Hello, and welcome to today's Journal Club Critical Care Medicine webcast. This webcast, hosted and supported by the Society of Critical Care Medicine, is part of the Journal Club Critical Care Medicine series. In today's webcast, we feature an article from the January issue of Critical Care Medicine. This webcast will be available to registrants on demand within five business days, and all you need to do is simply log into mysccm.org and navigate to the My Learning tab. My name is Tony Gerlach, and I'm a clinical pharmacist at The Ohio State University Medical Center here in Columbus, Ohio, and I will be the moderator for today's webcast. Thank you for joining us. Just a few housekeeping items before we get started. First, during the presentation, you will have the opportunity to participate in interactive polls. When you see a poll, simply click on the bubble next to your choice. Second, there will be a question and answer or Q&A session at the conclusion of the presentation. To submit questions throughout the presentation, simply just type the question into the question box located on your control panel. Third, if you have a comment to share during the presentation, you may also use the question box for that as well. And finally, everyone joining us today for the webcast will receive a follow-up email that will include an evaluation. Please take five minutes to complete the evaluation as your feedback is greatly appreciated. Disclaimer, this presentation is for educational purposes only. The material presented is intended to represent an approach, view, statement, or opinion of the presenter, which may be helpful to others. The views and opinions expressed herein are those of the presenters and do not necessarily reflect the opinions or views of FCCM. FCCM does not recommend or endorse any specific test, position, product, procedure, opinion, or any other information that may be mentioned. And now I'd like to introduce today's presenter. Dr. Christina Gutierrez is an Associate Professor of Critical Care Medicine at MD Anderson Cancer Center. She finished her medical school in Columbia, and after a post-doctorate position at Brigham and Women's Hospital, she completed her internal medicine residency in New York City. Her critical care fellowship was at the Memorial Sloan Kettering Cancer Center and introduced her to care of the critically ill oncological patient. Her efforts are now divided between patient care and research, which have focused mainly on immunotherapy and specifically CAR T-cell patients. Her collaboration and research within the Oncologic Critical Care Research Network are multidisciplinary and consist of complications of immunotherapy, ICU utilization, respiratory failure, neurocritical care, and most recently, COVID-19. Her work has led to research publication, guidelines and chapters, and different high-tier journals and critical care reference books. Besides research, Dr. Gutierrez has participated in different task force within MD Anderson to help guide care of the critically ill cancer patient. Thank you for being here today, and now I'll turn things over to Dr. Christina Gutierrez. Christina? Thank you, Tony, for the introduction, and hello, everyone. I'm very happy for this invitation and to be able to present our work. So I'm going to talk to you and go over some of the results of our manuscript that was just recently published. It's called Critically Ill Patients Treated for Chimeric Antigen Receptor-Related Toxicity. This is a multi-center study, and it actually includes multiple centers within the U.S. Our group is called the CAR-ICU Initiative, and I'll talk a little bit more about who these centers are. These are my disclosures. So I'll give you a little bit of background about what CAR T-cells actually are, in case you're not familiar. So CAR T-cells are part of what we call immune effector cell therapy. So the type of cells, the CAR T-cells that we're going to talk about in this paper, these were actually T-cells from the patients that get modified so that they express a receptor that will be able to recognize a tumoral antigen. In the case of the CAR T-cells from this manuscript, these are cells that will express a CD19 receptor, and they will target B-cell malignancies. We have right now about five CAR T-cell products. All of them are against B-cell malignancies such as multiple myeloma, diffuse large B-cell lymphoma, and also leukemias. And you know, what's interesting about these products is that patients that were known before to have refractory disease that were actually being considered for palliation and hospice and didn't have a survival longer than three months are now having responses of complete response of almost 50% to 60% and can be alive at two years after the treatment. So it's definitely made a significant impact in the oncological population. And I think for us as intensivists, it's helped us guide a little bit more or change a little bit more the focus on how we approach some of our patients once they get admitted to the ICU. Now, when a patient is going to be treated with CAR T-cells, usually what happens is they receive chemotherapy, then afterwards they will receive an infusion of the CAR T-cells. The CAR T-cells then recognize the tumoral antigen, the cells get activated, they replicate, and this leads to a release of cytokines and activation of other inflammatory cells. This will happen on every single patient, is sort of the normal process of how the response will actually occur. However, in some cases, this can lead to an exaggerated inflammatory response. This leads to endothelial dysfunction and then later on organ dysfunction. So the two toxicities that we see when we treat these patients with CAR T-cells, the two most common ones, I should say, are cytokine release syndrome and what we call ICANS, immune effector cell