CAR T-cell Therapy for Lymphoma: What's Involved, Potential Outcomes

For patients who have relapsed after standard treatment for lymphoma, CAR T-cell therapy may be an effective treatment.

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CAR T-cell Therapy for Lymphoma: What's Involved, Potential Outcomes

Presenter: Dr. Basem William, MD, Clinical Director of the Blood and Marrow Transplant and Cell Therapy Program, Medical Director of the Cell Therapy Laboratory and Immune Effector Cell Program, Adjunct Professor at the Ohio State University College of Medicine.

Presentation is 26 minutes long, followed by 19 minutes of Q&A

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

Summary:  CAR T therapy (chimeric antigen receptor therapy) is a new treatment strategy that has been shown to improve patient outcomes.  In this lecture, Dr. William reviews the steps involved, including T-cell collection, lymphodepleting chemotherapy, reinfusion of T-cells, and follow-up care. Potential side effects and their treatments are discussed as well.

Key Points:

  • CAR-T therapy involves collecting a patient's own T-cells, genetically modifying them to attach to the cancer cells and kill them, and then reinfusing them back into patients after lymphodepleting chemotherapy.
  • Patients receiving CAR T therapy are at risk for cytokine release syndrome (CRS) and neurotoxicity (ICANS). These can be potentially severe side effects, so patients need to be near the cancer center for four weeks after receiving their infusion of CAR T-cells.
  • CAR T-cell therapy has been successful in improving survival and cure rates for patients with various types of lymphoma.


(02:58): The reason why CAR T-cell therapy works, when chemotherapy fails, is because CAR T-cell therapy kills cancer cells using a different mechanism than chemotherapy.

(03:55): The FDA has approved CAR-T therapy for patients with relapsed or refractory diffuse large B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, B-cell acute lymphoblastic leukemia, chronic lymphocytic leukemia, and multiple myeloma.

(05:54): 60% of lymphoma patients treated with standard chemotherapy can be cured. The remaining 40% will need additional treatment to prolong their life and/or be cured.

(08:09): Once a patient is referred to a CAR T center, it can take 10-21 days to get insurance approval for the procedure and reserve a slot at the facility that will manufacture the T-cells. 

(09:00): Once the patient’s T-cells are collected, it can take 10-28 days for the manufacturing company to covert them into CAR T-cells.

(11:04): Once the T-cells are back at the center, patients receive lymphodepleting chemotherapy three days before the T-cells are reinfused back into the patient.

(13:11): Patients are seen by a provider daily for four weeks after CAR T-cell therapy. Remote monitoring technology is being used by some centers to help detect problems in a timely manner.

(14:16): Cytokine release syndrome (CRS) causes inflammation after CAR-T therapy. Symptoms include fever, low blood pressure and shortness of breath.

(16:21): Neurotoxicity, also known as ICANS (Immune Effector Cell-Associated Neurotoxicity), occurs when cytokines cross the blood-brain barrier. Symptoms include tremors, confusion, and seizures.

(19:35): While many patients do not experience long-term side effects of CAR-T therapy, some patients experience long-term loss of B-cells that requires ongoing intravenous immunoglobulin infusions and antiviral medication, and low blood counts. 

Transcript of Presentation

(00:03): [Michala O'Brien]: Welcome to the workshop, CAR T-cell Therapy for Lymphoma: What's Involved, Potential Outcomes. My name is Michala O’Brien and I will be your moderator for this workshop today.

(00:08): I'd like to thank Kite, a Gilead company, whose support helped make this workshop possible.

(00:20): Introduction of Speaker. It's my pleasure to introduce today's speaker, Dr. Basem William. Dr. William is the clinical director of the Blood and Marrow Transplant and Cell Therapy Program, as well as the medical director of the Cell Therapy Laboratory and Immune Effector Cell Program and an adjunct professor at the Ohio State University College of Medicine. Please join me in welcoming Dr. William.

