CAR T-cell Therapy for Acute Lymphoblastic Leukemia: Past, Present and Future Directions
CAR T-cell Therapy in Acute Lymphoblastic Leukemia: Past, Present, and Future Directions
Wednesday, May 7, 2025
Presenter: Rawan Faramand, MD, Moffitt Cancer Center
Presentation is 40 minutes with 9 minutes of Q & A
Summary: This presentation gives a thorough description of the CAR T-cell therapy process for B-cell acute lymphoblastic leukemia (B-cell ALL), and discusses short- and long-term side effects and toxicities, expected outcomes, and ongoing research related to this therapy.
Key Points:
- CAR T-cell therapy modifies patients’ own T-cells, important cell in the immune system, to help them identify and kill cancer cells.
- Three CAR T-cell products have been approved by the FDA to treat patients with relapsed or refractory B-cell ALL: tisagenlecleucel (Kymriah), brexucabtagene autoleucel (Tecartus), and obecabtagene autoleucel (Aucatzyl). Relapsed disease means that ALL recurred after initial therapy. Refractory disease means that the patient never got into remission after initial chemotherapy.
- CAR T-cell therapy has improved overall survival for patients with B-cell ALL, but short and long-term toxicities often occur such as cytokine release syndrome (CRS), neurotoxicity (ICANS), and infections.
(01:55): B-cell ALL is the most common leukemia in children, with a 5-year overall survival rate of approximately 90%. It is less common in adults with a survival rate of 55%.
(06:15): In patients with B-cell ALL, cancer cells have a target on their surface called CD19. All commercially approved CAR T products are targeting CD19.
(07:52): Several steps are involved in creating CAR T-cells for patients: collecting T-cells from the patient, modifying them in a special manufacturing facility to become CAR T-cells, and expanding their number, and then reinfusing them into the patient.
(12:56): While the CAR T cells are being manufactured, patients may receive additional chemotherapy to prevent their disease from progressing.
(14:34): After the T-cells are returned to the CAR T center, patients receive a different type of chemotherapy, called lymphodepletion chemotherapy, to make room for the CAR T-cells.
(19:57): Cytokine release syndrome (CRS) is the most common side effect or toxicity associated with CAR T-cell therapy.
(22:54): Neurologic toxicity, otherwise known as immune effector cell-associated neurotoxicity syndrome (ICANS), is the second major side effect in patients treated with CAR T-cell therapy.
(27:59): The vast majority of toxicities happen while patients are in the hospital, but we're also learning about toxicities that occur later and why some patients die from a CAR T-related toxicity.
(28:48): Infections are a common complication following CAR T-cell therapy and can occur in 20% to 60% of patients.
(30:41): As cure more and more patients are cured with CAR T-cell therapy, there’s a growing need to understand survivorship issues in this patient population and learn more about late effects and long-term toxicities.
Transcript of Presentation.
(00:01) [Susan Stewart]: Speaker Introduction. Welcome to the workshop, CAR T-cell Therapy in Acute Lymphoblastic Leukemia: Past, Present, and Future Directions. My name is Sue Stewart, and I will be your moderator for this workshop. Before we begin, I would like to thank Kite, a Gilead company, whose support helped make this workshop possible.
(00:22): It's now my pleasure to introduce to you today's speaker, Dr. Rawan Faramand. Dr. Faramand is a Medical Oncologist at Moffitt Cancer Center in Tampa, Florida. She specializes in blood and marrow transplantation and cellular immunotherapy. She's particularly interested in improving outcomes for patients with acute leukemias and myelodysplastic syndrome. Please join me in welcoming Dr. Faramand.
(00:54) [Dr. Rawan Faramand]: Thank you, Sue, for this kind introduction. I'm very excited to be here with you all today, and I'm looking forward to our discussion, looking at Chimeric Antigen Receptor (CAR) T-cell therapy for Acute Lymphoblastic Leukemia: Past, Present, and Future Directions.
(01:14): Overview of Talk. For the presentation today, we'll talk about acute lymphoblastic leukemia, the indications for CAR T-cell therapy, and an overview of what CAR T-cell therapy is. We'll talk about the patient's journey from the time of initial consultation to the time they get the CAR T infusion, the follow-up care, and key issues for survivorship. We'll discuss both the short and long-term side effects following CAR T-cell therapy for acute lymphoblastic leukemia. We'll wrap up by talking about expected outcomes from this novel therapy and future directions.
(01:55): B-cell acute lymphoblastic leukemia (B-cell ALL) is the most common leukemia among children. In fact, over 50% of patients diagnosed with acute lymphoblastic leukemia (ALL) are under the age of 18. It accounts for about 25% of all childhood cancers in the United States, with the average age of diagnosis being 17 years old. Fortunately, from the time I started my fellowship training to now, we've had tremendous improvement in the outcomes of patients treated for acute lymphoblastic leukemia with novel immunotherapies. Now, we have a five-year overall survival rate of approximately 90% among children.