associated neurotoxicity. So cytokine release syndrome, it usually appears a little bit earlier, usually within five to seven days of infusion of the cells. It presents first with fever, you should always have fever, and then later on your patients can progress to develop either hypotension or hypoxemia. Because of the hypoxemia, it's usually related to either pleural effusions or non-cardiogenic pulmonary edema, and it can be severe enough to lead to ARDS. When it comes to the hypotension and cardiac toxicities, majority of cases, patients respond just to IV fluids and whatever therapeutic approach you're going to give the patients for specific for CRS or to suppress a little bit the CAR T-cell activation. But in some cases, patients can require one to multiple vasopressors, cardiomyopathies can resolve usually once CRS resolves have also been described. And arrhythmias, most commonly AFib and heart blocks have also been observed. Patients can also develop acute renal failure. It's usually mild, resolves fairly quickly. Electrolyte imbalances, most commonly hyponatremia, are also observed. And some patients develop DIC, hepatotoxicity or elevation of your liver enzymes, and in some cases, your toxicity can actually progress to HLH, even though it's not as common. Now when it comes to ICANs, ICANs usually presents a little bit later after CRS, usually around day 7 or so. It can present either concomitantly with CRS, or sometimes what happens is once CRS resolves, you can have a sort of a second peak of ICANs, which occurs usually around day 10, day 14, and it will show up on its own. Now ICANs is a very interesting syndrome. You know, once you see a patient with ICANs, you will never forget the presentation. It's very, very typical. These patients initially start having decreased attention. You sort of see them just staring to places when you're talking to them. They can have some difficulty with word finding, some aphasia. In some cases, they can become agitated or slightly somnolent, something that is also very, very typical, and sometimes even the first finding that we observe is changes in handwriting. So we monitor these patients by having them write a sentence twice a day. The syndrome progresses. These patients develop seizures. Most commonly, they're non-convulsive, and they usually respond very quickly to benzodiazepines or an antiepileptic. Cerebral edema has also been observed, and when you think about the cerebral edema, you can have either focal findings or diffuse cerebral edema. In some cases, and this was really observed at the beginning of the trials of some of the CAR T-cell therapies, in which we actually had about four to five patients that actually died from cerebral edema. Motor deficits have also been described, and also uptendation, and in some cases, coma. So when you think about these toxicities of CRS and ICANs, as many as 40% of patients end up requiring ICU admission, and this percentage has not only been observed during trials when you could actually think that people are being a little bit more careful and admitting patients early, but when evaluating data around the country, I think within here in the US, once one of the products was approved for diffuse large B-cell lymphoma, they saw that the rate of ICU admission within all hospitals was around 40%. So this is fairly significant, and despite this, before we published this, it was really not much data going over the specifics of these patients while they were in the ICU. What we were treating, how we were treating them, and how they were doing. Moreover, something that we think that is important, and this was an area that we wanted to focus on the future, was sort of a lot of the practices that we have on how we support these patients in the ICU are based on the general ICU population, and we thought that we could actually create some interventions specific for this CAR T-cell population that could actually improve outcomes. So to begin with this, and do a better evaluation of all this, we created what we call the CAR ICU Initiative. These are 12 centers within the US, and as you can see here, these are large centers that treat quite a lot of oncological patients, or they're just primary oncological centers, and many of these centers have actually spearheaded a lot of the trials of CAR T-cells. Not only that, but they've also played a significant role in the evaluation of other cell therapies. And have created their own products. So these are centers that usually have, that usually know, that have a lot of experience in the treatment of these patients, recognition of their management. So to begin with, you know, we created a survey in which we wanted to see how all of us were treating these patients, and what was surprising is we found that there was a significant variability between centers on how we were monitoring these patients, how we were doing prophylaxis for seizures or antibiotics for these patients. The toxicities we were observing were also somehow different. We were also observing, you know, that how aggressive we were being for the treatment of cerebral edema, seizures, status epilepticus, and even respiratory failure, and how we were managing shock in this patient population, was very different within centers. So that's why we decided that we wanted to gather some data from our treated patients to really have a good assessment of how these patients were doing, and how we were managing them. So 11 centers participated on the study. We gathered all patients that were treated within November 2017 to May 2019. We chose this sort of random date just because this is exactly the month when the first product, axicaptogen, was approved by the FDA, and we found that 340 patients were admitted to the ICU, were treated during that period, I'm sorry. Of those, 34 patients were actually admitted to