Quality of Life after CAR T-cell Therapy

CAR T-cell therapy is a therapy that re-engineers the patient's own immune cells to fight cancer. Learn about short-term and long-term effects and quality of life after CAR T-cell therapy.

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Quality of Life after CAR T-cell Therapy

April 30, 2024

Presenter: Patrick Connor Johnson MD, Massachusetts General Hospital Cancer Center, Assistant Professor of Medicine, Harvard Medical School

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

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


Multiple studies have shown that most patients who receive chimeric antigen receptor (CAR) T-cell therapy report a good quality of life long-term. Learn how CAR T-cell therapy is performed and its short-term and long-term effects on patients and caregivers. Discover key differences between CAR T-cell, stem cell transplant and other and chemotherapy treatments.

Key Points

  • Quality of life and symptom burden generally improve over time after CAR-T cell therapy.
  • CAR-T survivors have quality of life similar to the general population.
  • Caregivers of patients receiving CAR-T may experience significant psychological symptoms.


(02:57): The cancers discussed in this talk are blood cancers that are very good at hiding from the immune system, which is normally able to clear abnormal cells from the body.

(05:40): CAR T-cell therapy is truly a personalized treatment. Instead of prescribing a drug to fight cancer, CAR T-cells are a living drug.

(07:51): CAR T-cell therapy is approved by the Food and Drug Administration (FDA) for patients with - lymphoma, multiple myeloma, or acute leukemia. treatments.

(10:53): CAR T-cell Therapy is different than traditional chemotherapy, so the side effects are different. Common side effects include cytokine release syndrome (CRS), neurologic or brain toxicity, low blood counts, low immunoglobulins and infections.

(14:54): Quality of life decreases two weeks after CAR T-cell therapy but, on average, improves by 3-6 months after CAR T-cell therapy

(15:49): Psychological symptoms – anxiety, depression and even post-traumatic stress disorder (PTSD) – are common during CAR T-cell therapy. These symptoms generally improve by six months after CAR T-cell therapy.

(18:56): Usually the patient and caregiver are required to stay within 30 minutes to two hours from the hospital for the first month after CAR T-cell therapy so they can be monitored closely.

(25:06): Long-term survivorship involves multiple things: cognitive function, physical function, psychological function and looking for other cancers and new conditions.

(26:41): Quality of life outcomes long-term appear good, based on research to date.

(29:37): A caregiver is required to stay with the patient for the first 30 days after treatment – primarily to identify and report potential complications quickly so that they can be managed promptly. This can be stressful for caregivers.

Transcript of Presentation

(00:00): [Michala O’Brien]: Introduction. Welcome to the workshop, Quality of Life After Chimeric Antigen Receptor (CAR) T-cell Therapy. My name is Michala O’Brien and I will be your moderator for this workshop.

(00:09): I'd like to thank Kite, A Gilead Company, whose support helped make this workshop possible.

(00:15): It's now my pleasure to introduce today's speaker, Dr. Patrick Connor Johnson. Dr. Johnson is an Assistant Professor of Medicine at Harvard Medical School and an Attending Oncologist at Massachusetts General Hospital. He specializes in cellular therapy such as CAR T-cell therapy and the treatment of patients with lymphoma. Please join me in welcoming Dr. Johnson.

(00:44): [Dr. Patrick Connor Johnson]: Overview of Lecture. Thank you so much, Michala. I'm delighted to be here today, and again, I'm Connor Johnson. As mentioned, my clinical specialty is the treatment of patients with lymphoma and the use of cellular therapies like CAR T-cell therapy. And today my goal is to talk about the longitudinal lived experience for patients going through CAR T-cell therapies. I hope to touch on some different studies and evidence to share a little about what we've learned about the lived experience of patients going through these transformative therapies.

(01:25): Shown here is an outline of the main topics that we're going to cover today. We'll review some of the basics that underlie how CAR T-cell therapy works. I know there are a number of different presentations talking about CAR T-cells, but I want to make sure that we're covering the whole journey.

(01:47): I then want to focus on steps within the journey that patients and caregivers experience in CAR T-cell therapy. Afterwards, we'll go through the physical and psychological symptoms that patients can experience, both during CAR T-cell therapy and following.

(02:08): Then we'll talk about the uncertainty that can be experienced with CAR T-cells, and finally dive into the recovery process: what side effects and symptoms can be experienced early and what side effects and symptoms can be experienced later on. Finally, we'll talk about long-term effects of CAR T-cells, which we'll refer to as survivorship.

(02:36) What is CAR T-Cell Therapy? As many of you have learned, CAR T-cells stand for Chimeric Antigen Receptor T-cell therapy. This is an immunotherapy treatment, a therapy that seeks to harness the power of the body's own immune system to better target the cancer.

(02:57): The cancers that we talk about in this discussion are blood cancers that – because they derive from the body's normal, healthy cells – are very good at hiding from the immune system, which in theory should be able to clear abnormal cells. CAR T-cells seek to help the immune system recognize the cancer better by genetically changing the immune system to target the cancer.

(03:27): This therapy first became available for any type of cancer in 2017, and we now have six fully FDA-approved products or treatments. And those treatments focus on, and are approved for, specific types of blood cancers: lymphoma, which is my specialty; a type of leukemia called acute lymphoblastic leukemia; and multiple myeloma.

