Transplant and CAR T-cell Therapy for Older Adults: Finding the Balance between Benefit and Risk

Transcript of Presentation:

(00:01): Susan Stewart: Introduction:  Welcome to the workshop Transplant and CAR-T cell Therapy for Older Adults: Finding the Balance Between Benefit and Risk. My name is Sue Stewart, and I will be your moderator for this workshop.

(00:14): Before we begin, I'd like to thank Bristol-Myers Squibb, whose support helped make this workshop possible.

(00:20): It's now my pleasure to introduce to you today's speaker, Dr. Amelia Langston. Dr. Langston is a professor and executive vice chair of hematology and medical oncology, and the medical director of the Bone Marrow Transplant and Stem Cell Transplant Center at Winship Cancer Institute at Emory University in Atlanta, Georgia. She's been a transplant physician and clinical investigator for over 20 years. Her research focuses on innovative strategies for both autologous (auto-) and allogeneic (allo-) stem cell transplantation, with a special interest in preventing and managing graft-versus-host disease. Please join me in welcoming Dr. Langston.

(01:06): Dr. Amelia Langston: Overview of Talk. Thank you so much, Susan. It's a pleasure to be here today with you to talk about a topic that I think is very important both to providers of transplant and cell therapy care, but also to patients and their families, and that is the issue of how do we approach the patient who is an older adult and could potentially benefit from either cell therapy or a transplant?

(01:33): Just today, in my inbox, in my emails, I received the published results of a survey that is particularly timely. It revolved around geriatric assessments in patients facing the possibility of transplant or cell therapy. It was a survey sent to transplant physicians around the country, and I think the bottom line was that transplant physicians have a lot of interest in geriatric assessment, but very limited knowledge and limited use of formal geriatric assessments in practice.

(02:09): But there was almost universal agreement that age is just a number, so it's really important that we think more deeply about how we approach our older patients.

(02:27): My objectives today are, to start with, why age matters when we're thinking about transplant and cell therapy. We'll cover some of the health issues and other factors that affect risk for the older adult. We'll talk about assessments and interventions we can use to reduce risks, and then we'll finish up with how older patients’ outcomes compare with those of our younger folks.

(03:01): A significant number of patients receiving autologous and allogeneic transplants are older than 65 years. Why is this an important topic? Let's think about the epidemiology of the diseases that we're treating with transplant and cell therapy. With the exception of Hodgkin's lymphoma and acute lymphoblastic leukemia, these are diseases that occur predominantly in patients in the later decades of life, mostly in patients above the age of 50, with a substantial proportion of patients above the age of 65, so it really is relevant given that epidemiology.

(03:40): These are registry data, from the Center for International Bone Marrow and Transplant Research, which demonstrate the increasing application of autologous transplantation to older patients. Currently, over a third of patients undergoing autologous transplants in the United States are 65 and above, and a significant fraction are in the 75-plus year range.

(04:14): This is the corresponding graph for patients undergoing allogeneic transplants and, as you can see, almost a third of patients getting allo transplants today are 65 and above. This is a group that we need to look at a little bit differently, but the reasons for this change are worth thinking about for a minute.

(04:42): There are multiple reasons why more older patients are now receiving transplants. What has changed? Certainly, we have better supportive care, better antibiotics, and in general better immune-suppressive medicines, than we did 10 or 20 years ago. We've also increased the use of reduced-intensity chemotherapy regimens for allogeneic transplantation. We've got new and evolving types of adoptive cell therapy, chimeric antigen receptor (CAR) T cell therapy, and beyond.

(05:14): Two points that are particularly important are: 1) advances in cardiovascular medicine, and 2) advances in the treatment of solid tumors. These sometimes lead to secondary malignancies that we treat as hematologic oncologists. In both cases, patients who would have succumbed to a different sort of disease earlier on are now living, whether it's atherosclerotic cardiac disease or whether it's a solid tumor. We're now more successful in taking care of them so they're living to get leukemia and lymphoma and other things that we then need to manage.

