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Frontline Response in Emergency Medicine: Best Practices for Early Recognition and Management of CAR T-Cell and Bispecific Antibody–Related AEs

What is CAR T-Cell therapy?

[00:13:46]

The Basics of CAR T-Cell Therapy

I think this stuff is so interesting. The basis of CAR  T-cell therapy, this is just a little graphic that gives a brief explanation. We do not have the time to go into it too much, but the  T-cells are collected from usually the patient or a donor. Then they are genetically engineered. They are modified to express a CAR protein or a chimeric antigen receptor. The  T-cells are then expanded, so you get a lot of them. They are infused back into the patient. Then these modified CAR  T-cells will attack the cancer cells, usually binding to them and releasing cytokines to kill the tumor cell.

[00:14:37]

Challenges With CAR T-Cell Therapy

Now some of the challenges with CAR T therapy are, you can get organ dysfunction, and that manifests itself with your—you get a transaminitis. Your liver enzymes go up. You can get hyperbilirubinemia, you can lung involvement, so you can get difficulty breathing. You can have hemodynamic instability. With CAR T it is basically a massive immune response that these modified CAR  T-cells are eliciting from the body. It presents almost exactly the same as sepsis. You get tachycardic. You get hypotension. You can have capillary leak syndrome. If you get neuro involvement, you can have delirium, aphasia, cerebral oedema, and seizures.

[00:15:31]

What Is Bispecific Antibody Therapy?

What is a bispecific antibody therapy?

[00:15:36]

Bispecific Antibodies

This is like, what a time to be alive. The antigens are identified that they want to use, and they want to use an antigen that is a bispecific because it is going to bind to a  T-cell and also the tumor cell, and that is going to alert the  T-cell to attack the tumor cell. After the antigens are identified, the antibody is designed. These are called Bites, bispecific T-cell engagers. Then they are mass produced, and they are infused into the patient, and it links the  T-cells up to the tumor cells, and you get a cytokine release which kills the tumor cells.

[00:16:19]

Comparison of CAR T-Cell Therapy With Bispecific Antibodies

This slide I think, is great because it is a comparison of CAR T-cell therapy with bispecifics. CAR  T-cells are actual living cells. Usually, they come from the patient, and then they are genetically modified, while bispecific antibodies is a protein. CAR  T-cells are personalized for the patient. Bispecifics are off the shelf. CAR T-cells have 1 antigen. Bispecifics usually are bispecific, so they have 1 antigen for the tumor and 1 for the T-cell.

CAR T can last months to years, while bispecifics hours to days. As a protein, it degrades. Dosing, you usually give CAR T once, while bispecifics, you can give it multiple times. Potency of CAR T is very high. Bispecifics is moderate to high, and the CRS risk that is the cytokine release syndrome, which we will discuss is very high for CAR  T-cells, moderate for bispecifics. Reversibility, we will talk more about that. Then the cost of CAR T is high, well, they are both high, but.

[00:17:27]

Management of key CAR T-Cell-Related and Bispecific Antibody-Related Toxicity: CRS and ICANS

Management of key CAR T-cell-related and bispecific toxicity: CRS and ICANS.

[00:17:33]

Timeline of Toxicities Associated With CAR T-Cell and Antibodies in Blood Cancers

CRS and ICANS are what we almost always discuss as adverse events with these treatments in the emergency room, because as we will talk about some of these other adverse events are not necessarily things that we are going to do much with in the emergency room other than stabilize the patient. It is helpful to understand the timeline of these, especially with CRS and ICANS. Immediately, you can have CRS.

As always, you can develop infections. Most of these people are very immune depleted and are at risk for infection. They almost all have neutropenia, and they can develop neurologic toxicity, which is ICANS. Within the first month, infections continue cytopenias, and you can have neurologic symptoms like ICANS as well.

After 6 months, you are looking more at infections. As always, many of these people are still cytopenic. Then you can have hypogammaglobulinemia, which predisposes you to infections as well. Long-term, you are almost always at increased risk of infections, cytopenias, and hypogammaglobulinemia as well.

[00:18:52]

CRS

Let us talk about CRS.

[00:18:56]

Cytokine-Release Syndrome

The typical onset is 2-3 days after treatment the duration of 78 days. If you look at this graph here, it is really the first 2 weeks after treatment where CRS can manifest itself. If you look after day 12, 13, 14, it is not that common. It can still happen, and it has been documented to happen after, but it is very, I should not say rare, but it is much less common.