(00:52): [Dr. Basem William]: Overview of Talk. Thank you so much, I'm grateful that I have the opportunity to speak with you today and I'll try to walk you through the current status of the use of CAR T-cells in treatment of lymphoma. This is what I'm going to try to cover today, I'm going to cover the rationale, why do we use CAR T therapy to treat patients with lymphoma? Who would be a candidate for CAR T therapy? What are the steps involved? What are the potential short and long-term risks? And also, what are the potential outcomes? I'm not going to cover myeloma but I'll allude to whichever is available in that space.

(01:55): CAR T stands for chimeric antigen receptor T-cells. This therapy uses the patient’s own T-cells, which have been genetically modified to attack cancer cells.  Let's start by discussing what CAR T therapy is. CAR T stands for chimeric antigen receptor cells. The idea behind it is that we take the patient's own immune cells, what we refer to as T-lymphocytes, and we genetically engineer them, typically with a virus. This makes them able to target a specific marker on the top of cancer cells. These T-cells when they encounter the antigen on the top of the cancer cell, will start attacking the cell.

(02:58): The reason why CAR T-cell therapy works, when chemotherapy fails, is because it kills cancer cells with a mechanism different than chemotherapy. With chemotherapy some of the cancer cells develop a mechanism which becomes resistant to chemotherapy. They modulate some of the genes that make the cells die and the cells become resistant to dying after causing DNA damage, which is typically how most chemotherapy drugs work. CAR T is different. It is using a living cell that came from the patient that has been reengineered to attack the cancer cell. Once it's engaged, it produces a substance that opens holes in the cancer cell and the cancer cell dies through that mechanism without the need to have a cascade that's dependent on DNA damage.

(03:55): Patients with diffuse large B-cell lymphoma who have relapsed after receiving 2 lines of therapy are eligible for CAR T therapy. Who are candidates for CAR T therapy? And maybe that question might be better rephrased: who has access to CAR T therapy? We believe that a lot of patients would benefit from CAR T therapy, but this question specifically states what has been approved by the FDA so a patient has access to it. This means these have been vetted through clinical trials and have demonstrated evidence of efficacy and improved survival. Patients who have diffuse large B-cell lymphoma, which is the commonest type of aggressive, rapidly dividing B-cell lymphoma we deal with, who have relapsed after receiving two lines of therapy, including autologous transplant. Just to clarify, a line of therapy doesn't mean a cycle of therapy, a line means a specific regimen.

(04:47): Patients with relapsed or refractory follicular lymphoma, mantle cell lymphoma, B-cell acute lymphoblastic leukemia, and multiple myeloma are eligible for CAR T therapy. Typically, a patient would have something like R-CHOP, and maybe after that they have another regimen like RICE or R-GDP, or an autologous transplant. That makes two lines of therapy. Or if they relapsed within the first year of therapy, like they had R-CHOP, and maybe that PET scan they get at the end of therapy shows progression. That's typically what we refer to as primary refractory disease. Or they enter remission and two to three months later they relapse. These patients are also eligible to receive CAR T therapy.

CAR T therapy is also available for patients with follicular lymphomas after two lines of therapy and patients with mantle cell lymphoma after one line of therapy. Patients who have B-cell acute lymphoblastic leukemia after one line of therapy. I prepared these slides before the recent FDA approval, so I believe now patients with myeloma are also eligible to receive CAR T after getting two lines of therapy, previously it used to be four.

(05:54): 60% of lymphoma patients treated with standard chemotherapy can be cured. The remaining 40% will need additional treatment to prolong their life and/or be cured. This nice slide show you the typical journey of a patient with diffused large B-cell lymphoma. This accounts for most of the lymphomas we see in the Western world. Right now, with the modern treatment regimen, especially with the introduction of the antibody, Rituxan or rituximab, about 60% of those patients can be cured, but 40% unfortunately aren’t cured and they progress. For those patients, who are healthy enough to get a transplant or CAR T, they may be cured. We're specifically talking about autologous transplant, using the patient's own stem cells. If they are not healthy enough to receive those therapies, and then they receive multiple second-line agents that could result in curable remission but are typically not curative.

