Transplant and CAR T-cell Therapy for Older Adults

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Transplant and CAR T-cell Therapy for Older Adults

April 28, 2024

Presenter: Mariam Nawas MD, Assistant Professor of Medicine, Director of the Transplant Optimization Program, University of Chicago School of Medicine

Presentation is 40 minutes long with 19 minutes of Q & A.

Many thanks to Kite, a Gilead Company whose support helped make this Survivorship Symposium possible. 

Summary: Advanced age has traditionally been seen as prohibitive for treatments like stem cell transplants and CAR T therapy. This presentation reviews evidence that overall fitness is a crucial factor in reducing non-relapse mortality and that otherwise healthy elderly patients can have successful outcomes after transplant and CAR T-cell therapy.

Highlights:

• Older patients are often not considered eligible for stem cell transplants for AML and CAR T therapy for lymphoma simply based on their age.
• Frailty and fitness can be more important than age in assessing a patient’s suitability for stem cell transplant or CAR T therapy. Frailty and fitness can be measured by a geriatric assessment that evaluates multiple domains of health.
• If older patients are well-selected through prior testing, they do not have much higher non-relapse mortality rates when compared to younger patients. Age alone should not disqualify older patients from eligibility for stem cell transplant or CAR T therapy.

Key Points:

(02:09): Blood cancers are primarily diseases of older adults.

(06:41): Transplants and CAR T therapy are underutilized in older patients with blood cancers because of a lack of referral by community oncologists who assume they are not good candidates based on their age.

(07:42): Perceived frailty among older patients often prevents doctors from making referrals for stem cell transplant or CAR T therapy.

(09:10): Frailty and age are related but age alone is not a good measure of frailty so fit, older patients may not be referred for transplant or CAR T therapy.

(14:00): Patient-reported data is also important in assessing fitness versus frailty in patients.

(21:20): Comorbidities like other health issues have a big impact on non-relapse mortality.

(23:24): A Transplantation Optimization Program (TOP) at the University of Chicago proved highly predictive of which patients were at risk for non-relapse mortality.

(26:37): Screening patients through tools like the TOP program and other measures of fitness can mean that older age does not increase the risk of non-relapse mortality.

(28:28): Reduced intensity conditioning before transplant can make it safer for older patients and they seem to do just as well as younger patients.

(31:54): Measured by efficacy and survival, outcomes of CAR T therapy in older patients are quite similar to those of younger patients.

Note: Throughout this workshop the terms bone marrow transplant and stem cell transplant may be used.  For purposes of this talk, they mean the same thing: transplanting  hematopoietic or blood forming stem cells into a patient.

Transcript of Presentation:

(00:00): [Elmer Velasco]:   Introduction. Welcome to the workshop, Transplant and CAR-T Cell Therapy for Older Adults. My name is Elmer Velasco  and I will be your moderator for this workshop. I'd like to thank Kite, a Gilead Company whose support help make this workshop possible.

(00:15): It's now my pleasure to introduce today's speaker, Dr. Mariam Nawas. Dr. Nawas is a hematologist /oncologist and an Assistant Professor of Medicine at the University of Chicago School of Medicine, where she specializes in bone marrow transplantation and cellular therapies for patients suffering from leukemia and other bone marrow disorders.

Her research is focused on better understanding and reducing transplant- and cellular therapy-related toxicities and symptom burden, particularly in older adults. Please join me in welcoming Dr. Nawas.

(00:53): [Dr. Mariam Nawas]:  Overview of Talk. Hello everyone. It's very nice to join you all this afternoon and thank you for joining in on this session. As mentioned, I will be speaking on the topic of transplant in CAR T therapy for older adults, which is a topic that is very near and dear to me and a big focus of my research.

(01:14):  Our learning objectives today. First, the million-dollar question that everyone wants to know: How old is too old for transplant or CAR T therapy, and are there upper age strict thresholds for these therapies?

Next, we'll talk about health issues that may preclude an older patient from transplant or CAR T therapy, and how health issues predict potential complications or outcomes.

We will talk about how outcomes after these therapies in older adults compare to those in younger patients. Again, how can we predict outcomes in older patients and how can we determine who is a good candidate for these therapies.

Then finally, we'll discuss some strategies that we use to tailor the therapy to the needs of older adults to make it safer and more tolerable.

(02:09): Blood cancers are primarily diseases of older adults. The first point that I want to make is that blood cancers are really diseases of older adults. This is a graphic here. On the bottom axis we can see different age ranges laid out from youngest all the way to oldest. And if we look here in the top half in the modern era, this shows us how the incidence of different types of blood cancers increases significantly with older age. This is looking at leukemias, multiple myeloma, and non-Hodgkin lymphoma. The greatest burden of these diseases in our society are in older patients.

(02:50): One exception may be Hodgkin lymphoma. In Hodgkin lymphoma we tend to see two peaks across the age span. There's a peak in younger age, but again, there is another peak in older age.

(03:05): This is another way of looking at that, but this is specifically for acute myeloid leukemia or AML. AML is by far the most common indication for donor transplants. This shows us who gets AML. The average age at diagnosis for AML is in the late 60s, and the incidence continues to increase as patients age and actually peaks in the ninth decade of life. This shows us who has AML.

(03:34): Most transplants for acute myeloid leukemia (AML) are for patients between 40 and 65 years old but most AML patients are 65 or older.  Then I'm going to show you now who actually gets transplants for AML, and it's not what you might expect, based on the incidence that I've just showed you in older age. This shows the number of transplants done across the years in the United States by different age ranges. Far and away the greatest number of transplants that we do are in patients who are 40 to 64 years. Then when we look at patients who are 65 and above - again, these comprise the greatest percentage of patients with AML - they are far less likely to receive a transplant.

