Weighing the Risks and Benefits of Transplant and CAR T-cell Therapy for Older Adults.

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[00:01] Moderator: All right, and good afternoon.

Welcome to the workshop, Weighing the Risk and Benefits of Transplant and CAR-T-cell Therapy in Older Adults.

My name is Jordan Sexton, and I'll be your moderator for this workshop.

Before we begin, I'd like to thank Kite and Autolus, whose support helped make this workshop possible.

It's now my pleasure to introduce you to today's speaker, Dr. Sarah Wall.

Dr. Wall is the Director of Clinical Operations for the Transplant and Cell Therapy Program and the Medical Director for the Remote Patient Monitoring at The Ohio State University, The Ohio State University Comprehensive Cancer Center - James Cancer Hospital.

Her clinical practice focuses on stem cell transplantation and cell therapy, especially for older adults. She also provides consultative geriatric oncology care with a multidisciplinary team in the Cancer and Aging Resiliency (CARE) Clinic at the James.

Please join me in welcoming Dr. Wall.

[00:54] Dr. Wall: Thanks, Jordan. Good afternoon, or late morning if you're further west.

I'm very honored to have been invited to participate in this symposium, and I'm very happy to be able to talk about this topic that I'm very passionate about, which is the role for these more intensive therapies, transplant and cell therapy in older adult populations.

I should call out to start that as with all things in medicine, there is not an appropriate one-size-fits-all approach. And I hope that by the end of this talk that participants feel empowered to actively participate in shared decision-making about treatment of their specific blood cancers.

[01:29] These are my more specific objectives that we'll try to hit on today's talk.

So, we'll talk about how old is too old for transplant or cell therapy, health issues or comorbidities that may preclude or make someone ineligible to undergo one of these therapies, strategies that transplant programs are using to make older adults more fit or to optimize their health ahead of these types of therapies.

Then we'll dig into outcomes specifically in older adults who undergo transplant or cell therapy, looking at things like survival, complications, quality of life, and comparing older adults to younger adults.

Before we get into transplant and cell therapy specific discussion, we'll start here by describing something that I think most of us know inherently, even if you haven't really thought about it directly.

[02:19] We don't all age in the same ways or at the same rate, and I sometimes share a slide that has pictures of Obama when he took office and Obama when he left office. Then we put that next to Paul Rudd, who is an ageless actor. You know, it just further drives home this point that we all age at different rates and it can be influenced by a lot of things.

So, this concept of differential aging is described as biological age, and it's driven by things that you encounter over your lifetime. 

That includes toxins and things that people often think of like chemical or radiation exposures, but it also includes things like diet, exercise habits, social stressors, and then underlying all of that, some of the things that you were born with, like genetic predisposition.

[03:04] The graph here depicts the divergence in aging. It starts with the black line here in the middle that depicts normal aging as a linear progression with chronologic age on the x-axis on the bottom and biologic age going up the y-axis on the left.

The green line here represents people who look, act or feel younger and are experiencing an age deceleration through things that they do that have modified the risk of aging or sometimes just by the luck of genetic lottery.

Then the red line represents those people who are, who have age acceleration, who may have been exposed to more toxic exposures, using that as a general expression, that have really aged them faster than the average person.

Thinking about these concepts typically raises some questions and one of them is how do I know what my biological age is? And it's a really excellent question.

[04:05] Unfortunately, there's not a standardized clinical response for how to answer that yet, but there are some research-based ways that we look at this, including there are blood tests that will measure senescence or aging at the level of your cells in your body.

There's a chromosome marker called a telomere that shortens over time, like an hourglass running out of sand that can give us an idea of relative speed of aging.

Then my favorite way to measure this is with a comprehensive assessment that includes assessing multiple domains of function in an individual person, like their physical fitness, nutrition, sensory inputs, like their vision or hearing impairment, memory impairment, and other domains.

[04:48] The reality though of all these methods is that none of them are a well-accepted standard, so biological age remains more of a concept currently.

The other question that comes up very often is, well, if you can change biological age based on exposures and some people can have age deceleration, then what can we do for people who are already on that red line and can we reverse that accelerated aging to get back to normal aging or even deceleration?

That's another really important question that's currently unanswered but is a very active area of research in both oncology and general science fields. Even to the extent that there are some very early phase clinical trials looking at medications, fountain of youth type pills to try to reverse aging.

[05:36] If people can differ in their speed of aging, and we don't yet have standard blood tests to tell us someone's biological age, what can we use as surrogates to try to measure this biologic age?

On the left here on the slide is this quote from Joan Rivers, and I will acknowledge that there's potentially a little bit of irony here from a woman who did a lot of cosmetic work to presumably look younger.

But the quote is, listen, I wish I could tell you it gets better, but it doesn't get better. You get better.

I fully subscribe to this sentiment. One of the concepts I like to talk to patients about is glass half full, glass half empty related to aging. So if your glass is half empty, you've reached a certain age. It feels like, and it may be true, that the majority of your life is behind you, numerically speaking, maybe even your best years. But if your glass is half full, and I always try to keep mine that way, you are healthy, resilient, and you had to be to live the years you have with the success you have. And that's the evidence that suggests you'll be able to continue to do that and may be a candidate for more intensive therapy.

