CAR T-Cell Therapy: Acute Lymphoblastic Leukemia- A Drive Through the Past, Present, and Future.
Thursday, May 4, 2023
Presenter: Haneen Shalabi, DO, National Institutes of Health.
Presentation is 58 minutes long including 13 minutes of Q & A.
Summary: This video will discuss why a patient with acute lymphoblastic leukemia (ALL) may need CAR T-cell therapy; the steps involved in making a CAR T-cell product; how CAR T-cells are administered to patients; and both short- and long-term side effects, and outcomes associated with CAR T-cell therapy.
- Childhood acute lymphoblastic leukemia (ALL) is the most commonly diagnosed cancer in children. In the United States, there are about 30 cases per million in children below the age of 20. It accounts for about 25% of all new pediatric cancer diagnoses.
- Acute Lymphoblastic Leukemia (ALL) in adults is a more rare diagnosis. It is, however, still the second most commonly diagnosed acute leukemia in aduls. There are about 6,500 cases/year in the United States. Only 40-50% of adults diagnosed with ALL will achieve long-term, durable remissions.with standard therapy.
- CAR T-cell therapy is a new form of treatment that may cure, or prolong the life, of patients who do not respond to standard chemotherapy or a bone marrow transplant.
(01:26): Why people may need CAR T-cell therapy for leukemia; the steps involved in making a CAR T-cell product; some of the short and long-term side effects associated with CAR T-cell therapy; and results following CAR T-cell therapy.
(04:22): 85 to 90% of patients diagnosed with leukemia will be cured of their disease with standard of care chemotherapy.
(05:24): Based on decades of research, survival for pediatric leukemia patients has improved. This is, in part, due to using multi-drug chemotherapy as well as giving intrathecal chemotherapies to prevent leukemia from attacking the central nervous system.
(10:22) . Healthy T-cells in the body fight infection and/or foreign objects in our bodies. Chimeric antigen receptor T-cell therapy converts normal T-cells, collected from a patient’s own body, into T-cells that can recognize cancerous cells..
(13:08): Making a CAR T-cell involves several steps, the first of which is apheresis. A patient is hooked up to a special machine that extracts the patient's blood, separates out white blood cells, including T-cells, and returns the rest of the blood product to the patient.
(14:05): The T-cells are then sent to a special laboratory where they are converted in to CAR T-cells. Prior to infusing the CAR T-cells into patients, the patient typically receives some chemotherapy to prepare the body for the CAR T-cells.
(23:37): In addition to CAR T-cell products that are currently approved by the Federal Drug Administration (FDA), there are clinical trials a patient may participate in test non-FDA approved CAR T-cell products. Information about these trials can be found online at clinicaltrials.gov.
(28:04): Cytokine Release Syndrome (CRS), is the most common side effect from CAR T-cell therapy. Over 80% of patients who receive CAR T-cells will get CRS, with such symptoms as fever, low blood pressure and/or shortness of breath.
(33:40): 30-87% of patients who receive CAR T-cells experience some degree of neurologic side effects.
(42:18): Research is onging into how CAR T-cell therapy psychosocially affects patients; how to reduce toxicities; and ways to improve survival after CAR T-cell therapy.
Edited Transcript of Presentation:
(00:02): [Michala O’Brien] Introduction. Welcome to the workshop, CAR T-Cell Therapy: Acute Lymphoblastic Leukemia-A Drive Through the Past, Present, and Future. My name is Michala O’Brien and I will be your moderator for this workshop.
(00:15): Before we begin, I’d like to thank Kite, a Gilead company, whose support helped make his workshop possible.
(00:21): It’s now my pleasure to introduce today’s speaker, Dr. Haneen Shalabi. Dr. Shalabi is an assistant research physician in the Pediatric Oncology Branch of the National Cancer Institute at the National Institutes of Health. Her clinical focus is on the treatment of relapsed/refractory pediatric patients with blood cancers, using CAR T-cell therapy. Dr. Shalabi is also interested in the neurocognitive effects of immunotherapy in pediatric patients, and bone marrow transplantation for patients with malignant and non-malignant diseases. Please join me in welcoming Dr. Shalabi.
(01:05): [Dr. Haneen Shalabi] Overview of Talk. Thank you so much for the kind introduction. It’s my honor to be here at the “Celebrating a Second Chance at Life Survivorship Symposium”. I will be presenting on CAR T-cell therapy.
(01:48): Blood Cell Growth Occurs in the Bone Marrow. Blood cells grow in the bone marrow. On the screen there is an image of a long bone. In the medulla of the long bone, or the bone marrow space, is where new baby blood stem cells have the ability to transform themselves into more mature blood cells of varying types. From the stem cells,several additional cells are born after that.