Cytokine Release Syndrome, as the name states, it is a systemic inflammatory response that occurs as CAR  T-cells activate and expand. They release interleukins and interferons, and there is a massive cascade that happens, and you develop symptoms that mimic sepsis. Patients present with flu-like symptoms. They are achy, they have fever, and these symptoms can progress. They can become hypotensive, hypoxic, and die. The more disease they have is correlated with the higher likelihood of a more severe CRS response.

[00:20:12]

CRS: Clinical Manifestations

Some of the clinical manifestations are fever, hypotension, hypoxia. You can have organ dysfunction. You can have transaminitis. Your creatinine can go up. You get a hyperinflammatory syndrome as we discussed. Shortness of breath. Headache, myalgias, nausea, vomiting, hypotension. Many times, patients have worsening back pain, tachycardia. These sound familiar. They are very similar to sepsis.

[00:20:48]

ASTCT Consensus: Grading of CRS

The grading of CRS, this is important. There is 4 grades. Basically, each grade goes up a notch from the previous one. Fever is required for CRS, and you can see that in every grade, you will see fever. Then in grade 1 hypotension you do not really have it. Grade 2 you have a mild hypotension that responds to fluids. Grade 3, you will have 1 vasopressor. Then grade 3, you will have multiple vasopressors because they are so hypotensive. Hypoxia in grade 1 is not really there. Grade 2 some nasal cannula, maybe a little bit of a face mask. Grade 3 is going to require more like a non-rebreather. Then grade 4 is going to be intubation, positive pressure stuff like that.

[00:21:51]

General Management of CRS

The management of CRS is first, you got to rule out infection, which you cannot really do in the emergency room. You are going to treat these patients as if there is an infection there as well. You are going to look at your timeline and see when their infusion was. If it is within that first 2 weeks, CRS is going to be in the front of your mind. For grade 1, you are going to do supportive care with antipyretics like Tylenol, hydration, and then broad-spectrum antibiotics like cefipime, vancomycin, or linezolid for your leukemic patients.

You will consider dexamethasone, but usually you do not need it for grade 1, and then you consider early tocilizumab use. The reason why you do not want to use steroids or tocilizumab too much is because you are blocking that inflammatory cascade, which is actually what you want, because that is what is killing the tumor cells. You have to be very careful about how you use tocilizumab and steroids, because you do not want to necessarily block that, because this is the patient's hope is that it is going to kill those cancer cells. If you block it, you are not letting the treatment work, but you have got to do what you got to do.

If they are sick and they are having these symptoms, you got to give these medications and the tocilizumab you want to get to prevent it from getting worse. Same with steroids. Grade 1 easily slides to grade 2 and 3, and 4, and many of these patients present with grade 1 and then slide quickly down. Grade 2, you give supplemental oxygen fluids, and tocilizumab, and if there is no improvement again with dexamethasone, and then grade 2 you usually give tocilizumab. Grade 3 you are going to give tocilizumab again, and dexamethasone transferred to the ICU.

These patients need to be watched very closely because many of them crash. Then you consider high-dose steroids and salvage treatment with anakinra. Anakinra is not something that I have ever even given, because usually you are giving fluids, steroids, pressors to arrest the symptoms. Anakinra is more like if everything you are doing is failing, which you do not know right away. Grade 4 tocilizumab plus high-dose steroids transfer to the ICU, supportive care as clinically indicated. For dexamethasone, we usually for grade 2 start with 10 mg. For grade 3, we usually do 20 mg and then high-dose steroids, we usually give methylprednisone 500 mg Q12 hours.

[00:24:51]

ICANS

Next, ICANS. This one I find fascinating. Absolutely fascinating.

[00:24:56]

ICANS With CAR  T-cells

The way to think of ICANs is CRS with neurologic symptoms. You have CRS symptoms, but you are getting neurologic symptoms on top of that. Neurologic symptoms include delirium, encephalopathy, aphasia, lethargy, difficulty concentrating, headaches, confusion. Sometimes they get tremors, agitation really any neurologic symptom can be precipitated by this typical onset is 4-6 days, but like CRS, it is usually within the first 2 weeks. CRS usually precedes ICANS, so CRS can slide into ICANS as well.

The reasoning, they think, is that this massive inflammatory cascade somehow just disrupts the endothelial barrier, and they cross into the brain through the blood-brain barrier, and they wreak havoc with the brain, which causes these neurologic symptoms that we see. There is some other theories as well, elevated levels of excitatory NMDA receptors, but we are not really sure.

[00:26:13]

ICANS: Clinical Manifestations

Here is the clinical manifestations that we can see. You get changes of orientation. This is important because this actually helps you grade how significant their ICANS is. They cannot name objects. They cannot follow commands, decreased level of consciousness. They can have seizures, focal motor weakness, changes in handwriting, and elevated ICP, cerebral oedema and coma.