(06:52): The first step in CAR T-cell therapy is to collect T-cells from the patient and then ship them to a laboratory that will convert them into CAR T-cells. Now I'm going to talk about how we make CAR T-cells. We have the patient sit at the blood bank on the apheresis machine. They typically will have a dialysis pipeline (intravenous access catheter) unless they have big, large veins where they don't need that. That draws their blood into the machine and the machine has a large centrifuge. It's all an automated closed system, that separates the blood. The red cells are the heaviest, they stay at the bottom, but plasma is the lightest, it stays at the top, and then the white cells form an interface between the red cells and the plasma. That's sucked through the machine into a bag and that bag is shipped to the company.

The company introduces a virus inside the cell, and with that virus you can include the genetic construct to make those CAR T-cells. And then after that, those cells are frozen and shipped back to the center. During that time, the center will give the patient some chemotherapy to deplete their T-cells so those new cells will work better. Then they infuse the new T-cells into the patient.

(08:09): Once a patient is referred to a CAR T center, it can take 10-21 days to organize the collection of T-cells.  This goes over the typical CAR T patient journey. There are proposed timelines. These are highly variable depending on multiple factors which have to do with the patient's geographic location, how many centers they have access to, how quickly they can get to a center, and how busy that center is. The first step is a referral to a CAR T treatment center, typically from a community oncology practice, but this really varies. After that, it takes a center about 10 to 21 days to get insurance approval, production request, where they submit a request to the company, and secure a slot for manufacturing.

(09:00): Once the patient’s T-cells are collected, the manufacturing company can take 10-28 days to process them. Before they collect the patient's T-cells they have to make sure the company has a slot assigned where they're able to make the cells. Then the patient will typically have to undergo an evaluation by a physician experienced in the administration of cell therapy to make sure they're healthy enough to receive it. Then there is about one to two weeks for the actual T-cell collection where they sit on the apheresis machine. It depends on how many slots are available on those apheresis machines, which varies according to how busy the center is. Then, the other process is what we refer to as post-manufacturing. This is where the company would introduce a virus with a genetic transcript inside the cells to genetically modify them and then grow them in a cocktail of agents we refer to as cytokines to make them grow and be more open. This can vary; it can be as short as 10 days, and it can be as long as 28 days.

(10:05): Manufacturing failures can occur. When this happens, sometimes the cells can be salvaged, or the patient’s cells can be collected a second time. Sometimes for whatever reasons those cells may fail to grow, what we refer to as a manufacturing failure. In that situation, typically the company will consult the physician and if those cells are healthy enough to be of some value, some paperwork is filed and the patient can still get access to the cells. If the cells are deemed to be just not effective enough and are likely to fail then the options are typically either to collect cells from the patient again, if that's an option, or the clinician can decide to abort the procedure and move on to something else. While the patient's waiting, they can undergo what we refer to as bridging therapy, which means another chemotherapy, immunotherapy, or another agent to keep the lymphoma controlled while the cells are being manufactured.

(11:04): Once the T-cells are back at the center, patients receive lymphodepleting chemotherapy  three days before the T-cells are re-infused back into the patient. Patients are then required to be near the cancer center for 4 weeks.  Then after that, after the cells arrive at a center in a container, the patient will undergo a low dose, what we refer to as lymphodepleting chemotherapy. That's usually a combination of Fludarabine and Cyclophosphamide (Cytotoxin) that's typically given as an outpatient over three days. After that the cells are thawed and infused into the patient. That could be done either as an outpatient or an inpatient depending on how the program is set up and depending on other factors that have to do with the patient's overall health, the expected rate of complication based on the specific CAR T product, and maybe perhaps the amount of lymphoma in the patient's body. Then after that the patient will be monitored for at least two weeks but up to four weeks. Typically, the first week or 10 days may happen as inpatient and then the rest will happen as an outpatient. The recommendation for most of the products is that the patient need to remain within a close proximity to the treatment center for at least four weeks after the cells are administered.

(12:20): Two common side-effects of CAR T-cell therapy are cytokine release syndrome (CRS) and neurotoxicity (ICANS). Cytokine release syndrome (CRS) and immune effector cell associated neurotoxicity syndrome (ICANS) are potential side effects that must be monitored for. Now we're going to switch gears and talk about some of the early toxicities that we would expect to see at the initial four weeks of receiving the cells, and we're going to cover those with some detail. These include cytokine release syndrome and neurotoxicity, or immune effector cells associated neurotoxicity syndrome.

