Transplant and CAR T-cell Therapy in Older Adults

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Transplant and CAR T-cell Therapy in Older Adults

Sunday, April 30, 2023

Presenter: Richard Lin MD, PhD, Memorial Sloan Kettering Cancer Center

Presentation is 35 minutes long with 22 minutes of Q & A.

Support provided in part by Kite, a Gilead company

Summary:  The age of patients undergoing a stem cell transplant or CAR T-cell therapy is increasing, but older patients are often not as fit as younger adults. Transplant and CAR T-cell therapies can be modified to increase the likelihood of success for old adults.

Highlights:

• Transplant and CAR T-cell therapy recipients over age 65 tend to have more comorbidities, functional impairments, and medications than younger patients.
• Older patients also vary in their resilience or their ability to recover from medical challenges. A geriatric assessment is a holistic tool that measures a patient’s fitness for transplant or CAR T-cell therapy. Functional status is measured by whether people can manage several activities of daily living. 
• Patients with impaired functional status may still be optimized for transplant or CAR T-cell therapy with exercise or cognitive rehab programs. There is evidence that such optimization programs can maximize survival chances for older patients undergoing these treatments.

Key Points:

(03:17): The majority of blood cancer patients who are considered for allogeneic transplant (using donor cells) are older patients.

(10:24): The first year after transplant is especially risky for older patients.

(11:51): For older patients going to transplant or CAR T-cell therapy, their treatment should be optimized so they can survive the first and most dangerous year after treatment.

(13:49): Older patients (over 65) have a survival rate similar to younger patients with CAR T-cell therapy.

(15:41): In geriatric care, older patients can be classified as fit/robust, average/vulnerable, or frail/sick.

(24:51): For patients with deficits in daily activities of living, their overall survival and progression-free survival after transplant or CAR T-cell therapy is significantly reduced.

(29:28): Despite its importance in improving patient outcomes, geriatric assessment is underutilized across the country. 

(30:09): A full recovery from transplant or CAR T- cell therapy is possible for older patients although quality-of-life improvement can take up to a year.

(32:36): Early referral and assessment is critical for older patients to be evaluated for their fitness to withstand transplant or CAR T-cell therapy.

(33:32): Average but vulnerable older patients can benefit the most from geriatric assessment and targeted interventions to increase their resilience before proceeding to transplant or CAE T-cell therapy.

Transcript of Presentation

(00:01): [Michelle Kosik]: Introduction. Welcome to the workshop, Transplant and CAR T-Cell Therapy in Older Adults. My name is [Michelle Kosik]: and I will be your moderator for this workshop.

(00:11):  I'd like to thank Kite, a Gilead company, whose support helped make this workshop possible.

(00:16): Introduction of Speaker. It is now my pleasure to introduce today's speaker, Dr. Richard Lin. Dr. Lin is a hematologist/oncologist at Memorial Sloan Kettering Cancer Center. His areas of expertise include transplantation and cellular therapy, leukemia, lymphoma, and geriatric oncology. He strives to deliver the best possible care to older patients with hematologic malignancies through both standard care and clinical trial options in transplantation and CAR T-cell therapy. Please join me in welcoming, Dr. Lin.

 (00:55): [Dr. Richard Lin]: Overview of Talk.  Hello, everyone. I want to first thank the organizer for giving me the opportunity to discuss with you transplant and CAR T-cell therapy for older adults. My goal today is to demystify a little bit about age and what we can do to help an older patient going through the transplant or cellular therapy. I'm a consultant for Kite, but I will not discuss a specific product from Kite. I also serve on the Independent Adjudication Committee for Priothera.

(01:37): Today, we'll start by discussing the age limit for transplant/cellular therapy; and what is the age, as a number, versus biological age that's measured by clinical tools. We'll specifically discuss health issues and comorbidities that may preclude older adults from transplant and cellular therapy. We'll specifically discuss outcomes of transplant and CAR T-therapy for older patients compared to non-intensive therapies, as well as comparison to younger patients. Lastly, we'll focus on strategies some transplant and CAR T-cell programs are using to attend to the need of older adults, which I think is going to be especially important because it's going to be used both prior to as well as following the treatment.

(02:34): Here's the presentation overview. We'll first describe the demographic of older patients with blood cancers. We'll describe older patient outcomes, we'll specifically discuss several principles, geriatrics principles of care, and then we'll focus on this very essential tool called the geriatric assessment and how it is used in transplant and cellular therapy for older patients. More importantly, how we use geriatric assessment to guide management of optimization for older patients. I'll conclude by briefly mentioning the various challenges facing us.