(04:11): The good news is that if you look over the last decade and you look at the trends, what you can see is that for most of the age ranges, we've had pretty steady number of transplants done each year, with the exception being the older age group. That is the age where we're certainly doing a better job year to year in terms of offering transplants to older patients. But certainly there is room for improvement and this therapy is still underutilized.

(04:41): Transplants are underutilized for older AML patients. This is a figure that looks specifically at patients who are 76 years and older, and it shows you, again, over the years we're definitely doing a better job doing more transplants in this older population. But even in this most modern era of 2017 to 2019, of all the transplants that we did nationally, only 0.6% were done in patients who are 76 and above. We're doing a better job, but this therapy is still highly underutilized.

(05:12): There is a similar pattern for CAR T therapy. It is underutilized in older lymphoma patients. Now looking at that type of data, but in CAR T therapy, we see the same thing. CAR T cell usage is low unfortunately in older patients with lymphoma. This graphic comes from a study that looked at Medicare data and patients who were 65 and above and who had diffuse large B-cell lymphoma. They wanted to look at the real-world utilization of CAR T therapy in these patients.

(05:39): They focused on patients who had lymphoma that had progressed through two prior lines of therapy. The reason that they're looking at that age group is because those patients are technically indicated for CAR T therapy or CAR T is approved for those patients.

(05:56): When we look at how many of those patients actually got CAR T therapy and we look based on age, you can see that from age 65 to 69, under 20% of patients who are technically eligible for that therapy, at least eligible from a disease standpoint, only 20% actually received it. The number was similar for patients aged 70 to 74. Then if you look at patients who are 75 and above, only 13% of those patients received CAR T therapy. Again, the average age of onset of diffuse large B-cell lymphoma is in the early '70s.

(06:29): I've shown you now that transplants in CAR T therapy are highly underutilized in older patients, but the question is why.

(06:41): Transplants and CAR T therapy are underutilized in older patients because of a lack of referral by community oncologists who assume they are not good candidates based on their age. There are a lot of reasons, but probably one of the most common reasons is non-referral. Non-referral is one of the greatest barriers to specialized treatment for blood cancers, meaning that if you were to see an oncologist in the community in order for you to get to a transplant or a CAR T therapy, you have to be referred to a center that does them.

(07:06): Very often, for oncologists and physicians as a whole, chronological age influences their decision making. They may have biases that, maybe, they think patients who are 70 and above may not benefit from these therapies or may not be able to tolerate these therapies. What I do a lot of my research on is trying to prove to people that chronological age is really not the best predictor of outcomes or the efficiencies of these therapies and that we have to use more scientific ways to determine who is and is not a good candidate for these therapies.

(07:42): Perceived frailty among older patients often prevents doctors from making referrals for stem cell transplant or CAR T therapy. That brings me to the concept of frailty. Frailty we know impacts outcomes after many different types of cancer therapy. Frailty is an aging related syndrome of diminished physiologic reserve that increases a patient's susceptibility to poor health outcomes. I think we all have a concept in our head of what we think frailty means, but medically there is a very precise definition for frailty. One of those definitions is listed here. If you meet three or more of the following criteria that are listed that qualifies for a medical definition of frailty, these criteria are weight loss, weakness, that can be measured in different ways.

(08:25): One of the ways that we measure it, which I'll show you a little bit later, is based on grip strength, poor endurance and energy or exhaustion. The way that I test for that is I ask a patient, "How many days in the last week did you feel like you just couldn't get going?" Or "How many days in the last week did you feel like everything felt like an effort?" If a patient answers three or more days on either of those questions, that's a positive screen for exhaustion.

(08:51): The next one is slowness, which means how quickly can a patient walk? We actually measure gait speed.

(09:00): Then the last one is low physical activity level. That's, again, based on patient report. How much are they doing during the day?

(09:10): Frailty and age are related but age alone is not a good measure of frailty so fit, older patients may not be referred for transplant or CAR T therapy. Frailty and age are certainly correlated, meaning that older patients are more likely to be frail than younger patients. But it is not a perfect one-to-one relationship. It's very possible to be young and frail, and it's very possible to be older and still very fit. Age is not the best determinant of that.

(09:31): The graphic that I have here is a study that looked at community-dwelling adults, meaning these were just healthy adults in the community who underwent frailty testing.

(09:43): What we can see is that as we look into older ages, certainly the prevalence of frailty increases. But even in this very older age of 82 and above, only 35% of patients are frail, meaning a big percentage of patients are still not meeting frailty criteria. Age is really not a good indication of fitness or frailty.

(10:09): Frailty can be measured by tools like a geriatric assessment that evaluates multiple domains of health. How do we measure frailty? There are different ways of doing this. One way that we have started to apply a lot in cancer care is something called the geriatric assessment. The geriatric assessment is basically a battery of testing that is aimed to evaluate a patient's health really holistically and comprehensively. The idea is that there is a lot more that goes into a patient's health beyond just their cancer and any other medical problem, but there's many domains to health.

(10:40): Those domains include things like physical performance and functional status. How strong a patient is? How functional are they at home? Are they independent? Do they need help with certain activities of daily living? Of course, the presence of medical problems and what medications and the number of medications that a patient takes plays into their health.

(11:01): Then there are other domains of health like cognitive health. There is psychological and mental health. There is nutritional health. Then finally, social support.