Infections could happen as well. Sometimes there is intense inflammation from cytokine release syndrome that can cause what we refer to as hemophagacytic syndrome or macrophage activation syndrome, which is basically a bone marrow failure state that typically is a dangerous situation that carries high mortality. Thankfully that doesn't happen very often.

(13:11): Patients are seen by a provider daily for four weeks after CAR T-cell re-infusion. Remote monitoring technology may also be used. Close monitoring is needed during those initial four weeks for that treatment. Some programs have a very good setup, including being able to see patients on the weekends in a clinic setting. As an alternative, patients could get the infusion and go home, they would have a good access to a provider through a phone, and they are seen daily for two weeks, including for over the weekend.

There are some centers that deploy remote monitoring technologies, which is like a patch that's put on the skin that can record fever. And there's a lot of interest now in utilizing devices like Apple Watches or whatnot or similar kind of things that already capture the patient's pulse and things like that. There's just a lot of interest in that space but nothing has been validated so far to make a recommendation, but many centers are using those remote monitoring technologies.

(14:16): Cytokine release syndrome (CRS) causes inflammation after CAR-T therapy. Symptoms include fever, low blood pressure and shortness of breath. Cytokine release syndrome happen because of the rapid expansion of T-cells. If the patient has a lot of lymphoma burden, typically they have a higher risk of having more cytokine release. The T-cells, when they see a lot of malignant cells, they expand and produce what we call cytokines, which are markers of inflammation.

Some products seem to be more toxic than others in that regard. Patients typically have fever, low blood pressure and shortness of breath. It is an FDA requirement that any patient who receives CAR T is given a wallet card. They keep that card in their wallet and whenever they go to an emergency they show the doctors that card. It typically has a number to gain quick access to the CAR T center to get some guidance.

(15:23): Cytokine release syndrome is treated with steroids and Tocilizumab. The easiest way to understand cytokine release syndrome is that it resembles a bad case of the flu or COVID-19. We treat cytokine release syndrome with steroids and tocilizumab. Tocilizumab is an anti-interleukin-6 antibody, and interleukin-6 appear to be the main mediator of cytokine release syndrome. During the early time of the pandemic Tocilizumab had also been employed in the treatment of acute COVID-19 infection, so there is some similarity between the cytokine storm that happens with acute COVID-19 and with cytokine release after CAR T. Severe cases will need to be monitored and managed in the ICU.

(16:21): Neurotoxicity, also known as ICANS (Immune Effector Cell-Associated Neurotoxicity), occurs when cytokines cross the blood-brain barrier. Symptoms include tremors, confusion and seizures. Neurotoxicity is also known as ICANS, and this happen because of cytokines, the same inflammatory molecules as interleukin-6 and others, crossing the blood-brain barrier. That's the layer of cells that protect the brain from the bloodstream, but with inflammation, that blood-brain barrier is open and those cytokines will gain access to the central nervous system and spinal fluid and cause a lot of inflammation there. Patients will typically present with tremors, forgetfulness, difficult comprehension and confusion. Sometimes they can have a seizure. It can look like a stroke. As you are in the hospital or outpatient getting CAR T you're going to get frequent standardized assessments. I'll show you the kind of questions that you'll be asked in a minute.

(17:19): ICANS often presents with CRS, but not always. It is treated with steroids. Most cases are reversible. Sometimes that question might seem silly that you're being asked the same question every day but that's purposeful just to make sure we can detect that problem early. It is rare that neurotoxicity happens without also having cytokine release syndrome. Usually, patients start to have fevers and tachycardia and then they evolve into having neurotoxicity. But that's not absolutely necessary, there have been patients where neurotoxicity happened without the preexisting cytokine release syndrome. It's more common with certain CAR T products than others. It's typically treated with high dose of steroids. Most cases are reversible, thankfully, but some will need monitored in the ICU.