(06:02): Stem cell transplant and CAR T-cell therapy are the most powerful tools for blood cancers but also the most dangerous treatments. Let's start with facts. Fact number one, stem cell and transplant and adoptive cell therapy are generally our most powerful tools for most blood cancers and marrow immune failure syndromes. And for many diseases, transplant or CAR-T cell therapy offers the best and maybe the only potentially curative option.

(06:30): But fact number two is that transplant and cell therapy are stress tests, and they clearly are also the most dangerous treatments that we use for hematologic malignancies and marrow and immune failure syndromes. We've got infections and sepsis syndrome. We've got all the toxicities of chemotherapy and the medications that have to be taken as part of the transplant process. For CAR-T cell therapy, we've got cytokine release syndrome and neurotoxicity and I'm sure there are going to be a lot of questions about that. In the allogeneic transplant setting, we've got graft-versus-host disease (GVHD), which can lead to a whole other set of complications that we have to deal with.

(07:14): We've got the side effects of therapies we use to manage complications of CAR-T and transplant therapy, particularly steroids and other immune suppressive medications that lead to a whole host of other problems.

(07:31): We've got the effects of a prolonged hospital stay. When everything goes great, that's terrific. But when things don't go well and the patient has to stay in the hospital for a more prolonged period of time, that's harder on our older patients than on somebody who's 25 years old, and we have to deal with the physical debilitation that goes along with that.

(07:58): A patient’s resilience is crucial to assessing who is a good candidate for transplant or cell therapy. The name of the game here is resilience. The Oxford Dictionary defines resilience as the capacity to withstand or to recover quickly from difficulties. And it's this concept of resilience that I'm going to focus on for the rest of the time because it is what separates the patient that is a good candidate for transplant or cell therapy from one where it may not be such a great idea.

(08:33): There are other risk factors like comorbid illnesses to consider in assessing a patient’s fitness for transplant or cell therapy. When we talk about risk and resilience, there are a lot of different dimensions of risk to think about. At the top of the list are comorbid illnesses that the patient may have that may coexist with their blood cancer or their immune deficit.

(08:54): These risks factors also include frailty, nutrition, cognitive function, caregiver status and financial pressures. We've also got frailty, which we're going to spend time on in a minute. Frailty is important because when there are complications and there is a prolonged hospital stay, the frail patient tends to become more frail and that can lead to a whole host of other things.

(09:14): We've got the nutritional status of the patient which becomes very important. We know that during cell therapy and transplant, patients are going to go through a period of nutritional deficit, and so we want them to be in shape going into the transplant and try to maintain their nutrition throughout the process.

(09:37): Then we've got some things that might not be so obvious. There's cognitive impairment of the patient and it's very clear and it's been repeatedly demonstrated that patients who go into transplant with cognitive impairment have less favorable outcomes than those who go in with intact cognition.

(10:00): We've also got a hidden issue in that the older patient is more likely to have an older partner or spouse. Caregiver age and caregiver fitness becomes very important, particularly if there are physical complications of the process that lead to the person becoming physically debilitated for a period of time.

(10:25): Finally, we've got financial stressors that exist for all of our patients, but particularly for our older patients who might be living on a fixed income. We must think about what the financial burden of these procedures and of being away from home is really going to be.

(10:50): As we start thinking about any patients – but particularly older patients – as potential candidates for cell therapy, we make an assessment of their comorbidities, and that's a very formal process. I'll show you in a minute.

(11:07): There are a number of ways that we can look at frailty and fitness, and we also need to think about the medical side of things. Can we make a medical treatment plan that makes sense for that person and that has a reasonable likelihood of success, given the tools that we have and the disease status of the person? At the end of the day, can we justify what that individual's risk is going to be?

(11:48): We now have a well-validated comorbidity index that we utilize in transplant medicine. We've had it for many years and it breaks down different types of medical problems outside of the arena of blood cancer and immune deficiency. It is a points system that was derived from complex statistical analyses. You get points for each of the different things that you have and then we tally up those points at the end. As I'll show you, this is very highly predictive of outcome, particularly after allogeneic transplant therapy and CAR-T therapy.