(11:12): Anyone who's gone through something as rigorous as a donor transplant can tell you it will test every single part of these domains of health. And we want to ensure that when we are taking our patients to these therapies, that we're optimizing all of these domains of health to make the transplant as smooth or the CAR T therapy as smooth and as successful as possible.

(11:35): Tests can be done to evaluate physical and cognitive status of potential transplant or CAR T therapy candidates. Here I am listing out some of the tests that we do to assess these different domains. Specifically, for physical and functional performance, one of the tests that we do is something called the short physical performance battery or the SPPB. This tests balance. It tests lower extremity strength and gait speed. We will have a patient do different balance tests. We will time them to see how quickly they can walk, and then the last one is a chair to stand test. Without using your upper arms, we ask the patient to sit and stand five times and then we time them, and according to how quickly they're able to do this, we put all that together into a score, and that score gives us a sense of that person's strength and physical fitness.

(12:28): This type of assessment has been tested in many different populations. For example, patients with dementia or patients with multiple sclerosis. Across diverse populations, it does seem that it associates with certain outcomes after therapy.

(12:48): These are some other physical performance-based tests. This is the walk speed on the left and then on the right, this is how we test upper extremity muscle strength. This is using a handheld dynamometer. This is a device that you use and you just squeeze and it tells us about upper extremity strength, and we use that as a proxy for overall muscle strength.

(13:11): From the domain of cognitive health, we do something called a MoCA or Montreal Cognitive Assessment. This is a roughly ten-minute test that is intended to test different cognitive domains such as memory, attention and concentration, language, abstract thinking, and delayed recall. You can see some of the questions listed here on the left. Then there is a scoring rubric for this, and based on the score that the patient achieves, if someone scores below a certain threshold that is considered a positive screen. That maybe they have mild cognitive impairment or dementia. That's something we, of course, want to be aware of, especially before something like a transplant or CAR T therapy.

(14:00): Patient-reported data is also important in assessing fitness versus frailty in patients. Then one of the final parts of the assessment is one of the most valuable parts, which is patient-reported data. Patient reported data is indispensable. A lot of the tests that I've shown you are objective tests. There's also parts of the assessment that are somewhat subjective according to how a physician feels that their patient is doing.

(14:21): But then we also ask the patient themselves, again, how are you functioning at home? Are you able to do your instrumental activities of daily living independently? These include things like managing your finances, managing medications, preparing food, household chores. I'll show you that there have been multiple studies that have shown that patients who report that they have limitations in what they're able to do, that report is very predictive of how they will do after something like a transplant or a CAR T therapy. It is very valuable information.

(14:58): Stem cell transplant brings many different medical stressors from chemotherapy, immune suppression, infections and the potential for graft-versus-host-disease (GVHD). Moving specifically now into donor transplants. Just big picture of how we do a donor transplant. Donor transplants involve many different chapters and many different medical stressors. We can see here... The whole idea with a donor transplant is we're trying to replace someone's immune system with a donor immune system. The way that we do that, we start by using something called the conditioning regimen. This is several days of a combination of chemotherapy plus-minus radiation therapy. That's the first stressor.

(15:34): Then comes day zero. That's the day that we give the patients the stem cells from the donor. Again, we're introducing a new immune system into their bodies, and with that comes a lot of potential complications, things like graft-versus-host disease. Also, things like infections because the new immune system is always pretty weak at the beginning and that makes the patient susceptible to infections. The point here is that throughout something like a donor transplant, a patient is going to be exposed to a lot of different types of medical stressors.

(16:06): This is, I know, a busy figure, but anyone here who's one of my patients knows that I've drawn something similar to this before transplant to explain to them what the process of transplant is like during that first month in the hospital. Again, this shows that there is just a variety of stressors.

(16:25): We start out with the chemo at the beginning and then the blood counts drop. When the blood counts drop, patients are susceptible to infections. That's also when patients have the most symptoms because their body is just very inflamed from the chemo and from having low blood counts, patients get very fatigued. They have diarrhea. They're not eating very well. Then eventually the blood counts will start to recover. Then with that comes a new set of potential complications, again, including things like graft-versus-host disease.

(16:58): Non-relapse mortality means a patient dies from complications of treatment rather than the disease itself. Non-relapse mortality is an important concept to understand in transplant. Non-relapse mortality is basically the worst possible outcome of a complication. It's the idea that, unfortunately, there are a subset of patients who go through donor transplants who are going to pass away of a complication of transplant that has nothing to do with the disease. Meaning these are patients who pass away either early or late after transplant in remission. It's not that the disease had anything to do with why they passed away, but it was purely related to a complication of transplant. In my opinion, when I do transplants, this is my worst-case scenario. This is what I want to avoid at all costs. It's something that's important for us to be able to understand and to be able to predict the risk of.

(17:50): The most common forms of non-relapse mortality are GVHD, organ failure and infection. These pie charts down here give you a breakdown of what are the most common causes of non-relapse mortality in patients of any age. And far and away, the big three that we worry about are graft-versus-host disease, organ failure and infection.

(18:07): Non-relapse mortality is a major barrier to successful donor transplant. The first question then we ask in the context of a talk like this is what are the rates of non-relapse mortality in older patients?

(18:22): Listed here, I have two big registry studies. Registries collect data across transplants all across the United States or all across Europe so that we have that information to study and draw conclusions from. When we looked at the European registry, and we looked at patients who were 65 years and above at the time of donor transplant, we found that within three years of the transplant, unfortunately 27% of patients passed away of non-relapse mortality.