(02:35): For this discussion today, we'll be focusing on patients with B-acute lymphoblastic leukemia since that's where we have FDA-approved CAR T-cell therapy products. It's also very important to keep in mind that there's a T-acute lymphoblastic leukemia, for which there are some CAR T-cell therapies in clinical trials, but none that are commercially approved, therefore we will not discuss them for today's presentation.
(03:02): An ALL diagnosis in adults is not as common. It accounts for about 20% of all leukemias in patients over the age of 18 years old. Although the outcomes have really improved in the past decade, the five-year overall survival is certainly not as good as we observe in children. It's about 55% in adults as compared to 90% in children.
(03:28): Another important area of research is the study of adolescents and young adults (AYA). As I pointed out on the prior slide, the average age of diagnosis is 17. We know that there are differences in the biology of disease in pediatrics or children as compared to adolescents and young adults. We consider anyone between the ages of 16 and 39 to fit into the AYA category.
(03:55): When we think of B-acute lymphoblastic leukemia, we think of it in three categories. Some patients carry the Philadelphia chromosome. You'll hear the terms ‘BCR-ABL’ or ‘Ph+’ to describe these genetic markers. There's also a Philadelphia-negative B-acute lymphoblastic leukemia, and then there's a ‘Ph-like’ acute lymphoblastic leukemia. That becomes important when we're trying to decide what the best therapy is and the expected outcomes for these different types of leukemia. It also helps us understand the differences in disease biology, as we're much more likely to see Ph+ ALL in adults compared to children, and we most commonly see Ph-like ALL among adolescents and young adults.
(04:43): Before we delve deeper into CAR T-cell therapy, I’d like to discuss some immunology to provide a better understanding of what T-cells are when we talk about this therapy. As cancer immunotherapy continues to progress, and the science continues to evolve, we have a much better understanding of what our own immune system can do to protect the body from threats, such as infections or cancer, and the importance of these T-cells.
(05:13): T-cells rely on detecting antigens found on the soft surface of abnormal cells, such as infections or cancer, to help identify these as potential threats. In patients who are diagnosed with cancer, the T-cells may not be able to recognize the cancer cells.
(05:33): How can we use our own T-cells to help identify and kill cancer cells? This is where chimeric antigen receptor therapy (CAR T) comes in. The first part of this process is apheresis, which we will cover in more detail in the following slides. This is a process in which the T-cells are removed from the blood. Since we know that these T-cells are unable to recognize the cancer cells, these cells are genetically modified with a CAR receptor. I think of it like a GPS, allowing us to help those T-cells identify the cancer cells.
(06:15): For B-acute lymphoblastic leukemia, we know that the cancer cells and malignant B-cells express a target called CD19. All commercially approved CAR T products are targeting CD19. In different cancers, different targets are used. These CAR-T cells are expanded in the lab and then infused back into the patient.
(06:44): There are three commercially approved products for B-acute lymphoblastic leukemia. The first one is tisagenlecleucel (KYMRIAH), which is approved for patients up to age 25 years who have either refractory or relapsed disease. This was the first CAR T product that was approved, back in 2017, so we're approaching nine years after this approval. That approval was based on the pivotal ELIANA study.
(07:12): Brexucabtagene autoleucel (TECARTUS) is approved for patients over the age of 18 with either relapsed or refractory disease. That approval came in 2021 based on the ZUMA-3 clinical trial. Most recently, we have obecabtagene autoleucel (AUCATZYL), which is approved for adults over the age of 18. It was just approved in late 2024 based on the results of the FELIX clinical trial. As you can see, only one of these products is approved for children. The other two products are approved for adults.
(07:52): After a patient has been approved for CAR T-cell therapy, the first step is to collect the patient’s T-cells using a process similar to donating blood. In terms of the steps in CAR T-cell therapy, I'd like to show this schematic, and we'll go over it in more detail in the following slides. The first step you can see in the top left is the apheresis, where we collect the T-cells. It's a similar process to donating blood, using a machine that looks very similar to a dialysis machine, that helps collect these T-cells.
(08:16): The T-cells are then sent to a manufacturing facility to create CAR T-cells. The T-cells are then sent off to a manufacturing facility to create CAR T-cells depending on which product was selected by your treating physician. These T-cells are genetically engineered and then grown in the lab to proliferate.
(08:29) In the interim, the patient receives lymphodepletion chemotherapy which allows the CAR T-cells to expand in the body and then ultimately, goes on to receive the infusion. And for patients with ALL, these CAR T cells will be targeting CD19.
(08:49): In regards to the patient’s journey, the first step of the process is the consultation, during which you meet with your clinical team to review indications for CAR T-cell therapy. At that time, if you are a candidate for CAR T-cell therapy, insurance authorization is submitted and the product is chosen based on the patient and disease-specific factors, in addition to things such as manufacturing time.