(12:33): We also have the Karnofsky Performance Status (KPS) scale, another very old measure which looks at the fitness of the patient in very general everyday terms – from the person that has no limitations down to limitations that may interfere with treatment during the course of prolonged hospitalization. Both the comorbidity index and the performance status of the patient predict non-relapse mortality (i.e., mortality following allogeneic transplantation that is not due to relapse but is due to complications of the transplant process). Both of these measures are highly predictive of overall survival of the patients when we correct for disease status and other things.

(13:42): These are elements that we routinely use in an everyday assessment of every patient that we see, not just the older set. But older patients are more likely to have comorbid conditions and they're more likely to be in the middle of that performance status measure. Right there we have a difference in terms of the average risk based on age.

(14:19): What about measuring fitness and frailty beyond just the very crude Karnofsky score? There are a variety of different tools that geriatricians use to try to assess this.

(14:34): Patient fitness and frailty can be measured in several ways. We want to look at several dimensions. We want to look at mobility, and the three-minute walk test is a nice test because anybody can do it, it doesn't take a geriatric specialist. You measure based on how far the person can walk in three minutes. It gives you a score that gives you an idea of the fitness and mobility of the patient.

(15:02): I find the Instrumental Activities of Daily Living Assessment (IADL) to be a very useful measure that I can do right in the office the day that I meet the patient. It's not just about whether this person is living independently, but can this person handle using a cell phone, emailing, doing their own shopping, their own cooking, driving the car, managing bills? That gives you a lot of different dimensions of how the person functions both cognitively and physically.

(15:38): Cognitive and mental health assessments typically involve a geriatric assessment, which should be done by a true geriatrician. Most transplant centers exist within the context of a university health system, so there are geriatric specialists that are available. What's not always available is a close partnership with the geriatric team where your doctor can dial them up and say, "I've got another person that I need you to see."

(16:17): Most transplant centers will also have nutritionists on staff who are part of the evaluation process. For anybody that I think has any nutritional needs, I have my nutritionist to see the patient pre-transplant and make a plan for how we're going to weather the storm of nutritional deficits surrounding the transplant or cell therapy maneuver.

(16:48): There are a number of other things to think about. I've mentioned the age and fitness of the proposed caregiver. That clearly matters because, if the patient does become debilitated, is that caregiver really going to be able to pick up the patient off the floor if they fall? Is that person really going to be able to manage medicines and other kinds of things?

(17:13): Sometimes tolerance of the treatments that led up to the question of cell therapy can tell us something about resilience. The person that sailed through intensive chemotherapy for leukemia has a much better chance of doing well with the transplant or cell therapy than the person who struggled at every step of the way and spent extra time in the hospital.

(17:43): It's also important for patients and their families to understand what their own goals are and what their own expectations are of undergoing a transplant, because if your goal is to be alive a year from now, the answer may be different than if your goal and expectations are to be alive five years or 10 years from now.

(18:11): It's also important for patients and families to be empowered to ask realistic questions about expectations, of both short and long-term outcomes, based on that pre-transplant assessment that includes a lot of different dimensions of testing.

(18:35): There is strong evidence that fit, older patients receive significant benefits from transplant or cell therapy compared to less intensive treatments and they often do as well as younger patients. How do patients do with these therapies in the real world? This is an analysis from the Center for International Bone Marrow Transplant research looking at patients undergoing autologous transplants for multiple myeloma. Across a range of ages, overall survival after transplant is no different for the younger patient versus the older patient across the spectrum of ages that encompass most myeloma patients. That's not to say that we aren't careful about assessing those older patients, but the fit older patient could certainly do very well with autologous transplantation.

(19:27): These are data looking at allogeneic stem cell transplant versus chemotherapy alone in patients with Acute Myeloid Leukemia (AML) in first remission. While there's a little bit of an early drop-off in terms of survival in patients undergoing transplant due to the toxicities of the transplant itself, at the end of the day transplant is more effective therapy than chemotherapy alone in this patient population, and that translates into a better overall survival as you look across time beyond that one-year mark.

(20:24): This is a real-world look at CAR-T cell therapy for diffuse large B-cell lymphoma, looking at patients 65 and older versus those under 65. I won't try to convince you that the over 65 set does better, but they certainly do not do worse. These are carefully selected patients, both selected by us and self-selected, but older patients can do very well with these types of aggressive treatments.