(18:56): Non-relapse mortality is a significant risk in older patients. Then in the American registry, the study is a little bit earlier 2017, looking specifically at patients who are 70 and above, the risk was even higher. Somewhere between 33 to 35% of patients will die of non-relapse mortality within the first two years. As we can see, non-relapse mortality is a major barrier to successful donor transplant. The next question is, now we've established those rates in older patients, how does that compare to younger patients? Is it much lower in younger patients? Many studies have investigated this question with slightly varying results.

(19:35): If older patients are well-selected through prior testing, they do not have much higher non-relapse mortality rates when compared to younger patients. In general, what we find are that well-selected older adults do not experience much higher rates of non-relapse mortality after donor transplants compared to younger adults. What I mean by well-selected is that I have no doubt that if I were to take a group of just average 70-year-old patients who did not undergo any kind of testing and just at random I selected a group of 70 year olds and I put them through a transplant and I compare them to, again, at random, a group of 40 year olds and put them through a transplant, I strongly suspect that the 40-year-olds will have an easier time and that they will have a lower risk of non-relapse mortality.

(20:16): But that's not what we do in the world of transplant. We're not randomly selecting people. We are well selecting them based on things like their health issues, their frailty and fitness, their social support. It appears that we do a pretty good job selecting people because if we compare the rates of non-relapse mortality in older versus younger patients, some studies say the rates are not higher at all and some studies say that maybe they're just a little bit higher, but it's not dramatic.

(20:45): Just to give you some examples. Myelodysplastic syndrome and acute myeloid leukemia, these are the most common indications for donor transplant. One study looked at this question of the rates of non-relapse mortality in younger versus older patients in MDS, and they found that non-relapse mortality and overall survival really didn't differ significantly between the younger and the older patients.

(21:09): This is an AML study that found that age maybe had a small effect on overall survival in non-relapse mortality, but it wasn't a dramatic effect.

(21:20): Comorbidities like other health issues have a big impact on non-relapse mortality. How do we predict the risk of non-relapse mortality? One of the most appreciated ways that we have been using for years in the world of transplant is something that we call a comorbidity index, which means that we look at the different health issues that a patient has, and we have a scoring rubric that allows us to create a score, meaning that if someone has kidney disease, perhaps they get a point for that. If someone has lung disease, perhaps they get a point for that. Then we add up all of the points to get a score.

(21:53): What this is supposed to illustrate here is that the higher the score... These patients had a score of four and higher, the risk of non-relapse mortality. The lower the score, these patients had a score of zero. The risk of non-relapse mortality is never zero, but it's significantly lower. This is a very effective way of brisk stratifying patients for complications after transplant.

(22:19): Older patients are more likely to have comorbidities so this factor must also be carefully considered in evaluating patients for transplant or CAR T therapy. This is relevant to older patients because older patients, of course, tend to have more health issues that just happens naturally with aging. To illustrate that, this is a graphic that is showing you different age ranges of patients who have gotten transplanted and what are their scores. If you look at patients who are 18 to 40, only 12% of them have a score that's five or higher. And then if we look at patients who are 65 and older who underwent a donor transplant, a quarter of them have a score that's five or higher. Again, this shows that older patients are more likely to have health issues. That is something we have to be very careful and considerate of when we are deciding whether a patient is a candidate for transplant.

(23:08): But it's not just a matter of health issues in terms of determining the risk after transplant. It's also a matter of frailty and fitness, which is what the geriatric assessment measures. The geriatric assessment predicts the risks of donor transplant in older adults.

(23:24): A Transplantation Optimization Program (TOP) at the University of Chicago proved highly predictive of which patients were at risk for non-relapse mortality. This graphic and this information here comes from a study that came out of the University of Chicago actually before my time. At the University of Chicago, we're very fortunate to have something called the Transplant Optimization Program (TOP). This is a half-day of clinic where patients come in and they go through all of the parts of the geriatric assessment. This was created by Dr. Andy Artz, who's currently now at City of Hope. They did this in dozens and dozens of patients, and they found that the geriatric assessment and the frailty that they were able to measure before transplant predicted the risk of non-relapse mortality after transplant.

(24:03): Patient-reported outcomes were most crucial in assessing risks of transplant for older patients. The parts of the assessment that seemed to be the most predictive, a lot of them were patient-reported outcomes. These are things like patient telling us, again, how are they doing in terms of instrumental activities of daily living. Again, things like managing finances, meals, housekeeping, et c, Patients talking about their functional health and then also the gait speed. We noticed that seemed to be very predictive of outcomes.

(24:32): The TOP program dramatically reduced rates of non-relapse mortality in older patients. What we showed is that in our program at the University of Chicago, the implementation of the TOP program dramatically reduced the rates of non-relapse mortality in older patients. That is due to two reasons. The first reason is that it made it clear to us who is fit, who is frail. And the geriatric assessment offered us information that previously we did not have available. Previously, we only really looked at patients' health issues and patient's age.

(25:04): Having this added data was very valuable in determining who is and is not a good transplant. Part of it, again, is we're selecting better patients. And the other part of it is that we are able to optimize some of the deficits that we uncover during the assessment, meaning that if we do the geriatric assessment and we find that someone has poor upper body strength or lower body strength or has poor nutrition, those are things that we can intervene on and try to optimize before the time of transplant to make the transplant safer for that patient.

(25:38): Dr. Artz has gone on to conduct this study across transplant centers across the country where he looked at patients who were 60 and older who underwent donor transplants. And in all of these patients, he had them do a geriatric assessment before the transplant. Again, he looked at all the different variables and the data that was collected in these patients to see which of these variables, which of these factors were predictive of how a person did after transplant.