(09:18): Once we receive the insurance authorization, the scheduling is completed for the apheresis process. It then takes an average of two to three weeks for those CAR T cells to get manufactured. In the interim, the patient undergoes testing to make sure they are in good shape and a good candidate for CAR T-cell therapy. An additional therapy called ‘bridging therapy’ may be needed at that time, and we'll go over that. Ultimately, the patient comes in for the CAR T treatment. That starts with lymphodepletion chemotherapy, which helps the CAR T cells expand in the body. The CAR T cells are then infused, and the patients are closely monitored.
(09:59): At the time of the initial consultation, one of the most important things is understanding what treatment the patient has had in the past, and what type of ALL they have. We look at things like Philadelphia chromosome positive or negative, or Ph-like disease. Luckily, we now have much more sophisticated testing that lets us know if there's still any minimal disease in the marrow, called minimal residual disease. Then we look to see if the patient is fit, and what other medical problems they have, to determine if they are a candidate for CAR T-cell therapy.
(10:33): All three commercially-available products are approved for patients who either have relapsed disease – which means their ALL recurs after initial therapy – or disease that unfortunately never gets the patient into remission after initial chemotherapy – known as refractory disease. Again, the type of CAR T-cell product we use will be determined by the treating physician. This will depend on patient factors, as well as things such as manufacturing time and product availability, as not every treatment facility has access to all three CAR T products that are approved. After the clinical team determines that you would benefit from CAR T-cell therapy, and of course taking into account the patient's choice and practicing shared decision-making at that time, the insurance authorization is then submitted.
(11:26): Before we start with the actual CAR T treatment, we like to complete tests to make sure there are no active infections or other major medical problems that increase the risk of complications from CAR T-cell therapy. For patients who've had a prior stem cell transplant, they're very familiar with this process, otherwise known as ‘vital organ testing’.
(11:49): This includes imaging studies – typically a chest X-ray or a CAT scan of the lungs – to make sure we don't see any pneumonia or any problems in the lungs. We do an echocardiogram – which is an ultrasound of the heart – to make sure that the heart is functioning normally. One of the most important things is getting a bone marrow biopsy, in addition to a lot of blood work, to look for prior infections, also called infectious disease markers (IDMs).
(12:18): The cells are then collected through apheresis; a process typically performed in an outpatient setting. It may include the placement of a central venous catheter, which is an IV catheter that looks similar to a port, except that it has a line protruding out of the skin, that helps us collect the cells. Sometimes, we're able to collect the cells with just a regular peripheral IV in the arm. The T cells are then shipped to the facility, which will take about two to three weeks to manufacture CAR T cells, depending on the CAR T product that is used.
(12:56): While the CAR T cells are being manufactured, we may give additional chemotherapy and perform a bone marrow biopsy, as it helps us understand how much leukemia cells are in the marrow.
(13:20): For patients with ALL, sometimes the marrow does not have any leukemia cells, but they have disease outside of the marrow, called ‘extramedullary disease’. In that case, we would also do a PET scan or a CT scan to see if there's any disease outside of the marrow. That might also include a lumbar puncture to see if there's any disease in the cerebral spinal fluid, which is the fluid surrounding the spinal cord and the brain.
(13:45): The reason these tests are important is that we know that the amount of disease correlates with outcomes. Patients who have a very little amount of leukemia cells in the marrow or in the extramedullary areas tend to have less toxicity, and a better chance at achieving remission. Typically, if a patient has a lot of disease in their marrow or a lot of extramedullary disease, the treating physician may choose to give additional therapy called ‘bridging therapy’, which will depend on what type of therapy the patient has had in the past, the subtype of their leukemia, and their overall medical fitness or well-being. This bridging therapy is completed typically after apheresis and before the next step, which is lymphodepletion chemotherapy.
(14:34): After the T-cells are manufactured and they're received back at the facility, we give a different type of chemotherapy called lymphodepletion chemotherapy, which is given typically in the outpatient setting over three to four days. This type of chemotherapy is typically very well tolerated. The most common lymphodepletion therapy we use is a combination of two chemotherapy drugs: fludarabine and cyclophosphamide.
(15:03): We give this type of chemotherapy because the goal here is to help the CAR T cells expand within the body, and this chemotherapy regimen helps prepare the body to receive them. The name “lymphodepletion” comes from the lymphocytes – which are part of the white blood cells – which we're trying to eliminate before giving the CAR T-cell therapy. This will allow those CAR T cells to grow and expand in the body so they're able to kill the cancer cells.
(15:37): After the lymphodepletion chemotherapy is completed, the next step is the actual CAR T infusion. The CAR T cells are given through an IV catheter. It looks very similar to receiving a stem cell transplant, if you've ever had one, or a blood transfusion, and it can occur either in the hospital or in the outpatient setting, depending on the treating facility. Then, most importantly, the patients will continue to be monitored for at least 30 days after the infusion.