[06:43] So the left side of the slide is about perception and beliefs. The right side of the slide is more concrete concepts. One of the reasons why our healthcare field in general, not just oncology, deals with increasing age as a negative prognostic indicator.

As we age, in general, we are more likely to develop more medical problems. Just like your house or your car will need maintenance or things will break down and need to be replaced, the human body does the same. It accumulates wear and tear over time.

[07:12] So in the bar graph on the right, this is a population-based study, the NHANES study, which is something that I think many people may be familiar with because it enrolled tens of thousands of people just to follow them over time and see how they age.

You can see starting from the left in the youngest age group of 18 to 44, diabetes, high blood pressure, hypertension, and heart disease are all relatively rare, occurring in 10% or less of the population.

But by just the next age bracket up, 45 to 64, all three of those conditions have nearly tripled in their prevalence. Then in fact, as you're even more likely than not to have high blood pressure with with more than 50% of people 65 and older showing high blood pressure.

[08:04] So, while chronologic age is just a number, if you're playing the odds, the older a person gets, the more likely they are to carry some kind of additional medical problems that are going to make delivering their care more complex.

I want to dive into this concept of comorbidity a little bit further because you would say, and rightfully so, so what I have high blood pressure, it's a treatable condition.

While that is very much true, and diabetes and heart disease are also treatable conditions, the more complexity you add to a system, the more opportunity there is for failure. And so the definition of comorbidity when we talk about it medically speaking is the presence of two or more medical conditions that are simultaneously present.

One of the ways we use this, especially in older patients, as an example here is the Beers Criteria. So, Beers is a comprehensive guideline that was developed a few decades ago by a pharmacist, Dr. Beers, who observed and documented the ways that older adults experience side effects from medications that we didn't see in younger patients. And so Dr. Beers is no longer living, but this is his legacy, and these consensus criteria continue to be reviewed and updated every few years.

[09:24] What I'm showing in the table here is one of the tables directly from the guideline that deals with comorbid conditions. In the left-hand column is cardiovascular diseases, the system, heart failure being the condition. In the middle, you've got a list of drugs or drug classes. Then on the right, in the red box, the rationale for why we care.

Why should we care about these drugs in older patients with heart failure?

You can see these examples that talk about the potential for promoting fluid retention with certain drugs, some drugs that are associated with higher rates of death in older patients with heart failure, and some causing QT prolongation, which is a change in the electrical signal that can make someone more prone to an abnormal heart rhythm.

It's not just age, but it's also the intersection of medical conditions and age that we look at in the Beers Criteria.

[10:22] Next we'll talk about how we measure comorbidities.

On the right in this slide is Dr. Charlson. Dr. Charlson is a name you may or may not have heard of. I'm trained in internal medicine. I had never heard of this or used it clinically through my training. I have only come to find it through working backwards from the transplant score on the right that we'll talk about.

But this is actually the Charlson Comorbidity Index is a really powerful tool for predicting someone's 10-year survival. It's based really purely on the presence or absence of a whole bunch of medical conditions.

The list is too long to put on the screen here, but readily available to find on the internet, but it's a list of very common medical conditions.

What she did with her study in developing this tool was looked backwards at how long people lived and then put weighted factors on each of the diagnoses they had. Then you arrive at a score that tells you which medical conditions are riskier than others as far as shortening someone's life expectancy.

[11:26] Then on the right hand side here, we're going to get more transplant specific. This is Dr. Sorror, and in the late 90s, he started working with comorbidity index. He specifically started with the Charlson index and he applied it to transplant recipients, and so the first incidence of use of this index was published in 2005.

But what he did was looked at how long people survived after transplant and specifically looked at something called non-relapse mortality, which is death from any cause other than the original blood cancer for which someone was transplanted, and we assume that most of these causes are complications of the transplant.

[12:07] This tool was shown to accurately predict the risk of one year non-relapse mortality after transplant. So get the transplant in remission, but die of a complication.

Not all of the same factors that are in the Charlson Comorbidity Index made it into the Transplant Index, and the Transplant Index similarly puts weighted scores on each of the factors that are included there.

This score is now used around the world at transplant centers for individual patient care, decision-making and prognostication and talking with patients. It's also used on a programmatic level, on a systems level as a quality metric for transplant programs.

For a given transplant program, you'll look at what's the predicted one-year survival or non-relapse mortality for that center based on the comorbidities of the patients they've transplanted. Then you look at what the actual was to give a scorecard of how well those transplant centers are doing.

[13:06] Okay, so if you didn't like the last slide, I don't blame you 'cause I'm not really a black and white kind of person either.  I think most of what we do in medicine, as I led off with, is a little bit more nuanced and shades of gray.

A disclaimer about this slide is I made it. I made this figure. So if you hate it or if you love it, I will take either set of feedback.

But the reality really with comorbidities is that they are not fixed, they're not static, and they're constantly changing.

What this figure depicts is we start over in the red box at the top, and this is what we don't want. This is a new symptom, an exacerbation of an existing condition, or a new positive routine screening like a cancer screening test.

We identify a new problem, and then we go into this cycle in the middle of evaluating the condition and treating, evaluating the response to treatment, seeing if that's the right treatment, and then eventually we exit that cycle to the right.

[14:05] For some conditions, and I'll use an example of pneumonia, they should go through a treatment cycle and resolve. We treat pneumonia with antibiotics, the infection resolves, we shouldn't be at risk for it coming back, so we get to sit over into the resolved category.