(21:03): These are data on patients with Myelodysplastic Syndromes (MDS) looking at allogeneic transplantation versus chemotherapy management, i.e., conservative management, alone. Not only do patients that have a donor and undergo transplant do better, but they also reported better quality of life than the patients that did not have a transplant. This is a strong argument for taking a fit patient with high-grade MDS, intermediate or high grade MDS, to an allogeneic transplant if a donor can be identified.

(21:48): Providers can do several things to improve patient outcomes. What can we as providers do to improve outcomes? We want to optimize the management of known medical conditions before we ever start the process of transplant or cell therapy. We need targeted evaluations by specialists Including geriatrics, cardiology, infectious disease if the patient has that in their history, the nutritionist and so forth.  We want careful evaluation and assistance from a social worker, which is part of pre-transplant evaluation at almost every center – looking at support system, looking at transportation, at lodging and so forth. These are all important elements that need to be nailed down before we ever get into the transplant or cell therapy episode itself.

(22:44): We as providers have an obligation to disclose what the risks are. If on balance, after evaluating the patient and looking at the whole situation, I think a transplant or the cell therapy is a bad idea or a particularly risky idea, I'm going to tell folks that rather than putting them through the paces because they came to the office.

(23:21): Patients can also take preparatory steps to improve their outcomes from transplant or cell therapy. What can you do to improve outcomes? Maximizing your physical status before the start of intensive therapy is important, as is fighting not to lose ground during the treatment itself. Time is an important element because, particularly for acute leukemia and the like, there may not be much time to do ‘prehab’ as we call it, i.e., intensive physical therapy and occupational therapy before the treatment begins. If there is time, it's worthwhile.

(24:01): Keeping the activity going in the hospital and after discharge is important, and I'm a real taskmaster in that respect. When I'm working in the hospital, the first thing I say when I meet a patient that's come in for their transplant is, "I expect you to walk a mile a day while you're in here and I expect to see you up in a chair with clothes on during the day and we're going to go to bed at night and have daytime and nighttime straight throughout your time here."

(24:34): A strong support team is also important to improving outcomes. What are some of the other things that you can do to improve outcomes? Optimizing your support team of caregivers is important. For patients who have an older spouse or caregiver, engaging multiple family members and friends is helpful, preferably having at least some parts of your caregiver team be young enough that they can pick you up off the floor if need be.

(25:03): It's helpful if you can designate somebody on the team to be the organizer and information keeper. There's a lot of information. There can be changes every time you come into the clinic and having somebody that just keeps track of the medicines and other things can be very helpful as you go through this process day to day and week to week.  

(25:33) Expect that there may be setbacks and changes to the plans. You have to be adaptable because there is no straight line from point A to point B. There always are going to be little forks in the road.

(25:50): Age is just a number. It's the comorbid conditions, the functional status, mobility and support that inform the risk benefit equation.

(26:06):  In my mind, it's not a question of who should get a transplant or cell therapy, but who shouldn't. When we find a patient who shouldn't, we need to be very transparent about that and participate in shared decision making.

(26:26): The critical assessment and decision making has to occur just prior to the proposed treatment. Lots of people come into the office for a consultation and we never get to the point of doing a procedure, but I'm happy to see patients and assess them. I may not necessarily make a judgment about whether or not they're a candidate for cell therapy or transplant at the time of that first meeting, but at the time of that last meeting, I've got to be convinced that there's a reasonable chance that this can go well.

Question and Answer

Susan Stewart: (27:15): Thank you, Dr. Langston, that was an excellent presentation, very comprehensive. And we do have some questions lined up. "I live close to my hospital, is it okay to do CAR-T cell therapy as an outpatient?"

(27:44): Dr. Amelia Langston: That's a great question. Different centers handle this differently, but I think if you live within 20 or 30 minutes of the transplant center and if your transplant center has the infrastructure to manage CAR-T cell patients as an outpatient, then it's perfectly safe. That's been demonstrated time and time again. When I say infrastructure to do that, I mean there needs to be a place other than the main hospital emergency room where you could go, or there needs to be a direct way to contact the treatment team day or night, because the complications of CAR-T cell therapy are an emergency and patients need to be assessed in real time, not take two aspirin and call in the morning sort of thing.