(03:17): The majority of blood cancer patients who are considered for allogeneic transplant (using donor cells) are older patients. So in this table, I list all major blood cancers, their median age of onset, and the role of transplant and sometimes cellular therapy. As you can see from here for AML, CLL and myelodysplastic syndromes, those are the diseases where allogeneic transplant is the only curative therapy. However, as you can see from here, the median age of onset of those diseases is all in late sixties and early seventies. So the majority of the patients considered for allogeneic transplant are actually older patients.

(03:56): Similar findings are applicable to non-Hodgkin's lymphoma and multiple myeloma, which have a medium age of onset of late sixties and early seventies. In the case of non-Hodgkin's lymphoma, autologous transplant traditionally has been considered curative therapy for relapsed Hodgkin's lymphoma. Now with the advent of CAR T-cell therapy, it's becoming the standard care for patients with relapse or refractory, now Hodgkin's lymphoma, and it provides definitely curative potential for many patients.

(04:32): Up to  a third of all stem cell transplant recipients in the United States are over age 65. So consistent with this demographic. Let's look at the recipients of transplantation in the United States divided by age groups. So on this slide, you can look at the composition of autologous transplant recipients divided by age. As you can see here, by 2019, more than one-third of patients are over the age of 65 years old.

(05:05): Similar findings are also seen in the recipients of allogeneic transplantation in United States. On this slide by year 2019, over a quarter of allogeneic transplant recipients are over the age of 65. This number is even increasing during the COVID pandemic. And I have the most recent number, which is now showing this slide in the year 2022. Close to 30% of the allogeneic transplant recipients are over the age of 65.

(05:47): In this slide, we divide age by decades, so it's a slightly different presentation. As you can see in the year 2019, over 10% of allogeneic recipients are over the age of 70 years old. I can say that the highest age limit for allogeneic transplant recipients in the United States about age of 81 years old. In our center is about the age of 80.

(06:15): Older transplant recipients tend to have more challenges and comorbidities. So with the increasing recipient age among transplant recipients, we're invariably facing a lot of challenges to care for those patients. So in this illustration and the list, I want to highlight important considerations for an older cancer patient. On the left-hand side you can see that many older cancer patients have comorbidities, meaning they have medical problems such as heart disease, diabetes, COPD, renal disease. Those are the comorbidities that may affect their outcomes for transplantation or their eligibility to be even considered for transplant cellular therapy, which is a high-risk, high-intensity treatment modality.

(07:07): Older transplant recipients may also have functional impairments and potentially inappropriate medications. Many other patients also have functional impairments which will explain that bit later. They could have difficulty walking, they may use an assistive device, they may also have cognitive impairments or have early signs of Alzheimer's disease. They will have impaired nutritional status and sarcopenia, which is a loss of muscle mass. Many older patients also take many medications. They could use what we call potentially inappropriate medications, which are a group of medications that are high-risk in older patients. Some of them are benzodiazepine and opioid pain medication. So all of those things could contribute to what we call the frailty phenotype for older cancer patient. We'll explain a little bit later about what frailty phenotype actually means.

(08:03): Older transplant recipients may also have higher risk of disease, lower response rates, and may develop geriatric syndrome. On the right-hand side, we also highlight the difficulties of older patients receiving cancer treatment. Many of them have a barrier to access high-intensity treatment such as CAR T or transplant. Many of those patients also have a much higher risk of disease than younger patients, thus their response rates may be lower. Many older patients have increased susceptibility to regimen-related side effects and many of them could develop what we call the geriatric syndrome, which are falls, sun-downing, incontinence following the treatment.

(08:42): Moreover, older patients often have older caregivers. They often have suboptimal social support. Now all of them contribute to the difficulty and the challenges facing an older cancer patient, especially when it comes to high-intensity, high-risk procedures such as transplant or CAR T-cell therapy. We're going to go back to this slide a little bit later.

(09:09): A study comparing transplant to no transplant in older patients with acute myeloid leukemia (AML) found that those who had a transplant had a better 5-year survival. So here what I want to highlight is a unique aspect of transplant and cellular therapy in older patients. So this is a study looking at a group of older patients with AML from the age of 60 to 75 years old. A group of them went on to receive transplant, that's in the top red line, and another group of patients who did not receive transplant but continued on their chemotherapy. As you can see here, over the time course of five years, this older group of patients who received the transplant did better, in terms of five-year survival, than the patients who did not receive transplant.

(09:52): However, what I want you to focus on is this area of the curve I circled. This is in the first year after their randomization either to transplant or the chemotherapy. What is surprising here is that the curve actually is in favor of the patient who did not receive transplant, who continued on the chemotherapy. They seem to survive even better than the patient who went on to receive the transplant. So why is it?

(10:24): The first year after transplant is especially risky for older patients. So this is where we're going to discuss during this talk. In the first year after transplant, for the older patient, this is an especially vulnerable period where a lot of patients could die. A lot of older patients die in the first-year post-transplant because of the complication from transplant or because the vulnerability of their health were not addressed adequately before the transplant. That's why they suffered the complications.