(02:34): How lymphocytes are created. Lymphoblasts are present at one of the steps; i the process and from those lymphoblasts, additional cells continue to be born. One type of these cells is a “B lymphoblast or a lymphocyte”, the other is a “T lymphocyte”. These two types of cells are the ones on which I will primarily focus.
(02:58): The T lymphocytes are the cells that are used to make CAR T-cells. From that lymphoblast, which is one stage above the lymphocytes, is where leukemia cells can occur. In general, leukemia is thought to occur when the lymphoblast acquires changes in the genetic material of that cell. The cell’s DNA contains special instructions that tell cells what to do. When those instructions become altered or changed, cells can sometimes become imbalanced and can continue to grow and proliferate, causing leukemia.
(03:58): Childhood acute lymphoblastic leukemia (ALL) is the most commonly diagnosed cancer in children. There are approximately 30 cases per million in children under the age of 20 in the United States, accounting for approximately 25% of all newly diagnosed pediatric cancer diagnoses. Some 85% to 90% of patients will be cured with standard-care chemotherapy. In this survival chart, published by Charles Mullighan in 2015, over the course the years, years, the survival in these young patients has substantially improved.
Each of the lines in the graph represents a study era or decade in which we learned about leukemia and the varying ways to treat pediatric leukemia. This study looks at the period beginning 1968 and ended between 2006 and 2009. Based on decades of research, we have noted a substantial increase in the survival rate in our patient population.
(04:48): Decades of research on how we should treat patients with ALL has resulted in improved survival. Things that have changed in the pediatric treatment space include utilizing multi-drug chemotherapy to attack cancer cells in a number of ways, as well as giving intrathecal chemotherapies to prevent leukemia from going to the central nervous system. [Intrathecal chemotherapy is when anticancer drugs are injected into the fluid-filled space between the layers of tissue that cover the brain and spinal cord.]
(06:01): Acute Lymphoblastic Leukemia (ALL) in adults is a rarer diagnosis. It is, however, the second most diagnosed acute leukemia in adults. There are approximately 6,500 cases per year in the United States. However, only 40 to 50% of adults who are diagnosed with ALL will achieve long-term durable remissions.
(06:28) When a pediatric patient is diagnosed with leukemia, they receive chemotherapy for approximately two and a half years, done in varying phases. The first phase, usually lasts a month and involves intense chemotherapy.. Depending on their response to that first month of therapy, our patients will receive additional months of therapy in varying degrees of intensity, meaning some months will be more intense, and may require hospitalization while some months will be less intense, and patients may receive therapy in an outpatient venue. In the final year and a half of therapy, called maintenance therapy, patients are primarily treated as outpatients, they receive lower doses of chemotherapy to maintain remissions.
(07:28): For standard of care treatment in adults, patients receive chemotherapy for several months. The therapy may be intensified if needed or reduced to a more-or-less outpatient regimen if complete remission is achieved. Remission means that the patient’s leukemia has “gone away”.
For both pediatric and adult ALL patients, bone marrow transplants may be considered after a patient achieves a remission, for patients that have high risk features of their leukemia. That can be determined by looking at the genetics of the leukemia, which is normally performed within the first month of diagnosis.
(08:13): Recently, immunotherapy has moved into more “upfront settings” in the treatment of both pediatric and adult [acute lymphoblastic leukemia] (ALL). BLINCYTO® (blinatumomab) is a bispecific T-cell engager. Its job is to target CD19 cells, which s a marker acute lymphoblastic leukemia (ALL) has when it starts. Another immunotherapy, Besponsa® (inotuzumab) targets the CD22 protein on leukemia cells and has been moved into more upfront settings in treating both pediatric and adult patients.
(08:57): Treatment for patients with relapsed ALL. Unfortunately, we sometimes need to deal with patients who have relapsed after standard of care treatments. We take a step back to think about each patient individually and look at what types of therapies they have received in the past, and what their side effect profile has been. Thus, in this era of immunotherapy, we have an opportunity to think thoughtfully about what toxicities patients have experienced in the past and try to provide them with a type of therapy that is new to their disease, to help them achieve a remission, that they have not seen before.
(09:42): When we have patients that are relapsed or are refractory [their disease did not respond to prior treatment], there is a therapeutic challenge. We must consider how much chemotherapy has impacted organ functions such as cardiac [heart] function, your kidneys and your liver. This may limit treatment options, moving forward. It makes us think about how we can create novel treatments for acute lymphoblastic leukemia for both pediatric and adult patients.
(10:22): What are the steps involved in undergoing CAR t-cell therapy (chimeric antigen receptor T-cell therapy? Chimeric antigen receptor T-cell therapy [CAR T-cell therapy] is what we will focus on for the remainder of our presentation, specifically with regards to ALL. Going back to the blood cells and how blood cells are made, we all have normal healthy T-cells, the cells that our body uses to help fight foreign objects that have been inserted into our body, be it it infection or cancer Normally, T-cells cannot recognize cancer cells. What the chimeric antigen receptor, or CAR T-cell, therapy does is to re-engineer the T-cell from a patient’s own body so the T-cell can recognize cancer cells.