(03:57): Beyond this, there are hundreds of clinical trials examining the use of this therapy in various different types of malignancies, including solid tumor and blood cancer disorders. On top of that, we're beginning to see CAR T-cells used for non-cancerous processes such as autoimmune disorders, which is in the clinical trial phase.

(04:23): Here's a diagram that tries to show how CAR T-cells are different from a regular T-cell. A T-cell is a type of white blood cell that has a very important role in getting rid of invaders, whether those be infections or abnormal cells. With regards to the T-cell in CAR T-cell function, we use viruses to change the DNA of the normal T-cell and, by doing this, we then allow the T-cell to express a protein or a latch that can bind the cancer.

(05:03): For lymphomas and leukemias, that latch is called CD19, and for myeloma it's called BCMA – but these are basically just proteins that are engineered into the T-cell that allow the T-cell to better see and bind to the cancer cell so that the T-cell can act on the cancer cell in a more efficient manner than it would otherwise. This really underlies how CAR T-cells are able to treat cancers when the normal immune system cannot.

(05:40): Creating CAR T-Cells. CAR T-cells are a relatively complicated treatment compared to some other treatments, and the reason for that is that this is truly a personalized treatment. The actual treatment is derived from the patient. In other words, as opposed to prescribing a drug, this is a living drug – and in order to produce it, we actually have to get a sample of T-cells from the patient being treated. That process is called leukapheresis, which is the filtration of white blood cells.

(06:15): Usually this involves placing a specialized IV or catheter into the arm or neck and in a process that takes three to four hours. The white blood cells are filtered out of the body and the rest of the blood is filtered back in. You end up with sort of a little baggie of white blood cells, a portion of which are shipped to the company that makes the CAR T-cells – or if it's a study, to the hospital that makes the CAR T-cells.

(06:47): In order to do so, the T-cells are filtered out from the rest of the white blood cells. Then, using a virus, that latch is genetically engineered into the T-cell so that it expresses this protein, making it like a bionic T-cell. It's then grown up and tested to make sure that the characteristics and profile are appropriate for treating the patient. Finally, the cells are sent back to the treating hospital.

(07:19): Preparing the Patient for CAR T-Cell Therapy. Before giving the CAR T-cells, we administer some chemotherapy over a period of two to three days to lower the body's blood counts and essentially allow the CAR T-cells room to grow; in other words, we prevent the CAR T-cells from not expanding or growing as they're supposed to. Then the CAR T-cells are given as a single infusion, because they're a living treatment that can grow and reproduce on their own and target the cancer.

(07:51): As mentioned, the main role for CAR T-cells in FDA-approved or already proven cancer treatments is with lymphoma, multiple myeloma, and acute leukemia. For lymphoma, there are two types of major categories. For aggressive lymphomas, patients are usually eligible after one or two prior treatments. For indolent lymphomas, leukemia and multiple myeloma, patients are often eligible after multiple prior treatments. Although, just recently, multiple myeloma experienced another FDA approval making some patients eligible after one prior line of treatment.

(08:42): The Patient’s Journey Through CAR T-Cell Therapy. This slide summarizes the patient journey going through the CAR T-cell process. The first step is the pheresis process, where the white blood cells are collected over a three to four hour period, occasionally five hours. This is generally very well tolerated with no side effects, although there can be a little bit of temporary lightheartedness.

(09:05): It takes about three to four weeks to make the CAR T-cells. That process is called manufacturing. As you might imagine, sometimes we have to choose a treatment to try to control the cancer while we wait for the CAR T-cells to be manufactured. That treatment is called bridging therapy; It's like building a bridge to get to the CAR T-cells. And that can be chemotherapy, radiation, or other treatments, like a targeted pill or really anything we think can be effective at keeping the cancer in check while waiting for the cells.

(09:43): When the cells are ready, we administer two to three days of chemotherapy. As I mentioned, the goal there is simply to lower the body's normal blood counts so that the CAR T-cells will grow like they're supposed to.

(09:56): Patients can receive CAR T-cells in the hospital or as an outpatient, meaning in the clinic. Most patients get it in the hospital, and typically people are hospitalized for seven to 14 days. The goal for that hospitalization is to monitor for side effects and manage them appropriately.

(10:15): After that, patients are monitored very carefully for the first month after receiving the CAR T-cells and typically we begin assessing the response of the CAR T-cells on the cancer 30 days post the CAR T-cells. In the long term, we have several things we look for in terms of survivorship, and we're going to go through that on a subsequent slide.

(10:43): CAR T-cell Toxicities. This is very important for you to understand, to get a sense of how these differ from other treatments.

(10:53): CAR T-cells are different than traditional chemotherapy, so the side effects are different. The most common and important side effect to know about is called cytokine release syndrome, or CRS. This occurs because of the CAR T-cells growing and secreting chemicals of inflammation to treat the cancer. So it's an expected side effect, and it occurs frequently. The chance of it occurring depends on the CAR T-cell therapy product – as I mentioned, there are six different ones. The most common symptom of CRS is fever. I sometimes compare it to having a flu or influenza infection, as other common symptoms are muscle aches, chills, fatigue and loss of appetite. When it's a more severe form of CRS, people can have low oxygen and low blood pressure. Rarely, people can have organ injury or even require care in the intensive care unit.