When these patients present, and before they get treatment, the patients will usually have a preselected sentence that they write, and as they are being monitored in the first few days after infusion nursing around the clock will have them write that sentence, and most of these patients remember the sentence weeks after because of they have to write it so much. What they do is they compare the sentences to previously. If there is a change in handwriting, that is 1 of the first symptoms that loss of fine motor control, so they know, and then that helps them diagnose ICANS quickly.

[00:27:18]

ASTCT ICE Scoring Tool

Now, going on to understanding how to grade so we can treat ICANS. There is an ICE scoring tool that we use, or ICANS scoring tool, and it is a 10-point scale. Here you can see that there is grade 1, 2, 3, and 4. Grade 1 is the least symptoms. Grade 4 is the most. You ask them orientation to year month city, and hospital.

You ask them to name 3 objects, you will point to a clock, your pen, maybe a button or a tie, and then you ask them to follow a very simple command, such as show me 2 fingers, close your eyes, or stick out your tongue, but not really compound commands. Then writing, they write their sentence that they had chosen before. Sometimes, if the ICANS is bad, they will not remember the sentence, so you have to just have them write something, but you need something to compare it to. Then, for attention, the most common one is you have them count backwards from 100 by 10s.

[00:28:27]

ASTCT Guidelines: ICANS Grading

Now, with that ICE scoring then you can go into ICANS grading here. Here you can see the ICE score at the top, and we are going to have 4 scores as well. For grade 1 there is minimal symptoms. Grade 2, they are a little somnolent. They awaken to voice grade 3, you really have to do that. Moving them to get them to respond, and then grade 4 is like sternal rub, or they are not responsive at all. You can have seizures with grade 3. Seizures are managed as the same way as seizures are with benzos and anticonvulsants. Motor findings, you can have stroke-like symptoms with grade 4, and then you can notice cerebral oedema on imaging with grade 3 and 4.

[00:29:35]

Team Management of CRS and Neurotoxicity

Here we can see that the team management of CRS and neurotoxicity. When it comes to managing CRS and neurotoxicity is the oncologists are heavily involved. They need to be consulted early and often because they are very knowledgeable about this stuff. They will help guide treatment because, as I mentioned before, giving steroids and toci are not without risk for the patient because you do not want to necessarily undo their treatment. Then again, you do not want to not treat them to find balance as is everything in the emergency room. CRS, I talked about how ICANS is a CRS plus neuro symptoms. For grade 1 of these, you can see that there is supportive care with steroids or dexamethasone.

Usually, we start with dex and then if that is not working, we go to methylprednisolone as it is much more potent. Grade 2, we go dex. For grade 1 we do not usually give steroids, but grade 2, yes, that is when we start with our steroids. Grade 3 steroids, and you can - for ICANS, because it is neurologic and so much worse, you can consider anakinra. Usually they give toci for CRS, and then you got your high-dose steroids.

[00:31:18]

Risk Evaluation and Mitigation Strategies (REMS) Requirements

When CAR T therapy was—for the past, ever so often, it was managed by the FDA, and the FDA created a risk evaluation and mitigation strategy requirement for institutions that wanted to give it. However, in June of 2025, the FDA limited the need for institutions to have these requirements. This is significant because it expanded who can give his treatments significantly. Before, you had to be tied to an institution that met these requirements, which MD Anderson was one. When I first started there, we had to do a significant amount of training for this. Now these treatments are becoming more commonplace and are going out into the community, and so these entities are going to be seen more in the community than previous. That is why it is important.

[00:32:33]

Example Patient Wallet Cards for CAR T-Cell Therapy

Here is an example of a wallet card that patients with CAR T will often carry with them, or should carry with them. On it, it will have the oncologist name and phone number, and they need to be called. They want to be called.

[00:32:51]

Risk Evaluation and Mitigation Strategies (REMS): No More

Again, this is just reiterating how in June of 2025, the REMS criteria was done away with by the FDA.

[00:33:03]

Other AEs Potentially Not Related to CAR T-Cell or Bispecific Antibodies

CRS and ICANS get a lot of attention.

[00:33:10]

Risk Factors for Infection

There are other adverse events that can occur such as GVHD, immune effector enterocolitis. You can have derm manifestations, endocrine manifestations such as thyroid issues, hypophysitis, diabetes. Basically, anything that can be attacked and become inflamed from these infusions. Colitis is a big one, and it is very important that is discovered because steroids can help prevent rupture. Nephritis is another one. We do see a lot of pneumonitis as well.