(18:05): ICANS will be assessed every day using the ICE  (immune effector cell) score. It is a series of questions and a handwriting task to monitor for changes in cognition, which can be a sign of neurotoxicity. Unfortunately, part of the challenge, especially with elderly patients, is they will get so sick that even after the inflammation resides, they become quite deconditioned. They end up needing something like a frailty stay (nursing home care), just from the intensity of central nervous system inflammation. This is the typical neurologic assessment that we refer to as the ICE score. If you went through the CAR T process you know what that involves. They'll typically ask you what year and month it is, what’s the hospital you're in and what city you are in. They'll ask you to name three objects. They will ask you to follow simple commands like, "Stick out your tongue."

(18:53): They'll ask you to write, and then they will ask you to count backward. All of this has been validated to detect early signs of neurotoxicity. This is a typical patient as she went through neurotoxicity. We frequently have the patient write a sentence every day.  The sentence may be about their situation, where they are, their town. You see here how as the patient went through neurotoxicity, their handwriting became more scrambled and how it reverted back to normal as they recovered.

(19:35): Loss of B-cells can be a long-term toxicity of CAR T therapy. Shifting gears, we're going to talk about delayed toxicity that can happen 30 days or more after the CAR T-cells have been administered. One of them is a long-term loss of B-cells.  With all of the currently approved CAR T products in lymphoma they target the same antigen, which is CD93. That same antigen is present on those malignant and normal B-cells and some patients will experience long-term loss of B-cells. What we have been learning lately is that some patients may recover some of their B-cells. I don't believe we have accurate statistics about the incidence of this. It typically takes at least two years before that happens, and your doctor can measure the B-cells in the blood by flow cytometry.

(20:28): Low immunoglobulin levels and low blood counts, especially neutropenia, may be long-term toxicities of CAR T therapy. To decrease the risk of infections, patients are given prophylactic antimicrobials and IVIG infusions.  Also, they would measure the immunoglobulin level as the patient starts recovering B-cells and can make their own immunoglobulin. But some patients will need to remain on intravenous immunoglobulins infusions long-term, unfortunately. Some patients who experience low blood counts, neutropenia, will need drugs like filgrastim, and sometimes that can be challenging because of insurance reasons. Patients would need to be on long-term antivirals and prophylaxis for pneumocystis pneumonia.  Patients would also need to have repeat vaccinations. A patient's COVID-19 vaccinations would need to be repeated.

(21:34): After CAR T therapy, there is an increased risk of secondary malignancies such as skin cancers, myelodysplastic syndrome and acute myeloid leukemia. There is some increased risk of non-melanoma skin cancer, skin cell carcinoma. There is increased risk of having myelodysplastic syndrome or acute myeloid leukemia. Some patients experience what we call brain fog, which is typically a lingering form of neurotoxicity that we're still trying to further define.

(21:56): Approximately 50% of patients with aggressive B-cell lymphomas can be cured with CAR T-cell therapy. This is the list of all of the currently available CAR T products in both lymphoma and myeloma and their indications. I'm not going to go through them but that will be in your handout if you choose to download it from the site. I thought this would be a very helpful thing to show to you.

This is a survival curve; this is not the same trial; these are survival curves from two trials that have been superimposed from each other. One of them, which you see on the bottom in red, this group was cohort one which basically a cohort of patients with aggressive B-cell lymphoma before the introduction of CAR T. We are looking at an overall survival performance. The top curve is from the clinical trial, ZUMA-1 that led to the approval of Yescarta. This is just to show to you that in a similar patient population separated by time, the overall survival improved from four months to 24 months. About 50% of patients could be cured with CAR T therapy compared to 12% of historic controls.

(23:16): This is just to give you a visual about the positive impact the CAR Ts have had in this space. To finish up, this just gives you a snapshot of the different products approved in lymphoma and their indications, their response rates and the survival outcomes. Also, the toxicity, the incidence of cytokine release and neurotoxicity or ICANS is shown. I'm not going to walk you through all of that, but I want you to appreciate it.

If you look at the median survival at one year, you're looking at number that improved from 60 to 80 or 90%. These are pretty impressive numbers compared to the 12% numbers that we have seen earlier in the scholar one cohort. So, really, there is a huge difference, but also, if you move your attention to the left column and then look at the cytokine release and the ICANS, you're going to see that some products appear to be more toxic than others. And certainly, as you meet your doctor in the CAR T center and talk to him or her, he'll be able to recommend the best product that will fit your specific needs.