(11:55): The second important CAR T-cell side effect to be aware of is a neurologic or brain toxicity, and this also occurs because of the inflammation created by the CAR T-cells treating the cancer. We don't fully understand why this side effect occurs, but in almost all cases it is reversible – though it needs to be managed, or at least monitored. Oftentimes it’s managed with steroids and anti-inflammatory treatment. The most common symptoms are confusion and difficulty with speech or writing. Rarely, there can be more serious symptoms like a seizure or swelling in the brain.

(12:36): Other common side effects with CAR T-cell therapy include:

  • Low blood counts, which occur in about a quarter of patients;
  • Low immunoglobulins. Immunoglobulin is a protein that's used to fight infections, so the immunoglobulin or protein level can fall after CAR T-cell therapy;
  • And as you might imagine, because of low blood counts and low immunoglobulins, infections are common after CAR T-cell therapy – most commonly viral infections. So we monitor for that and think about that in care.

(13:13): There are very rare reports of second cancers after CAR T-cell therapy. I want to emphasize this is very, very uncommon. The risk of that is low and certainly the benefits of CAR T-cell therapies are high.

(13:37): Symptoms associated with side effects. This is a study that reported on common symptoms. Pain was the most common symptom, followed by trouble swallowing. And you can see that also cough and shortness of breath occurred in more than 9% of patients. The most common symptom by far is fatigue, occurring in the majority of patients. Lack of appetite, headaches and chills are also very common.

(14:06): Those are usually related to CRS and sometimes to the lowering of blood counts. The other symptoms listed, like confusion and memory changes, are typically related to that neurologic side effect we discussed. I want to emphasize that both CRS and the neurologic toxicity are reversible in almost all cases.

(14:36): How symptoms can change over time. This is a chart from a study that I led and published where we looked at the symptoms experienced over time by patients receiving CAR T-cells for blood cancer, so lymphoma, multiple myeloma and leukemia.

(14:54): I want to focus on the red: About half of patients a week after CAR T-cells experienced a severe symptom, most commonly fatigue. That rate of symptom dropped by three months, and after six months it was almost cut in half, highlighting that symptoms do improve with CAR T-cell therapy treatment. And remember, some of these symptoms are from the cancer itself, so by treating the cancer we improve symptoms.

(15:24): Maybe about a quarter of patients still have significant symptoms six months after CAR T-cells. So although that's not the most common thing we see, there's still a significant set of patients where it can happen. So you're not alone if you do experience ongoing significant symptoms.

(15:49): Similarly, psychological symptoms – anxiety, depression and even post-traumatic stress disorder (PTSD) – are common during this treatment. It's stressful and difficult going through cancer therapy. Remember, everybody in these studies had already received treatments for cancer, and that alone can cause a lot of burden in terms of psychological symptoms.

(16:14): Before treatment, close to a third of patients mentioned that they had clinically significant symptoms, and nearly half of patients reported depression a month after CAR T-cells. That number improved significantly by six months after CAR T-cells. And about a fifth of patients still had ongoing symptoms, but overall the burden of these symptoms psychologically improves over time, especially by six months after CAR T-cells.

(16:46): These charts show that evidence in another way. What you can see is that the depression symptoms in general got a little worse after CAR T-cells one week later, but by the time we got to three months after CAR T-cells they were decreasing and significantly improving.

(17:03): A similar story for anxiety shown here where the symptoms of anxiety just improved consistently from where things were prior to CAR T-cells to after CAR T-cells on average. A similar story for PTSD symptoms shown here. So all of these symptoms tend to improve by the time we get to three to six months after CAR T-cell.

(17:24): Uncertainty surrounding CAR T-cell therapy. We mentioned the prior cancer therapies that patients experience, but I want to highlight that there can be a lot of uncertainty around CAR T-cells – and by that I mean, ‘What does the future hold for me?’ The reason for that is these treatments are very transformative and many patients can have incredible responses that last years or even can have cures, but we're not very good at predicting who's going to have that response. That's why I say there can be some uncertainty that patients and their families experience. Similarly, we're not very good at predicting who's going to get the side effects from CAR T-cells. Not everybody gets the side effects we've talked about and we're just not great at being able to predict ahead of time who's going to have them.

(18:16): So those two things together create some uncertainty, and that's very normal when you go through the process. If you feel that uncertainty, again, everybody experiences that. I think the challenge is how to focus on living well day by day – to understand that these side effects can occur, but also to balance that and focus on living well and on controlling what you can control. Here's a quote that summarizes some of that challenge, which is the uncertainty of not knowing what the response may be or whether those side effects might occur.

(18:56): Monitoring for side effects. Usually the requirement for centers is to stay within 30 minutes to two hours from the center for the first month after CAR T-cells, as you're followed very closely in the first 30 days after treatment. At our center, you are usually seen daily through the first 13 days and then twice a week from day 13 to day 30. After that, patients can go home. So you're living in that city for the first month after treatment. Following the first month, I typically see patients once a month until we get to about six months after CAR T-cells. Although sometimes I'll see patients every two to three months, depending upon how they're feeling.

(19:41): We do this because we need to have close monitoring for CRS and neurologic toxicity. We want to make sure that those side effects are detected and managed quickly and appropriately. So that's the rationale for the close following for the first month in particular.