the ICU, and then we decided to exclude those patients that were not admitted for CRS or ICANS, and the reason why we wanted to do that is because we feel that there's enough data out there to support how patients who develop, who have hematological malignancy, who have refractory disease, and how once they are critically ill and they get admitted to the unit for either septic shock, respiratory failure, cardiac arrest, we know these patients do poorly. There's enough evidence about this. We all know it. So we felt it was very important to be able to share with the rest of the ICU staff and group sort of specifics about just these toxicities. So when excluding those patients, we had 113, and then we saw that the majority of the patients were actually patients with axicaptogen. So the axicaptogen product is also a CD19 product, and it's the first FDA-approved product, and it's used for diffuse large B cell lymphoma. So we thought we would exclude the other eight patients that were receiving other products just to avoid any generalization of our findings to other products, and the reason why that is important is, you know, and I'll talk a little bit more about it later on, is every product there are definitely differences. There's a difference in the incidence of toxicities. There's a difference in the incidence of severity. Onset of toxicity also varies. So we thought it would be important to just focus on one group of patients rather than generalizing our findings. So with this in mind, we had 105 patients all with diffuse large B cell lymphoma treated with axicaptogen, and we observed that almost 62% of patients while being in the ICU presented with both toxicities, 23% with only ICANNs or neurotoxicity alone, and 50% with just CRS alone. Now when we looked a little bit deeper into those patients that developed CRS while being in the ICU, we found that 34% of those patients had grade 3 or 4 toxicity. A grade 3 or 4 toxicity, when you're talking about CRS, it means any patient that requires vasopressors or any patient that requires for the hypoxemia support with either high flow, BiPAP, or mechanical ventilation. Now besides the fact that a lot of the patients were presenting with any of these symptoms of hypoxemia or hypotension, which is the triage that you should be looking for, we did observe that as many as 76% of patients had another toxicity associated to the usual presentation of CRS. So we found that 26% of patients had symptomatic arrhythmias, meaning that they needed some intervention of which the majority were actually atrial fibrillation. Cardiomyopathy was not as common, which we actually thought was fairly common when we did the survey. The patients that developed hypoxemia, the majority were actually from pleural effusions rather than non-cardiogenic pulmonary edema. Hepatotoxicity was also fairly common, renal failure not as much. And we did find that even though hepatotoxicity was fairly common, patients that developed later on HLH were not that many, only 4 patients. The range of time from infusion to maximum CRS, and I should say also of ICANs, it was actually within what is reported in the literature. Now when it came to ICANs, we found that about 75% of patients developed grade 3 and 4 toxicities. When it comes to ICANs, and you're referring to grade 3 and 4 toxicities, you're talking first about an ICE and a CAR TOX score that is low. The ICE and the CAR TOX scores, they were actually designed specifically for those patients that are receiving any self-therapy really. And what it usually does, it's evaluating your patient's attention, recall, and degree of aphasia, and also the handwriting. So the lower your score, the sickest your patient is. Patients with an ICE score less than or equal to 2, you already have grade 3 toxicity. And these were the majority of patients. They had about 70% of these patients. Seizures is also part of a grade 3, 4 toxicity. As I said before, the majority of the seizures were non-convulsive, but it is important to note that 6 patients, or 33% of those that developed seizures, did progress to status epilepticus. The incidence of cerebral edema was not that common, only 8% of patients, but what I do want to focus on is the fact that we found that most patients actually had findings of what we call focal cerebral edema. So when doing an MRI, instead of finding diffuse cerebral edema, these were just small areas that were picked up mostly on MRI where there was edema. And this sort of highlights a little bit the pathophysiology of VIKINs. Usually what happens is once your CAR T-cells get activated, you have this inflammatory response and endothelial dysfunction, this also affects your blood-brain barrier. So you're going to be seeing trafficking of inflammatory cells, CAR T-cells, and cytokines into the CNS, and this will also lead to activation of inflammatory cells within the CNS, so your microglia. So it's possible that this focal edema is actually reflecting that, that sort of local inflammation that is occurring while the patient is sick. I should also mention that only one patient developed cerebral edema, and as you see here, the treatment for cerebral edema, which when we did our survey, we actually found that everybody was being fairly aggressive with the management and use of hypertonic saline, mannitol, acetosolamide even, was not really that common in our patient population. And this probably has to do with the fact that, one, the majority of patients had focal cerebral edema, and we have actually noticed that in these cases, what is important is to actually treat directly, you know, this exaggerated CAR T-cell proliferation, being with corticosteroids or anakinra, an IL-1 beta receptor blockade, rather than actually focusing on any of these medications that can probably cause more harm in this patient population, rather