(10:57): Given the vulnerability of older patients going to transplant or CAR T-cell therapy, this treatment should be carefully considered by clinicians and patients. So this highlighted the importance for clinicians and patients to form a partnership to identify the vulnerability and the difficulties of older patients prior to transplant, so that they can appropriately decide whether they should go to transplant or CAR T-cell therapy at all. And the second was this partnership between the physicians and the patients to decide what will be the optimal strategies to optimize the patient, both prior to the treatment as well as in the first year following the treatment, so that the patient does not suffer these complications and can reap the rewards of survival benefit in the later years. So this is the important concept we'll circle back to later.

(11:51): For older patients going to transplant or CAR T-cell therapy, their treatment should be optimized so they can survive the first and most dangerous year after treatment. In the next slide, this is a different group of patients. This is a group of older patients in a similar group, but with myelodysplastic syndrome [instead of AML]. This is a similar type of study, but this time there are two studies. Again, I'm highlighting that over time, the transplant groups did better than the chemotherapy-only groups. However, again I circled these two areas of the first nine to 12 months after transplant where the chemotherapy patient actually did as well as the transplant patient. Even some of them may be better. So those findings are consistent with the studies from AML patients, highlighting the importance of identifying the group of older patients who are vulnerable, who may be susceptible to complications and deaths in this first year post-transplant, so that we can either not offer them transplant or try to find ways to optimize them prior to and following the transplant so that they can survive the first year.

(13:12): This is a simple study just looking at a group of older patients over the age of 65 with MDS who receive the transplant compared to a group of younger patients about age 55 to 64. As you can see here, their survival is largely similar. Toward the end of the follow-up over four years, there may be some slight difference in favor of younger group of patients. But the message from this slide is that older patients can do as well as younger patients following allogeneic transplant or MDS.

(13:49): Older patients (over 65) have a survival rate similar to younger patients with CAR T-cell therapy. What about CAR T-cells? So these are two studies that, again, compare a group of patients who are over the age of 65 to a group of patients under age of 65. As you can see here, these two graphs are survival and you can see that there's not much survival difference between the younger group of patients versus the older group of patients. On the left-hand side, this is the original prospective study, on right-hand side, this is our single institutional study of patients treated at our institution.

(14:34): Now, we discussed that they are a group of vulnerable patients who may have complications from transplant and cellular therapy. On the other hand, older patients can derive as much benefit, if not more, in terms of survival, compared to younger patients as shown in the slides before.

(14:57): So I'm coming back to this slide. How can we identify those difficulties or challenges among older patients so that we can learn how to optimize them, how to take care of them after treatment, and so that we can maximize their long-term survival?

(15:18): Before we discuss the clinical tools, I want to introduce, briefly, a few basic concepts in geriatrics. So geriatrics is a specialty that specifically cares for older patients. You can think about as a primary care physician for older patients.

(15:41): In geriatric care, older patients can be classified as fit/robust, average/vulnerable, or frail/sick. So on this slide, I'm describing the life expectancy of the US population. This is the data of the life table from the United States census of 2017. What I want to highlight is that for each age among each age group of older adults - I'll use the example of an older woman aged 70 - there are actually three groups of older adults within this age of 70. One group of older adults is what we consider fit/robust. You can think about those marathoners, those people who have almost no medical problems, take no medications and this comprises 25% of the population. Their lack dependency is over 22 years, even at the age of 70. So this is a group what we call the fit/robust.

(16:49): And then, on the other hand, there's another 25% of patients whom we consider frail or sick. So this is a group of older adults who have lot of medical problems, who have been very sedentary and are not eating very healthy. This group of older adults will have a much lower life expectancy compared to the fit/robust group.

(17:19): Then you have the middle group whom we call average or vulnerable. They may have some minor medical problems and they may not exercise every day, but they generally live a reasonable quality of life. So this is actually the majority of the older patient population.

(17:38): So the reason I'm highlighting these three groups is that I want you to think about, within a single age number, that there are these three groups of older adults. And we want to identify in which group the patient belongs, and whether there are ways we can remedy the patient's deficits. So this is the concept of life expectancy and the vulnerability among same age group of older adults.

(18:15): Older patients also tend to have atypical disease presentations and more complex challenges than younger patients. So the second concept is that we tend to think about diseases in an older patient as somewhat different than in younger patients. They tend to have many different causes. They have atypical disease presentations. Older patients tend to value quality of life and functional independence over quantity of life. There's a high prevalence of cognitive impairment or memory problems and other geriatric syndromes we discussed, things like sun-downing, incontinence, frequent falls, those are the things that are not common in younger patients. And lastly, older patients tend to have complex medication management problems. We tend to start low and go slow. We actively de-prescribe medication.