(24:57): It takes a team of committed professionals to care for patients who undergo CAR R+T cell therapy. Trying to move to the next slide. Yep, here we go. Thank you for your attention. This was just a snapshot of my center at Ohio Health and the wonderful team of people I work with. As you realize, it takes a whole village to administer this complicated treatment and prepare patients to receive it. We have folks who collect the cells from apheresis, we have folks in the lab who store the cells and ship them to the company. We have nurse practitioners and nurses who take care of the patient in the clinic or the outpatient floor. We have administrators and other supportive personnel who are responsible for insurance authorizations, making sure all of the medication are approved. Sometimes we need to establish single sponsors for a particular patient who doesn't happen to have approval to receive therapy at our center. It really takes a whole village of people beyond the physician, him or herself, to get this therapy to patients.   Again, I'm grateful that I got the opportunity to speak with you today, and I'll gladly answer any questions you have.

Question and Answer Session

(26:33): [Michala O’Brien]:  Thank you, Dr. William, for this excellent presentation. We will now begin the question-and-answer session "When is a CAR T-cell therapy treatment considered successful?" When do you, Doctor, know whether or not CAR T has cured a person?

(27:07): [Dr. Basem William]: That's a great question. I believe that if the patient is in remission for one year after receiving the CAR T therapy, they have a very high incidence of being actually cured. There is a small chance that they would relapse later, but what we have seen from many of the big trials that led to the approval of those agents, as well as from our cumulative individual experience. Patients who are in remission for one year after they receive the cells tend to remain in remission.

(27:45): [Michala O’Brien]:  Okay. I think this is a question from your slide regarding collecting CAR T-cells. "Is one viral vector more effective for lymphoma patients considering CAR T-cell therapy?" And then could you please explain to the audience a viral vector and the transferring of the cells?

(28:15): [Dr. Basem William]: Sure. The viral vectors typically used now for all of the commercially approved agents are a lentiviral or a retrovirus. That's an inactivated virus from the HIV virus family. It's not HIV, it's certainly not going to give the patient HIV, it's just an HIV like activated virus. And those viruses are very potent in inserting genetic material inside lymphocytes.

It's not the virus that made one cell more active than the other, it's actually the structure of the genetic construct. The genetic construct will include a piece that will make the cell recognize the antigen on the surface of cancer cells. That's typically a part of the immunoglobulin molecules. But also, there is a T-cell costimulator, and that would make the cell grow and expand.

(29:14): The T-cell costimulator is what varies from one product to another, and that's why we hear that some products may be more effective than others and potentially more toxic. Something to note, those products have not been evaluated head-to-head are believed, by many of the experts in the field, to be pretty much comparable after about one year. But it is the T-cell costimulator that's introduced that would make more products seem to be at least more active earlier, but sometimes that comes at a cost of increased toxicity as well.

(30:05): [Michala O’Brien]:  Okay. "For follicular lymphoma is initial chemotherapy followed by relapse and autologous transplant considered two lines of therapy?"

(30:18): [Dr. Basem William]: Yes.

(30:21): [Michala O’Brien]:  Okay. "Can CAR T cause pituitary problems?"

(30:28): [Dr. Basem William]:   Not directly, not to my knowledge. But what could happen is, if the patient develops a severe cytokine release syndrome and develop circulatory collapse and shock and they drop their blood pressure significantly or develop macrophage activation syndrome, they're sick. They're in the ICU, they are on blood pressure medication to raise their blood pressure, sometimes that would cut the blood supply to the pituitary gland. Or if they have sustained sepsis from a severe infection, then that would lead to damage to the pituitary gland. But that could happen with any sepsis or with any infection, it's not particularly unique to CAR T.

(31:18): [Michala O’Brien]:  "You mentioned CAR T-cell therapy is used for patients with mantle cell lymphoma, is it also an option for geriatric patients?"