However, a diagnosis of pneumonia in someone with lung disease, obstructive lung disease like emphysema or chronic bronchitis, they may develop a pneumonia that causes exacerbation that puts them back into this evaluate and treat cycle, and hopefully we treat the infection and get it under control. But at best, we're going to return them back to that top blue box on the right, the controlled chronic condition.

So when I think about this as a transplant physician, my goal is that any condition my patients have had is resting solidly in one of those blue boxes where it's either well-controlled medically or resolved. But the reality, again, is that these things are often in flux and we have to constantly evaluate and treat comorbidities.

[15:08] So on the next slide, I want to give a little bit more specific example related to transplant.

These are semi-hypothetical patients. They're parts of reality pulled from them, from people I've met.

So, I have here Marianne and Mitch. They're both in their early 70s and both of them carry a diagnosis of atrial fibrillation. If you look at the bottom of each of their side-by-sides, they each get one comorbidity point. They both have atrial fibrillation and abnormal heart rhythm carries one comorbidity point.

However, when we get into these details, bullet pointed in the middle, you're going to see that they're different.

So, Marianne was diagnosed during an episode of severe infection, her abnormal rhythm resolved when her infection was treated and she's never had a recurrence, it's never come back.

Mitch, on the other hand, has been dealing with this for 12 years. Whenever he goes into AFib, he gets short of breath and symptomatic. He's been shocked three times to try to keep him in normal rhythm, and he's had two ablation procedures to try to knock out the abnormal signaling pathway.

[16:10] If you're a cardiologist, you're probably not going to think that these patients are the same, and you're probably not going to approach their management in the same way.

I also don't think that from a transplant or a cell therapy treatment decision-making that we should consider these patients to be the same, even though they have the same comorbidity point.

[16:32] Now, before we get too carried away into gray areas, I'm going to bring us back to a little bit more black and white, and we're going to cover in the next two slides some conditions that are excessive risk and maybe conditions that make transplant not feasible, not safe.

On this slide, the cardiovascular system, heart failure, which is weak heart muscle where the blood's not being pumped out adequately, is a condition that's associated with a higher risk of needing breathing tube support during the stress of transplant or cell therapy with more intensive therapy. Also the risk of sudden cardiac death because this is a system that's already under stress.So additional stress can be enough. It can be the straw that breaks the proverbial camel's back.

[17:22] Valve stenosis or regurgitation stiffness or leaking are things that are common as people get older. Those are both situations that can cause similar heart failure type symptoms where people are more likely to require breathing tube support and at risk for sudden cardiac death. In the kidney or renal system in particular people who have end-stage renal disease, so are already requiring dialysis or very nearly requiring dialysis. They're going to have a very different clearance of chemotherapy drugs, which may increase the toxicity they experience and put them at higher risk of death due to toxicity. And then this also creates some difficulty in dosing medications because of the different metabolism and clearance.

[18:07] We see the same phenomenon with the liver because our liver is also important in chemotherapy clearance and medication metabolism, and so the liver represented by cirrhosis being end organ damage.

It is important to note that with all of these organ systems, there are severity and grading systems for each of these conditions.

A diagnosis of early cirrhosis, a diagnosis of chronic kidney stage, chronic kidney disease stage three, these are things that we should take note of, but they are not necessarily going to be a hard contraindication to transplant.

It will be very important to talk with your doctor and involve your specialist if you have any of these conditions to try to determine what the severity of these conditions is and how much they would increase the risk with transplant.

[19:00] On the second side, we'll look at lungs and brain as system.

We do measure lung function. Patients have to go through pulmonary function tests for transplant recipients on the call. You'll remember those fondly. And these are a way that we measure for signs of obstructive lung disease or asthma, which is the top one listed there.

[19:21] For patients with obstructive lung disease, they are at higher risk of needing breathing tube support and higher risk for infections in the lungs because they don't clear bacteria as efficiently as someone with more healthy lung tissue.

Then interstitial lung disease, which is a different type of lung disease where the tissue is stiffened, is often associated with an impairment in gas exchange.So oxygen getting in and carbon dioxide getting out and increases the risk for needing a breathing tube.

[19:47] Shifting to the brain or the neurologic system. For people who have severe cognitive impairment at baseline, there are actually a number of issues here. The chemotherapy and the so-called chemo brain can worsen an already impaired cognition. Transplant and hospitalization associated with it are often drivers of delirium that can exacerbate an underlying dementia.

And then there's safety concerns. If someone has severe cognitive impairment, they may not remember to take medications and may not be able to maintain the medication profile that they need to be successful with a transplant.

[20:29] There's also some ethical issues depending on the severity of cognitive impairment. It's unclear whether patients with severe cognitive impairment have the processing to really understand the entire process and risks and benefits of the transplant process.

The other neurologic condition that we see more commonly in blood cancer patients than the general population are strokes. We see both bleeding and clotting types of strokes in patients with blood cancers. And so when there's been a stroke, there are a couple of considerations.

[21:04] It often is not something that keeps a person from going to transplant, but it may require that they need more time to be optimized before transplant and to recover because neurologic pathways notoriously heal slowly.