(11:15): The goal of CAR T-cell therapy. The goal is for CAR T-cell therapy to modify the patient’s own T-cells, taking their immune system and changing the T-cells so that they can be redirected against a leukemia cell. In this image you can see that the blue circle is a schematic image of a leukemia blast. In this example, all leukemia cells present with CD19, which is a protein on the surface of the leukemia cell.
In the gray area, you can see that this is a CAR T-cell. So, the gray area would be a patient’s own T-cell that we take out through a process called apheresis, which we'll talk about on the next slide. With those T-cells, we are able, in the lab, to introduce a vector that changes how the T-cell functions and allows the T-cell to go in and recognize an antigen that it potentially would not have been able to recognize before.
(12:27): In this picture, you can see that the long gray area with the two triangles on top, would be the CAR that is inserted into a patient’s T-cell. When this T-cell or CAR T-cell is infused [into the patient], it has the ability to recognize this diamond-shaped CD19. It binds to the CD19 and then allow the patient’s own T-cell to bind to and destroy the leukemia cell.
(13:08): How are CAR T-cells made? Making a CAR T-cell product involves several steps, the first of which is apheresis. Apheresis includes either placing two large IVs into the elbows or arms, or putting in a temporary line, that is a large IV, so that we can remove patient’s blood’.The apheresis machine, shown here, spins the blood so we can extract the white blood cells, including T-cells. The rest of the patient’s blood product (hemoglobin and platelets) is returned to the patient through the IV in the second arm. From the bag of cells that is collected, we can remove the T-cells to make the actual CAR T-cell treatment product.
(14:06): In the lab, as you see on the screen, steps two, three, and four occur. The T-cells are depicted here in the greenish blue color and the actual CAR, or the chimeric antigen receptor, is put into the same media with other stimulation so that the CAR T-cells can interact; they can actually express themselves on the outside of the T-cell and then expand. When we talk about cells expanding in the lab, we are attempting to make doses for patients so they receive the appropriate dose. All the second, third, and fourth steps occur in the laboratory.
(14:59): Lymphodepleting chemotherapy prepares the patient to receive the CAR T-cells. After that, while the cells are growing, or after they have completed growing, and there is a dose available, patients receive lymphodepleting chemotherapy. This could differ based on the trial, although most trials utilize fludarabine and cyclophosphamide as lymphodepleting regimens, meaning chemotherapy that that is given before the CAR T-cells to prepare the body to accept the CAR T-cells and create a nice home for them so that there is enough food and nutrients for the CAR T-cells to grow.
(15:35): Finally, step six, is when patients receive the CAR T-cell infusion, which, based on the center in which you are receiving it, could be done on either as an inpatient or outpatient.
(15:55): Who is able to access CAR T-cell therapy to treat their leukemia? Typically, the way that the FDA-approved products are now, and what the indication is for that CAR T-cell therapy, CAR T-cell therapy is given to patients who have relapsed, meaning their leukemia has come back or, in patients that have refractory ALL, meaning that their leukemia has not responded to chemotherapy, and it has, in fact, never responded to chemotherapy after either chemotherapy and/or a transplant.
(16:30): FDA-approved CAR T-cell therapies currently available to treat patients with relapsed or refractory acute lymphoblastic leukemia (ALL). Currently, there are two FDA-approved CAR T-cell products for acute lymphoblastic leukemia. One is Kymriah® (tisagenlecleucel), which is a CAR T-cell product that is approved in the pediatric leukemia setting for patients younger than 25 years of age, and which was approved in 2017. A new product, Tecartus® (brexucabtagene autoleucel), received FDA-approval for adults older than 18, in 2021.
(17:17): Kymriah® for pediatric patients with acute lymphoblastic leukemia (ALL). The Kymriah® trial looking at tisa-cel or tisagenlecleucel was performed globally. It demonstrated remarkable response rates in pediatric patients that had relapsed or refractory B-ALL. Twenty-five centers across the world participated in this trial. The initial trial reported on 75 patients that were infused, and they had remarkable responses with over 80% of those patients achieving complete remission, meaning their leukemia went away completely. At twelve months, the event-free survival rate was approximately 50%, meaning that 50% of patients who achieved remission after receiving CAR T-cells, were still in remission at the one-year time point.
(18:43): This is excellent news since these patients had severely refractory leukemia, which had either come back after chemotherapy or a transplant, or the disease had never completely gone away. In this era and in this specific patient population, having a 50% event-free survival rate is remarkable, although obviously there is room for improvement because we want all patients to survive and to have their leukemia stay in remission. Also, to note, this gray line is the overall survival, meaning that patients were monitored for several years after they received CAR T-cells and 75% of patients had survived at that one-year time point.