than really giving us any benefits, unless your patient has diffuse cerebrality. Motor deficits, we observed in about 12% of patients, and uptendation was not that common, a little bit less than 7% of patients. All patients underwent EEGs. They were done either in the ICU or on the floors right prior to transfer to the ICU. The most common finding, which has definitely been reported in the literature, is slowing on EEG. So here came the part where we were most interested about. We really wanted to know how we were intervening in the ICU. So I do want to start with the fact that about 21% of patients had documented infections. The majority of them were bacteremia or viral infections, and 85% of these cases were actually on patients that had developed either severe toxicities, grade 3 to grade 5. This is well known. This has been reported as an association of severe CRS with documented infections, and our incidence was actually not higher than what has been reported in the literature. It is important to note that the majority of infections usually occur within 10 days of giving CAR T-cell therapy, which is probably what we were observing in the ICU. Now when you look at severe toxicity, when the patients got admitted to the unit, about almost 67% of patients had it on admission. However, 10% of those patients progressed to have 3 to 5 toxicity. So 10% of patients got worse while they were in the unit. Now despite 76% of patients having severe toxicity, we were surprised in a way to see that only 23% of patients required any organ support. And by that I'm talking about vasopressors, respiratory support, renal replacement therapy. So as you see here, only 18% of patients required vasopressors, of which the majority were only requiring one vasopressor. When it came to respiratory support, it was fairly low, just 10%, and it occurred mainly on those patients with ICANs for airway protection. Use of high flow and BiPAP, high flow, use of BiPAP was actually rare. We used mostly high flow. It was definitely only used on those patients with just CRS. And as you can see here, the use of renal replacement was extremely low. We also found that the higher our toxicity grading, the longer the patients were actually staying in the ICU. And most of all, what was nice about this manuscript was to actually be able to prove what we already suspected, that patients who develop CRS or ICANs have a very low mortality. So only one patient with CRS died, only two patients with ICANs died. And this is significant. The mortality of only 8% on a patient with a hematological malignancy who is critically ill is extremely low when you consider what is reported in the literature. Hospital mortality was also low. And what I do want to focus on is the fact that those patients that died were not really because of complications, direct complications from the CAR T cell therapy, meaning CRS or ICANs, but it was due more from progression of disease or infections, sepsis. So this is something very important to keep in the back of your mind when you're treating these patients. Now we wanted to see what were the factors associated to increase mortality. Unfortunately, due to the low incidence of mortality, we weren't able to do a multivariate analysis. However, we did find that some factors that are usually associated to poor ICU outcomes on admission, meaning any patient with refractory disease, so those that have received multiple lines of chemotherapy, patients with high SOFA score on ICU admission, and those patients that have renal failure on admission or during ICU stay are usually thought to have increased mortality. And that was not the case in our study. Moreover, we also observed that those patients, however, once they got sicker while being in the ICU, meaning higher SOFA score, need for vasopressors, and mechanical ventilation was usually associated to increased mortality. And it makes you wonder, you know, if we found that the majority of patients that died were from sepsis or progression of disease, it makes you wonder if these markers of organ failure during ICU stay, if they are associated to sepsis or progression of disease, that's when mortality increases. Moreover, we looked at the treatments that are given to these patients. We found that mainly that corticosteroids, and specifically cumulative doses of corticosteroids, higher doses were associated to increased hospital and ICU mortality. Now when looking at our overall survival, we found that our overall survival was 10.4 months, and this is significantly higher to what is observed in critically ill hematological patients. Our center just published a study looking at hematological patients that get admitted to the ICU with severe sepsis, and what we actually found is that by 90 days, 81% of patients are already dead. So an overall survival of 10.4 months, it's actually striking. We also observed that no organ support, the presence of organ support or rate 3 or greater of CRNs or ICANs were not associated to decreased overall survival. However, when we looked further into corticosteroids, we found that any cumulative dose of 1.1 grams of methylprednisolone were associated to decreased overall survival and decreased progression-free survival. And these findings, they've actually been published in the same product, execaptogen. So there's efforts right now trying to look into what other treatments we can actually offer to these patients once they develop severe toxicity so that we can cut down a little bit on these corticosteroids and hopefully improve survival. So what are the clinical applications of our study? So I think, first of all, I should definitely clarify that from the time that we collected our data until now, there's a significant change in the practices of how these patients are cared for. So, and there's been more products that have been