(16:04): Each program has specific guidelines regarding local lodging requirements. Some of those guidelines also come from the FDA, in which some patients may need to be closer to the treating facility, such as living within an hour of the treating facility. This is also the time where our program, and the majority of programs, will require a caregiver, meaning someone remaining with the patient 24/7 for at least 30 days. The caregiver is not required when the patient is in the hospital receiving treatment, but we do heavily rely on the caregiver when the patient is in the outpatient setting.
(16:46): There are both short-term toxicities, and delayed-onset neurologic toxicities that can occur post CAR T-cell therapy. I like to think of them in three separate buckets. The most common is cytokine release syndrome (CRS). The second most common is neurologic toxicity, also known as immune effector cell-associated neurotoxicity syndrome (ICANS). We previously discussed CD19 and its expression on malignant B-cells, also known as cancer cells. CD19 is also expressed on normal B-cells, and unfortunately, CAR T cells will not discriminate. Eradicating some normal B-cells causes something called B-cell aplasia, which impacts the immune system and can increase the patient's risk of infections. Because of this B-cell aplasia, patients may also have low blood counts, even beyond the first 30 days of treatment. Then we worry about toxicity to other organs, which we'll review in the next few slides.
(17:51): There are a handful of risk factors for these immune-mediated side effects. I also like to think of these in three separate buckets. One is the CAR T-cell product we are using because they all have different toxicity profiles. Second are patient-related factors, such as the patient's performance status or fitness level, and other medical problems they may have. Third, how many leukemia cells are in the bone marrow, what is the subtype of leukemia, and do we expect that to be associated with more or fewer side effects?
(18:29): There is a general timeline of when these toxicities occur. Typically, the first week of treatment is when we're giving this lymphodepletion chemotherapy, and we count the day of the CAR T infusion as ‘day zero’. Everything that comes before that will be in the minuses. For example, if chemotherapy starts five days prior to the CAR T infusion, that day will be, “day minus five.”
(18:55): Typically, during the few days of lymphodepletion chemotherapy, patients do very well, with very few side effects outside of potential nausea, which is very well managed with anti-nausea medication. On day zero, the CAR T-cell product is infused. We typically see the main side effects, which are cytokine release syndrome (CRS) and neurologic toxicity (ICANS), within the first two weeks of treatment.
(19:21): Delayed-onset neurologic toxicity can happen up to eight weeks after the CAR T infusion, but it's much more common for delayed-onset neurotoxicity to happen with other diagnoses than to ALL. For example, for patients with multiple myeloma, there can be adverse events that happen after 30 days. Most of those are related to infection and low blood counts.
(19:57): We'll first discuss cytokine release syndrome (CRS), as it's the most common side effect or toxicity associated with CAR T-cell therapy. It occurs in the vast majority of our patients – at 70% to 90% – and can potentially be life-threatening.
(20:07): The reason CRS happens is because these T-cells are very active, and when they identify the cancer cells and kill them, they can release a lot of cytokines or chemicals. This causes a lot of inflammation, like an inflammatory storm in the body.
(20:23): Cytokine release syndrome typically occurs within the first week of CAR T-cell infusion, depending on the product we're using. Some can happen earlier, and some can happen later. We grade CRS as grade one through four depending on the severity of symptoms. The goal is to prevent this life-threatening complication, while still making sure the CAR T cells are effective.
(20:53): This schematic illustrates potential outcomes associated with cytokine release syndrome. When patients get cytokine release syndrome, typically, the first sign is a fever. When a fever happens, we also want to make sure it's not related to infection. We do blood cultures, urinalysis, and imaging to make sure it's not an infection, and we typically start the patient on IV antibiotics. We may be in discussion with infectious disease specialists, and once we determine there is no infection, then typically we can safely discontinue the antibiotics.
(21:31): Because there is this inflammatory storm, our patients can develop a fast heart rate – known as tachycardia – or low blood pressure – known as hypotension. We can also see the impact on other organs, particularly when the blood pressure is very low. We can observe impacts on the liver, which may cause elevation of certain liver enzymes, or in some cases, patients may develop respiratory distress or difficulty breathing.
(21:59): The management of CRS depends on the severity of symptoms. Typically, management of depends on the grade. For patients who only have a fever, normal blood pressure, no problems breathing, and no other major side effects, typically we manage that with supportive care, meaning things like acetaminophen (Tylenol) to control the fevers and IV hydration.
(22:21): For more severe cases, treatment includes anti-cytokine therapy. With cytokine release syndrome, there are a lot of cytokines – such as Interleukin 6 – that can be released. Luckily, we have medications specifically designed to get rid of those cytokines, such as tocilizumab or anakinra. We can also give steroids. Very severe cases of cytokine release syndrome may require additional support in the intensive care unit.