(31:29): [Dr. Basem William]:   Yes, I believe there is no age limit. And in my prior institution at OSU, I have treated an 80-year-old patient with CAR T and he did really well. That's true for transplant and CAR T. We don't look at age as a number, we look more at the fitness of the individuals. There are 80 and sometimes 90 years old who walk and cycle and exercise, and there might be a 40 or a 50-year-old health is so impaired, they cannot get any treatment safely. We don't look at age anymore, we look more at functional status. Sometimes, depending on the patient's insurance or other things, they might be denied certain treatments based on age, and in that situation the clinician can try appeal for you. They may or may not be successful.

(32:33): [Michala O’Brien]:  "Which vaccines do you recommend after CAR T-cell therapy when a patient was revaccinated just a few years earlier after an autologous stem cell transplant?"

(32:47): [Dr. Basem William]:   I don't really have a lot of evidence to guide it, programs have different approaches to that. There is no unified consensus, but there are multiple options. You could revaccinate again and there is absolutely no harm in doing that. Some centers, they also measure the titers. They could measure, "Okay, do you have enough measles or mumps or rubella or whatever immunoglobulin level in your blood?" If they're high enough to protect you, then you don't need to be revaccinated.

One word of caution, your doctor would have to order the right test. If they just order mumps IgG without the number, and it comes back as positive, that's not going to help you much. What's required is a titer, and there are certain validated titer numbers that could say that you have a protective immunity. That would be the other option compared to revaccination. Not all clinical laboratories run those tests, but certainly there are some reference laboratories that run those tests. That could be an alternative to revaccination.

(34:03): [Michala O’Brien]:  "Can you talk briefly about full functionality in recovery with regards to quality of life after CAR T-cell therapy?"

(34:15): [Dr. Basem William]:  Extremely variable, it really depends on how severe or what toxicity the patient developed. If the patient develops severe neurotoxicity, if they are in the ICU, if they had a seizure, and especially if they're older, their quality of life may be impaired for a very long time. There are certain factors that will predict such thing though.

Some centers, they developed a geriatric clinic and they perform what they call a complete geriatric assessment, which is a daylong assessment of cognitive assessment and physical therapy. There are some validated simpler methods. My most favorite method I use is the “get up and go”. I have a patient in my clinic, they're sitting on a chair and then I ask them, "Okay, get up and go to the door, open the door and walk out," I observe how quickly they can get up from a chair and go out. That get up and go test has been validated to show how healthy the person is. I use that frequently; it takes five seconds and it's a very useful test.

(35:30):The other factor in evaluation is how much tumor they have. If the individual is loaded with tumors and we give CAR T, we know up-front that you have a higher risk of cytokine release and neurotoxicity. Sometimes I pre-medicate those patients with a steroid or tocilizumab. There is data that doesn't impair their response to the CAR T, it might be protective of toxicity.

 There's a lot we can do to make sure we select the best therapy for the patient. We also to try to prevent toxicities up-front but it's not always as easily predictable. The other factor is that some CAR T agents are more toxic than others, and your clinician will be able to guide you in choosing the right product for you. Generally, if I have a borderline patient, I wouldn't give them the most toxic product because I know if they develop neurotoxicity they may not survive or they might be very impaired. All of those factors, your doctor will be able to guide you on what should be the right product choice.

(36:46): [Michala O’Brien]:  "Is CAR T-cell therapy used for small B-cell lymphoma?"

(36:52): [Dr. Basem William]:   Yes. Small B-cell lymphoma, there is one product that has been recently approved for CLL which is also called small B-cell. Small cell lymphoma is the same as CLL, so I think if it is submitted as CLL it will be approved in that regard. This is just something that came on in the past months or so.

(37:23): [Michala O’Brien]:  Okay. This patient had their stem cells collected for their autologous transplant and some remain in frozen storage. "We would like to use these to boost their system either before or after CAR T procedure, is that possible or even advisable?"

(37:42): [Dr. Basem William]:  I wouldn't advise it but it's a great advantage that you have those, because if you haven't received CAR T yet and you happen to  develop a severe toxicity and your count didn't come up, those cells would come in as a life-saver. It's great you have those; I don't recommend that you use them if you don't run into any trouble. They might become handy to you in the future.