approved since. So to begin with, we feel that our rate of ICU admissions has decreased significantly. And this is something that we have observed in our hospital. So despite the fact that our number of patients being treated has not decreased significantly, what we are observing is that as oncologists get more comfortable and staff on the floors get more comfortable with managing some of these grade two, and maybe some grade three neurotoxicities on the floor, we end up admitting less patients to the unit. These numbers are also probably affected by the fact that we have now different products approved by the FDA. And a lot of these products actually have a lower incidence of severe toxicities. Moreover, there's some data to support that early interventions, meaning early use of corticosteroids can actually decrease the severity of toxicity. So instead of waiting until your patient reaches grade three, grade four toxicities to start the corticosteroids, starting them earlier in some cases grade one, even grade two could have an impact on how many patients actually develop severe toxicities. The other point that I really want to make emphasis on is these patients have excellent short-term and long-term survival. And I think this is something that we had already suspected with our clinical practice we knew, but we thought it was a message that was very important for everyone within all of our readership, I guess, to know that these patients do well and that we have to be aggressive on supporting these patients while they're in the ICU, even if they're developing respiratory failure, shock, even some degree of acute kidney injury, the majority of these patients and their toxicity will do well, their toxicities will resolve and we should be aggressive at treating them. And we should take into account, I guess, the fact that the majority of these patients that die are those that develop progression of disease or sepsis. So a conversation with the oncologist should always be occurring to sort of assess if a patient is definitely not improving. They've already been in the unit for a prolonged period of time, whether or not your findings of shock, respiratory failure could be due to an infectious process or it could be due to progression of disease. And of course, in those cases, the conversations about goals of care can actually change. Moreover, when you're training and when you practice oncological critical care, you sort of get ingrained this idea of the ICU trial, that you let these patients with poor prognosis come into your unit and you reassess after three to five days and if they have not improved, then you start conversations about limitation of care. However, if we had done that in our patient population, if we had limited care after five days, we would have actually withdrawn care in as many as 50% of patients who had survived. So as I said before, you just have to be very careful and in a way almost refocus your way of thinking when it comes to approaching these critically ill patients. Now, I think one of the most important questions and that we are even thinking about after we saw these numbers is, do these patients really need the ICU? How many of these patients are actually benefiting from being in the unit? And I think one of the things that we saw is the fact that yes, we have severe toxicities in as many as 76% of patients, but only organ support is very low, just 23%. So what does that really mean? So when you consider vasopressors, only 18% of patients ended up on vasopressors and the majority of those were actually only requiring one and the median duration of that vasopressor was just one day. So it almost means like those patients needed that extra time and support until the corticosteroids and the tocilizumab sort of kicked in before they could actually improve. So it makes you wonder if this patient population could actually be treated in an intermediate unit where you have maybe a critical care staff such as nursing and maybe even mid-levels that are able to recognize a patient that is getting worse early on, but that you probably don't need to admit a patient to the ICU if they're really not looking ill and there's a thought process that maybe they'll improve fairly quickly. When it comes to ICANs, which is the most common toxicity that you're gonna be seeing in the ICU, especially the majority of them are gonna have grade three toxicities, but then the question is, do all of these grade three, grade four toxicities need to come to the unit? So grade four, probably those are the patients that are tended with cerebral edema and seizures. However, how about those patients with a low high score? 70% of those patients. So that's the patient that could be slightly agitated and not answering any of your questions that can be a patient that is awake, but just completely a basic, so won't answer any of your questions or a patient that is slightly somnolent, but not necessarily of tundid or comatose or anything like that. So the question is, could these patients be monitored at a very high, or at a high acuity or specific CAR T cell floor or unit? Also with the support, I think will be important of ICU nursing or ICU mid-levels so that they can recognize early those patients that get worse. Now you could also say the opposite, right? That may be the reason why these patients did so well was because they were admitted to the ICU where there's staff there that is able to recognize early on when a patient is deteriorating, when staff is able to intervene quickly whenever it's needed. And then if you take into account up to 10% of patients actually progress to severe toxicities while being in the unit. So this is something that we have to sort of keep in the back of your mind. It would be nice to have a better idea of which are the patients that are gonna deteriorate early on. And