(20:00): In the first two months you're not supposed to drive, so there are functional and physical limitations because of that. And remember, there are patients that may have ongoing symptoms that can persist in the first three to six months after CAR T-cells.

(20:15): Fatigue is especially common and can persist in the first six months after CAR T-cells, though it generally improves with time. Our biggest concern after CAR T-cells is often risk of infection, with viral infections being our top concern because of those low immunoglobulins and sometimes low blood counts. So these are important things to think about in the early period after CAR T-cells.

(20:41): Now I want to show you some evidence about quality of life with CAR T-cells over time. That's really our main focus. This is a study I led that showed how quality of life changes with CAR T-cells. In this study, higher is better.

(20:57): If you look on the left, you want the highest number you can get. Going into CAR T-cells compared to one week after the CAR T-cells, patients tended to have their quality of life decrease, and that was probably because of the side effects of CAR T-cells. By the time patients were a month after CAR T-cells, on average their quality of life was back to where it started, and then by three to six months after CAR T-cells, average quality of life was better than when it started.

(21:28): On top of that, the quality of life score was pretty similar to that seen for the general U.S. population. And this was a study of patients with blood cancer, so they had lymphoma, myeloma or leukemia. I'll note that there weren't any specific groups of patients that had a bad outcome, so we weren't able to predict and say, ‘this group of patients is less likely than this group to do well.’ So this is generally all patients going through CAR T-cells.

(21:59): For lymphoma specifically, we have some other evidence to talk about long-term quality of life. This is another study focused on a type of CAR T-cell called Breyanzi, which is one of the main CAR T-cells for lymphoma. With this CAR T-cell, you're seeing patients up to a year-and-a-half after treatment. And essentially what you're seeing is that a year-and-a-half after treatment, 60% of patients had improvement in their global quality of life and another 28% were the same. It was pretty rare, about one in 10, for patients to have a drop in their quality of life 18 months after CAR T-cells. And the group of patients saying that their quality of life was getting better, that percentage was continuing to improve compared to one month after. This is encouraging data for how people recover their quality of life.

(22:54): Here's data from the same study, but focusing on physical function. So again, that number, the group of patients saying, ‘my physical function is getting better, improving over time’ is really growing and growing and growing when you get to 18 months after CAR T-cells. And functional decline is relatively uncommon, seen in about less than a quarter of patients.

(23:16): A common question I get is, “How does this compare to going through chemotherapy?” Well, here's a study – these graphs show how quality of life changes over time. CAR T is in blue, chemo's in red. And this was a CAR T-cell called axi-cel, a CAR T-cell produced by Kite. It also goes by the name Yescarta. It's for patients with lymphoma.

(23:45): What you see is that long-term – close to a year-and-a-half later – both groups of patients recover pretty well. But in the early part – the first 150 days, the first nine months, really the first year after treatment – the recovery is faster for the CAR T-cell patients, so a harder recovery process for chemotherapy. So I think this emphasizes that quality of life recovery in general in this study appeared to be better for those getting CAR T-cells for lymphoma.

(24:19): What about multiple myeloma? I just showed you a few studies focused on patients with lymphoma. I didn't as much talk about multiple myeloma. Well, here's a study looking at Cilta-cel or Carvykti, which is a CAR T-cell product specifically for those with myeloma. What we see is that, over time – this is close to over a year, about a year-and-a-half after CAR T-cell – the quality of life improves. You can see that quality of life just generally getting better and better over time, especially when you get to a year out after CAR T-cells. And similarly on the right you see that most patients reported improvements in pain, fatigue and global quality of life. So the vast majority of patients noted improvements in that by a hundred days after CAR T-cells.

(25:06): So long-term recovery, not just the first year but long-term. Survivorship involves multiple things: cognitive function, physical function, psychological function and looking for other cancers and new conditions.

(25:23): This chart summarizes the concerns of patients and doctors after CAR T-cells. Throughout, but particularly in the first year, the biggest concern is infection. Fungal infections early and a rare type of pneumonia called pneumocystis pneumonia. Then, the first six months to first year, the main infections are bacterial and, most importantly, viral infections. And that's because of the low immunoglobulins and impairments in the immune system and low blood counts. Most low blood counts improve and get closer to normal by six months after CAR T-cells. So that's part of why that first six months is particularly important for infections.

(26:06): As far as long-term side effects, neurologic or brain side effects are uncommon. But those are things we look for months or years after CAR T-cells. Second cancers – which are called subsequent malignancies – and other autoimmune type of events are very rare. But we do look for those, primarily a year and beyond after CAR T-cells. The FDA recommends we follow patients for 15 years after CAR T-cells to keep an eye on things.

(26:41): This is a study in leukemia. Essentially what you're seeing is, the black bar is three years after treatment, and what I'm pointing out here is that people's function and their general quality of life tend to steadily improve all the way out to three years after. So it tends to be a general improvement as we work closer to three years after treatment.

(27:08): Another study looked at quality of life scores one to five years post CAR T-cells and, very importantly, when compared to the general population there did not, did not, keywords, there did not appear to be a significant difference in quality of life or physical or mental health between CAR T-cell survivors and the general population. I think, though that's not a perfect study, that's very encouraging data about the chance of long-term improvement in quality of life and health in CAR T-cell survivors.