(26:08): What he found is that albumin, which is a blood test that's a marker of nutrition. weight loss - obviously a marker of nutrition, the comorbidity index, which is the score of health problems...if you combine those three things into a score, that is very predictive of the risk of non-relapse mortality, and that offers us additional information beyond the risk scores that we already have, like the comorbidity indices that I showed you.

(26:37): Screening patients through tools like the TOP program and other measures of fitness can mean that older age does not increase the risk of non-relapse mortality. The other very important conclusion from the study is that the patients who are transplanted were between ages of 60 and all the way up to age 82, and they found that increasing age did not impact the risk of non-relapse mortality. Again, chronological age is not a good predictor of how a patient is going to do.

(26:57): How old is too old for transplants? There is no very clear upper age limit, but I will say that our experience nationally and internationally transplanting patients who 80 and above is extremely limited. Even in this study that I just showed you, the oldest patient was 82.

(27:16): Looking in the European registry from the years 2000-2021, the oldest patient was 80. But we are continually pushing the envelope forward on age. I do think 10 years from now we'll be a lot more comfortable transplanting patients who are fit maybe in their early 80s, but for the time being, I think, the data to support safety extends up to age 75, maybe up to age 80 and beyond that we're still learning.

(27:46): This is something I wanted to discuss is how we do the transplant to make it safer for older patients. The first few days before you get the actual transplant, before day zero, we start with conditioning chemotherapy plus-minus radiation. This is chemo or radiation over a course of five to seven days.

(28:11):  In the early days of transplant, that chemo and radiation were very intensive or what we call myeloablative. That was the only thing that we had to offer and so patients who are older, it just was not safe to offer them something this intensive and therefore we couldn't safely offer them transplants.

(28:28): Reduced intensity conditioning before transplant can make it safer for older patients and they seem to do just as well as younger patients. In the last decade or so, there has been the advent of what we call reduced intensity conditioning. This is conditioning that is not quite as strong as this, but still strong enough to be pretty effective. I will say it's not nearly as effective as a very high intensity chemo against preventing relapse, but it is much safer than the high intensity chemo. We find that patients who are 60 and above, if we offer them reduced intensity transplants, they seem to do just as well as younger patients who get the higher intensity. That is commonly the strategy that we use in older adults.

(29:10): Age alone should not disqualify older patients from donor transplant candidacy. The conclusions that we can draw from donor transplants and age is that age alone, at least up to age 75, shouldn't exclude an older patient from donor transplant candidacy. Well-selected older adults do not experience dramatically higher rates of mortality after donor transplant compared to younger adults. Finally, health issues and the geriatric assessment, which includes frailty measurement, can determine an older patient's risk for this procedure.

(29:39): And now moving into CAR T therapy in the last few minutes. Just briefly one slide on what CAR T cells are. CAR T therapy is currently being used to treat certain lymphomas and multiple myeloma. To make a CAR T cell, T cells which are a type of white blood cell, are collected from a patient and then they are modified or genetically engineered in a lab.

(30:05): In the lab what they're trying to do is to get the cell to express something on its surface that is going to be better able to recognize cancer cells once it's back in the patient's body. Once that genetic engineering is done, those T cells are infused back into the person's body and their job is to patrol around the bloodstream, look for cancer cells and attack them.

(30:30): CAR T therapy poses different risks than transplant including cytokine release syndrome and neurotoxicity. This is a very different therapy than transplant and it has very different and unique complications. One of the biggest side effects after CAR T therapy is something called cytokine release syndrome (CRS)and also something called neurotoxicity. Both of these things stem from inflammation.

(30:51): When those T cells are in the patient's body and they encounter a cancer cell and they start to attack it, that is a very inflammatory process. They release a lot of inflammatory proteins and that can manifest through cytokine release syndrome, through fevers, sometimes drop in blood pressures, sometimes difficulty breathing. That's what cytokine release syndrome is.

(31:13): The neurotoxicity is basically these inflammatory proteins leaking into the space around the brain and to the cerebrospinal fluid and clouding someone's thinking and their judgment. That's what we call neurotoxicity.

(31:28): You can see here the timeline. Usually the cytokine release syndrome happens first and then neurotoxicity, which is also called ICANS, which is not as common, tends to happen after the CRS. The side effect profile for every CAR T therapy is very unique to that specific product and to the disease. But broadly speaking, these are the big things that we run into.

(31:54): Measured by efficacy and survival, outcomes of CAR T therapy in older patients are quite similar to those of younger patients. How are outcomes of CAR T therapy in older adults? In general, CAR T therapy is associated with favorable outcomes from the standpoint of efficacy. It seems to be equally efficacious in older patients compared to younger patients. And survival seems to be pretty similar from what we can tell compared to younger patients.

(32:15): Some side effects, however, specifically neurotoxicity and also non-relapse mortality do seem to be a little bit more common in older adults. Again, in donor transplant, the next question we ask is, "Well, how can we predict these things? How can we risk stratify our older patients?"

(32:35): Similarly, health issues influence outcomes after CAR T therapy, but I will say it's not as rigorous and it's not quite as big of a concern for us after CAR T therapy as it is after an allo transplant. During cytokine release syndrome, which again is this period of inflammation, patients can run into a lot of cardiac issues, a lot of pulmonary issues. This is what this figure is trying to relay. What we know is that patients who already have some type of cardiac issue, like an abnormal heart rhythm or abnormal heart function, are patients who are more predisposed to these types of pulmonary and cardiac complications. However, these things are not necessarily prohibitive.