in a way to sort of help triaging some of these patients. And then when it comes to mortality, as I told you, mortality from CRS and ICANSS is rare. Usually think of substance and progression of disease if your patient is not getting better. Now we found that corticosteroids were associated with pre-survival, short-term and long-term. So we know that there is an association between sepsis in these patient population and doses of corticosteroids. It has been reported in some of the literature and also with progression of disease. So a focus is actually, there's some emphasis now when creating research in corticosteroids-bearing therapies. An example is using an Akinra. There's actually an ongoing trial right now in hopes that using these medications can actually stop progression of disease or maybe even at least cut down on the amount of doses of corticosteroids that we're requiring for those patients that are severely ill. As I said before, infection is definitely an important complication of this patient population, especially in the first 28 days and definitely on the first 10 days right after infusion. There have been reports of PGAP and viral infections such as CMV even two years after a CAR T-cell therapy. So antibiotic prophylaxis is extremely important on this patient population. And you should keep this in the back of your mind whenever you have a CAR T-cell patient that has already passed through the acute phase of CRS and ICANS, thinking about infectious complications in this patient population. And then looking at short and long-term risk factors for infections on these patients. How do you differentiate them from CRS? So I'd like to thank everybody that was a part of this study. It was a lot of work. It was interesting, very interesting work, and we're all very excited when we're putting together the manuscript. I wanna thank especially Anne-Marie Brown, who did a lot of work during this project, all of our oncology team, ICU team, and the CAR Talks Committee in our institution who made us a part of their committee and guidelines since the beginning. And everybody within the CAR ICU initiative, everybody worked really hard to get some of this data, analyze the data, and put the manuscript together. Okay, so these are the polling questions. So the first question, okay, so a patient receives CAR T-cell therapy and gets admitted to the ICU with shock due to CRS. When you are discussing goals of care with that patient, what would be your advice? So first, A, you stop all support because the patient has advanced malignancy. B, you conduct a three-day trial and the patient doesn't improve after three days, you recommend withdrawal of care. C, if shock is due to sepsis, there will be no impact on the patient's outcome. Or D, you continue aggressive support as this complication is usually reversible. Okay, very good, you guys did great. So yeah, definitely, this is something that you should definitely take from this talk. These complications are reversible and you should be aggressive. It doesn't matter if your patient has a poor prognosis from their malignancy. Okay, so the second question, as part of ICU staff, you're asked to evaluate the ICU resources and considerations that are gonna be needed in your hospital once they institute a CAR T-cell program. All variables must be considered except the following. A, as doctor comfort level increases, your need for ICU beds will decrease. You can calculate the need for ICU beds according to the CAR product that will be used. Or C, there will be a significant increase there will be a significant rise in deaths in your ICU as soon as the CAR T-cell program begins. Perfect, very good. I guess for this first question, this is really an observation. This is something that we should really look into a little bit further. But yes, we believe that as doctors and I'm talking more about oncologists on the floor as they become more comfortable with the use of CAR T-cells, their toxicities, how to manage these patients, it's very likely that you'll see initially a rise on patients coming to the ICU. And as they get more comfortable, the amount of patients admitted to the ICU will actually decrease. Okay, and any questions I'm happy to answer. Well, thank you very much, Christina. That was a very informative presentation. And this is just a reminder. Oh, you're so welcome. To the audience, if you have any questions, feel free to type them into the question box located on your control panel. The first one I have for you is, is there any questions that you have The first one I have for you is, how do you differentiate between CRS and sepsis or infection? Can pro-capitonin be useful in that? That's a great question. And I think that's an area where a lot of people actually have interest starting with the oncologist, where you wanna avoid overuse of antibiotics on these patients. And also specifically in the unit, I think the presentation of severe CRS it's exactly the same as septic shock. So I think at this point, there's really no clear data to support any test over another to actually be able to differentiate one from the other. There's a study in the pediatric population suggesting that a combination of looking at some cytokines like interferon gamma, IL-1, and I think it was TNF-alpha the other one. So there's like a formula for these three, and it had about like a strong correlation with either with telling you whether if it was CRS or icons. The problem with using cytokines is that there's definitely a significant variability on patients on when you actually take the samples. And also, you know how quickly you're able to get those samples. The turnover of a lot of these cytokines is very long. So by the time you make that decision, it could be too late. And then I'm, apologies. And also it's expensive. It's an expensive test. Now, when it