So again, I think it's just important to note, these are all things that could lead to a conversation where the discussion ends in the risk of transplant outweighs the potential benefit.

For some of these conditions, the risk of dying from the transplant may be associated with a shorter life expectancy overall compared to life expectancy with ongoing treatment of a cancer, even if it's without curative intent.

[21:42] Okay, so now we're going to talk about less dark things, more optimistic things.

After we talk about medical conditions that give us pause, we're gonna talk about my favorite way to measure biologic aging that I mentioned earlier, which is the comprehensive geriatric assessment.

This is where we stage staging the aging, and I did not coin that phrase, but I will use it.

So, this is a multidisciplinary, multi-dimensional approach to evaluate older adults' health, functional ability, and their interaction with their environment and social situation around them.

It is a tool that is used to guide personalized care planning. And you'll notice that nowhere on this slide does it say this is a decision maker about whether you can or cannot have transplant.

At Ohio State, we have the Cancer and Aging Resiliency Clinic or the CARE Clinic. A lot of patients get referred to the CARE Clinic and don't know the A stands for aging. So, sometimes they get a little offended before they come around and decide that they like what we're doing.

[22:47] This is me with one of our really lovely patient volunteers at the James who helped us pose for pictures for marketing material.

On the right here, you can see this is the construct of our clinic. Not every clinic is built this way. It depends on the resources available at a specific center.

But ideally, more and more transplant and Cell Therapy Programs will be building programs like this that get at some kind of multidisciplinary, multidimensional aspect of assessing older patients.

This clinic space was new for us three years ago, but we've been doing the CARE Clinic for almost 10 years now. We're about to have our 10th anniversary. We've got a lot of experience, and it's been an iterative process of learning and growing.

When we got to design this center, it's a very cool space. We have a gym built into our hallway where we see patients for physical therapy assessment. We have a sound booth to complete the audiology assessment. We even had them build in a wet lab space around the corner so we can collect blood samples and process them for aging research.

[23:56] And then my favorite detail, and you probably can't see it because it's very small, but it's over my, just under my shoulder in the picture. We have these white tile floors and the physical therapist asked if they could put in a line of red tiles every one meter. And what that does is it allows them to measure someone's gait speed without even trying because we can see exactly how many meters they've walked and time it.

So it was truly a space designed for assessment of aging and to best accommodate older adults who may have some comorbid conditions.

[24:29] I did mention a few of the staff as I was talking about the things we have, but just to run through the lineup here on the right.

So within the clinic, we have a physician, an audiologist, a pharmacist, a dietician, a physical therapist, and a case manager or social worker. We also have the most exceptional nurses who keep this whole round robin of people moving to get our patients through clinic in about two to three hours to see all of these people. Our nurses also perform our cognitive screening test.

[25:02] In the next few slides, I'm going to walk through some of the testing we do there. So if you're someone who's considering transplant or cell therapy, this can be like your prep course. So you can start preparing.

One of the tests that we like to use to look at physical fitness for our patients is this one called the short physical performance battery.

This is done by the physical therapist, and it's a three-stage test. It includes, starting from the left, a five-time sit-to-stand test. So this is seated in a chair, no hands. Ideally, you don't use your hands to push up at all, and you're going to get up and sit down five times, and we're going to time you.

The next in the middle is gait speed. So, this is normal walking speed, not a power walking competition. And again, we measure that with our fancy red tiles on the floor.

Then the right there is a picture of the tandem and semi-tandem stance, and this is a measure of higher order balance, where patients are asked to stand with their feet parallel and shoulder width apart and close their eyes. They'll hold each pose for 10 seconds. Then they'll move to a semi-tandem stance with one foot slightly in front of the other.

[26:09] And then finally you finish with one foot directly in front of the other with your eyes closed. And that's going to be a measure of balance.

It is really important to note that these are performed under the supervision of a physical therapist who has walked this patient over to the gym and already has a good idea of what their stability is going to be because we don't do falls in clinic.

[26:29] Next, we'll talk about cognition. In our clinic for the last six or seven years, we've been using the Montreal Cognitive Assessment. If this sounds familiar as the MoCA, it might be because our current president very famously shared the results of his MoCA test during his first term. 

But this is what the form looks like. The top of the form is one that's handed to the patient and you complete these tasks where you're going to connect the lines. You're going to draw a cube, you're going to draw a clock, and then you're going to name the animals. 

And then we move down to the bottom part of the form, and this is where the tester is giving questions to the patient. So we give memory words, which were not camera, TV, man, and person or whatever, whatever was said as an example.

But the patient's given five words to remember and repeat back, and then they're supposed to tuck those in their back pocket until the end of the exam. Then we do some things to try to distract you by repeating back a series of numbers, tapping your hand when you hear a certain letter. My favorite, which is serial sevens, where you have to subtract seven from 100, which is not hard. It just takes a lot of attention because it's more complicated than fives and tens.

Language is repeating back sentences. And then the F test is another great one. The fluency test is you just name as many words as you can in one minute to begin with a certain letter. And the primary form for this uses the letter F, which always gets interesting because you get people who either use colorful language or people who don't. And then finally, some abstraction questions before you're asked to name the memory words again.

[28:14] With the Montreal Cognitive Assessment, it has been validated in what we call community-dwelling older adults, so not specific to oncology. And in that setting, a score of 26 out of 30 or higher is considered normal cognition, not a positive screen.

