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Understanding Possible Side Effects of CAR T-Cell Therapy

Understanding Possible Side Effects of CAR T-Cell Therapy from Patient Empowerment Network on Vimeo.

What side effects should you be aware of when considering CAR T-cell therapy? Dr. Adriana reviews the issues that may occur after undergoing CAR T-cell therapy and how the side effects are managed.

Dr. Adriana Rossi is co-director of the CAR T and stem cell transplant program at the Center for Excellence for Multiple Myeloma at Mount Sinai Health System in New York City. Learn more about Dr. Rossi.

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Considering CAR T-Cell Therapy? Key Advice From an Expert

Transcript:

Katherine Banwell:

Of course, we know that CAR T-cell therapy comes with some potential side effects. Let’s talk about some of those side effects and how they’re managed. You mentioned cytokine release syndrome earlier. Let’s start with that. What is it, exactly?  

 Dr. Adriana Rossi:

As I mentioned, cytokines are molecules that the cells of the immune system use to communicate with each other. With this therapy, we are asking the T cells that have been infused to expand, meaning make multiple copies of themselves, and sweep through the body looking for myeloma and basically picking a fight with them.  

So, CRS is what happens when the T cells are too good at their job and they overachieve and then picking a little fight kind of make a big ruckus. The result is what we call inflammation, which the patient will experience usually as a fever.  

But if it does not go – if it continues to go unchecked, that fever can be accompanied by low blood pressure because of these inflammatory markers, difficulty breathing or low oxygen levels. And all of these things are now vastly prevented. CRS is usually treated very quickly and doesn’t get to these higher grades, more complicated fields.  

Katherine Banwell:

How is CRS managed?  

Dr. Adriana Rossi:

We have a couple of very good antidotes. CRS by itself is not just a fever. Certainly, a fever in any patient who is undergoing these kinds of therapies, we will try to rule out any infections. But there are markers in the blood that we can follow. When the blood markers and the fever occur at the same time, we know that cytokines are driving that effect. If it seems to be driven by something we call IL-6, we use tocilizumab (Actemra). If it seems to be driven by IL-1, we use anakinra (Kineret). These are all drugs that are themselves monoclonal antibodies which then will shut down that overreaction and cool things down.  

Katherine Banwell:

Another possible side effect is neurotoxicity. Would you define that term for us?  

Dr. Adriana Rossi:

Yes. That one is harder to define because neurotoxicity in itself is very broad. We usually think of something called ICANS, which is the neurotoxicity associated with the effector cells. That specific neurotoxicity tends to happen in conjunction with CRS.  

And while CRS probably occurs in about 85 percent of patients, the ICANS is usually in the order of 5 percent. So, much, much more rare. And the antidote for that, which most patients know, love, and hate, is steroids.  

Katherine Banwell:

Ah, yes.  

Dr. Adriana Rossi:

I should mention there are other parts of neurotoxicity which I think the most concerning is something that has been known as Parkinsonian symptoms. It’s really just movement disorder. These are exceedingly rare and so we haven’t had a chance to learn very much because there are so few patients who have had this complication. We have learned from the first six patients who had this how to avoid it. And so, I think it’s now even more rare and it really goes into patient selection, to making sure, as I mentioned, that the myeloma isn’t growing very much.  

We monitor to see if the T cells grow too fast, if the CRS is of a high level. These are all predictors of delayed neurotoxicity.  

Katherine Banwell:

What are the signs of neurotoxicity in a patient?  

Dr. Adriana Rossi:

Very specifically, for the ICANS, we have tool called the ICE tool, which is a series of questions to test memory and attention and ability to write and understand and speak. So, most commonly, it would be an inability to speak properly or, if someone is writing a sentence, it’s really a very classic finding. It is no longer spread across the page.  

These are not subtle findings. Part of, again, being in the hospital is to allow us to have this tool twice a day and look for these signs very early on, interfere with their development by giving the patients steroids – usually for a day or two – and resolving it.  

Katherine Banwell:

And is there a potential for long-term issues associated with neurotoxicity?  

Dr. Adriana Rossi:

Certainly, there is always the potential. But the vast majority – again, the ICANS tend to be self-limited while the patient’s in the hospital, and that is why we’re watching during that window. The delayed neurotoxicities, in addition to these very rare movement disorders, we do see some cranial nerve palsies. The seventh cranial nerve, usually recognized as Bell’s palsy, has happened a few times. We really don’t understand the mechanism of what is driving it. It’s inflammation but why there, why that way. So, we tend to use acyclovir, which is the classic treatment for Bell’s palsy and steroids.  

Katherine Banwell:

Dr. Rossi, a suppressed immune system is something that a patient undergoing CAR T-cell therapy should consider. What does it mean, and what precautions should patients take?  