(28:43): Susan Stewart: "I'm 74 years old. I was diagnosed with Angioimmunoblastic T-cell lymphoma (AITL), which is a type of lymphoma. I did an autologous stem cell transplant in 2024, then relapsed in five months, did a clinical trial with CAR-T cells for lymphoma, and did a T cell transplant in 1/25. It's been suggested that I do an allogeneic transplant while in remission. My major problem is that Medicare says it's not a covered diagnosis. Have you seen Medicare cover allo transplant for lymphoma? I have no other comorbid diseases."

(29:25): Dr. Amelia Langston: Yes, there was a determination a while ago that Medicare can cover allogeneic transplants for lymphoma. There are certain hoops we have to jump through in terms of making sure that patients are registered, but yes, Medicare has made a determination to cover that.

(29:51): Susan Stewart: "Is there a difference in outcome between people who have been fit for many years versus someone who just became fit before going into transplant or CAR-T?"

(30:05): Dr. Amelia Langston: That's a great question and I don't think I have an evidence-based answer for that. But I think that the fitness of the patient at the time that they're coming to CAR-T or transplant therapy is probably the most critical element. And I've certainly seen patients go both ways where they got fit later in life and did very well. I've seen patients that were fit all of their lives that had a really rough time. I don't know whether that's been critically studied.

(30:48): Susan Stewart: "Does baseline neurocognitive deficit impact the risk of Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS) late neurotoxicity after CAR-T cell therapy?"

(31:01): Dr. Amelia Langston: That's a great question and I'll tell you what we know. We know that it is harder to assess ICANS in someone who has baseline neurocognitive deficits. Because the way that we assess things is by doing repeated testing. It's hard, if a person at baseline has some degree of dementia, to assess how much is hospital delirium, how much is the baseline dementia and how much is ICANS. We also know that older patients, whether they have neurocognitive deficits or not, have a little bit of a higher risk of ICANS than younger patients. And we know that people who have a higher disease burden have a higher risk of both CRS and ICANS.

(32:03): Susan Stewart: "Do you find immune reconstitution is slower or less likely to fully recover after CAR-T cell therapy in older patients?"

(32:15): Dr. Amelia Langston: That depends a little bit on what we mean by immune reconstitution. For most CAR-T cell products that we use commercially, one of the major issues that we see is that we essentially ablate the B cell compartment of the immune system and that deficit may or may not ever come back. That's not so much an age-related thing as it is associated with different incidents in different products.

(32:55): But other aspects of immune reconstitution and count recovery are different and more unpredictable. The bone marrow function and immune function of a person in their 60s or 70s is different and is less robust than a person in the younger decades of life, so we would expect that immune reconstitution in those dimensions might be a little bit less robust and less rapid.

(33:34): Susan Stewart: “How old is the oldest patient you've treated with CAR-T?

(33:45): Dr. Amelia Langston: Probably 81 or 82.

(33:48): Susan Stewart: “Does left temporal lobe seizure disorder that's under control with meds pose a danger for CAR-T cell therapy?”

(34:01): Dr. Amelia Langston: Seizures are a known complication of ICANS. Everybody who gets CAR-T therapy gets anti-epileptic medicines. It may not be an absolute contraindication, but I would be a little leery of that and I would be working closely with a neurologist to optimize the management of anti-epileptics if such a person were going to go to CAR-T.

(34:46): We do CAR-T on occasion in patients with primary central nervous system (CNS) lymphomas or in patients with lymphomas who have had CNS involvement in the past. And by and large the risks associated with that, while they may be slightly more likely to get ICANS, generally the outcomes have not been different than people that had other forms of lymphoma. I think you'd want your neurologist to be really plugged into the situation and to give the thumbs up.

(35:35): Susan Stewart: “Could give some examples of the kinds of cognitive problems that you see after CAR-T cell therapy and how long it takes for them to resolve if they do?”

(35:50): Dr. Amelia Langston: The cognitive problems associated with ICANS range from a little bit of difficulty with word finding, all the way to deep coma and kind of everything in between. We can see seizures, we can see times when patients, while not unresponsive, may not be verbally responsive. One of the hard things is telling the difference between some of the more subtle neurotoxicities that are associated with the CAR-T cell product versus the kind of delirium that occurs most often in older people just because they're in the hospital.