Dr. Tissotissotui Cole, working at the University of Nebraska, did this fantastic study about 10 years ago now where she did this test in patients with hematologic malignancies, not even necessarily getting active treatment, so not just the effect of chemo brain, but also the potential effect of low blood counts, and showed that a threshold of 21 is probably more specific and we're going to be less likely to alarm people and tell them they might have dementia if they score 23.

A score of less than 21 is probably something to take more note of and more concern with in patients with blood cancer here.

[29:08] Then finally for nutrition, we use the mini nutrition assessment, which is displayed here in pretty small print, but I'll tell you what it includes, which is we talk about how much food are you eating? Has there been weight loss? What's mobility like? Has there been psychological distress?

And the default is we start with a yes there. It's pretty rare we find somebody who has not been psychologically distressed by their diagnosis recently. And then the presence of memory impairment.

[29:38] Our dietician, if they have time, will also do a little bit more in-depth assessment. They'll do a physical exam to look for muscle mass loss and they'll look at weight trends to see about percentage body weight lost. They do a ton of education with our patients during these visits to focus on how we maintain weight during treatment.

[29:56] Then finally, wrapping up what we do in CARE Clinic, the next four slides are an example of a prescription that we give to patients after they come to CARE Clinic.

This particular patient was scored vulnerable on this scale, which is called the Rockwood Clinical Frailty Scale. It's a great tool. It's used just on the day of assessment. How does this person match up to other people of their chronological age?

It doesn't account for what's happened in the last month or what's happened, you know, where you were three months ago. It's just where we are right now.

[30:26] A lot of the consideration for this is how much people are able to do independently, like transportation, heavy housework, things that are instrumental to maintaining independent living. Then gets down into categories of frailty for people who aren't able to do their very basic functions like getting dressed or bathing without somebody helping or at least standing by.

In general, for our patient population, we want anybody who we're considering for transplant or cell therapy to be a managing well or higher. But again, this is a starting point. We can do these assessments repeatedly.

Our hope is that if we see somebody who comes in as vulnerable, that we give them the prescription on the following slides, we'll click through, and then they come back and have moved up to managing well or well.

[31:12] So nutrition, this is the longest version of a nutrition note we get. They typically will give three to six bullet points. There's a lot of emphasis here on multiple meals and snacking, on high protein sources. We give everybody a goal for how much fluid they should be getting in a day.

And then our dieticians have all kinds of great tips and tricks. Like they've got in this one a recipe for a homemade protein shake. And then the instructions for, you know, how can we try to work around taste changes caused by chemo, which is a common, you know, extra insult on top of nausea and other reasons people are losing weight.

Next are the physical therapy and cognition summaries. This particular patient was very borderline. They scored at risk for falls or balance impairment on some tests, but normal on others. So, this is a person who was actually referred to continue with outpatient physical therapy to try to continue to optimize this.

For people who have normal function at their initial assessment, they will often be given a home exercise program to continue to maintain that. We talked about the MoCA already and the scale there.

[32:21] And then this last page shows our pharmacy recommendations. This is someone who knew their medications very well. But for people who have some Beers criteria medications, things that may be risky, we may recommend stopping medications, or we also will often refer patients back to their primary care specialist to talk about the risk benefit and if there's an alternative therapy that may be safer.

Our audiologist does provide an audiogram to every patient, and if they are someone who's a candidate for hearing aids, they can take that to a hearing aid specialist to be fitted and start using those. 

Then our social worker, our case manager, helps connect people with things like the local area agency on aging, which you see here down at the bottom.

And then we also have, we have some James Care specific programming, survivorship programming that we give to everybody as additional supports.

[33:08] So how do we use a geriatric assessment? I have this broken out into stakeholders. We think this is a tool that can help patients to better engage in the shared decision making with their patients with their physicians and their treatment teams.

We think it's also a great way to help identify what a patient's goals of care are. When you're seeing a specialist, you often can lose the forest for the trees getting into the details of treatment. So we take a step back and try to get it. What are the big picture goals we're trying to achieve here?Then for anybody, regardless of what treatment they go on to do from our clinic, we hope that we're helping improve quality of life.

For caregivers, the assessment can be helpful to identify available resources that can help to lighten their load or to help them prioritize areas where they may need additional support.

For our healthcare providers, again, this is not a pass-fail test. So this is hopefully a way to help engage in shared decision-making with patients, to help create a personalized care plan for an individual patient, and a consideration to modify a chemotherapy protocol or treatment based on comorbid conditions or early signs of frailty.

[34:11] From a systems approach, we think this comprehensive assessment helps to highlight within our hospital system, the need for age-friendly accommodations. We're going to talk a little bit more about that in two more slides here.

Just another note on the timing of these assessments, these have to be graded on a curve. They are best done early so that you have more time to intervene before a given treatment needs to be done because diseases don't always wait for us to optimize a patient's function. 

Our goal is to see people at least a month before a transplant or cell therapy. We typically don't want to see people if they're not going to need a transplant for more than six months because they have a slow acting disease because so many things can change in the meantime. We're always happy to see them, but we don't enforce it.