(33:24): Heart and lung health in older patients need to be considered before CAR T therapy but if patients have good functional status they are not prohibitive. These are some statements I pulled from a paper that was written by a cardiologist, a lung doctor, and an oncologist who see a lot of CAR T therapy, and they were expressing their experience of how they handle health issues in patients prior to CAR T therapy. And what they believe is that among patients who have good functional status, heart and lung issues are not prohibited. They really shouldn't prevent a patient from being offered CAR T therapy, unless clearly that person has very poor functional status or very decompensated or end-stage heart or lung disease that is not well controlled. In those circumstances then likely the risk is too high. But in general, it's something that we can accommodate for in the process of CAR T and watch out for and manage side effects for relatively well.

(34:20): Another important point is that we don't use specific cutoffs. Though in the world of donor transplant, there are specific numbers that sometimes we use as cutoffs - for example, if your kidneys are functioning below a certain level, if your lung is functioning below a certain level - that may be prohibitive. But there is no threshold or cutoff after organ function for the most part in the world of CAR T therapy.

(34:45): That's health issues, but what about frailty? Again, going back to data that we've collected from our TOP clinic at the University of Chicago. So, here we see all patients who are 70 and above who are about to undergo CAR T therapy, and we do the geriatric assessment.

(35:03): Patients who were frail but still had CAR T therapy were prone to more complications than those who were fitter. What we found is that patients who were found to be frail by the assessment but nonetheless went on to receive CAR T therapy, their hospital stays were longer and they were more likely to need rehab at the time of discharge. They were a lot more likely to end up in the ICU. And unfortunately, they were a lot more likely to run into non-relapse mortality or death related to transplant as compared to patients who tested well on the geriatric assessment.

(35:32): What we found is that the reason that these patients weren't living as longer was due to safety. The process was more complicated in these patients. We didn't necessarily find that in frail patients CAR T cells were not as effective, but some studies actually have shown that.

(35:52): This is a study that's always intrigued me. This came out a couple of years ago. They looked, again, at older patients. They did a geriatric assessment and they categorized patients as fit or frail and they looked at something that we call CAR T expansion.

(36:08): Anyone who's gotten CAR T therapy knows that when you get the cells, it comes in a very small bag. It's actually not a huge number of cells. The idea is that once those cells enter your bloodstream, they should expand, they should proliferate and create more cells. The amount of expansion is important in predicting the efficacy of the therapy and how successful it's going to be. We want to see those cells expand.

(36:31): Fit patients respond better to the expansion of CAR T cells and are more successful than frail patients. What they found is that in fit patients, that expansion of these CAR T cells was a lot better compared to patients who were frail, and these fit patients actually were more likely to have successful CAR T therapy compared to frail patients.

(36:48): Then one last study along these lines that I wanted to share. This came out last year and this looked at body composition and nutrition and how that impacts survival after CAR T therapy. If you remember back to the frailty criteria, a lot of it is like weight loss, muscle strength. A lot of these things have a very close interplay with frailty.

(37:12): What the study found is that patients who had a lot of fat tissue and a lot of muscle tissue were most likely to do very well and to live longest after CAR T therapy and patients who had low muscle tissue and low-fat tissue did not do as well. It actually seemed like the CAR T cells were just not as effective in those patients.

(37:34): Frailty versus fitness is more informative than age in determining who is a good candidate for CAR T therapy. Our conclusions here, frailty is more informative than age in determining patient candidacy for CAR T therapy. Based on available data, older patients are just as likely to benefit from CAR T as younger patients and there is no strict upper age limit for this therapy, the same way that there may be in donor transplants. As long as the patient is fit and they don't have any very uncontrolled or decompensated health problems, they deserve a very fair evaluation and chance at receiving the therapy. Thank you all again for joining and listening and I'm looking forward to the question and answer discussion we're about to have.

Questions and Answer Session

(38:21): [Elmer Velasco]:    Thank you very much Dr. Nawas for this excellent presentation. We will now begin the question and answer session. Our first question is: A side effect of CAR T therapy could be low blood pressure, creating a fall risk. How do you manage low blood pressure? Does this side effect ever go away?

(38:52): [Dr. Mariam Nawas]:  Great question. Yes, absolutely. That is a side effect that we worry about and one of the potential negative outcomes of that could fall among other issues. If and when cytokine release syndrome happens, I will say it almost always happens, but it doesn't always drop someone's blood pressure. Usually if we catch it early and we treat it aggressively, we can manage it before it gets to that point, but sometimes even if we do treat it aggressively, the blood pressure can still drop.

(39:21): The good news is that this is a very reversible complication. It's not something that should last for weeks and weeks. Usually cytokine release syndrome will last for just a matter of days. The ways that we can handle low blood pressure... Again, we treat the underlying inflammation the best that we can. We give people fluids. Sometimes, if needed, we can take them to the ICU and give people IV medications that will raise the blood pressure until the body recovers from all of that inflammation.

(39:55): [Elmer Velasco]:   Thank you for that Dr. Nawas. Let's move on to the second question here. A 75-year-old with high-risk myeloma, are there any additional risk factors for this patient if they should get CAR T therapy in the future?

(40:16): [Dr. Mariam Nawas]:  The CAR T approvals for myeloma have been more recent just in the last couple of years, and the reason I am bringing that up is because our data and our experience and patients who are 75 and older getting these therapies is pretty limited.