comes to procalcitonin, it can help guide. I think, unfortunately, a lot of the data that I have seen out there, it's not as sensitive or as specific. As many as, I think it's been like 30% of patients can actually have a positive procalcitonin even before starting CAR T-cell therapy. And I saw recently on this same product, you know, recently they published an abstract looking at procalcitonin and CRS. And they found that about like 40% of patients had a positive procalcitonin once they developed CRS, but there were only two documented infections in this patient population. So I think, unfortunately, we don't have clear data to sort of see what is the best way to sort of decide whether if it's one thing or another. Well, the good news is I'm glad that you have a research group to really look into this, because I think that's gonna be a hard thing for clinicians to be cognizant of, is this CRS or infection. So thank you for those answers. And I think based on your polling question, another question is, who should be managing these adverse effects of the people who get CAR T in ICU? Should it be the ICU team, oncology, both of them, or should other people be involved? And should they go to a specific ICU who should be caring for these patients? That's a very good question. So I believe that it should definitely be a combined effort. I think working together oncologists and intensivists is definitely gonna be extremely important, just to have the sort of frequent communication of when a patient is deteriorating, just sort of have a conversation, what will be the next step? Do we increase corticosteroids? Should we start anakinra? Any of these things. Also, the other thing that will be important about that close communication is what I was saying, if your patient is not improving, not only what else can you actually offer, but start thinking about other causes of why your patient is not improving. Should we be start thinking about whether or not if this patient has progression of disease and that maybe he never responded to the CAR Ts, and do we need to address goals of care? Now, what you are gonna find is that a lot of other specialties could get involved. So neurology is definitely important for them to be involved. You wanna have their input, especially because you wanna be able to do AEGs quickly and as frequently as you need to, even continuous AEG if it's necessary. So other specialties that you'll see that can get involved once these patients develop severe CRS is cardiology. If you have any life-threatening arrhythmias and you want their input, nephrology can also get involved if your patient develops a severe AKI. So I think it's definitely a multidisciplinary effort with both the oncologist and intensive as sort of, or the ICU team sort of leading these efforts. And whether or not, if you need a specific unit, I'm not really sure. I think it all depends on staffing within each institution. I think what we found with this manuscript is that it would be really nice to sort of have an intermediate unit where you could sort of observe some of these patients with neurotoxicity that are not necessarily extremely ill and that you could just watch further. Even those patients on low dose vasopressors, could you just manage them in an intermediate unit with support from ICU staff? I think that would be ideal. I think the problem that everybody's facing right now is staffing restrictions. And I think opening something like that would be very difficult at this point, but it's definitely something that has been sort of in consideration. And we've actually discussed a little bit, even within our institution, whether that's something that should be done. Now, I think this is definitely not the time with the pandemic happening to look at that, but that's something that definitely I think you might need to consider in the future is really doing some education, especially for those intermediate care units. Now, what I thought was interesting specifically as a pharmacist, is that those who died had that significantly higher corticosteroid dose, as you very well discussed in the presentation. Is there an optimal dose, or is there a point where more steroids are harmful that you could elucidate? Yeah, so that's a very good question. So the cutoff that we actually found where it made a difference, so when we did that initial analysis, we divided the doses of corticosteroids into quartiles. And then we found that the cutoff, where it actually made a difference on overall survival, was 1.1 grams of solumetrol. Now, when you consider the guidelines of how you treat patients with severe toxicities, meaning those with grade four, that's a very low dose. It's usually as soon as a patient develops grade four toxicities, the recommendations tell you to give a gram of solumetrol a day. So when you think about it, as soon as your patient hits grade four toxicities, you're already putting them at risk of having decreased survival. So that we found extremely interesting, because it's definitely not what we would consider a very hefty dose. So that is sort of what we observed. What we have found as this data came out that corticosteroids could have an effect on mortality and progression-free survival, at least within our institution, what we're starting to do is more, instead of leaving corticosteroids to sort of schedule throughout a prolonged period of time, is just giving small doses of dex and observing the patient, see what they do. We used to be very aggressive early on, which probably reflects some of these findings on our manuscript. But if I had to guess, if we were to look at our corticosteroid use right now, it might be a little bit lower. You know, that's quite interesting. And I'm wondering, kind of in this follow-up question that I had, is why do you think those who died in developed CRS had a