The expertise of your geriatric team is important here. Within our group, we have medical oncologists and we have a palliative care doc. So they don't have hands-on experience with transplant and cell therapy, but we've done some education internally to try to get people to a comfort level. But that is important with interpretation that this geriatric assessment is not a, you should or shouldn't get a treatment. It's a framework for assessing somebody's fitness. And then your specialist using that information should be able to continue a conversation with you about whether a certain treatment is safe or what things make it more concerning and what we need to work on to optimize.

[35:44] Okay, so age-friendly healthcare, a couple of slides about this.

The Hartford Association, the Institute for Healthcare Improvement with The Hartford Association does this age-friendly healthcare systems designation. We are an age-friendly designated center and we're proud of that. These are centers that follow an essential set of evidence-based practices. 

I think we all want to cause no harm, but they mean specifically here causing no harm related to geriatric conditions. And then we want to make sure we're aligning with what matters to older adults and their family caregivers. So a little bit more about that on the next slide.

[36:20] The four Ms, what matters is that goal concordant care, that shared decision-making. So, understanding what a patient's goals are when we make treatment decision-making.

Medication here refers to things like the Beers criteria and understand that medications are handled differently in older adult patients, and there are some medications that should be avoided.

Mentation refers to higher incidence of dementia and memory loss and depression in older patients, but also the increased risk of delirium when you have someone in a hospital setting that's foreign to them. 

Then mobility refers to ensuring that older adults keep moving. Hospital systems are definitely built to prevent falls, but often in doing so they're very restrictive to mobility. So, the 4Ms really help to try to remind people that we don't want people on bed rest unless it's absolutely necessary. We want to keep people in motion.

[37:18] Specific to transplant, at our center, we talk about age-friendly care delivery in these two ways.

Ancillary support like physical and occupational therapy, seeing patients before, during, and after their treatment, and our dieticians following them before, during, and after. We're continuing that comprehensive care throughout, recognizing that people's needs will change.

Then a really important piece is the setting in which care is delivered, so inpatient versus outpatient. Outpatient transplants and cell therapy administration are available at many transplant centers.

A lot of the treatments we're doing now have toxicity profiles that allow for feasible outpatient administration as long as you can safely get people admitted to the hospital quickly to manage those toxicities when they come up.

[38:05] A couple of brief slides about the importance of caregiving support, which is not an indication of the weight of caregiving, but I love this slide from ProMedica that this is not specific to oncology care, but it highlights at the bottom there in black that only 20% of our health is determined by healthcare and in healthcare settings. The other 80% is made up of these other factors.

In orange, the health behavior, some of the things we talked about as being modifiable for biological age and things we assess in the geriatric assessment. And then up in the purple, the socioeconomic factors, a lot of these things that happen way before you get to the hospital play a big role in your health. Caregiving and support is an important part of those two categories.

[38:52] Specific considerations for caregiving for older adults. Our center, we've looked at this. The most common thing is that a spouse or a partner is the primary caregiver for someone who receives a transplant or cell therapy. But there are often a lot of other considerations when that doesn't work.

For older adults, they may be looking at children who have their own families who have work, need time off work. We've also had some scenarios where we look at hired services, but those are paid for out of pocket and can get expensive very quickly.

[39:24] We have really worked hard to try to incorporate area agencies on aging as another resource to help provide some of the caregiving needs without having them all fall on one caregiver person.

So meal delivery like Meals on Wheels. A lot of these companies provide homemaking services which would cover some of the heavy housework and cleaning type of things.

[39:47] Okay, so finally, and I'm running a little long. These are really dry slides. So stay awake with me if you can.

We're just going to talk a little bit more about outcomes for older adults in transplant and cell therapy. 

So the important thing to remember here just because you can doesn't mean you should. I think this is really something that patients and caregivers need to remember as much as physicians need to remember both parties when we're doing shared decision-making. 

Everything comes with risks and benefits. We have to find the right balance of those things.

[40:19] So this is a slide looking at CIBMTR data and that's the Centers for International Blood and Marrow Transplant Research. This just shows the growth and use of all of these transplant and cell therapy products.

The navy blue line on top is autologous transplants who have really plateaued in the last decade. That's owing to this huge growth in the light blue line at the bottom with increasing use of CAR-T-cell for diseases that previously would receive autologous transplant. And then the maroon line is that steady growth of allogeneic transplant.

So CAR-T outcomes in older adults, there are lots of single center experiences of like five to 10 patients who are 70 or 80 years old. There's a lot of individual experience with older adults.

This is one of the larger, better data sources I can find, which was a large retrospective study that used nationwide readmission database data. They defined older adults as 66 or older. This study found no difference in early death, early readmission, prolonged hospitalization, or length of stay for older versus younger adults.

[41:28] Now they did see that non-home discharge, so discharge to a nursing home or inpatient rehab, occurred twice as often in older adults. Predictably, probably, older adults have slightly higher rates of heart and kidney complications because those organ systems are probably slowed down a bit in general in older populations compared to younger.

[41:49] Regarding auto-transplant, I have two studies to talk about here. One is all auto-transplants, So this includes any disease that would get an autologous transplant, your own stem cells. This was single center study in the Bronx, but it looked at the old, old population, 75 and older, compared to the young old population of 55 to 65, and this is interesting because autologous transplant has been done for decades.

Most transplant physicians, there's a survey study that showed most transplant physicians don't have an upper age limit in mind for who they would offer an autologous transplant to. So this study showed that there was no difference in early mortality, early readmission, ICU, length of stay, and overall survival up to five years. 