(22:54): Neurologic toxicity, otherwise known as immune effector cell-associated neurotoxicity syndrome (ICANS), is the second major side effect in patients treated with CAR T-cell therapy. It's not as common as CRS. It can occur in about 20% to 60% of patients, but it's particularly concerning for the caregivers or loved ones who are with our patients during this time. The symptoms can include confusion and difficulty speaking. It may look very similar to a stroke, and include weakness, seizures, or very rarely, a life-threatening complication of swelling in the brain known as ‘cerebral edema’.
(23:36): The onset of neurotoxicity can happen in various phases. It can sometimes occur concurrently with cytokine release syndrome, within the first week of CAR T-cell infusion. Typically, when a patient has a very high fever, sometimes they can develop some confusion, so it could be more related to the cytokine release syndrome. Or it can occur after the cytokine release syndrome symptoms have completely resolved. In some cases, neurotoxicity can happen weeks after the initial CAR T infusion.
(24:13): We grade ICANS using a scoring system called the immune effector cell encephalopathy (ICE) score, which you can see on the screen. We ask patients these questions every single day, and then we grade them using the results of the ICE score. We also look at other important factors such as level of consciousness, any seizure activity, any weakness, or any evidence of increased cerebral pressure or cerebral edema. While this is a very scary symptom that can happen with CAR T, and it’s very common, the vast majority of our patients will completely recover from any neurologic toxicity.
(25:02): We do recommend anti-seizure medications for the first month of CAR T treatment to prevent the risk of seizures. For patients who've had a prior seizure history, or have ALL in the cerebral spinal fluid, sometimes we ask our neurologists to see these patients prior to treatment just so they're aware that these patients have a higher risk of neurologic toxicity. It's also important to note that even patients who do have ALL in the cerebral spinal fluid have been successfully treated with CAR T-cell therapy. Since we have not actually seen a significantly higher rate of neurologic toxicity, we know this therapy is both safe and effective, even in patients who have cerebral spinal involvement.
(25:49): Patients with mild toxicity can be managed with supportive care. In patients who have a more severe toxicity, we sometimes do additional imaging – such as a brain MRI, CT scan and lumbar puncture – to rule out other neurologic problems. The majority of these patients who do develop neurologic toxicity can be managed with things such as steroids, and we can also use additional medications to combat cytokines to treat the neurologic toxicity.
(26:23): How common these toxicities are depend on the specific CAR T-cell therapy they receive. It's important to note that these clinical trials had different scoring systems that were used for grading of CRS and neurologic toxicities, and they have had different management schemas. Some of the initial data with tisagenlecleucel (KYMRIAH) is now over 10 years old. As the science has progressed, there have been changes in both the identification and treatment of these toxicities.
(27:03): In patients treated with tisagenlecleucel (KYMRIAH), cytokine release syndrome was observed in 77% of patients, with approximately 46% experiencing a grade 3 or higher cytokine release syndrome. 40% of patients developed neurologic toxicity with 13% of patients having a grade three or higher neurologic toxicity.
(27:15): For patients treated with brexucabtagene autoleucel (TECARTUS), cytokine release syndrome occurred in 89% of patients, with grade three or higher occurring in 24%. Any grade neurologic toxicity occurred in 60% of patients with grade three or higher at 25%.
(27:35): Most recently, obecabtagene autoleucel (AUCATZYL) was approved. For this product, cytokine release syndrome was observed in 69% of patients, but grade three or higher toxicity was low at 2%. Any-grade neurologic toxicity occurred in 23% of patients, with grade three or higher toxicity occurring in 7% of patients.
(27:59): While it's important to note that the vast majority of toxicities happen while patients are in the hospital, and most of these toxicities are cytokine release syndrome or neurologic toxicity, we're also learning about late effects and reasons why some of our patients unfortunately can die from a CAR T-related toxicity. In about 50% of patients, this is related to infections, but we also worry about organ toxicity, secondary malignancies, severe neurologic toxicity, or severe CRS. One other important item to note is that this pie graph is looking at all patients with CAR T-cell therapy and is not specific to patients treated for acute lymphoblastic leukemia.
(28:48): Infections are a common complication following CAR T-cell therapy and can occur in 20% to 60% of patients. While the vast majority will occur in the first 30 days after CAR T-cell therapy, late infections can occur in about 20% to 40% of patients.
(29:06): We know infections are very common, and the best way to prevent these infections is to put our patients on antimicrobial therapy. That also includes medications to prevent viruses. We usually put our patients on a medication called acyclovir, as well as on an antimicrobial called sulfamethoxazole/trimethoprim (Bactrim), to prevent a specific lung infection called pneumocystis jiroveci pneumonia (PJP pneumonia).