There are risk factors for infection. Infection for these patients is the biggest problem, and it has to do with their age. Many of them have comorbidities such as renal insufficiency, failure, heart problems. Before they even get treatment, they have to be immune depleted. Cytopenias are extremely common. The tumor burden lends itself to becoming immunosuppressed.

Many of them have already gone through multiple lines of treatment. Many of them have been on steroids to further suppress their immune system. They might have had chemotherapy. Maybe they had previous infection. They have been in the hospital. Risk factors for infection are very high for these patients.

[00:35:01]

Long(er)-term AEs in Patients Receiving CAR  T-cells: Immune Effector Cell-Associated Enterocolitis

This is what we talked about with the GVHD. It can be delayed toxicity with CAR T therapy or bispecifics. There is acute and chronic. Acute is less than a year. Chronic is greater than a year. The most common GVHD that we see would be skin rash. You can get liver damage, kidney damage, or pneumonitis, so they have chronic issues, and they need steroids. If it gets really bad, they can be put on immunosuppressants and ruxolitinib. The enterocolitis that we talked about earlier.

If they have grade 3 diarrhea after the first 3 weeks, we start to think about this. Grade 3 would be greater than 7 stools a day. It is diagnosed with CT, and usually we consult GI to do a colonoscopy, and they do a biopsy and then steroids. If it is really bad, they can do immunosuppressants as well. Again, these are not everything. These are 2. We talked about nephritis, pneumonitis endocrine, and derm manifestations are all side effects of these treatments.

[00:36:35]

Managing Common Long-term Toxicities

You can get B-cell aplasia or hypogammaglobulinemia. These are not something that we are going to see much of in the emergency department. The diagnosis would probably be done by the oncology team. These patients are going to need IVIg in many cases and antibiotics because their immune system is suppressed. Cytopenias are almost universal for these patients. Their blood counts are always wacky. They are always anemic. They have got a low platelets. Sometimes they got low white blood cell counts. Then infections occur in up to 70% of patients who receive these treatments. They are very common.

[00:37:24]

Sample of Available Therapies Associated With CRS and - CAR T-Cells

Here is some therapies on the left that are available with CRS and ICANS. I am not going to go through this in depth because the therapy is constantly changing.

[00:37:38]

Sample of Available Therapies Associated With CRS and - Bispecific Antibodies

Here is some more. These are bispecifics. You really have to look up the medication they are on to see if it is a bispecific or if it is a CAR T, because this is such a novel treatment that is rapidly growing. While it started with treating blood cancers and lymphoma, they are starting to expand it in the treatment of other types of cancer as well. It is rapidly growing. The list is dynamic, so I just listed them here so we can see some of them.

[00:38:18]

Let Us Go Back to Our Patient Cases

Let us go back to our cases. Here is a 66-year-old lady with myeloma. She presents with confusion, tremor, chills, joint muscle pain. Her daughter noticed her handwriting had changed. This is starting to look like ICANS, especially when she had teclistamab 3 days ago. She is anemic. She has got cytopenias. We talked about unexplained cytopenias. Her lactate is low, though, which is good. CRP and ESR are elevated. Chest X-ray clear. CT chest is clear. CT head is clear.

[00:39:02]

Posttest 1

Post test 1, what is the initial step in managing a patient with multiple myeloma and suspected ICANS in the emergency department?

Kevin: The poll is open. Please vote. Five more seconds for incoming answers. Thank you. We will close the poll and share the results.

Dr Cameron: Yes. The answer is C, supportive care and steroids. She has grade 1 ICANS. Her ICE score was 7 to 9. She has no seizures, no motor findings. She is mentating pretty well. There was no change in her consciousness, so supportive care and steroids for her.

[00:40:23]

Patient Case 2: 65-Yr-Old Man With Multiple Myeloma

Next case. A 65-year-old man with multiple myeloma has a fever and chills. He received a bispecific 3 days ago. We got fever. We got chills, but no other symptoms. Now, because he got bispecific 3 days ago, we are thinking CRS with the fever. There is no neurologic symptoms involved to suggest ICANS. He is a little hypertensive. Does have a fever. The rest of his exam is fairly unremarkable. Again, he has got some cytopenias here. CRP and ESR, greatly elevated, chest X-ray shows no abnormalities, so you are thinking this might be CRS.

[00:41:18]

Posttest 2

Based on the American Society for Transplantation and Cellular Therapy consensus, what grade of CRS would you note for this patient?

Kevin: Poll is open. Please vote.

Dr Cameron: Again, we have fever from constitutional symptoms. Blood pressure is not really that bad. Maybe a little soft. There is no elevated respiratory rate, no hypoxia.