Dr. Adriana Rossi:

That is such a good question, and it is specifically true for patients who are receiving therapies that target BCMA, which both commercial CAR Ts at the moment target.  

Because it is such an effective therapy at bringing down cells that express BCMA, your immune cells that make antibodies, one of the side effects is the immunoglobulins, which are the antibodies, are all very, very low. So, that is one level of immunosuppression.  

The other is the chemotherapy that we use to quiet the T cells can also lower all the blood counts. So, red blood cells and platelets may be low as well and those are not involved with immunity and can be transfused. So, that is a supportive mechanism. For the immune therapies, we usually use IVIG, which is intravenous immunoglobulins to support the patient until they’re able to make their own.  

We also protect them from viral infections with acyclovir or valacyclovir. Protect them from something called PJP pneumonia, which is a virus that specifically appears when you’re very immunosuppressed. Should their neutrophil count be low, that is another type of white blood cell – make sure they’re protected with antibiotics.   

The Latest in Myeloma Research: Updates From ASH 2021

The Latest in Myeloma Research: Updates from ASH 2021 from Patient Empowerment Network on Vimeo.

Myeloma specialist, Dr. Omar Nadeem, shares promising research advances in myeloma from the 2021 American Society of Hematology (ASH) annual meeting. Dr. Nadeem discusses the future of personalized medicine for myeloma, as well as positive results from a clinical study on quadruplet therapy.

Dr. Omar Nadeem is the Clinical Director of Myeloma Cellular Therapies Program and Director of Myeloma and Plasma Cell Pathways at the Dana-Farber Cancer Institute. Learn more about Dr. Nadeem, here.

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An Expert’s Hopeful Outlook on Myeloma Research and Treatment 


Transcript:

Katherine:

Personalized medicine for myeloma is slowly becoming more of a reality for patients. Can you provide an update in testing in myeloma? Are there specific markers that you’re looking for when considering patient care?

Dr. Nadeem:

So in multiple myeloma, right now the only targeted therapy that’s in development is looking at venetoclax (Venclexta), and that’s in patients that have the t(11;14) translocation.

So, this has been studied for a while, both as single agent and in combinations and the big BELLINI study, which is looking at it in combination with bortezomib (Velcade) and dexamethasone (Decadron), really has had a lot of buzz over the last few years because there was a toxicity signal with the venetoclax arm.

But now with, again, updated results, etcetera, you’re starting to look to see which are the patients that benefited and which are the patients that didn’t.

And it’s becoming very, very clear that patients that have the t(11;14) translocation tend to benefit tremendously with the combination of venetoclax and bortezomib and dexamethasone. It’s really the patients that don’t have t(11;14) or high BCL2 expression, which is something that they’re also studying, those are the patients that didn’t benefit.

So, really fine tuning that to that particular population and using a combination like that is, I think, an example of where things are headed in myeloma. However, outside of that right now with where things stand, we don’t have targeted therapy to that extent beyond that.

Katherine:

Dr. Nadeem, with the ASH meeting closing out 2021, what are you excited about in myeloma research right now?

Dr. Nadeem:

We’re seeing very impressive results with using quadruplet therapies for newly diagnosed multiple myeloma patents. So, they get a combination of a CD38 monoclonal antibody like daratumamab (Darzalex), and then combining it with our typical agents. So immunomodulatory, drugs, proteasome inhibitors, and steroids. So, an update at this meeting with the phase-2 GRIFFIN trial, which was presented by my colleague Dr. Jacob Laubach, basically giving an update after 24 months of maintenance therapy.

This trial looked at a combination of dara plus RVD, which is lenalidomide, bortezomib, and dexamethasone, with transplant and maintenance, for patients with newly diagnosed myeloma. And what we’ve seen with each update of this study, that the response rates with the quadruplets are significantly better with the triplet. And more notably, we’re seeing very high rates of minimal residual disease negativity in favor of the quadruplet, which usually translates into a greater prognosis for patients.

So, median PFS is still not reached for this particular study, but you can start to see now that the curves are starting to separate and hopefully with longer follow up, we’ll see even a clearer result showing that patients that receive a quadruplet therapy at the newly diagnosed phase of their myeloma therapy benefit tremendously. So, this was a really important update at ASH this year.

Is the COVID-19 Vaccine Safe for Myeloma Patients?

Is the COVID-19 Vaccine Safe for Myeloma Patients? from Patient Empowerment Network on Vimeo.

 Should myeloma patients get the COVID-19 Vaccine? Dr. Joshua Richter encourages all patients to get the vaccine but notes important considerations around treatment.

Dr. Joshua Richter is director of Multiple Myeloma at the Blavatnik Family – Chelsea Medical Center at Mount Sinai. He also serves as Assistant Professor of Medicine in The Tisch Cancer Institute, Division of Hematology and Medical Oncology. Learn more about Dr. Richter, here.