(29:34): Other approaches to prevent infections include using an intravenous immunoglobulin called IVIG to help boost the immunity, because we know CAR T-cell therapy can lower IgG levels. We also recommend vaccines to prevent infections with the caveat that we're still learning about the efficacy of vaccines following CAR T-cell therapy.
(29:57): We have extrapolated a lot of this data from the transplant literature since transplants have been around for a lot longer than CAR T-cell therapy. This is an area of active research where we're still trying to learn what the best approach is to prevent these infections. Because each program may have specific recommendations, there can be generalized recommendations as well as program-specific recommendations. Typically, in our program, we recommend that patients can return to work or school six months following CAR T-cell therapy. Of course, that depends on patient-specific factors and how well they're doing after treatment.
(30:41): As we've been able to cure more and more patients with CAR T-cell therapy, we have a growing need to understand survivorship in this patient population, and are continuing to learn more about late effects and long-term toxicities. Some of those areas of research include understanding the financial burden, or financial toxicity, of CAR T-cell therapy overall. Also, understanding how CAR T-cell therapy can impact things such as mood and fatigue. We're trying to understand any late effects of neurologic toxicity and the development of hyperkinetic movement disorders, which are much more common in patients treated with CAR T-cell therapy for multiple myeloma.
(31:25): Infections, prolonged cytopenias, or low blood counts following CAR T-cell therapy are common, and we're learning a lot more about therapy-related secondary cancers, such as the development of AML or myelodysplastic syndrome following CAR T-cell therapy.
(31:47): There are specific needs that are unique to various patient populations. One need I'd like to highlight is in adolescents and young adults (AYA), understanding fertility and sexual health needs following CAR T-cell therapy. We completed a small study here at Moffitt Cancer Center. It included 13 AYA patients, where we evaluated their sexual health, health-related quality of life, and the way they communicated about their sexual health needs with the healthcare providers.
(32:17): We learned about three common themes. One is that young adults perceived a lack of healthcare provider awareness of the importance of sexual health to this patient population, and that there was a lack of sexual health communication and information about what they should do following CAR T-cell therapy. One of the barriers to asking questions and learning more about sexual health and fertility post-CAR T was that many of these patients had their parents as their caregivers.
(32:49): We also identified that the average interest in sex was lower after CAR T for females but not males. Females reported worse fatigue, more impaired social function, and worse emotional experience following CAR T-cell therapy. Most of our patients did not recall discussing any sexual health needs with their healthcare provider either before or following CAR T-cell therapy.
(33:12): With the help of the Leukemia and Lymphoma Society, we are conducting a trial that will be a patient-facing survey to understand more about fertility following CAR T-cell therapy. It is assessing whether patients were provided with any type of fertility education or resources, and for those patients who wanted to grow their families, whether they've been successful in conceiving following CAR T-cell therapy, either on their own or with the assistance of reproductive therapy. That survey should be up, and if you want more information about that, you can email pact@lls.org.
(33:49): For the next section of our presentation, we'll be talking about expected outcomes following CAR T-cell therapy.
(34:00): What is the outcome when the CAR T product tisagenlecleucel (KYMRIAH) is used to treat B-cell ALL? As we discussed earlier, tisagenlecleucel (KYMRIAH) was the very first CAR T product approved, and this is specifically for pediatric children and young adult patients up to age 25, and we already know the data from the ELIANA study was a pivotal clinical trial.
(34:17): It's also important to look at real-world data and get data from treating facilities across the U.S. That is where the Center for International Blood & Marrow Transplant Research (CIBMTR) comes in.
(34:26): This looks at data from 73 centers across the United States. We saw that 55% of patients developed cytokine release syndrome, but only 16% had a grade three or higher of more severe toxicity. Neurologic toxicity was seen in 27% of patients, and about 9% to 10% had a more severe neurologic toxicity. At the 12-month mark, 52% of patients were alive without evidence of relapsed disease. At the 12-month mark, the overall survival – the percentage of patients who were alive – was 77%. It's important to note that about 16% of patients did go on to receive a stem cell transplant. It's also important to note that many patients who received CAR T-cell therapy had already undergone a prior transplant as part of their initial treatment.
(35:20): What is the outcome when the CAR T product brexucabtagene autoleucel (TECARTUS) is used to treat B-cell ALL? Brexucabtagene autoleucel (TECARTUS) was the second product approved based on the ZUMA-3 study. With this product, 73% of patients were able to achieve remission, and the overall survival was 71%. A recently updated analysis was presented last year showing an average survival of approximately 25.6 months. In the patients who achieved remission, their average survival was 47 months.
(35:54): What is the outcome when the CAR T product obecabtagene autoleucel (AUCATZYL)is used to treat B-cell ALL? The most recently approved product is obecabtagene autoleucel (AUCATZYL). One important thing to point out is that this product is given in two infusions, and they're separated by at least one week. The starting dose of the cells depends on how many leukemia cells are in the bone marrow prior to the start of lymphodepletion chemotherapy. More than half of patients treated on this clinical trial had a prior stem cell transplant, which is very similar to the other approved products. The oldest patient treated here was 81 years old. The average leukemia cell count was about 40%, and 23% of patients had disease outside of the bone marrow. With an average follow-up period of about 22 months, 78% of patients achieved a remission with an average event-free survival. 50% of patients didn't have relapsed disease, and the average overall survival rate at one year was 61%.