(19:16): Older patients also vary in their frailty and resilience or their ability to recover from medical challenges. So the last geriatric principle I want to discuss is what we call frailty and the resilience. This is how we think about how an older person would do when they are considered for high-intensity treatments such as transplant and cellular therapy. So I want you to focus only on the last row here. The first two rows are more clinically oriented measures we're not going to discuss, but I want you to think about this concept of resilience, which is a measure of your homeostasis in the face of stressors. You can think of it as a Golden Gate Bridge. So when a Golden Gate Bridge is encountering stressors such as wind, traffic and water ,if they're resilient and sturdy, they will come out with the same strengths, and if they're not, if they're frail, the bridge can break down.

(20:15): So when it comes to individual patient like you, you can think about your past response to things such as infection, such as COVID infection, or your response to chemotherapy, induction chemotherapy for your leukemia or MDS, or recovery from surgery. If you recover from them relatively quickly, we will say that you are considered resilient. In contrast, some patient after they have surgeries or chemotherapy, they have prolonged hospitalization. They often need to go to a rehab facility to gain strength. Or someone can tell you, "I never felt that I was able to get back to my normal state." So those are the patients we will consider frail. This is an easy concept for you to think about when you consider yourself for a high-intensity treatment such as transplant or cellular therapy.

(21:21): A geriatric assessment is a holistic tool that measures a patient’s fitness for transplant or CAR T-cell therapy. Okay. So now we have discussed what geriatricians think about an older person. What can a transplant physician or CAR T-cell physician do to assess an older patient? So this is where the geriatric assessment, the tool we use, a holistic approach, to analyze or examine other person's functional status, their memory cognition, their polypharmacy, mental health, nutrition, social support, and comorbidities, in order to gain a comprehensive review of a person's candidacy and to identify their vulnerability so that we can know what to target to improve and optimize an older person.

(22:10): Functional status is measured by whether people can manage basic activities of daily living.  I just briefly want to mention what it means to be functional status of ADL and IADL. ADL stands for Activities of Daily Living. So there are six basic activities of daily living: bathing, dressing, toileting, transferring, continence and feeding. If you can do all six of them on your own, you are called functionally independent.

(22:34): This next level of function, it's called Instrumental Activities of Daily Living. That includes using the telephone, shopping, food preparation, housekeeping, laundry, transportations managing medication, and handling money. When a person is deficient in any of the ADLs, we usually see them as frail and a high-risk candidate for transplant and cell therapy.

(23:02): When a person has a deficit in one of the IADLs, where you really think they need to be optimized, they still are considered high risk but they potentially could be optimized and considered for transplant and CAR T-cell therapy.

(23:19): Another way we do it in the clinic is to use a simple task called Timed Up and Go. We'll have the older person sit in a chair, put their hands on their legs to help them to get up from the chair by themselves, walk three meters and walk back and then sit down. We call them fit if they take less than 10 seconds, vulnerable if they take 10 to 20 seconds, or more than 20 seconds, we call them frail.

(23:48): And likewise, we can also examine an older person's cognitive performance in a very easy way. It can be done in the clinic in three minutes. The name of the test is called the MiniCog. We ask patients to recall three words and draw a clock and if you cannot recall any words after five minutes or draw an abnormal clock, then we set you up for more in-depth screening for cognitive impairment.

(24:21): So why do we do those tests? How are they relevant to transplant or cellular therapy? So in this table, I summarize the association of those impairments with allogeneic donor transplant outcomes. I'm only going to highlight those two deficits: high comorbidities, meaning you have a lot of medical problems; or functional deficit - a deficit in the ADLs and IADLs.

(24:51): For patients with deficits in daily activities of living, their overall survival and progression-free survival after transplant or CAR T-cell therapy is significantly reduced. As you can see here, if you have deficit in ADLs, IADLs, your overall survival and progression-free survival after transplant is significantly reduced. There's increased toxicity and increased non-relapse mortality, which is death without relapse. Similar findings are applicable to high comorbidities. So those geriatric deficits we identified actually are important for transplant outcomes.

(25:22): So the next question becomes, what can we do about them if we identify them? So this is a similar study showing older patients prior to CAR T-cell therapy. We can also identify a high prevalence of geriatric impairments. As you can see here, about 50% of patients have impairment either ADL or IADL and close to 80% have high comorbidities and nearly 40% have cognitive impairments.

(25:59): And again in this setting of the CAR T-cells, if you have cognitive impairment prior to the CAR T-cells as measured the by Objective Cognitive Performance test, the survival is impaired. So as you can see here, the bottom line here is the patient who has impaired cognition prior to the CAR T-cell treatment.