(27:40): I will note, about a third of patients did report some cognitive changes or cognitive difficulty. Now, that can be reported in people who didn't go through CAR T-cell therapy as well. So that's not to say that that was necessarily caused by CAR T-cells, but just to say that there are patients who do report that, and whether it comes from some of the other treatments that people receive like chemotherapy – because remember, in this study patients had received other treatments for cancer like chemotherapy – we don't know, but there are some patients who will report some cognitive changes.

(28:14): We've actually done a study at my institution looking at how people perform on neurocognitive tests after CAR T-cells. Reassuringly, we did not see a difference in scores by how patients perceive their cognitive function or by how they did on tests. These were tests where we had them do skills, like try to perform different tasks that measure people's brain function. And with both perceived cognition and brain function, there did not appear to be a significant difference. There were a few patients, but it was rare for patients to report a decline in their cognitive function. And this included patients who didn't necessarily respond to CAR T-cells. So remember, people can have changes in their cognitive function because of treatments that they end up having to receive after CAR T-cells if they're not cured from CAR T-cells.

(29:11): In addition, we found that patients that didn't respond to CAR T-cells were the ones that tended to have a trend towards not having the best neurocognitive recovery – and I think that's reassuring when we talk about recovery from CAR T-cells, highlighting that it appears that for most patients there's a good neurocognitive recovery after CAR T-cells.

(29:37): I think it's very important to point out that as part of the CAR T-cell process, we require a caregiver to stay with patients for the first 30 days after treatment – primarily to try and identify if there are any of those brain side effects, because we need to know about those and manage those quickly. So that's the rationale for having that requirement when we talk about CAR T-cells.

(30:06): Because of this, there's a lot of stress with caregivers. They provide a lot of support for patients as they go through the treatment. They help monitor for the side effects and the recovery period and this is very stressful and in any cancer situation, but especially with CAR T-cells, given the unique side effects. We know that this is stressful for relationships, we know it's stressful for caregiver health and we know that there can be a financial burden going through this process. It's not easy to take a month off of work and go to a city and receive CAR T-cells. We recognize that these are very real and very significant things.

(30:43): We conducted a study at my institution that my colleagues and I led that tried to measure the psychological symptoms – like anxiety, depression – experienced by caregivers going through this process. About half of caregivers reported some symptoms of depression and anxiety going through the process, and generally it looks like those raw numbers get better over time as you get further out from the process, six months out from the process. So this study highlights that this is common, that family members go through a lot and it can be stressful and that these symptoms are important and because of that, we make sure that every single patient and caregiver has a consultation with a social worker at our institution.

(31:36): Summary. I want to summarize a few important things that we've talked about in this presentation. Firstly, I think reassuringly, we have studies that show, including a study that I led, that quality of life and physical symptom burden appear to generally improve over time for CAR T-cell therapy for blood cancers. We saw that quality of life generally dropped or got worse in the first two weeks after CAR T-cell therapy, probably because of the side effects that people experience – especially cytokine release syndrome and sometimes neurologic toxicity. But on average, patients had improvements of their quality of life to better than where they started three to six months after CAR T-cell therapy. We also have other studies led by other folks that showed that, for CAR T-cell survivors, their quality of life appears similar to the general population a number of years after CAR T-cells. We still need to do more studies to understand this even better, but those are reassuring findings.

(32:43): Similarly, we saw that physical and psychological symptoms do generally improve, especially when we get to three to six months after CAR T-cells. There are a set of patients, maybe about a quarter of patients, where there can be persistent symptoms that are important to acknowledge. So we need to continue to improve upon our ability to manage those symptoms. And you're not alone if you experience that. Though most patients, as I mentioned, had improvement.

(33:12): Cognitive recovery after CAR T-cells does appear good based on the studies so far. I certainly think we need more studies to understand this very, very well, and we're working on that. But so far the cognitive long-term studies show good recovery after CAR T-cells.

(33:29): Finally, we mentioned that it's very important to acknowledge that caregivers for those patients receiving CAR T-cell therapy also experience a significant burden of symptoms, particularly psychological symptoms. So I think it's very important that there be a social work consultation because of the challenges logistically of going through CAR T-cells.

(33:53): With that, I'd like to thank you all for taking the time to listen to this talk. Again, I'm just absolutely delighted to be here today and I'm excited to spend some time talking about questions and going through anything that we can on CAR T-cells.

Question and Answer Session

(34:09): [Michala O’Brien]: Question and Answer Session. Thank you Dr. Johnson for this excellent presentation. We'll now begin the Q&A session of this presentation. We will answer as many questions as possible. Our first question is, for what percentage of CAR T patients does it take over a year for low blood counts to recover?

(34:40): [Dr. Patrick Connor Johnson]: First of all, that's a great question. As we talked about, low blood counts after CAR T-cells are common, it's probably about 25% of patients that have low blood counts one month after CAR T-cells. Among that group there's probably about 10% to 15% of patients that'll have it last longer term or closer to a year. So what that means is probably about half of those patients with low blood counts at 30 days are going to have those improved steadily by the one year mark. And we're continuing to study this because you're right, this is an important topic within CAR T-cells, but I would say it's about a quarter of patients at the one-month mark and it's probably closer to 10% to 15% of patients that still can have some low blood counts much longer term, months, even a year out.