(37:00): We know we have three commercially approved products, one of which is only approved for patients who are pediatric or young adults up to age 25. Overall, across those three products, we have excellent initial response rates, but we're focusing research on how we can improve the response rates and the durability of response to decrease the risk of relapse that can still occur following CAR T-cell therapy.
(37:34): There is ongoing research regarding what happens after CAR T-cell therapy is completed and remission is achieved. You saw across the three products that the vast majority of patients will respond to CAR T-cell therapy. Some of these patients may require a stem cell transplant. There are trials, mostly in the pediatric space, to look at who can benefit the most from stem cell transplant after CAR T-cell therapy. This is an area of active research where we don't have all the answers yet. We're trying to identify whether some patients can be treated with CAR T-cell therapy alone and potentially be cured from their leukemia, or if patients still require a stem cell transplant following CAR T-cell therapy. It is very important that after CAR T-cell treatment, patients continue to check in with their treatment team to monitor for potential complications, such as infections, and to track for any signs of relapse.
(38:30): I will say that the future is very bright for patients with acute lymphoblastic leukemia. In the past decade, there's really been a shift in the way we treat patients with ALL, and luckily, there are several new therapies that have been approved for patients with ALL. The future of CAR T-cell therapy research is vast, and there are many things going on that we could spend hours discussing.
(38:56): There are specific approaches currently being studied for CAR T-cell therapy. One is using healthy donor T-cells. These are called allogeneic CAR T-cells, or ‘off-the-shelf CAR T-cells,’ that would be readily available. A different approach is targeting two or more antigens instead of CD19 – which is the main antigen that the commercial products are approved for – as well as developing new CAR T-cell products that might be able to persist longer to decrease the risk of the disease coming back.
(39:29): There are ongoing trials in identifying the patients who can be treated with CAR T-cell therapy alone, versus the patients who may benefit from a stem cell transplant. We're also looking to see if using CAR T-cell therapy as an earlier line of therapy – such as for patients who have minimal residual disease – might translate to better outcomes in the future.
(39:52): Conclusion. We're very excited about all the science that's going on to hopefully improve outcomes for patients with acute lymphoblastic leukemia. With that, I'm happy to take any questions. Thank you so much for attending this session.
Question and Answer Session
(40:08): [Susan Stewart]: Thank you, Dr. Faramand, for a very comprehensive look at CAR T-cell therapy for ALL. We'll start our question-and-answer session now. How long do CAR T cells survive in the body?
(40:37): [Dr. Rawan Faramand]: We don't know the full answer to that. We know they can survive for months to years following CAR T-cell therapy, but it depends on the product that is used. We don't have any commercial assays or blood tests to know if the CAR T-cells are there after the patient is treated with CAR T-cell therapy. It is an area of active investigation, but we know they can last a long time.
(41:03) [Susan Stewart]: What are some indications that CAR T-cell therapy is working? Is this something a caregiver could identify?
(41:14): [Rawan Faramand]: Unfortunately, there is nothing that would tell us if CAR T-cell therapy is working outside of a bone marrow biopsy or imaging scan. But the caregivers have a very important role to identify any side effects of CAR T-cell therapy.
(41:31): [Susan Stewart]: Are infections after CAR T-cell therapy more common or more severe compared to the kinds of infections one gets from an allogeneic stem cell transplant?
(41:46): [Dr. Rawan Faramand]: That is another area where we're learning more and more. It seems similar in terms of severity for patients who've received a prior stem cell transplant.
(42:00): [Susan Stewart]: How long will a patient's immune system be compromised after CAR T-cell therapy?
(42:09): [Dr. Rawan Faramand]: We know the time the immune system is at its weakest is typically within the first six months to a year of CAR T-cell therapy. There are some blood tests we can do that are surrogate markers to help us identify if there is anything we can do to boost the immune system. We recommend checking blood work for IgG levels, for example. Then, we recommend providing IVIG to help boost those immunoglobulin levels to improve the immune system’s ability to fight infections.
(42:45): [Susan Stewart]: How long does a patient need a 24/7 caregiver, and what specifically are the caregivers expected to do?
(42:57): [Dr. Rawan Faramand]: We recommend a caregiver until day 30 of CAR T-cell therapy. The main thing we're expecting from the caregivers is to identify any cytokine release syndrome. So, if there's any fever, or if there's any evidence of neurologic side effects – such as confusion, difficulty speaking, or someone not acting like themselves – they must take the patient to the treatment center. It can be very subtle changes that prompt the caregiver to call the treatment facility and bring the patient in.