The only difference was that the older adult population was just slightly slower, a day or two longer to get their counts back.

[42:41] In this study that's specific to patients with myeloma receiving auto-transplant, we look at real-world and aggregate medical record data, so this was a huge collaborative work between 89 transplant centers. It used kind of a combination of data, which means it's probably not the cleanest data, but a very large data set.

Here, older adults defined as 65 and older. And so this looked at just this older adult population. And they showed that in more recent transplants from 2021 up to present, there was a better five-year overall survival prediction for the most recent transplants compared to historic transplants.

So, it tells us that even though autologous transplants been around for a long time, we're getting better at doing those transplants and especially in an older adult population.

When you compare these patients to people who did not receive transplant, older adults with myeloma who underwent an autologous transplant had a lower early mortality rate, so lower risk of dying within the first year of diagnosis, but they did have higher rates of falls in emergency department visits, probably related to the intensity of their treatment.

[43:53] Finally, allogeneic transplant, donor transplant outcomes in older adults.

This is a CIBMTR study that looked at older adults, 70 and older who underwent allogeneic transplant, which was really a foreign concept before 2000. It basically didn't happen.

You can see in the graph here that on the blue line, the more recent cohort from 2008 to 2013 has a better overall survival compared to the earlier, to the 2000 to 2007 cohort, where the two-year overall survival was about 30% and it's approaching 50% in that more recent cohort.

[44:30] In this population, we saw that comorbid, more comorbid conditions is associated with worse survival and bad leukemia or blood cancer is also associated with worse survival, so disease that's not responding to chemotherapy. Those are both things that are true for younger patients. So we're not seeing a huge difference in this older adult population.

[44:52] The final slide I wanna present with new information is I think the next place we need to go with these conversations around older adult transplant and cell therapy, and I brought back Dr. Sorror from the comorbidity index.

Something he's very interested in now is looking at treatment decision-making. We don't have a good denominator for how many people are diagnosed with a blood cancer that would qualify them for one of these treatments. That's what he's working on with this, with his ongoing research in this study I'm presenting here.

[45:21] He worked with 13 other transplant centers to study newly diagnosed older patients or what he called medically infirm, so patients with multiple comorbid conditions with leukemia.

What he found in examining their experience is that transplant recipients experienced a decrease in quality of life, which we expect, and that the post-transplant quality of life for transplant recipients was reported to be similar to those patients who did not undergo transplant. It didn't seem to make a difference on quality of life.

Another important finding was the difference between physician and patient reported goals of treatment. Patients in this study reported a higher likelihood of being cured with their planned treatment than their physicians did, which highlights the importance of better communication around what our expectations are for these treatments and the risks associated with them.

[46:18] Finally, this study really highlighted that there is a selection bias in transplant and we need a lot more data around this, but we have a selection bias to transplant only the fittest older patients.

When we talk about transplanting people who are 70 and older, that's not representative of all people who are 70 years old because there were certainly a lot of people that were probably weeded out in the process for having other medical problems or being considered too high risk.

[46:48] In summary, staging the aging is a very important tool for evaluating older adults considering intensive transplant or cell therapy. It should be an aid in shared decision-making between patients, caregivers, and providers, and it's a great way to help ensure that we have adequate resources and support.

[47:05] Outcomes like survival, readmissions, and length of stay are not different for older adults compared to younger adults with auto, allo, and CAR-T-cell therapy, and then outcomes research does still very much reflect selection bias for older patients who get treatments. So, we need more real world data and we need a lot more non-transplant data to understand if transplant really is improving people's lives, especially at extremes of age.

And with that, I am finished and I'm sorry I took so long, but I am very happy to take questions.

Questions & Answers

[47:38] Moderator: No, I think that was awesome, Dr. Wall. Thank you so much. That was an excellent presentation.

We'll get to some questions. If you have a question for Dr. Wall, please use the question box on the lower left side of the screen. We're going to try to answer as many of these as possible.

So, the first question we have for you is, is infection the highest risk post-transplant and CAR-T-cell therapy?

[47:57] Dr. Wall: That's a good question.

The short answer is probably not. It's probably relatively equal in donor transplant to the risk of graft-versus-host disease and to organ failure that can be related to chemotherapy toxicity.

CAR-T, there are some other competing risk, infection is a high risk and it's a different mechanism where we see lower antibody production. A lot higher risk for viral infections, and we keep people on prophylaxis to try to prevent that.

But one of the things we see fairly often is low blood counts after CAR-T-cell. We have a number of patients that will continue to need blood and platelet transfusions even after. But all that to say, you know, infection is a very important risk for both of those therapies and our immune system ages like other systems age. Older immune systems are probably not quite as adept as younger immune systems.

[48:57] Moderator: All right.

Our next question is regarding the Montefiore study, is there a difference between older adults receiving an initial auto transplant versus those receiving a second auto transplant due to a late relapse?

[49:16] Dr. Wall: That's a really good question, and I want to answer it accurately, and I don't think I can based on my knowledge of the study because I don't recall it with that level of specificity.

I also will disclose I work at a place where the chief of our myeloma section is giving a Grand Rounds talk about how transplant is dead and we won't need it anymore soon because we're just going to do CAR-T.