(40:32): I can tell you from our own experience at the University of Chicago, really what seems to matter, again, is this concept of frailty. Patients who are a lot more frail or the people who are susceptible to poor health outcomes and complications. But as a whole, I think we just need more time and more experience doing CAR T in older patients to figure out specifically what puts someone at risk. Is it kidney issues? Is it heart issues? 75 is by no means prohibitive to this therapy. If you're not already doing this, I highly encourage you to be evaluated because you may very well be a good candidate for CAR T.

(41:16): [Elmer Velasco]:   Great, thank you. The next question is how do you measure the amount of myeloma still there after CAR T therapy? Do you prescribe a PET or a CAT scan?

(41:30): [Dr. Mariam Nawas]:  I will say I personally don't treat myeloma, but what I know from my colleagues who do, I believe that they repeat a PET scan and they repeat a bone marrow biopsy at day 30. Usually that's the first time point that they're evaluating for response is 30 days after the CAR T. Then I believe they look again around day 90 or so. But usually, yes, it's combination of imaging and bone marrow biopsies.

(41:56): [Elmer Velasco]:   Great. The next question is how do you get a geriatric assessment? I have never heard of this at my cancer center.

(42:04): [Dr. Mariam Nawas]:  Yeah, a great question. One thing I probably should have mentioned is that this is not necessarily being employed across all transplant or CAR T centers. It is something that is definitely emerging and I think is entering the mainstream slowly. We're very fortunate at the University of Chicago that we have this whole clinic dedicated to a geriatric assessment.

(42:26): A lot of places may implement like an abbreviated geriatric assessment that's not necessarily a full half-day, but something you can do just within a few minutes to get grip strength or walk speed, things like that. But not all places, to be honest, are using this type of testing quite yet. I would just encourage you to ask your transplant doctor or your CAR T physician, is this something that they are using in their center? And hopefully we'll find more and more that the answer is yes.

(43:00): [Elmer Velasco]:   The next question, how long should patients be on Bactrim after CAR T therapy?

(43:07): [Dr. Mariam Nawas]:  Oh, good question. I believe that is very specific to the patient's immune function reconstitution or improvement after CAR T therapy. In the world of transplant, we use a cutoff of something that's called a CD4. This is a type of T cell which is a type of white blood cell and we wait for that to reach a certain number. And once it does, we feel confident that the person can protect themselves against the infection that we use Bactrim for and then we can stop the Bactrim. There honestly may be a specific center to center position to position in terms of their preferences.

(43:51): [Elmer Velasco]:   Thank you. Then the next question, what are the outcomes for autologous stem cell transplant in older adults over 65?

(44:00): [Dr. Mariam Nawas]:  Good question. For the sake of time, I focused on donor, transplants and I focused on CAR T transplants. I myself have done a lot of work on geriatric assessment in older patients. And what I can tell you from my own research, my own data is it's very similar to donor transplants. Meaning, that well-selected older patients do just as well as younger patients and age is not a very good predictor of outcomes.

(44:27): In my personal study that I did when I was at the University of California, San Francisco, we looked at like 200 patients who are older in age, who had auto-transplants. The things that were most predictive, again, were patient-reported outcomes. These are things like how a patient saw their performance status? How a patient considered their functional status to be. It was really this kind of patient-reported data that was very, very predictive. But as a whole, if you look across the population, it's a very similar story. Well-selected older patients do just as well as younger patients.

(45:05): [Elmer Velasco]:   Great, thank you. The next question is do you need to take all of the vaccines all over again after CAR T therapy? Baby vaccines, pneumonia, shingles? If you had them before CAR T?

(45:22): [Dr. Mariam Nawas]:  Good question. Again, this may differ center to center for donor transplants and even for non-donor transplants, auto-transplants. We have a schedule of how we repeat vaccinations beginning one year after.

(45:36): In the world of CAR T, I think part of it is that you have to wait to have some type of B-cell reconstitution or the cells that respond to vaccines have to come back in order for someone to get any benefit from vaccines. We do repeat some vaccines after. Again, I don't personally do CAR T in my clinic. I don't know that schedule off the top of my head as well, but there are absolutely repeat vaccines that are done at certain time points.

(46:10): [Elmer Velasco]:   Great. We have another question here. Is there a difference in outcomes between persons who have been fit for many years and someone who has become fit just before going into conditioning?

(46:23): [Dr. Mariam Nawas]:  That is such a good question. And to be honest, I don't know. That has not been studied. The assumption that we're making, those of us use a geriatric assessment is that if we uncover some frailties and then we try to optimize them, meaning we put a person through physical therapy and they become fit, that they might do just as well as a person who is always fit. But we don't know that for sure. I do suspect there is benefits to getting back into shape even if it's not as good as being in shape the entire time. I don't know the answer to that and that's something that we still need to study and to figure out.

(47:04): [Elmer Velasco]:   Okay. Well, the next question here is does baseline neurocognitive deficit impact the risk of ICANS (late neurotoxicity)? Does CAR T therapy itself, as a treatment, impact neurocognitive health?

(47:21): [Dr. Mariam Nawas]:  Really good question. The first part, which is does cognitive deficits at baseline impact the risk of neurotoxicity after CAR T therapy? It depends on the study that you look at. In general, our sense is yes, that patients who do have mild cognitive deficits or early dementia probably suffer more neurotoxicity, but it's very difficult to tease apart when you're in the hospital and you're treating a CAR T patient, what is neurotoxicity and what is just delirium that happens in older patients who have early dementia in the hospital anyway? Those may not necessarily be the same thing. It does seem that people who have, for example, lower scores on the MoCA, the cognitive assessment, seem to have a little bit higher rates of neurotoxicity, but that hasn't come out in every data set.