(26:21): Patients with impaired functional status may still be optimized for transplant or CAR T-cell therapy with exercise or cognitive rehab programs. So if we identify those deficits, what can we do about them? I'm highlighting in this slide some potential ways we can optimize them prior to transplant or CAR T-cell therapy. If you have physical or functional limitations, you should be referred for physical occupational therapy exercise programs, and there are also cognitive rehab programs for patients with cognitive dysfunction.

(26:50): We involve caregiver heavily and for patient who has polypharmacy, we review potentially inappropriate medications, we actively de-prescribe and similar things can be done for patients who have nutritional deficit issues with mental health or lack of social support.

(27:10): So can those things be done in the setting of transplant or CAR T, especially when time is of essence? The answer is yes. So this is a representative study from the University of Chicago. So they have a multidisciplinary clinic for older patients undergoing transplant with donor cells. What they have done is that once they determine an older patient has geriatric deficits using the surveys and performance tests, they design an individualized multidisciplinary transplant optimization program involving physical therapy, the geriatric nutritionist, and social work. And they perform this tailored intervention, called a tailored optimization, over the course of six to 12 weeks.

(28:02): There is evidence that optimization programs can maximize survival chances for older patients undergoing transplant or CAR T-cell therapy. And what they found is... This is a graph looking at the survival of a group of patients who have done the most recent optimization program versus, the initial optimization program, versus the pre-optimization program. So they found that the patient who have recently completed the modern optimization program had the best overall survival and the lowest non-relapse mortality. So this suggests that this is doable that we can optimize an older person prior to transplant in order to maximize their chance for survival.

(28:41): If you recall, we know that in the first one year after the transplant, those older patients are at an especially increased risk of death. And I should mention that a similar program is also performed in many other transplant centers including ours. We have a large transplant optimization program for older patients prior to CAR T and transplant.

(29:12): So if an older person develops geriatric syndrome such as delirium or fall after the transplant, they will have reduced survival, which is not surprising as you can see from this study.

(29:28): Despite its importance in improving patient outcomes, geriatric assessment is underutilized across the country.  So since geriatric assessment is so important, why don't we perform this in every single centers in the United States? The answer is there are still many barriers to use geriatric assessment both from the physician as well as from support staff perspective. As you can see from this slide, there are many potential barriers such as uncertainty about which assessment tools to use, lack of training, lack of support, lack of time, which is why this type of comprehensive assessment and optimization is only performed in certain large transplant centers.

(30:09): A full recovery from transplant or CAR T-cell therapy is possible for older patients although quality-of-life improvement can take up to a year. Lastly, I want to spend the next last couple of minutes to mention the impact of transplant and CAR T-cell therapy on an older person's quality of life. So in this schematic presentation, I illustrate the recovery and quality of life after the transplant from the time of transplant all the way to recovery and reintegration. The quality of life is related to the patient's age, comorbidities, conditioning therapy, social support and, obviously, the development of graft-versus-host disease (GVHD). As you can see here, as times goes on, the physical symptoms of fatigue and sleep and other symptoms gradually reduce, as well as the psychological burdens of anxiety and depression, and there's a gradual increase of social functioning and reintegration of an older person's life. And one important thing to keep in mind is for older person to recover, this process of quality-of-life improvement and recovery can take up to nine to 12 months.

(31:22): Quality of life measures for older patients who undergo transplant versus those who continued with chemotherapy are quite similar. And this is study actually looked at quality of life of those patients who either underwent transplant, or who did not undergo transplant and just continued with chemotherapy. As you can see here, I'm not going to go into the detailed numbers measured by two specific questionnaires. The quality of life actually is quite similar among those two groups of patients. So it's not that if you go to transplant your quality of life will significantly suffer compared to if you don't go to the transplant. The reason is because, if you don't go to the transplant, your disease most likely will progress at which time you will need additional therapy, lots of transfusions, a lot of infections, those things will decrease your quality of life as well.

(32:12): Again, I circle back to this slide. So we have talked about the challenges facing older cancer patients before transplant and CAR T-cell therapy. We talked about the ways to identify those challenges, those vulnerabilities, and the ways to remedy them and optimize them.

(32:36): Early referral and assessment is critical for older patients to be evaluated for their fitness to withstand transplant or cellular therapy. So now if we put them together and we think for an older person over the age of 60 years old to consider a high-intensity, high-risk procedure such as transplant or cellular therapy, we really need to start thinking about early referral and early assessment. As long as you have adequate baseline function and non-severe comorbidities, which means you are not having end stage heart failure, end stage renal disease or oxygen-dependent COPD, you should consider being evaluated by a transplant physician as well as geriatrician for the geriatric assessment. If you are considered a candidate, we will be undergoing three parallel optimization strategies to improve your outcomes.

