to have a caregiver, the issue is, that we can't leave you in the hospital forever. And while you're monitored in the hospital, it's very easy to to detect cytokine syndrome and neurologic toxicity. But once you're home. You may not be healthy enough if you're having bad CRS, or you may not be, frankly, neurologically aware enough to notice that you're having these side effects, and the time to intervene really does seem to be correlated with how well people do so. It's important to identify quickly and then intervene appropriately. The timing for that. We typically prefer that someone have a caregiver for the first four weeks after the car T cells. For some people, that can be really hard. Maybe you don't have a lot of family nearby. Maybe your kids are all grown up and live in Europe, and so it's may or may not be practical, but we're very flexible on who a caregiver is. That can be a friend, that can be church folks from church or synagogue. That can be anyone who's a reliable adult. Occasionally we've even had folks hire help or use neighbors. Even so, you don't have to be someone that you know that you are family with or is your is your spouse. And so I think that's one part which is to cast a broader net for who a caregiver may be, and also of identifying caregivers, challenging to really be honest about that with your cartilage team because sometimes we can also find resources to help you out with that piece too. So don't just assume that even if you don't have an obvious caregiver, that means Car-T cell isn't for you. Let your team try to help with that piece. the other major question that we get a lot of is when can I drive again? And similar to how long do you have to stay close to the hospital? Driving is the same duration, which is two weeks after the Car T-cells, but that one is also very hard. So we have a lot of people who take the train or really do, unfortunately, if they're rely on others to help them in those first two weeks, which can be challenging. Want to feel more prepared for every step of car T cell therapy. Continue with Health Tre University's Car T treatment step by step course. The course guides you through the entire Car-T journey, from testing required before insurance approval to T cell collection, bridging therapy, lymphoma depleting chemotherapy, Car-T infusion, and inpatient versus outpatient care. You'll also learn what side effects to watch for, how they are managed, and what to expect during monitoring and recovery.