(19:46): Tecartus® for the treatment of adult patients with acute lymphoblastic leukemia (ALL). This next slide refers to the adult trial that led to the FDA approval of Tecartus®( brexu-cel). This study demonstrated that this CAR T-cell product was effective at treating adult patients with B-ALL. This was a multi-site study that occurred in the United States, done at more than 19 hospitals.They reported on 45 patients who received CAR T-cells for relapsed or refractory B-cell ALL. The study demonstrated that almost 70% of the patients that received these CAR T-cells achieved complete remission rates. They found was that the median duration, or the duration of remission of half of the patients evaluated, was approximately seven months.
(20:41): This graph is taken from the study and demonstrates a patient’s best overall response. As you can see, about 70% of patients achieved complete remissions, denoted here in the CR. We had 4% of patients achieving blast-free or having their leukemia gone. However, they didn’t have cells evaluable in the bone marrow. Some patients achieved partial remission and, unfortunately, some patients had no response.
(21:26): How long does CAR T-cell therapy take? How do patients get CAR T-cells? The process of receiving CAR T-cells for treatment of relapsed or refractory ALL can be quite a lengthy process. You need to have insurance approval for one of the FDA-approved products, which can take about two to three weeks. You need to be referred to a CAR T-cell center. At the present time, I think this is less of a problem, although access still remains a problem if you live in a more remote area. However, there are several centers now that have access to FDA-approved products and who have the experience needed to administer these products and do the collection and send the cells out for manufacturing. If your home hospital doesn’t do CAR T-cells, you would have to go through a referral to a CAR T-cell center.
(22:24): The apheresis is the T-cell collection. This is usually done in a one-day time period, potentially done in a two-day time period if a patient’s blood counts are very low. Once the T-cells are collected, they are shipped to a central location where CAR T-cells are made. That takes two to three weeks for the cells to actually grow, depending on what type of product or what type of CAR T-cell you would be receiving.
(22:58): The chemotherapy that is given before CAR T-cells are infused is usually given four to five days before the patients receive the CAR T-cells, and they usually have a rest day followed by the CAR T-cell infusion.
(23:12): We then monitor patients closely for side effects and toxicities for the first month. Depending on what the patient’s response is at the end of that month, we follow-up with patients at different intervals.
(23:37): Clinical trials, testing CAR T-cell products that are not yet approved by the FDA, may be a treatment option for some patients. There are also several treatment options in the CAR T-cell space to use non-FDA-approved CAR T-cell products. There are several clinical trials for pediatric and adult patients with relapsed or refractory ALL. An excellent website to investigate options for you or a loved one is www.clinicaltrials.gov. This site is updated regularly to demonstrate what trials are available, so you will know what the actual trial is as well as the eligibility criteria.
(24:19): Typically, these trials for non-FDA-approved CARs are either Phase 1 or Phase 2 trials. In Phase 1 trials, it’s the first time that this study is being done in humans. We’re looking at what the side effect profile is, while trying to find the appropriate dose for the CAR T-cell product that is being studied.
Phase 2 trials are generally done after Phase one trials are completed. Phase one would determine what dose would be appropriate, and phase two would look at that dose and use it in a larger patient group so that we could continue to look at the side effect profile.
(25:00): What I feel is most important to our patients and their families, is ‘does it work’? Phase 2 and Phase 3 trials examine how this product would work in a larger patient population in terms of does it get rid of leukemia and what side effects do patients encounter?
(25:23): The last thing I’d like to note on this slide is that the eligibility process and criteria differ depending on the trial. It is very important to collaborate with your home doctors so that they can look at all of the trials available and determine which one you may be eligible for, and then reach out to the team that is running that particular clinical trial.
(25:54): Receiving chemotherapy while CAR T-cells are being manufactured. During the process of making the CAR T-cells, which could be between two and three weeks, you may receive chemotherapy at either your home institution or the hospital that you were referred to for CAR T-cells. That is for one of two reasons. One reason is to keep the leukemia disease process controlled. Perhaps you have low burden disease or low leukemia in your bone marrow, and we want to keep it that way.
(26:45) A second reason you may be given more chemotherapy is to try to decrease the amount of leukemia you have in your bone marrow. Recent studies are emerging that demonstrate that patients with a high leukemia burden in their bone marrow before receiving CAR T-cells, could have more severe side effects and also have a lower chance of getting into remission with CAR T-cell therapy.