(36:43): This usually happens at night, and the doctor slang for it is ‘sundowning’. It's very, very common in older patients that have to be in the hospital for any length of time. But that's not necessarily neurotoxicity caused by CAR-T.

(37:18) They asked how long it takes for neurotoxicity to evolve and that is highly variable. There are people who have get one dose of steroids and the neurotoxicity resolves, and there are other people who can have ongoing neurologic deficits for periods of a month or more. There are some patients that occasionally do not return to their pre-CAR-T baseline in terms of cognitive and neurologic function. It is a serious problem.

(37:54): Susan Stewart: “Is it possible to get CAR-T cell therapy if you relapse after an allogeneic stem cell transplant for chronic lymphocytic leukemia (CLL) and have chronic graft-versus-host disease GVHD?”

(38:12): Dr. Amelia Langston: CAR-T cell therapy in principle can be given after an allogeneic transplant. Most of the experience that exists has been in the context of either acute lymphocytic leukemia or diffuse large B-cell lymphoma. It is generally less effective in the post-allergenic transplant setting for a patient with chronic graft-versus-host disease who is at presumably actively on significant immune-suppressive medicines. It's probably ill-advised because you're probably not going to get a very healthy T cell product in terms of the manufacturing. The CAR-T process itself and the cytokine storm that it creates may stir graft-versus-host disease on even more. In principle, it can be done. It's a question of how effective it's likely to be and what the outcomes are going to be.

(39:39): Susan Stewart: “What is the average remission time after CAR-T cell therapy for multiple myeloma is for someone in their late 60s?”

(39:54): Dr. Amelia Langston: That depends on a lot of things. As with many new therapies, the first patients with myeloma that were treated with CAR-T cell therapy had very advanced disease. They might've been through 9 or 10 or more lines of therapy before CAR-T was given. As you might imagine for that group of patients, while CAR-T could create remissions in the majority, it's also the case that the vast majority of those patients eventually relapse and typically relapse within a year or so.

(40:39): We've moved CAR-T cell therapy in myeloma to much earlier in the course of the disease. What that means is that, in essence, we're treating a different disease. We're also taking the T cells at a time when they're not so beaten up, so the T cells that we're using for the manufacturing process are more resilient. The outcomes are much more hopeful today. This is something that's under active study, but the hope is that, if we move CAR-T cell therapy into second and third line treatment, there will be the possibility of long-term cure.

(41:28):  Susan Stewart: “Do you need to take all the vaccines all over again after CAR-T cell therapy like baby vaccines, pneumonia, shingles if you had them before CAR-T?”

(41:43): Dr. Amelia Langston: Typically we will re-vaccinate people after both transplant and CAR-T cell therapy. I think what is still a question mark is particularly for B cell and plasma cell directed CAR-T cell therapy is when should we do that? When we do a transplant, the antibody-producing cells come back reasonably quickly, so we usually start post-transplant immunizations, or the baby shots, at about six to nine months after the transplant. And for some vaccines, like COVID, we actually do it even earlier. We recommend that to people and have good data that COVID vaccine is effective a hundred days after a transplant.

(42:39): We have a lot less data about CAR-T and what the optimal timing is. Generally, we'll do it at about the one-year mark. If there's a question, we may check titers to see if the person has mounted an immune response. We get very nervous if someone has continued B cell aplasia, meaning that they don't have not recovered their B cells. We generally take a dim view of them getting any kind of a live vaccine like measles, mumps, and rubella (MMR). And this is obviously a very timely topic right now with everybody coming in asking if they should go and get MMR. We generally do not want patients to get a live vaccine like that until and unless they have very good immune recovery because of the danger that they get sick from the vaccine. The worst danger if you get the flu vaccine or a pneumococcal vaccine or something is that it just doesn't work, but it's not going to make you sick.

(43:56): Susan Stewart: “What's involved in being a family caregiver for a CAR-T patient.” Could you describe in a little more detail what someone would be expected to do? Will they need to take off work? Do they truly need to be there 24/7? And what are they doing when they're there 24/7?