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Transcript:

Katherine:

Is the COVID-19 vaccine safe for patients with myeloma?

Dr. Richter:

Absolutely, 100 percent yes. Everybody with myeloma should absolutely get the vaccine. What’s a little more complicated is the timing of it. So, one is in relation to stem cell transplant or CAR T-cell therapy. If you’ve had one of these, obviously, consult with your provider. But the general recommendation is to wait about 60 to 90 days after a high-dose therapy like that. And it’s not a question of safety, it’s a question of efficacy. Vaccines are like vegetables, seeds, you have to put them in the ground to grow. If you give yourself a vaccine right after a stem cell transplant, well, your bone marrow is not ready to work with it. It’s like planting a seed in the desert.

You want to make sure your immune system can take in that vaccine and give you immunity. So, you have to wait at least 60 to 90 days. The other question is, what happens if you’re getting continual therapy? And we don’t know the answer for most of these drugs, but one of the things is dexamethasone (Decadron), which is a steroid. Almost all myeloma therapy comes with some steroids. And we like to separate the vaccine from the steroid dose by a little bit if we can. Again, always important to talk with your care team as to risk/benefit about holding certain treatments.

What Should You Know About Myeloma Treatment Options?

What Should You Know About Myeloma Treatment Options? from Patient Empowerment Network on Vimeo.

Dr. Peter Forsberg outlines options in the myeloma treatment toolkit, including targeted therapies, chemotherapy, immunotherapy, and combination approaches —and explains how the recovery process from stem cell transplant has improved.

Dr. Peter Forsberg is assistant professor of medicine at the University of Colorado School of Medicine and is a specialist in multiple myeloma. More about Dr. Forsberg here.

Download Program Resource Guide

See More From The Pro-Active Myeloma Patient Toolkit

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Transcript:

Katherine:                        

Would you walk us through the currently available myeloma treatment approaches and who they might be right for?

Dr. Forsberg:             

At this point, we’re lucky that we have a much broader toolkit to treat myeloma than we have had in the past. Myeloma is one of the successes in modern oncology in that way. At this point, we have a number of targeted therapies. Some of those are pill-based options, some are injections or infusional medicines. We have some immunotherapies, which are things like monoclonal antibodies, which help to work.

We use some conventional or older fashioned chemotherapy, often lower doses and as part of combinations. And steroids. Steroids are always the medicine that is one of the backbones of our combinations. In myeloma, we do often use combinations. So, it’s usually a mixture of targeted therapies. Sometimes immunotherapies or chemotherapies.

As well as steroids to try to treat the myeloma. And some of the considerations are, which combination makes the most sense. Are there other medical problems or disease related factors like disease aggressiveness that may influence which ones we wanna choose or how many. Also, is a three-drug combination the right fit or is a four or a two drug the right. And it does continue to evolve.

Our options and our ability to use multi-agent regimens has continued to improve as we’ve gotten better and better therapies that’re well tolerated and that allow us to use really active combinations, even in patients who may have substantial other medical problems. So, I think it’s been something that continues to evolve over time and will continue to evolve. But the good news is that it’s been an issue of just how to incorporate more and better options.

How do we bring these good new tools into the mix as early as is appropriate? To control the myeloma in really substantial ways. And again, as I mentioned, the question of the role of stem cell transplant continues to be an important one. That is a way for us to still use older fashioned chemotherapy at a high dose to help to achieve a more durable remission. But usually, the way that we parse through these targeted immunotherapies and chemotherapies, is something that may be individual.

Although, we have some broad principals that help guide us for how we manage patients across different types.

Katherine:                  

How do you decide who stem cell transplant might be right for?

Dr. Forsberg:             

The good news in the United States is that we’re able to be fairly broad in terms of our consideration of stem cell transplant. There is no age restriction above which it’s not. We’ve gotten better and better at supporting patients through stem cell transplant. We have better medicines to deal with potential toxicities. And so, patients do better and better in going through transplant. But it is still an intensive treatment modality. So, in considering it, it is an option for a large portion of myeloma patients at diagnosis. After we get the myeloma under control. But the decision remains an individual one. Some patients may prefer to defer stem cell transplant until a second line therapy or later.

Whereas others feel very comfortable moving forward with it in the first-line setting. I would say that it is certainly something that we try to demystify for patients. It can sound a little bit intimidating, certainly because it is a little more intense and requires more support. But it is something that we have gotten quite good at navigating patient and supporting them through.

Katherine:                  

What about maintenance therapy, how does that fit in?

Dr. Forsberg:             

Following initial treatments to get the myeloma under control, whether that includes stem cell transplant or not. Usually we transition into a maintenance therapy. Maintenance therapy is a way for us to sustain control or remission of the myeloma. And make that longer lived. So, what we use for maintenance may be different patient to patient. But it is a important part of our treatment approach for many patients.