(27:07) Prior to infusion of CAR T-cells, patients receive chemotherapy to make room for the cells. So, during the CAR T-cell therapy, as I discussed earlier, about five days prior to the infusion, lower doses of chemotherapy, typically with two drugs called fludarabine and cyclophosphamide, are given in order to prepare your body to receive the cells to create space for CAR T-cells to grow, and be able to use cytokines or the vitamins and nutrition that your body makes on its own so that these cells can grow. We also try to give it to patients to keep the disease under control while the CAR T-cells are growing in the body.
(27:46) Infusion of the CAR T-cells – Day zero. On day zero, the CAR T-cell infusion is done and can be administered as an inpatient or outpatient, depending on the center. Side effects are monitored very closely over the first month after infusion.
(28:04): The most common side effect of CAR T-cell therapy is cytokine release syndrome (CRS). Moving along to some of the most common side effects...cytokine release syndrome, or CRS, is the most common side effect from CAR T-cell therapy and it can involve every part of your body. I like to think about it as more of a generalized side effect in terms of the entire body. It is a group of symptoms that are caused because your body is producing higher than normal cytokines, or inflammation markers, in your body.
(28:46): Over 80% of patients that receive CAR T-cells will get CRS.The onset of cytokine release syndrome is within hours to days after the infusion. The most common symptoms of CRS include fever, low blood pressure, and difficulty breathing or shortness of breath. Looking at the image on the screen, it shows how it could affect multiple areas of a patient’s body including the lungs, heart, kidneys, liver, blood counts, stomach and intestines, muscles, bones, as well as the neurologic system, the brain and nerves.
(29:29): As these CAR T-cell treatments continue to be used, the research continues. And what we’re learning from patients continues. Some of the things that we have learned over the last 10 years since CAR T-cells have come more into the clinical space, is that cytokine release syndrome severity, or how severely a patient experiences this side effect, really depends on the patient and the CAR T-cell characteristics. We have already mentioned that patients that have higher tumor burden and patients that receive more CAR T-cells have an increased risk of developing more severe cytokine release syndrome.
We also know that some products may have increased risk of cytokine release syndrome, or increased severity of cytokine release syndrome, and that timing of CRS varies depending on the patients and which CAR T-cell they receive. These side effects typically occur within the first two weeks after infusion.
(30:44): The symptoms of cytokine release syndrome vary. It is important to know that not all patients will get every symptom. We monitor patients very closely during the first month to see what/if types of symptoms patients are having; we then grade them based on the severity of their symptoms.
(31:07): Low blood pressure due to cytokine release syndrome can occur. Are you experiencing low blood pressure? Is that blood pressure low enough that you need extra IV fluids? Is that blood pressure low enough that you need extra IV fluids plus blood pressure support with medication that would be needed in the ICU? These are the types of things that we watch for. It is important to note that we do know that there are some characteristics that may increase the chance of having more severe symptoms, but we are still learning.
(31:46): How is the severity of cytokine release syndrome graded?. The way that we look at how severe cytokine release syndrome is, there are new grading establishments that have come out over the past few years so that everybody grades cytokine release syndrome in the same way. Grade 1 is the mild type of cytokine release syndrome that is represented by fever only. Grade 2 cytokine release syndrome is represented by fever plus either low blood pressures and/or low oxygen saturations. We define severe cytokine release syndrome as either Grade 3 or 4, if there is fever with need for blood pressure supportive medications, or extra oxygen support that requires ICU level care.
(32:38): Treatment for cytokine release syndrome. Typically, the first line treatment for cytokine release syndrome is supportive care, meaning giving patients fluids and, perhaps Tylenol® (acetaminophen) to attempt to control the fevers, and other supplementation that may be needed. If patients start to get more severe cytokine release syndrome, we try anti-cytokine therapy or a medication called tocilizumab (Actmera®), which is FDA-approved for the treatment of CRS, that can help reduce some of the inflammation in the body. We typically reserve steroids for more severe cases of CRS.
Generally, cytokine release syndrome is reversible with little long-term toxicity noted, although we are still collecting data.
(33:40): Neurological side effects of CAR T-cell therapy (ICANS). The other side effect that is important to speak about is neurotoxicity or the neurologic side effects that can come from CAR T-cell therapy. This has been termed ICANS or immune effector cell associated neurotoxicity syndrome. It is considered one of the most severe side effects and has a black box warning for CAR T-cell therapy. There have been varying rates of neurotoxicity across the trials that have been done looking at CAR T-cells, ranging anywhere from 30% of patients having some neurologic side effects all the way up to 87% of patients who receive CAR T-cells.
(34:24): There are multiple reasons why neurotoxicity occurs, including cytokines, or those inflammatory agents that your body produces. Patients can have a breakdown or a disruption in the blood-brain barrier. Our brain is protected by a specific barrier against invaders of your immune system, or infections that can occur throughout your body. Sometimes during the CAR T-cell process, due to reasons that are still being evaluated in a research setting, the blood-brain barrier can be disrupted, making it easier for some of the cytokines to go into your neurologic system creating inflammation there.