(48:13): I will say our data set from the University of Chicago, we did not see an association there, but our sense as clinicians who do this and treat these patients is that it does predispose to neurocomplications.

(48:24): Then the second part of your question is do patients who go through CAR T have long-term neuro issues? That's a good question that we don't know. I don't think anyone has studied long term. Again, because this is a newer therapy, we don't have that much long-term follow-up data, but that is very worth studying. In the world of transplant, I will say there is evidence that cognitive function can be impaired.

(48:54): [Elmer Velasco]:   And as a follow up to that question, is a patient able to recover from neurotoxicity?

(49:01): [Dr. Mariam Nawas]:  In general, neurotoxicity that happens is reversible, but I will say not 100% of the time. For example, especially with the CAR Ts that we're using for multiple myeloma, we are seeing some very rare but nonetheless present toxicities. Things like Parkinson's-like which are a lot harder to reverse. But the traditional ICANS, the traditional neurotoxicity that we talk to people about almost always is reversible.

(49:33): [Elmer Velasco]:   Thank you. We have another question here. Do you find immune reconstitution is slower or less likely to fully recover post-CAR T in older patients?

(49:45): [Dr. Mariam Nawas]:  Good question. I also don't know if data has specifically looked at immune reconstitution by age. For everyone, immune reconstitution unfortunately is pretty slow after CAR T therapy because the cells that are being targeted are B- cells.

(50:02): I think someone asked a question about this concept of B-cell aplasia. We're kind of wiping out the B-cells and it can take months and months to come back, even in young patients. For donor transplant, absolutely, the immune system does not recover as well in older patients. Part of that is that the thymus is necessary for immune reconstitution and immune recovery and the thymus becomes involuted and is not as active in older patients, so they never get to the same level of immune recovery as younger patients. I don't know if that is true for CAR T therapy patients.

(50:43): [Elmer Velasco]:   Thank you. Another question here. Do you mandate a caregiver for receiving CAR T therapy? Some patients may have challenges having a dedicated caregiver, and does that preclude them from pursuing CAR T therapy without having a dedicated caregiver?

(51:01): [Dr. Mariam Nawas]:  Another good question. After the time of discharge, our center at least, we do have a strict rule for the presence of a caregiver at least through day 30. It may not be for a very long time. For a while we went back and forth on whether we were mandating that that caregiver is present even within the hospital stay, like 24/7 in the hospital stay. That's no longer something that we have as a strict criteria, but we do encourage it.

(51:30): If someone is fortunate to have the social support to have someone with them, one of the greatest benefits of having someone with you in the hospital for CAR T therapy is that they can figure out if you are having neurotoxicity probably earlier than we can because they're with you all the time. They know you better than we know you. And if you are behaving a little bit off or speaking a little bit off, they may be able to pick that up before we can. We know that the earlier we treat neurotoxicity, the better it is.

(51:59): But that's not to say that if you don't have that type of support and you don't have someone with you in the hospital at all times that you can't do it or you can't do it safely. But I do think once you leave the hospital for at least a couple of weeks, most places will mandate some caregiver support for a couple of weeks.

(52:17): [Elmer Velasco]:   Thank you. Another question here. Regardless of age, if a person has an autoimmune disorder such as lupus, are they still able to undergo CAR T treatment? If so, are there different precautions that this patient would need to take?

(52:36): [Dr. Mariam Nawas]:  I can say we have done them in patients with lupus before. I really think it's a matter of how active that the disease is and what are the sequelae. For example, sometimes patients with lupus will have kidney problems. How bad are the kidney problems? If there's lung issues, how bad are those lung issues? It's not so much the lupus itself, it's the things that come along with it and those warrant just an evaluation. Like I said, for CAR T, for the most part we don't let comorbidities be prohibitive, but they are important. They do predict risk and so it's definitely worth an assessment.

(53:15): [Elmer Velasco]:   Another question here. How long should patients be on acyclovir and IVIG after CAR T.

(53:29): [Dr. Mariam Nawas]:  Good question. That is definitely patient specific according to how the immune system recovers, when the B-cells recover, and that can differ patient to patient. Acyclovir, we tend to keep on for a while in the world of donor transplant. I tend to keep it on for up to two years even, if not longer. But that may be center-to-center, patient-to-patient specific.

(53:57): [Elmer Velasco]:   Great. Thank you very much. We are running a little bit of a time here. I'm going to ask the last question and that will be, where can a patient go for more information on this particular topic around transplant and CAR T-cell therapy for older adults?

(54:18): [Dr. Mariam Nawas]:  Good question. The Leukemia & Lymphoma Society, I know definitely has some resources because I've given a couple of talks on these issues for them and they have patient-facing podcasts, web seminars and so on. I would recommend looking there. I'm sure BMT InfoNet also has resources. I've seen their website recently. There's tons of resources on there and worth looking into. Then, honestly, just Googling the topic of geriatric assessment, transplant CAR T therapy. That's going to bring you some resources and some studies. Yeah, I'd recommend checking those things out.

(54:58): [Elmer Velasco]:   Closing. Great. Thank you. On behalf of BMT InfoNet and our partners, I'd like to thank Dr. Nawas for such a helpful presentation. And thank you, the audience, for your excellent questions. Please contact BMT InfoNet if we can help you in any way. Enjoy the rest of the symposium.

(55:22): [Dr. Mariam Nawas]:  Thank you so much.