(33:32): Average but vulnerable older patients can benefit the most from geriatric assessment and targeted interventions to increase their resilience before proceeding to transplant or cellular therapy. The middle arm is the one we have talked most about. It is to maximize resilience using the geriatric assessment targeted interventions. We leverage your own strengths, your own resilience, we prepare your ecosystem of support and we perform ongoing assessment to optimize, maximize your resilience prior to transplant and cellular therapy.

(33:59): So with that I want to go back to this Golden Gate bridge model. When we think about how you, as a patient, have gone through all the stressors prior to your transplant or cellular therapy, we use your past experience, we leverage your own health motivation and your ecosystem. We optimize your disease treatment and transplant platform so that we can balance the stress and resilience so that the Golden Gate Bridge will maintain this integrity after the transplant and cell therapy. And this is something we do continuously from prior to treatment all the way to one to two years after the transplant or cellular therapy.

(34:51): With that, I want to stop here and thank you all for the attention and happy to take any questions. And again, if we don't have time to go through all the questions, please feel free to email me directly, I can answer through email as well. Thank you.

Question and Answer Session

(35:10): [Michelle Kosik]: Thank you Dr. Lin. What an excellent presentation. We will now begin the question-and-answer session. Our first question is, how are you defining polypharmacy, Dr. Lin?

(35:36): [Dr. Richard Lin]: So excellent question. So polypharmacy is usually defined in the older patient who has taken five or more medications and those medications should be your standing medications not as needed medications or herbal medications. Studies have found that if a patient had taken more than five medications, they usually have issues with drug-to-drug interactions during the transplant or cellular therapy that may affect their treatment outcomes and increase their side effects. So we look at a medication list very closely to make sure they are all essential medications. We actively de-prescribe non-essential medications with the consultation of your primary physicians or specialty physicians.

(36:32): [Michelle Kosik]: Terrific. Several of our viewers are asking questions about caregiver support. I'll read one specifically that says, "Do you recommend an older patient for CAR T-cell therapy or stem cell transplant if a patient does not have a 24/7 caregiver at home after the procedure is performed?"

(36:57): [Dr. Richard Lin]: Thank you. This is an excellent question. Many older patients, like I discussed, sometimes have older caregivers and a suboptimal social support system. What we usually recommend, with the help a social worker, is to identify resources not just from the family perspective but also from friends, extended families, and local community supports and sometimes hired caregivers. VNA Service offers hired caregivers, especially to older patients. And also, keep in mind, the caregiver support for 24/7 is only applicable for a hundred days post-stem-cell transplant and the first 30 days is usually in the hospital. And in the case of CAR T-cell therapy, 24/7 caregiver support is only required for the first 28 days post CAR T-cells. And the first two weeks may be in the hospital where you actually do not need a 24/7 caregiver. So it's mostly the caregiver requirement that is temporary and could be managed by a team approach.

(38:19): [Michelle Kosik]: Wonderful. There are so many good questions here. Is there data on what the risks are for secondary cancers in patients who have had successful CAR T treatment?

(38:36): [Dr. Richard Lin]: Excellent. So this is another age-specific question but there is a risk of secondary malignancy, mostly in the case of secondary myeloid neoplasia such as MDS or AML. The percentage is not very high, somewhere between one to 3% over the course of next five to 10 years. They usually happen with patients who already have issues with their bone marrow prior to the CAR T-cell treatment. We do not have 20-30 years of data because, as you can imagine, the CAR T-cell therapy has not had that long term of existence yet.

 (39:25): [Michelle Kosik]: Is there an app that you're aware of, Dr. Lin, that could improve cognitive impairment?

(39:33): [Dr. Richard Lin]: So that actually is an area of active research. We do not have validated tool or validated treatment that can improve cognitive performance in a short period of time prior to either CAR T or stem cell transplant. So the most important issue is to identify those deficits early and to do extensive rehab and preventive programs in the hospital as well as post-treatment.

An example is those patients who have a higher risk of developing sun-downing or delirium during their hospitalization. And so those patients will be prioritized, at least in our hospital, to get a larger room with a window facing the street  and will also get frequent caregiver orientation and a cognitive rehabilitation program during the hospitalization.

And the other aspect is once the cognitive impairment is recognized, the caregiver will need to take a more active role in terms of helping the patient with some cognitive impairment to identify their period of confusion and to alert the clinical teams. So those are the things that we can do now but we do not have a magic medication or treatment at this time to reverse the cognitive impairment.

(41:18): [Michelle Kosik]: Dr. Lin, what is the longevity for a CAR T after you successfully get that infusion?

(41:26): [Dr. Richard Lin]: So that's actually a very good question as well. Is not specific to the older patient, but generally speaking for patient with lymphoma, about a third of patients who receive a CAR T will remain in long-term durable remission. The long-term means actually five, 10 years without disease recurrence and without any additional treatment. So for lymphoma, especially, the CAR T is curative in a subset of patients. Right now, this subset of patients is about one-third. We're working on many different ways, try to improve this number.