prolonged time to their maximum symptoms? And is a steroid just something else causing the secondary insult, or were those just patients sicker when they were admitted to the ICU? That's a very good question. I think it's probably a combination of all, in a way. It's definitely a lot of those patients that actually had a very prolonged stay and onset. Some of those were patients that developed HLH. And we do know that HLH usually, it's almost in a way a spectrum of CRS, sort of like this heightened inflammatory response. And it usually tends to appear later on in the course. So that might be some of those findings of why it's sort of later on, the incidence of this toxicity. Whether corticosteroids play a role, I don't really think so unless there was a chance that infection could be masquerading as CRS. However, when we did a deep dive into those cases, they were definitely considered as CRS and there was really no documentation of infection. So that's why they were still included. And yes, and these were definitely patients that were extremely, extremely sick. I mean, as you know, those patients that develop HLH, they just develop multi-organ failure. They're fairly refractory to the treatments that we can offer and they do poorly. Very good. And that's very interesting to know. The next question I have for you is, do you know of any predictive models for those that will develop higher toxicity, like grade three or higher in these patients who might benefit from maybe even earlier ICU care? Yeah, so we do know that patients that have high tumor burden, and this is actually representative to all malignancies. So leukemias, lymphomas, multiple myeloma, anyone who's actually receiving an immune effector cell therapy. We know that those patients with high tumor burden are usually the ones that develop severe toxicities, and they usually develop them earlier. We also know that those patients with comorbidities, while they might not do worse, they might not be able to tolerate these degrees of toxicities as well as any other patient. So your patient with already underlying heart failure, if they develop severe CRS and they're having capillary leak syndrome, they might not tolerate that as well as your patient without any history of any cardiomyopathy whatsoever. So those patients, they usually recommend to sort of watch them closely. We tend to watch most of our patients on telemetry, but specifically those patients with high comorbidities, high tumor burden, definitely. And I know within our institution, also, you know what? Those patients that have high CRP and high ferritin at baseline, those are usually also patients that are prone to develop severe toxicities. And within our institution, you know, they created a score that includes different markers that have been used also in the stem cell transplant population to predict toxicity and capillary leak and multi-organ failure. And this score uses LDH, platelets, creatinine, and lactate. And there's a formula for it. But if you use these values at baseline, it can actually predict those patients that will develop grade three and four toxicity. So you could also always think of those patients admitting early into the ICU, knowing that those are the patients that will probably develop severe toxicity or not turn around quickly. That kind of leads to the follow-up question. It makes sense why most of these patients receive tocilizumab. Did you collect any data on timing and symptoms? And is there a time when it might be too late to administer the tocilizumab, especially when we've had some shortages because of the pandemic? Yeah, definitely. So when we looked at the specifics of the use of tocilizumab on corticosteroids, the majority actually followed guidelines, meaning tocilizumab, you can start it in patients usually with grade two toxicities or those who have refractory fevers. But the majority of people were using it right at the onset of these toxicities. What we did find that was, I guess not striking, but common, I guess, during that time was that we would give multiple doses of tocilizumab at the beginning when treating these toxicities. And we actually saw some patients that received more than three, four doses during these events. So there's some things that we know right now. We definitely know that fevers, you can just observe it, and you don't necessarily need to use tocilizumab. If your patient is not responding after a second dose, don't even bother. And that's sort of the changes that we have seen. So at this point, and oh, and I guess the other thing is tocilizumab, it's not recommended for patients that have Eiken's alone. So those things have definitely helped and guide, cut down a little bit on the use of tocilizumab. So yeah, that's sort of the information that we gathered. Well, thank you very much. And I'm sure that'll be helpful to others on this line of the call. And I don't see any other questions. So this ends our question and answer session. And Christina, I very much wanna thank you and our audience for attending. I will say, this is something I don't take care of on a daily basis, but I do cross cover our medical cancer ICU every so often. So it was very helpful to me, and I learned a lot, so thank you very much. And again, to everyone who joined us for today's webcast, there will, you will receive a follow-up email that will include an evaluation. Please take five minutes to complete the evaluation as your feedback is greatly appreciated. And on our final note, please join us for our next journal club on Thursday, March 24th, and this concludes today's webcast. Thank you very much. Thank you.

CAR-related toxicity

CAR T-cell therapy

intensive care unit

cytokine release syndrome

immune effector cell-associated neurotoxicity syndrome

toxicities

organ support

short-term survival

alternative treatments