(44:19): Dr. Amelia Langston: I will go back to the question that was asked earlier about outpatient CAR-T. The responsibilities of the caregiver depend in part on whether the CAR-T process is happening entirely in the outpatient setting or whether there's a hospital stay. I will just describe what the caregiver has to do for the period of time that patient is an outpatient. Yes, you do need to be with the person 24/7.

(44:54): Patients who have had CAR-T are not able to drive for at least a month after they get the CAR-T, regardless of whether they are having neurologic problems or not. We ask caregivers to be available and present 24/7 because these complications can occur at any time of the day or night. We ask that the caregiver be the organizer of the medicines, particularly during the early phase, because of the possibility that the patient might get mixed up and might not be taking the right medicines throughout things.

(45:43): Simple things that you're doing to care for that person, maybe helping with meals and, again, being a witness at clinic visits, which if you're going to do during the outpatient phase, you're going to be coming in frequently for assessment. That caregiver has to be astute enough to recognize something is wrong. You have to be able to take somebody's temperature, you've got to be able to make your own kind of assessment of, "Is this person off mentally? Do I need to call somebody about that?"

(46:26): Susan Stewart: “Are there any restrictions on the kind of food people can eat after CAR-T cell therapy, similar to some of the restrictions that are imposed after an allogeneic transplant?”

(46:42): Dr. Amelia Langston: Most centers today follow what we would call a food safety diet, meaning that you're not eating things that would be of obvious danger, like raw meats, raw fish, unpasteurized dairy, moldy cheeses, things like that. But you can eat vegetables, you could eat raw vegetables and salads as long as they're clean. We ask patients during the time that they're neutropenic maybe not to go to the salad bar because you haven't witnessed how that material was handled. But in terms of saying, "You can't eat this food or that food," other than unpasteurized dairy and raw meats and things, we don't really have big restrictions.

(47:41): Susan Stewart: "What is the incidence of ICANS in the older myeloma patient receiving CAR-T?"

(47:54): Dr. Amelia Langston: That's a hard question because we have several different myeloma products and they have different properties, and we prescribe them in different patient populations. But in general, if we include any degree of ICANS, we are probably talking about something between a 15 and a 30% risk of significant ICANS that we need to intervene with.

(48:22): Susan Stewart: "Regardless of age, if a person has an autoimmune disorder such as lupus, are they still able to undergo CAR-T cell treatment?"

(48:38): Dr. Amelia Langston: Autoimmune disorders come in a number of different varieties and severities. I think that if a patient has an autoimmune disorder that requires ongoing immune suppression, we would probably be very nervous about doing CAR-T. If on the other hand it's a patient that has had something in the past and it's been controlled and has immunologically ‘burned out’, then it may be a different circumstance. That's a situation where we would consult with the person's rheumatologist and make a plan together using shared decision making.

(49:28): Susan Stewart: “How do you get a geriatric assessment?” She's never heard of this at her cancer center.

(49:45): Dr. Amelia Langston: Generally a geriatric assessment is something that can be done within the context of the pre-transplant evaluation by referral by the transplant physician. If you want a geriatric assessment for some other reason or as part of your own process of thinking about whether or not this type of therapy might be for you, then your primary care doctor can refer you to a geriatrician. More detailed kinds of assessments and cognitive assessments are best done by a true geriatric specialist.

(50:30): Susan Stewart: “What percentage of people who undergo CAR-T actually develop neurotoxicity?”

(50:43): Dr. Amelia Langston: It is very dependent upon the product that is given, the indication, and the disease burden going into CAR-T. In some circumstances with some products, for some patients the risk may be 50%. For other patients that go in with well-controlled disease with some of the less neurotoxic product, the risk may be 10% or so. But there's always a risk. Every single product carries that risk.

(51:27): Susan Stewart: We had a question about CAR-T after an allogeneic transplant. What about the reverse? If you go to CAR-T cell therapy and you relapse, can you then get an allogeneic transplant if you didn't have one before?