[49:44] Moderator: All right.

Our next question is from someone who is a five-year AML stem cell transplant receiver or survivor at age 66.

The cGVHD of the skin, eyes, and mouth, if they were to relapse, would they be a good candidate for a second transplant in your opinion?

[50:05] Dr. Wall: So, the first part of the answer is that is a really important shared decision-making question to talk about with your transplant doctor and potentially as a second opinion with somebody else, depending on how that conversation goes, second transplants are hard.

I would say we're doing them a little bit more at Ohio State, and we haven't looked really into why that is.

My sense, though, is that we're getting people through transplant probably in a little bit better shape than we used to because of things like reduced intensity conditioning, where we're really trying to minimize the toxicity of the initial transplant.

Having active chronic GVHD is a huge concern though, for considering a second transplant. It's a little bit of, it's a lot of unknown territory.

When we introduce a third immune system into the mix, assuming that there's still your original parts, plus your new donor's immune system and a second donor, we can see flare-ups and life-threatening progression of GVHD too.

We have some loose policies around it, but I think every transplant center is different. And it's typically going to be a scenario of, we want the GVHD to be very mild or under very good control on a low level of immune suppression before we would stir the pot big time with putting in a second transplant.

[51:34] Moderator: And I do want to point out, not going to call out this person's name, but it seems like you had one of your patients just pop in to say hello, so it sounds like you've left a great impression on them, Dr. Wall.

We have about five minutes left for questions. So, if anybody has any questions, please do use the question box on the lower left side of your screen, and we'll hold for a little bit for some more.

Dr. Wall, what is your opinion on CAR-T after autologous stem cell transplant?

[52:20] Dr. Wall: That's a whole other talk.

It's a great question, and I think both, we asked the questions about sequencing about CAR-T before transplant or CAR-T after transplant.

I think there's probably some synergy that we don't want with those two in sequence in either order where we can see, higher rates of infection.

But CAR-T, especially in ALL, there's a lot of growing interest in acute lymphoblastic leukemia to use CAR-T as a way to try to mitigate relapse after transplant. So low level molecular disease.

It's certainly doable, but I think it's, I would categorize it as being in a place where we're all learning best practices.

We tend to order lots of tests and try to, to try to understand every aspect of an immune system before we do CAR-T after transplant, just to understand if the immune system is in pretty good shape or if it's kind of limping along.

[53:31] Moderator: Good deal. All right.

We have a question that someone who's 79, having CAR-T-cell in two months, or CAR-T-cell, they've had myeloma for eight years, had a stem cell transplant eight years ago and looking to be in remission.

Do you have an idea of the survival rate at their age and they're concerned about the potential for side effects?

[53:50] Dr. Wall: That's a really good question, and I would point you back to a myeloma specialist to get more specific conversation about that.

But the survival rate with CAR-T is really pretty high. We don't have a lot of mortality related to CAR-T complications.

It can be tough, especially if we see some of the neurologic toxicity. We've had patients who, you know, stay in the hospital for a week or two trying to work through that neurologic toxicity that can be seen after CAR-T.

That can be further compounded by delirium and all the other things we talked about that are more common when you're hospitalized for a long time. But CAR-T has been very promising.

Like I mentioned earlier, our head of myeloma doesn't think we need transplants anymore and that CAR-T is the future. So we are seeing some really good durable remission with CAR-T-cell therapy.

[54:52] Moderator: I think we have time for one more question here.

This person says that quality of life is the only thing that matters to them.

Will CAR-T result in improved quality of life in a 78-year-old who is relapsing after autologous stem cell transplant?

[55:07] Dr. Wall: I love that question because it starts with the answer, which is quality of life is the only thing that matters.

I think that is a really important statement and conversation to have with your treating team about what your priorities are, because not every patient will make that statement, and we all view quality of life differently and have different values.

CAR-T tends to be, I described this to a patient just this week as CAR-T being, it's not a quick treatment. It doesn't require quite as much long-term follow-up as a donor transplant.

It is similar to an autologous transplant in the sense that you're getting your own cells back, so we don't have to worry about that risk of a reaction with someone else's immune system. I think the concern with CAR-T is getting through the immediate phase of toxicity.

The rate of CRS is anywhere from 70 to 80 percent in most CAR-T products, regardless of disease. So very high rates of seeing that fever. But it's very treatable and it typically resolves within a day or two.

The neurotoxicity is much less common. It happens in 15 to 30 percent in general across CAR-T products, but can be a longer complication to deal with.

Then like we talked about a little bit earlier with one of the other questions, infection and ongoing supportive care needs, we don't know how to predict very well who's going to have those needs when we start CAR-T.

So for as many stories as I can tell you about complications and people who've had to stay in the hospital, there are probably at least two or three times as many people who I've never seen again because they went back to their primary clinics and are going on their merry way without ongoing complications.

So, I think it does have the potential to improve quality of life. Probably similarly to transplant, we may see some initial decline during the early phases of therapy and then assuming there's recovery, but there is the potential that there are some ongoing side effects after CAR-T.

[57:18] Moderator: Awesome. Well, thank you so much, Dr. Wall.

On behalf of BMT InfoNet and our partners, I'd really like to thank you for this informative presentation, and thank you to the audience for all of your excellent questions, or if we couldn't get to all of them.