(43:28): For many products, we don't allow patients to drive for about eight weeks following CAR T-cell therapy because of the risk of delayed neurologic toxicity. We rely on the caregiver to be able to drive the patient, help with medication management, and alert the treatment team to any side effects.
(43:46): [Susan Stewart]: If your clonoSEQ result is zero, and you had a brief relapse in the lumbar fluid, should you go early to CAR T-cell therapy?
(43:59): [Dr. Rawan Faramand]: I'd say that is more of a clinical question. It really depends on what prior treatment the patient has received. That's something that I would encourage them to discuss with their treatment team. We know that CAR T-cell therapy can be effective even in patients with only central nervous system (CNS) disease or those with only extramedullary disease.
(44:22): [Susan Stewart]: Why isn't CAR T-cell therapy available to patients with other types of leukemia like AML?
(44:33): [Dr. Rawan Faramand]: In AML, we have a more difficult time identifying the perfect antigen to target. For patients with ALL, we know that CD19 is expressed on those leukemia cells, but for patients with myeloid leukemia such as AML, we have a much harder time identifying what that perfect antigen is. So far, we haven’t been able to identify one that works across the board. There are several CAR T trials for patients with myeloid diseases, but none that are yet commercially approved.
(45:08): [Susan Stewart]: Have there been any positive reports about CAR T-cell therapy for solid tumors like breast cancer?
(45:19): [Dr. Rawan Faramand]: There are different types of T cell immunotherapy that have been evaluated for patients with solid tumors, but we don't yet have any CAR T-cell products that are approved for patients with breast cancer or GI cancers, although they are currently being studied in clinical trials.
(45:40): [Susan Stewart]: How long do the CAR T cells remain in your body? Do they have to stay in your body to keep you in remission?
(45:50): [Dr. Rawan Faramand]: That is also an area of active investigation. We know there are some patients who still have CAR T-cell persistence, but their disease recurs. We know there are other patients where we can no longer detect the CAR T cells, but the patients continue to be in remission. That's a question that I don't have the full answer to yet. We're hoping to be able to answer that question in the next few years with ongoing research studies.
(46:22): [Susan Stewart]: You mentioned that there might be medical problems that a patient might have prior to CAR T that would preclude them from going to CAR T. Can you expand on that and talk about what kinds of medical problems might make them an inappropriate candidate for CAR T?
(46:42): [Dr. Rawan Faramand]: It really depends on the treatment facility. For example, at our institution – Moffitt Cancer Center – we don't have a specific age cutoff for CAR T-cell treatment, but some other centers may have an age cutoff. Mostly, we're looking to make sure that their cardiac function is good, so no history of really severe heart failure. We also want to make sure that the respiratory status is good and that patients are not on oxygen at home, but those are not set in stone. It's always a risk-benefit discussion with the patient; looking at them from a holistic lens and not one specific thing that would exclude patients.
(47:24): [Susan Stewart]: How do you make a decision between going to a stem cell transplant versus CAR T-cell therapy first?
(47:44): [Dr. Rawan Faramand]: A transplant is most effective in patients who don't have any evidence of ALL. We use it as a consolidation therapy for our patients who are in a really good remission. We use several studies or tests to really make sure there's no leukemia at all. Some of these tests are called minimal residual-disease testing to see that even beyond just looking under the microscope, there are no leukemia cells at all.
(48:11): We know that patients who are in a really good remission prior to a stem cell transplant are the patients who do the best following stem cell transplant. CAR T-cell therapy is used for patients who have relapsed or have refractory disease, so the indication is a little bit different. Typically, we use CAR T-cell therapy for patients who have some evidence of leukemia cells either in the marrow or outside of the marrow.
(48:38): [Susan Stewart]: If you're trying to choose a CAR T-cell center, what are some of the factors you should consider? Does the number of procedures that they do make a difference in terms of outcome?
(48:53): [Dr. Rawan Faramand]: I think it's important to go to a facility that has a lot of experience with CAR T-cell therapy. I would want to make sure they've been doing CAR T-cell therapy for a while and have the expertise to manage these side effects. I'd also want to make sure it is a facility that is close to home and manageable for the patient to continue to follow up. They must be able to remain in the area close to the CAR T-cell center, because it's very important to have long-term follow-up after the CAR T-cell therapy is administered. That's where we form these collaborative relationships with our community oncologists. Many times, our patients must travel for CAR T-cell therapy. We continue to work with their oncologists in the community to make sure they're getting the best care, without having to come to the treatment facility as often.
(49:45): [Susan Stewart]: Closing. That is the end of our questions. I want to thank you, Dr. Faramand, for a very helpful presentation. I also want to thank the audience for the excellent questions that you asked during this presentation. If there's anything BMT Infonet can do to assist you, please don't hesitate to contact us.