(35:16): And then there are more recent studies that have demonstrated that some of the targets for CAR T-cells can also be found on nerve cells or in the brain. So, the CAR T-cells, if they are targeting a protein like CD19, could potentially bind to other cells that have CD19 and create the side effects from that.
(35:47): Symptoms of neurotoxicity after CAR T-cell therapy. Some of the symptoms of neurotoxicity include confusion and difficulty writing, speaking or following commands. Some of the more severe symptoms of neurologic side effects that could occur in up to 30% of patients include seizures, encephalopathy, or an altered mental status, or brain swelling. Typically, neurotoxicity is seen after cytokine release syndrome, although patients have a wide presentation variability, and the duration of their symptoms differs dramatically.
(36:31): We use frequent assessments, including daily exams and standardized questions to ask patients before they get CAR T-cells and after they get CAR T-cells. For adults, this includes five questions and a handwriting sample. The adult questionnaire is put up on the screen for you to see.
(36:51): For pediatric patients under 12 years of age, we do an observational assessment, between the physicians and the nursing staff, looking at the patient over a course of time to see whether or not we know how these patients are responding to their family members in the room or the nursing staff. Depending on what a patient’s symptoms are, we will determine if they may need additional workups, which could include imaging of the brain using CTs or MRIs, doing a spinal tap or, if there are symptoms that we are concerned may be seizure activity, we would order a seizure EEG.
(37:37): Grading the severity of neurotoxicity after CAR T-cell therapy. Like cytokine release syndrome, we look at neurotoxicity and grade it. Patients with minimal symptoms would be Grade 1. Those with moderate symptoms would be Grade 2. And those with more severe symptoms that need intensive care unit care would be Grade 3 or 4. Those include seizures, brain swelling or weakness or difficulty moving their limbs.
(38:04): Treatment for neurotoxicity after CAR T-cell therapy. The first line treatment for neurotoxicity is supportive care where we increase the frequency of assessments. We may consider adding anti-seizure medications. For patients who develop more severe cases, we would consider giving steroids for the treatment of neurotoxicity.
(38:24): There are several ongoing studies determining if we can use anti-cytokine therapy and/or spinal taps, administering chemotherapy and steroids into the spinal fluid. Neurotoxicity is generally reversible. However, just like CRS, we do not know the long-term effects patients may have from this.
(38:50): Another side effect of CAR T-cell therapy can be low blood counts. Other areas that CAR T-cells may affect, is lowering a patient’s blood counts. You can have low blood counts, including platelets, neutrophils or red blood cells after CAR T-cell therapy for a couple of reasons. One is due to the chemotherapy that was received to get your body prepared for the CARs. Two, it could be due to CAR T-cell induced inflammation.
(39:16): Most patients recover from having low blood counts within 30 days after the infusion. We do supportive care measures to help patients until they start to make cells on their own, including transfusions and GCSF, which is a stimulation to help your white blood cells mature more quickly.
(39:40): We have noted some risk factors that are associated with patients having low blood counts for more than three months These include having a baseline low blood count to start, having severe cytokine release syndrome, and the number of prior lines of therapy you have received.
(40:02): Infections are a possible side effect of CAR T-cell therapy. Infections in CAR are also one of the side effects that we look for. CAR T-cell therapy is often administered to highly immunocompromised patients. We give chemotherapy beforehand, and that can contribute to the risk of infection. We know that infections can occur both early,, less than 30 days after the infusion, as well as any time after the 30-day time point.
(40:26): In general, patients receive prophylaxis medications ,or medications that may reduce the risk of infection, for viruses, fungal infections, and bacterial infections. For patients with either ALL or lymphoma, because of the target that we use for the CAR, healthy cells can also be decreased. There is a medication, or a transfusion, called IVIG, that may be administered for at least three months after the CAR T-cell infusion time period.
There are potential risks of long-term infectious complications, and it depends on institutions in terms of how long they keep these medications on.. When we vaccinate patients after the CAR T-cells have been performed is also institution-specific.
(41:24): What is the patient’s quality of life after CAR T-cell therapy? Another area that we are analyzing is the quality of life of patients after they receive CAR T-cell therapy. We know that patients experience a decline in their quality of life, and an increase in symptom burden that is correlated with cytokine release syndrome.
(41:43): CAR T-cell patients had, in one study, less decline in their quality of life, physical and functional wellbeing, when compared to patients who received a bone marrow transplant. In the pediatric setting, we have been able to look at this. One of the studies, that was published a few years ago, demonstrated that pediatric patients had improvements over the 3-12 month time point after CART-cell therapy in their emotional health, social functioning, school functioning, physical functioning, and in their psychosocial health.