(35:33): [Michala O’Brien]: Do you have any data that shows which blood cancers have responded over longer periods, and how have multiple myeloma patients compared with those other blood cancer patients?

(35:46): [Dr. Patrick Connor Johnson]: That's a great question as well. I think another way to say that is, what have we seen so far among different cancers? For aggressive lymphomas and leukemia, it's clear that CAR T-cell therapy can cure those patients. For the disease that I specialize in, which is aggressive lymphomas, about 40% of patients are cured using CAR T-cell therapy, so a little less than half of patients. For indolent lymphomas or low-grade lymphomas and multiple myeloma, we don't know yet whether any patients are cured using those therapies because patients can relapse with those diseases even long after receiving a therapy. And so we're going to have to have much longer follow-up to know whether some patients are cured.

(36:39): In terms of the length of remission after receiving CAR T-cells, both multiple myeloma and indolent lymphomas appear to have, on average, long remissions that are multiple years on average. And so I would say the responses to CAR T-cells are probably similar with low-grade lymphomas and multiple myeloma, and are different for patients with aggressive lymphomas because the goal of the treatment and what we've seen is a little different.

(37:11): [Michala O’Brien]: Does B-cell aplasia reverse after CAR T-cell therapy two to three years after treatment? And the second part is, do you know of any clinical trials that might be studying this?

(37:30): [Dr. Patrick Connor Johnson]: First of all, these questions are great. As we mentioned in the talk, hypogammaglobulinemia, meaning low immunoglobulins or B-cell aplasia, is very common after car T-cells. In some studies, as many as two-thirds or 70% of patients have this at some point after car T-cells. Most patients will have recovery by six months to a year after CAR T-cell therapy. But there are reports of some patients actually having low immunoglobulins years after CAR T-cells and B-cell aplasia for years four or five years after CAR T-cells. So most patients are going to eventually get some recovery of the B-cells with time. And so I would expect for the vast, vast majority of patients that eventually you'll get some B-cell recovery, but it can take years. And there aren't a lot of trials studying therapies yet in this context, but there are people looking at doing a study of empirically giving Intravenous Immunoglobulin Therapy (IVIg), or immunoglobulin replacement, before CAR T-cell therapy.

(38:46): Immunoglobulin replacement is what we are doing for people who have low immunoglobulins after CAR T-cells, especially if they get infections. We don't give it to everybody because it can be burdensome to get immunoglobulin infusions, but that is typically our strategy for people who have low immunoglobulins and are getting infections. But I think that we'll see trials of trying to do some of this replacement early on to try and protect. I do think as people become more and more aware of how important this issue this is, we may continue to see some other trials in this space including vaccine trials to try and boost immunity afterwards.

(39:28): [Michala O’Brien]: This is a question from a caregiver. Her partner has low blood pressure after CAR T-cell therapy and she wants to know, is there anything besides 30 ounces of fluids per day and physical therapy that will help her partner deal with a low blood pressure, and will this low blood pressure ever go away?

(39:52): [Dr. Patrick Connor Johnson]: That's a side effect that we don't fully understand yet, which is probably related to when there's a lot of inflammation in the body – and we know that there's a lot of inflammation after CAR T-cells, blood vessels can become leaky. So the blood vessels, especially when you stand, have to tighten up so that the blood, when it falls to your feet, stays in your blood vessels and that you can actually not be dizzy. It's actually a whole system in the body to allow that to happen successfully, just to stand up. It's kind of amazing that the body does that. When you've had CAR T-cells and you have a bunch of inflammation, the blood vessels are leakier, so it's harder for them to tighten up when you stand – and that's usually what's driving the low blood pressure. Probably the number one thing is just time for the inflammation to fade, because the inflammation does generally improve over time. And you can help by maintaining good hydration status.

(40:58): Another thing to keep in mind when you have low blood pressure, there are some medications that can be given if that's not effective. In other words, if the blood pressure is still low despite hydration and time, there are things like fluorine F and midodrine which can be used to try and raise the blood pressure and protect it from falling so much when people are standing. The person's medical history has to be taken into account to know if these medicines are safe to give.

(41:27): Finally, if someone is having dizziness and low blood pressure, it's important to make sure that something called adrenal insufficiency has been ruled out; this is where the adrenal glands aren't secreting as much cortisol or stress hormone as they should, which causes the blood pressure to be low. So that is something that should be tested for and ruled out for people with persistent low blood pressure, because that can be treated with a medication.

(41:57): [Michala O’Brien]: This patient had CAR T nine months ago and they're still fatigued and napping during the day. They want to know will their energy return, or when will their energy return?

(42:12): [Dr. Patrick Connor Johnson]: As you pointed out, fatigue is the most common symptom, so you are definitely not alone with persistent fatigue. It's one of the most challenging symptoms, not just with CAR T-cells but with cancer treatment in general. The other thing I'll say is that we don't really have a good way to predict who's going to have fatigue that last six months, who's going to have fatigue that last nine months, who's going to have fatigue that lasts longer. Most people with symptoms will gradually just continue to improve with time because symptoms from CAR T-cell inflammation generally get better with time. We just don't know exactly what that time's going to be, other than to say it should continue to get better.