Kevin: Five more seconds for incoming answers. Thank you. We will close the poll and share the results.

Dr Cameron: The answer is grade 1 because of the elevated temperature and there is no hypertension that is significant—maybe a little on the soft side. Might be leaning into grade 2, but mostly grade 1. Again, these are not distinct boxes, but more of a spectrum.

[00:42:44]

Patient Case 3: 62-Yr-Old Woman With R/R Large B-Cell Lymphoma

Case 3, a 62-year-old woman with large B-cell lymphoma, has confusion, fevers, chills, cough, shortness of breath. She received a bispecific 2 days ago. Blood pressure is a little soft. Febrile O2 SATs a little on the lower side, but not that we need to, intubate or anything like that. The rest of her physical exam is unremarkable. She has a white count. She is COVID negative, flu negative, RSV negative. Lactate is high at 3.6. This is the one that had a chest X-ray that showed an infiltrate and the CT chest that was revised. The radiologist called you to tell you that there is pneumonia there. Now we have got symptoms and a source of the infection.

[00:43:43]

Posttest 3

What is the first step in the emergency department management of a patient with large B-cell lymphoma and pneumonia in the setting of a recent epcoritamab infusion? This one we are thinking, because we have documented findings on a chest X-ray and a CT scan to indicate an infection and indicated pneumonia, we do steroids, toci, supportive care, antibiotics or supportive care, antibiotics, steroids, and toci.

Kevin: Five more seconds for incoming votes. Thank you. We will close the poll and share the results.

Dr Cameron: The answer is D antibiotics. I would add supportive care as well.

[00:44:57]

Question and Answer Session

Question and answer.

[00:45:03]

Key Program Takeaways

The key takeaways from today are, we talked about making sure we discussed the case with the oncologist whenever possible, because they are heavily involved in the care of these patients, and they want to be notified. Most patients will have a card if they are not from your institution that will explain what is going on and explain who to contact. These oncologists, if you are lost, welcome your call. We discussed what the signs are of CRS and ICANS, and we also discussed the treatments involved.

[00:45:40]

Poll 4

Poll 4. Do you plan to make any changes in your clinical practice based on what you learned in today's program?

Kevin: Poll is open. Please vote. Five more seconds. Thank you. We will close the poll and share the results.

Dr Cameron: Almost half of you said yes.

[00:46:35]

Poll 5

Please take a moment to text in 1 key change that you plan to make in your clinical practice based on this education. You can scan the QR code here.

Kevin: As Dr Cameron said, you can please scan the QR code on the screen either online or in the room. Also, if you are online, we do have a polling box open where you can simply type in your response and we will leave that polling box open for a few more seconds while our program moderator moves us on.

Speaker 1: Thank you so much, Dr Cameron. If you could just move forward 1 slide, I believe that will take us to our QR codes for the program, and I will finish this up. Thank you so much. At this time, we are taking questions for Dr Cameron. I do see a couple that have been submitted. I will read those momentarily. Just a reminder, if you do have any additional questions, please, for those online, please put them in the Q and A or in Zoom using the Q&A button. At this time, I am going to draw your attention to the screen where you will see the QR code for the program evaluation on the left, and then the QR code for additional program resources on the right.

Just a reminder, you must be logged in to or create an account and log in at deceraclinical.com/education. I have also put both of these links into the program chat online. Just a reminder it does take usually maybe 15 to 30 minutes after the program for the evaluation to actually open up and begin accepting evaluations and claiming credit. At this time, I do see a couple of questions that were submitted. I will read them to you, Dr Cameron. The first is, how does infusion timing influence triage and diagnostic urgency?

Dr Cameron: Can you repeat that question?

Speaker 1: How does infusion timing influence triage and diagnostic urgency?

Dr Cameron: I do not know if it necessarily does because patients presenting with sepsis initially, we do not know if they are septic, or if they are having one the CRS or ICANS. Everybody is going to be getting antibiotics right off the bat. If their blood pressure is low, they are going to be getting IV fluids, and then we are going to start an infection hunt to see if we can find a source of infection.

It is after during this process, when you are trying to put the pieces together of what could be going on with this patient, because you got to make sure the patient stabilized first with fluids and maybe pressors. That you look at the timeline of when they got their infusion, and you can say, oh, you know what? There is a good likelihood that this is CRS or ICANS.

Speaker 1: Then I have 1 more. Can ICANS present without fever or hypotension, and how would or does that alter workup?

Dr Cameron: ICANS can present without fever. It does not alter the workup or the treatment, but it can present without fever. You will get the neurologic findings and not necessarily the fever.