(42:18): These are just some of the things that we need to consider when looking at some of the late effects of CAR T-cell. How does this psychosocially affect patients? What are the toxicities of other organs? Can we improve survival in these patients? What are the neurologic side effects? And how do patients recover their immune system post CAR?
(42:49): What is the future for CAR T-cell therapy to treat patients with acute lymphoblastic leukemia (ALL)? This is a slide looking at whether we think CARs will be the answer for ALL. There are several exciting things in this upfront treatment setting in CAR T-cells, but there is still a lot of work to do. Some patients have CAR product failures, so we can’t make enough CAR T-cells for these patients. Their cells don’t expand, or even after CAR T-cells, they can relapse. They can have severe side effects from the CARs. There are, of course, several other areas of disease that require further treatment options for these patients.
(43:34): For future directions, looking at more CAR T-cell constructs, newer targets that we can use for other disease subtypes; trying to optimize the CAR T-cells that we already have in clinic; reducing the side effect profile; monitoring for long-term outcomes; and improving access are all areas of future direction. I would like to thank you all for your attention and I think it is time to start the Q&A session.
Question and Answer Session
(44:11): [Michala O’Brien]: Thank you Dr. Shalabi for this excellent and informative presentation. Our first question is, how long will a patient’s immune system be compromised following a CAR T-cell therapy?
(44:41): [Dr. Haneen Shalabi]: We have fairly strict guidelines in terms of the types of agents or prophylaxis medications that patients have to take for at least three months after CAR T-cells. It is patient-specific after that. Most institutions will have the patient on some type of antiviral, antifungal and possibly an antibacterial drug for three months; it all depends on your blood counts. Your immune system can be low for several months, based on what your counts were going into CAR. This is monitored very closely for the first three months post CAR infusion. The majority of patients face the highest risk of infection within the first 30 days of CAR therapy.
(45:47): [Michala O’Brien]: What are some suggestions in patient care once we are home with our daughter after CAR T-cell therapy? Is there anything we should be looking for once she’s home from the hospital?
(45:59): [Dr. Haneen Shalabi]: Most of the things that can be monitored are fairly standard for patients with leukemia; things such as her temperature and how she is responding. In most cases, within the first month when toxicities are more likely to occur, you would want to stay closer to the hospital where you received the cells. I would watch for such signs as extreme fatigue; elevated fever; symptoms of illness such as runny nose, cough, or congestion; and experiencing any unusual bleeding. The care in the post CAR T-cell phase is similar to what you would look for following chemotherapy, with the addition of watching for specific signs of neurologic side effects.
(47:13): [Michala O’Brien]: What else is in the media besides CAR T-cells and T-cells? What helps the CAR T-cells grow?
(47:25): [Dr. Haneen Shalabi]: CAR T-cells are grown in the lab, and they administer different cytokines or different nutrients for those T-cells to grow. Depending on the actual product that you are receiving, those cytokines differ. These are normal cytokines that would be found in our own body to help make and produce T-cells. Of course, because the cells are now outside of your body, they need those same nutrients, or cytokines, to grow. The different types of cytokines are what are added to continue to keep the cells healthy and happy and to grow and expand.
(48:13): [Michala O’Brien]: I have one more bag of my stem cells left from an initial collection in 2014. Can that bag of cells be used for CAR T-cell therapy?
(48:25): [Dr. Haneen Shalabi]: I think it depends on which stem cells there are. If they are donor stem cells and there has not been an interval transplant, it is a possibility. But CAR T-cells are made from actual T-cells, so there may not be enough T-cells in that stem cell product. Thinking back to the way that the blood cells are made, if this is an actual stem cell product from a transplant, those baby stem cells may not have already matured into these T lymphocytes that you need to create the CAR T-cell product. If that is what the question is referring to, I don’t think that you would be able to use that bag of stem cells as a CAR T-cell product. But if these are T-cells that have been collected for making a CAR product in the past, then yes, there would be potential to use those if they have been cryopreserved or frozen appropriately, and there has not been a transplant that has happened in between the initial CAR T-cell product and a potential next CAR T-cell product.
(49:48): [Michala O’Brien]: For how long is CAR T-cell therapy effective?
(49:53): [Dr. Haneen Shalabi]: This is a great question, and one that is very patient specific. It can be curative in some patients. Data is coming out in the pediatric experience using tisagenlecleucel (Kymriah®). Long term, if patients are in remission at that one-year mark, it is becoming increasingly evident that those patients will likely have continued remissions at the three- and five-year time point. However, there is a substantial number of patients in that first year who relapse; we are unable to predict, at this time, which patients are going to have prolonged remissions and actually have a cure from CAR. We are working to determine what some of the things are that we can look at to see which patients will have these durable remissions or have CAR T-cells be the cure. Unfortunately, I don’t have a great answer to say that this is how it’s going to be for all patients, because we’re still learning. But what we do know, since we’ve had this FDA approval for the pediatric CAR since 2017, is that if a patient is in remission for a year, the odds are in their favor that they will continue to be in remission for a longer term.