(42:55): I think the most important thing that we have in terms of treating CAR T-cell fatigue is to try and get on a steady exercise regimen. It can be very challenging to regain exercise strategies after going through a treatment like this because sometimes you'll have some energy, do too much, and then you'll be exhausted and then not do anything, and then have some energy and then do too much, and it can be a roller coaster. So trying to get a steady exercise plan is probably the number one thing that people can do to try to facilitate energy recovery. And the second is usually just time – and typically it can be months, but also it can be a few years. As you saw on most of those charts, if you looked at the percentage of patients noting quality of life improvement over time that number got higher at 18 months. So it really is a steady recovery, and you absolutely can get improvement after nine months.

(43:58): [Michala O’Brien]: This is kind of a follow-up question to the exercise and fitness. Does exercise and overall fitness at the time of CAR T have a significant impact on reducing the side effects?

(44:10): [Dr. Patrick Connor Johnson]: What I would say is not directly. In other words, it does not affect the chance that you're going to have cytokine release syndrome or neurologic toxicity. We don't fully understand what causes that risk, but there are two factors that we do know. One factor is which CAR T-cell treatment you get. Among the CAR T-cell products, they have different risk for the cytokine release syndrome and neurologic toxicity. The second is how much tumor the patient has going in, or how much cancer. The more cancer there is, the more work the CAR T-cells must do, thus the more inflammation and thus the higher the risk of cytokine release and neurologic toxicity. So those are the two main factors that we understand for patients when we talk about CRS and neurologic toxicity.

(45:03): For other things though, when we talk about long-term fatigue, I do think that trying to be in good physical function going through can be helpful for your recovery. We don't have a trial or a study saying that the amount of exercise you're doing pre-CAR T-cells affects your recovery post, but I think it's probably good common sense to say that if you have a good exercise routine, if you're active going into CAR T-cells, your body is likely going to have more functional reserve and recovery to try and facilitate that improvement in terms of your fatigue long-term. So again, I would say no in terms of chance of response to CAR T-cells, in terms of cytokine release from neurologic toxicity, but I would probably say yes when we talk about recovery from fatigue and just general function.

(45:56): [Michala O’Brien]: If a multiple myeloma patient gets CAR T and relapses, is it possible to receive a second treatment of CAR T?

(46:06): [Dr. Patrick Connor Johnson]: It's possible. This is one where I would say it is very important to consult a CAR T myeloma specialist or a myeloma specialist because there's a lot of treatments for multiple myeloma, not just CAR T-cells, but there are bi-specifics for multiple myeloma and various therapies. So it's not always the case that another CAR T-cell is the right treatment. But there are patients that have received second CAR T-cell treatments, and whether that's the right treatment often depends on a very specific scenario. So yes, it can happen. Usually they'll choose something else, a different type of treatment to try and choose something that the body hasn't seen before, works by a different way or something new and has a different strategy. But there are patients who've received multiple CAR T-cells for myeloma.

(47:00): [Michala O’Brien]: This is a question regarding your quality of life graphs. Why did their sample sizes decrease so much over time in these quality of life graphs?

(47:10): [Dr. Patrick Connor Johnson]: Usually that's because CAR T-cell therapy for the first month is given pretty much only at an academic center as of now. So for example, I live in Boston. In Boston, after one month, but certainly after maybe two or three months, some patients want to go home and they may want to be treated or taken care of by their local doctor at that point, especially if they're doing very well. So the sample size goes down because they some patients don't want to come back in and fill out a chart on quality of life. That's a common reason that you'll see the sample size drop.

(47:53): A second reason is there are patients in any study where the cancer will not be cured by the CAR T-cell, so they may go on to another treatment or even pass away of their disease, and so that can lower the sample size as well, because of course if a patient is busy getting another treatment or if they passed away from their disease, they can't fill out the survey. That's why you'll see for pretty much all of these quality of life studies, the sample size will drop.

(48:29): [Michala O’Brien]: Can you give a percentage of CAR T-cell survivor population that still has pancytopenia a year or more later after treatment?

(48:41): [Dr. Patrick Connor Johnson]: It depends on the study, but it's probably on the order of 10% to 15%.

(48:47): [Michala O’Brien]: Are there any sexual side effects of CAR T?

(48:53): [Dr. Patrick Connor Johnson]: Thank you for that question. That's a very, very good question. As have all of these been. We don't have a good study that has focused on sexual side effects of CAR T-cells. In theory there shouldn't be a lot of direct sexual side effects from the CAR T-cells themselves, but you do get the two to three days of chemotherapy, and there's the prior treatments that people have received, and sometimes chemotherapy treatments can affect people's libido or their desire to have sex. And sometimes for women, if a woman is premenopausal, it may push them into early menopause, which itself can affect sexual side effects. For men, chemotherapy can sometimes affect erectile function. Again, there's not any evidence that CAR T-cells would affect erectile function, but we still need good studies to look at how this affects long-term. I think the predicted risk of direct sexual side effects from CAR T-cells themselves would be low.

(50:00): [Michala O’Brien]: How do you test for longevity of the T-cells for CAR T-cell treatment?