(42:20): [Michelle Kosik]: Terrific. Can you address the need for donated IVIG plasma transfusion post-CAR T-cell treatment for older patients with the low IgG?

(42:34): [Dr. Richard Lin]: Yeah, so this question also is not completely specific to older patients but older patients are at a little bit higher risk. The reason is because the CAR T-cells deplete the B-cells in the body, and without B-cell you cannot produce immunoglobulins. And immunoglobulins can last a few months in patients and that's why periodically after CAR T-cells you will need immunoglobulin replacement. Most frequently is about once a month. They help you fight infections. If they're very low or if you have frequent infections, the B-cell will start to come back about one year after CAR T-cell treatment. And hopefully, by that time you will not need immunoglobulin replacement.

(43:31): [Michelle Kosik]: Thank you. Do you have any advice for caregivers, especially in the first three months after CAR T-cell therapy?

(43:44): [Dr. Richard Lin]: I think the CAR T-cell therapy compared to the transplant, it's a little bit less intense and the recovery is much faster. Usually 28 days after the CAR T-cell treatment, patients can return to their home and they can be almost back to normal. Many of our patients can start working as well. So I will say the caregiver impact, for the first three months, is mostly concentrated in first few weeks because after the first one to two months, the caregiver requirement is much lower. And one thing, again, as I highlighted in the slide, is that cognitive impairment is relevant to CAR T-cell outcomes. So the caregiver will need to pay more attention to the cognitive ability of a patient post-CAR T-cell treatment.

(44:47): [Michelle Kosik]: Terrific. This is a great question and it comes up often in our practice as well. Which specialty physician should review the medications and prescribe, since each physician that we see is specialized in their own area of focus and thinks the patient needs the medication?

(45:09): [Dr. Richard Lin]: Yes. So this is again a great question. It ties into the question about polypharmacy. So since you are overseeing many physicians, many subspecialty physicians, each of them have their own medication they want to prescribe. My suggestion, for older patients, is to have your transplant CAR T-cell physician review your medication list with the help of a geriatrician, especially if you already take many medications, and then to consider certain medications that could potentially be held during the intensive treatment period. And those medications should be discussed, obviously, with the specialty physician as well.

One example would be blood pressure medication, cholesterol medications. Those medications are commonly held during transplant and CAR T-cell therapy. And this is something that you should be prepared to also discuss with your primary care physician or the cardiologist. But start with the transplant and CAR T-cell physician and the geriatrician to review your medication list.

(46:22): [Michelle Kosik]: Terrific advice. This one's specific to a viewer. I am a 67-year-old, very fit female with no comorbidities, status; post stem cell transplant for solitary primary brain type B anaplastic non-Hodgkin's lymphoma three years ago. Can I do a CAR T in case of a relapse? I'm still doing every four-month brain MRI for surveillance.

(46:51): [Dr. Richard Lin]: The answer is definitely yes. However, since you have been in remission for over three years, the chance of relapse is relatively low but CAR T-cells should still be a backup.

(47:08): [Michelle Kosik]: Can you comment on post-CAR T patients and COVID?

(47:14): [Dr. Richard Lin]: So this actually ties into the question about the IVIG. So patients post-CAR T, because they do not have any B-cells, their ability to fight COVID or generate an immune response to the COVID is significantly impaired. We mostly depend on the pre-CAR T vaccination for COVID so that you can have enough antibodies post-transplant to prevent you from getting COVID. And the COVID re-vaccination for CAR T-cell patients usually starts at around the six-month mark. And in terms of the risk, yes you are at increased risk for COVID infections post-CAR T.

(48:08): [Michelle Kosik]: Thank you. Are you aware of any research with patients with CMML or chronic myelomonocytic leukemia?

(48:20): [Dr. Richard Lin]: The CMML, we treat it sometimes similar to patients with MDS. And in situations like this, if they are considered higher risk category and their curative option is allogeneic transplant, we really consider them in the same group as patients with MDS. So MDS or MDS-related research would be relevant to a patient with CMML.

(48:56): [Michelle Kosik]: Dr. Lin, do you have any vaccination recommendations for patient post-CAR T? We know that our stem cell transplant patients need to be re-vaccinated. Are you seeing any similarities with CAR T-cell therapy?

(49:13): Yes, correct. So our standard of care right now is re-vaccinate everyone post CAR T at the one-year mark. That including all the childhood vaccinations that you would receive as a stem cell transplant patient. For COVID vaccinations, we can start as early as six to nine months.

(49:38): [Michelle Kosik]: Thank you, that's great advice. Another one of our viewers asked if there are unique CAR T issues with older patients.