(51:24): [Michala O’Brien]: This is another question on CAR T-cell therapy success. How successful is this therapy? And will it become available on a large scale soon?
(51:40): [Dr. Haneen Shalabi]: I have a lot of hope in CAR T-cell therapy. Ten years ago, we did not have a good treatment repertoire for our patients. We were without many alternatives in terms of what therapies we could offer besides chemo. This has reignited our field to do more, and to develop more therapies. I believe that this is here to stay since I think the remission rates are very remarkable in this population.
(52:22): The fact that there are two FDA-approved products for B-cell ALL bodes well, but as everybody listening to this webinar knows, that is not enough. We continue to encourage the pharmaceutical companies to invest in these platforms so that we can have additional CAR T-cells for more patients.
(52:51): I hope that this continues to be at the forefront of how pharmaceutical companies, Congress, and anyone who is involved in the manufacturing of these products sees the importance of making these products more accessible, since accessibility is still a challenge. Unfortunately, not everybody who needs CAR T-cells can get them. That is something that doctors are trying to improve; if a patient is able to get this therapy and it is FDA approved, it should be available to all patients who would benefit from the treatment.
(53:33): [Michala O’Brien]: Is an enlarged spleen a side effect of CAR T-cell infusion? Has it been observed in trials, and is it an example of a relapse? Should I be worried?
(53:47): [Dr. Haneen Shalabi]: Leukemia normally originates from these stem cells as well as from sites where you make blood; the spleen is an area where blood cells are made outside of the bone marrow space. It is conceivable that CAR T-cells have gone to that area, if there was disease present there before. If this is a new finding on imaging, it would have to be monitored closely for other signs of leukemia or relapse. It is very difficult to know specifically in this case, without knowing the background and whether the spleen was previously enlarged.
(54:42): [Michala O’Brien]: Another question, more for adult patients. Do you see CAR T-cells for adult patients more as an alternative to BMT or as a conduit to it?
(54:59): [Dr. Haneen Shalabi]: This is actually a question in both pediatrics and adults leukemias. Are CAR T-cells curative and should they be stand-alone therapy, or should they be a conduit to a stem cell transplant? If you ask 10 different doctors, they are going to give you 10 different answers. It really depends on the treatment center where you are receiving the CAR T-cell at and whether or not the patient has had a previous transplant.
(55:37): In my experience, in our pediatric patients who have not received a transplant who come to us for CAR T-cells, we would strongly suggest that if they achieve remission, they should consider a transplant since we have decades of experience of transplants,and outcomes from transplants, as opposed to only 10 years of outcomes in CAR T-cell therapy.
(56:06): The other caveat to my answer is that it depends on what type of CAR T-cells you are receiving. Depending on the way the CAR T-cells are constructed, they may be present for a long period of time - CAR T-cells in your blood, in your body and circulation - so the persistence may be there. Or the CAR T-cells may be manufactured in a way that the persistence could potentially be shorter. Those are the types of things that need to be discussed to determine whether or not transplant, as a consolidation therapy after CAR, would be indicated.
(56:46): We have tried to look at it in both the adult and pediatric space for patients that have received CAR; If they didn’t go to transplant or if they did go to transplant and what any outcomes were. Unfortunately, we don’t have a clear answer because some studies show that transplant offers a better survival advantage, while other studies looking at other CAR T-cell products show that transplant doesn’t offer a survival advantage and patients have an overall survival, or an overall event-free survival, that is equivalent or the same to patients that have just received CAR T-cells.
(57:27): It was the hope when CAR T-cells were developed, that this would be a stand-alone therapy, but in practice, it depends on a number of things, including whether patients have had a prior transplant or not, as well as what type of CAR T-cell the patient received.
(57:50): [Michala O’Brien]: In your practice, can you briefly describe any differences between the product Yescarta® and Kymriah®?
(58:01): [Dr. Haneen Shalabi]: Yescarta® (Axicabtagene ciloleucel) is a CD19-directed CAR that generally is thought to have shorter persistence, meaning it stays in the body for a shorter period of time. Kymriah® is the FDA-approved product in pediatric B-ALL that it is believed to have a more prolonged persistence in the body and in the blood. Yescarta® is not FDA approved for B-ALL, although it is FDA-approved in the lymphoma arena. In lymphomas it can have a prolonged remission rate, but it is not FDA-approved in adults with B-ALL at this time.
(58:43): [Michala O’Brien]: Okay, on behalf of BMT InfoNet and our partners, I’d like to thank Dr. Shalabi for a very helpful and informative presentation. And thank you, the audience for your excellent questions. Please contact BMT InfoNet if we can help you in any way.
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