(50:05): [Dr. Patrick Connor Johnson]: Unfortunately we don't yet. There's not an approved test. In a research study these can sometimes be sent. Someone needs to develop this for sure, but we would love to have a test that you could send to say, oh, how many CAR T-cells are left? How many are alive? We just don't have that test. So instead we tend to follow people's blood counts over time and their inflammatory markers to try to get a sense of things. But there is no test yet to measure CAR T-cell therapy.

(50:41): [Michala O’Brien]: This is a caregiver question. You mentioned the role of caregivers relating to the monitoring for side effects, but in addition, what are specific duties that are needed in that 24 hour care of someone undergoing CAR T treatment?

(50:57): [Dr. Patrick Connor Johnson]: The number one thing is monitoring for side effects. That's really what it's about. It's primarily to call if: A, there's a fever; or B, there's any change in someone's neurologic or brain status, if they seem more confused, if they're not acting the way that you're supposed to be acting. That's really number 1, 2, 3, 4, and 5 when you're doing that, is the primary thing you're there for is to try and identify those side effects and call the team if they're there. Because remember, if the patient's confused, they probably aren't going to realize that and they're not going to call, and those side effects need to be managed. That's really the big thing. It is less common for people to have to do functional things in terms of you may not have to wheel the patient around or something like that because patients can feel fine with CAR T-cells or feel fatigued, but otherwise be doing well. The biggest thing is identifying those side effects and calling when those happen.

(51:52): [Michala O’Brien]: What is the longest one of your MCL patients have been in remission after CAR T?

(51:59): [Dr. Patrick Connor Johnson]: CAR T-cells for mantle cell are relatively new. So remember the trials that published these were close to 2020, so we're not that far from that, but I have patients that are in the three-year mark and still in remission.

(52:13): [Michala O’Brien]: Great. Is CAR T-cell therapy appropriate for a combination of multiple myeloma with amyloidosis?

(52:24): [Dr. Patrick Connor Johnson]: In full disclosure, I'm not a myeloma specialist or an amyloid specialist, so would always recommend that someone get a specialized consult for someone who focuses on amyloid, but CAR T-cells have been used for myeloma and amyloid in patients. So this is absolutely something that has been done, not necessarily as much in the trials, but it has been done. I would certainly recommend a formal consultation with a myeloma CAR T-cell specialist.

(52:57): [Michala O’Brien]: Are you aware of any eye side effects from CAR T-cell therapy?

(53:02): [Dr. Patrick Connor Johnson]: There's no direct ocular side effect from CAR T-cell therapy. Remember that the steroids which are given for management of some of the high inflammation can cause ocular side effects, but CAR T-cells themselves haven't shown a direct ocular side effect.

(53:26): [Michala O’Brien]: Do you have to retake all the original vaccines as well as shingles and pneumonia after CAR T-cell therapy?

(53:35): [Dr. Patrick Connor Johnson]: That's a little controversial. We're still trying to figure out what people should do vaccine-wise after CAR T-cells. Different centers in the United States and elsewhere do it differently. Remember, it's not a transplant, so it's not that your immunity gets obliterated or that you lose all of your immune function. That's not what happens here. You get a one-time CAR T-cell infusion. But you do lower the immunoglobulins, which have a role in immunity. At our institution, we revaccinate for COVID and the flu, but not for everything else. If you haven't had vaccines for other stuff, we certainly recommend those be given afterwards. Like if you haven't had an ammonia vaccine, haven't had RSV vaccine or shingles, we do those, but we don't just revaccinate people for everything at our institution. Other places sometimes do a series of vaccines. We don't yet know what the right answer is.

(54:35): [Michala O’Brien]: Does a patient get more infections after CAR T-cell therapy?

(54:41): [Dr. Patrick Connor Johnson]: Yes. The short answer is yes. In one study about three quarters of patients got an infection in the first two years after CAR T-cells. So these are more common after CAR T-cells. Most of these infections are manageable. The chance of dying from an infection after CAR T-cells, that's uncommon. The biggest issue usually is viral infections, especially respiratory infections. So I think being cognizant of COVID-19, thinking about what vaccines you've had and talking to your doctors about what vaccines you had, haven't had and need, I think those and having good hand washing strategies are important considerations.

(55:24): [Michala O’Brien]: We are running out of time, so this is going to have to be our last question. What type of chemotherapy is used for three-day prep prior to the CAR T transfusion?

(55:35): [Dr. Patrick Connor Johnson]: There are two main regimens. One regimen is two days and is called Bendamustine. That's less common, but it is used and it can be very effective. The most common regimen, what was used in most of the clinical trials, is three days of therapy using cyclophosphamide and Fludarabine. Those are the two chemo drugs. The common side effects of this cocktail are fatigue, which is temporary, diarrhea and nausea. There can be more serious side effects, but that's rare. Usually those are the common things people experience. And generally speaking, most of my patients feel that the chemotherapy they get for that is not as difficult as the chemotherapy they had for lymphoma in the first line.

(56:22): [Michala O’Brien]: On behalf of BMT InfoNet and our partners, I'd like to thank Dr. Johnson for this very helpful presentation, and especially you mentioning the emotional side effects and situations that patients and the caregivers are placed in. And we do have a workshop that is available for people up on our website riding their emotional roller coaster. Thank you audience for your excellent questions and please contact BMT InfoNet if we can help you in any way. 

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