Katherine:                  

Are some therapies less intense than others, and what are some possible side effects of those?

Dr. Forsberg:             

So, certainly there are treatments with varying degrees of intensity or potential toxicities. The good news is that as we’ve gained more and more treatment options, we’ve also gotten better at using the ones we have had for a while now to minimize some of their toxicities. So, by adjusting dosing schedule and routes of administration, we’ve gotten better at fine tuning the tools we have toward minimizing those toxicities.

So truthfully, many myeloma patients after you start treatment, actually feel better than before they started chemotherapy because the myeloma itself is a destructive process and the treatments are quite often well tolerated. That being said, certainly over time, treatment related side effects often emerge. Some of the treatment toxicities may cause some challenges in terms of managing patients through their myeloma process. But usually, those can be overcome. Even if that means needing to adjust the treatment protocol.

Adjust doses, change medicines. And so, while there are varying degrees of intensity, we’re usually able to find the right balance for any given patient to still have a very active anti-myeloma regimen while trying to be very cognizant of potential treatment toxicities and taking steps to mitigate that.

What Are the Treatment Options for Myelofibrosis?

What Are the Treatment Options for Myelofibrosis? from Patient Empowerment Network on Vimeo.

When choosing a treatment for myelofibrosis (MF), where do you start? Dr. Laura Michaelis reviews the available options for MF therapy, including a discussion of stem cell transplant. 

Dr. Laura Michaelis is hematologist specializing in myeloproliferative neoplasms (MPNs) at Froedtert & the Medical College of Wisconsin, where she also serves as Associate Professor of Medicine. Learn more about Dr. Michaelis here.


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Transcript:

Dr. Michaelis:                       

So, myelofibrosis is among the most aggressive of the myeloproliferative neoplasms. And yet, it still has a broad swath of risk associated with it. And that means that compared to essential thrombocythemia and polycythemia vera, myelofibrosis – primary myelofibrosis tends to be more aggressive and needs to be treated more aggressively.

There are a group of patients who have what we call low-risk or even intermediate 1 risk myelofibrosis who don’t need treatment – who can be followed, whose blood counts can be checked, who can be regularly seen by their doctor, and who can avoid treatment for some period of time, depending on their risk factors.

And so, if you’re diagnosed with primary myelofibrosis, the first question is do I need treatment? And the second question – if the answer to that is yes, then you have to figure out why you need treatment. There is currently only one intervention that is known to be curative in myelofibrosis, and that’s the use of stem cell transplant.

Stem cell transplant, which is also called bone marrow transplant or allogeneic hematopoietic stem cell transplant, is basically a procedure where a donor is able to have their stem cells collected. And then the recipient, who’s the person with the myelofibrosis, undergoes a series of chemotherapy treatments to basically wipe out the bone marrow that they have. And it’s then replaced, using basically a blood transfusion of the stem cells of someone else, which then grow up into the recipient.

This has been shown to be safe in myelofibrosis – well, relatively safe – if done in the right person, who’s relatively fit, and done at the right stage of disease. It’s not a procedure that everybody can tolerate. People need to be pretty fit. And it should be performed at a place that has done numerous transplants for myelofibrosis since it’s a relatively complicated form of stem cell transplant. That being said, in the right person at the right time, it’s an excellent opportunity and option for these patients.

Now in patients who can’t tolerate transplant or where that’s not the right step to go, we have medications. And those medications can sometimes delay the worsening of symptoms. They can certainly control spleen size, improve people’s quality of life, and often improve survival. And the medications that we’re talking about here are called JAK-STAT inhibitors.

And the first approved, and the one that’s most commonly used, is a medicine called ruxolitinib.

This is an oral pill – a pill that you take twice a day and has excellent data that supports that it shrinks the spleen in people with myelofibrosis, that it improves symptoms. And in people with advanced polycythemia vera, decreases the blood count without leading to iron deficiency and also improves symptoms and spleen size.

There’s another JAK-STAT inhibitor that’s approved. That’s a medicine called fedratinib. And it was recently approved in people who had progressed off of myelofibrosis or even in people – or after ruxolitinib or in people who – instead of taking ruxolitinib.

Now in essential thrombocythemia, polycythemia vera, and other times even myelofibrosis, we have other treatments that are commonly used that can be exceedingly helpful in controlling symptoms and blood counts. Those include, for example, hydroxyurea, pegylated interferon, and sometimes treatments aimed at helping anemia, like steroids or derivatives of thalidomide.

And finally, I don’t want to let this end without saying that clinical trials are often an excellent possibility for patients with these conditions, like myelofibrosis.

So, when you are contemplating starting a treatment, it’s really important to ask your physician whether or not there’s any clinical trials that are right for you.