(51:43): Dr. Amelia Langston: This is a question that we come up against very frequently in particular with acute lymphocytic leukemia. We oftentimes ask the question, particularly in adults, is CAR-T likely to be curative for that disease by itself? And we will sometimes actually do a preemptive allogeneic transplant so we get the patient in remission with the CAR-T and then go on to an allogeneic transplant.

(52:16): In the area of lymphoma, we certainly consider patients who have failed CAR-T as potential candidates for allogeneic transplant. I saw a man yesterday that was in that exact circumstance who had gotten back into remission using something after the CAR-T and looked like a great candidate for an allogeneic transplant. For multiple myeloma, not so much, because in general allogeneic transplantation for myeloma does not have a major role.

(52:54): Susan Stewart: “Speaking of remission, how many people do relapse after multiple myeloma CAR-T cell therapy or CAR-T cell therapy for lymphoma?”

(53:08): Dr. Amelia Langston: That's a bit of a hard question to answer. I'll start with lymphoma because that's a little bit easier. The most common indication for CAR-T cell therapy in the lymphoma arena is diffuse large B-cell lymphoma. That was the first type of lymphoma for which CAR-T was approved. About 30 to 40% of patients will achieve a complete remission with CAR-T cell therapy and about 75% of those patients that achieve a complete remission will be cured.

(54:01): That is not the case for some of the low-grade lymphomas like follicular lymphoma and chronic lymphocytic leukemia. The response rates are lower, and the relapse rates are higher. That is reason to question whether or not CAR-T is likely to be curative for many of those patients. Clearly there are some that are cured, but it may not be the majority of patients that respond by being cured. With myeloma, the majority of patients that have had nine or 10 prior therapies who get CAR-T will eventually relapse.

(54:54): For patients who get CAR-T earlier on in the course of the disease, we're still learning about how durable those responses are going to be. Clearly they are more durable than when the patient is transplanted later on in the course when their T cells are a lot more beaten up and maybe not as effective as killers as they would've been earlier on.

(55:23): Susan Stewart: “Is there an advantage to having CAR-T using your own re-manufactured cells versus CAR-NK using donor re-manufactured NK cells?”

(55:41): Dr. Amelia Langston: This brings up a whole area that I think people are very excited about in principle, and that is the idea of an off-the-shelf CAR-T product. I think all of us in the field feel that the idea of having to make a personalized autologous CAR-T product is not going to be a sustainable model going forward when we start to treat more patients, and when we start to treat patients with common diseases. Blood cancers are not that common, but breast cancer and colon cancer and pancreatic cancer are. I think we all believe the future is in off-the-shelf products, and NK cell products certainly are one candidate in that respect.

(56:43): We're not there yet, and chimeric antibody receptor NK cells are not ready for prime time yet. They are still in the investigational stage, and I think we haven't yet figured out how to create a situation where those cells persist for long enough to be fully effective and certainly to be curative for the diseases that we treat. I'm not going to say that it's better or worse, but it's where we are. We hope that's where we will go in the future, toward allogeneic products, whether it's NK cells or gamma delta T cells or T cells that have been manipulated to get rid of their own identities. But right now, we don't have that for commercial use.

(57:42): Susan Stewart: "I'm 78 years old. I've been having Vidaza injections and taking Venclexta pills for two years. Can I still have a stem cell transplant?"

(57:56): Dr. Amelia Langston: I assume that this person probably has acute myeloid leukemia (AML) given the medicines that are ongoing, and whether or not that person can have a transplant really is going to depend on all the things we talked about today in terms of fitness, but also upon whether or not the disease is in remission. There's no reason why just having been on those medicines would preclude being able to do a transplant.

(58:32): Susan Stewart: "How do anxiety and depression that are in remission with medication impact CAR-T cell therapy?"

(58:43): Dr. Amelia Langston: Anxiety and depression are incredibly common and a natural reaction to someone having a malignant diagnosis. As long as the anxiety and depression are well controlled and actively managed going forward, and the person is supported as need be, it really should not be a barrier to any of the therapies we've talked about today.

(59:18): Susan Stewart: Closing. On behalf of BMT InfoNet and our partners, I'd like to thank Dr. Langston for a very informative presentation. And I'd also like to thank the audience for the excellent questions that you submitted. Please let BMT InfoNet know if we can be of help in any way.