(49:49): [Dr. Richard Lin]: So the unique issue applicable to CAR T-cell patients are cognitive issues. So like I showed you on the slides before, patients who have cognitive impairment prior to the CAR T definitely have worse survival. And so this is something new, as relevant to the older patients. And there's also emerging data, which I didn't show on my slide, that for patients who have functional impairment as measured by either they have reduced ability to mobilize or if they are dependent on assistive device in terms of their mobility, or if they require help in terms of their ADLs and IADLs, those patients have increased risk to develop CRS or ICANS.

So the CRS is the specific CAR T specific side effect called the Cytokine Release Syndrome. ICANS is the neurotoxicity specific to the CAR T-cell therapy. So as you can see here, similar to the transplant, cognitive impairment as well as functional impairments are associated with toxicity as well as survival after CAR T-cell therapy. We are still in the early stage of identifying an approach to address those deficits for CAR T-cell therapy. So stay tuned for new research in this area.

(51:35): [Michelle Kosik]: Dr. Lin, one of our viewers wanted you to repeat your response to the re-vaccination of all vaccines post CAR T, please.

(51:44): [Dr. Richard Lin]: Okay. So at one-year post-CAR T-cell therapy, if your blood count is normal and you are otherwise healthy, you'll be getting all the childhood vaccines back in three series. So all the childhood vaccination will be repeated around one year mark. And COVID vaccination can be started earlier, around six to nine months mark.

(52:18): [Michelle Kosik]: Terrific. Is there a curative option for myelofibrosis? Is CAR T-cell therapy an option for myelofibrosis after a stem cell transplant?

(52:31): [Dr. Richard Lin]: So the only curative options right now for myelofibrosis is allogeneic transplantation. However, there are also many available new drugs for myelofibrosis these days. Many of those drugs keep the patient in remission for many years with an acceptable quality of life. And this actually goes back to my initial discussion with you, that there will be certain older patients who will not be candidate for transplant. And there's also a group of older patients who choose not to proceed transplant even though it’s considered a curative option. This is a very applicable to the patients with myelofibrosis because there are drugs that potentially can keep them alive with reasonable quality of life for many, many years even though they're not curative.

In terms of the CAR T-cell treatment for myelofibrosis, right now the CAR T-cell success is only limited to lymphoma and ALL and some cases of myeloma. It has not been shown to be successful yet for patients with myeloid malignancy, myeloid blood cancers such as AML, MDS, or myelofibrosis.

(54:05): [Michelle Kosik]: Thank you. Are you, in your practice, seeing cognitive issues six to nine months post-CAR T-cell therapy?

(54:14): [Dr. Richard Lin]: So this is an excellent question. We actually are conducting a prospective study looking at cognitive impairment or cognitive recovery post-CAR T-cell therapy. I can say that from our initial experience, and some of the research data, by nine months to a year or even earlier, for some patients, like by six months, there's no cognitive impairment or no evidence of cognitive decline after CAR T-cell therapy, if the CAR T-cell therapy is successful.

If the lymphoma has relapsed, then obviously you'll be needing many different therapies. Then the cognitive issue will be related to the subsequent treatment. So the conclusion is that so far, even though we show cognitive impairment prior to CAR T is detrimental, for a patient who went through the CAR T and remains in remission, there's really no issues of cognitive decline long term.

(55:25): [Michelle Kosik]: How long do you recommend that patients mask after getting CAR T-cell therapy or stem cell transplant?

(55:34): [Dr. Richard Lin]: So that's a great question. It's actually much more optional than you would think. We usually advise patients for the first 100 days after the stem cell transplant and the first 28 days after CAR T-cell treatment. But again, after those treatments, you are immunocompromised to a certain extent, but that is not to say that wearing a mask will completely eliminate all infections. You have to be cognitive, cognitive about being around sick people. Wash your hands and do the due diligence. So I will say after the requirement period, the mask is optional.

(56:26): [Michelle Kosik]: This will be our last question. We are now running out of time. I had SHINGRIX® several years back. After my CAR T treatment, my doctor suggested I receive it again, but the pharmacy would not do it because the protocol does not allow more than one regimen. What do you suggest I do? I take Valtrex to ward off shingles and other infections for now.

(56:51): [Dr. Richard Lin]: Definitely, you need to get SHINGRIX® again because of the CAR T-cell treatment. What I would do is after one year, you should have your doctor write a specific letter detailing the requirements, stating that you are post-CAR T-cell treatment and you should be re-immunized. That will be the best approach to give to your pharmacist.

(57:18): [Michelle Kosik]: Closing. Thank you, Dr. Lin. On behalf of the BMT InfoNet and our partners, we would really like to thank you for your very helpful presentation. Thank you to the audience for your excellent questions. Please contact BMT InfoNet if we can help you in any way.