Let's say if, God forbid, you get CAR T and you relapse and maybe your doctor would do an allo transplant on you and then after that you have problem recovering counts, your own cells could come to rescue. I don't recommend you use those if you're doing fine, but this will become a very handy tool for your doctor to save you, should you develop a severe complication from CAR T-cell therapy.

(38:38): [Michala O’Brien]:  This person's husband is 77 years old and has diffuse B-cell lymphoma. "He's three months post-CAR T-cell therapy using Yescarta, how many people get B-cell aphasia after CAR T? And is there any hope for those B-cells returning? And if so, when?"

(38:58): [Dr. Basem William]:   There is hope for those B-cells returning, most of them, they don't return before one to two years. They typically do not return that early. I actually don't want them to return that early, usually if you start seeing them returning back early it means that whatever is returning is really the cancer cells. There's some hope for recovery, I don't believe we have accurate statistics yet because we don't have very good, validated methods of measuring B-cells in blood. Many centers are able to do flow cytometry on the blood, but most recoveries will take at least two years to happen.

(39:46): If B-cell recovery doesn't happen it's really not the end of the world. As long as a patient's able to get an intravenous immunoglobulin, then they're usually protected. A joke in the transplant cell therapy world, we say B-cells are dispensable, you can throw them away. That's why we have a challenge in trying to get CAR T for T-cell lymphomas, because T-cells are not indispensable. If you get rid of all T-cells the patient will not survive, but B-cells, you can live long-term, a healthy life without B-cells as long as you have access to intravenous immunoglobulin.

(40:27): [Michala O’Brien]:  The follow-up, is age a consideration?

(40:34): [Dr. Basem William]:   It likely is, but I don't think we have an evidence-validated answer to that. I think what's more likely a consideration is the number and the intensity of prior therapies. Whatever the patient has been exposed to previously is going to be a major factor in their ability to recover T-cells. For instance, if they have had autologous transplant before getting CAR T it is probably less likely that they will recover.

(41:08): [Michala O’Brien]:  "Can you comment on why a 24/7 caregiver is required? And what does that caregiver need to do or need to know about this CAR T-cell therapy treatment and their role in assisting the patient?"

(41:24): [Dr. Basem William]:   I think the challenge is those patients can get very sick very quickly in a very unpredictable way. Let's say if the patient is in their home or they're staying in a hotel because they live in a rural community and they need to stay in close proximity of that treatment center, they can get very sick very quickly and just collapse in their home or in their hotel with nobody knowing.

Now, would that change if we have access to remote monitoring? Maybe. But the problem is, let's say just for argument's sake, we have a remote monitoring platform. Who's going to sit on that platform and monitor patients 24 hours? If the patient removes the patch from their head, maybe they'll have a sweat and the patch will fall off, or maybe I'm seeing the patient have tachycardia and I try to call them and they don't answer, what I'm going to do? Then I have to maybe call the law enforcement to come and check on them.

(42:24): It just creates a lot of logistical problems. I would say, in summary, the rationale behind it is that patients can get unpredictably very sick within a very short period of time. They may not have time to call for help sometimes. What that caregiver needs to know, they need to be educated about what to watch for; fevers, shortness of breath, dizziness or confusion, things like that. It's very simple, they don't need a lot of education, they just need to be committed and be there all the time and know when and how to call for help.

(43:05): [Michala O’Brien]:  Okay. "What are some options for aggressive lymphoma patients if CAR T-cell therapy fails?"

(43:14): [Dr. Basem William]:  There are quite a few There are clinical trials, and we encourage all patients who fail after CAR T to go on a clinical trial. Sometimes, depending on the lengths of remission after CAR T, a second CAR T infusion might be also tried if the company still has cells and they're willing to do so. There are other agents that could be given after CAR T that have not been tried before. And if the patient can enter a remission with any agent or have their disease controlled enough and they're healthy enough, they can undergo an allogenic transplant as well. I have seen that actually, in a handful of cases.

(44:04): [Michala O’Brien]:  Okay. "How long does it take for low blood counts to recover after CAR T-cell therapy?"

(44:09): [Dr. Basem William]:   Great question, very valuable. Some patients might take months, some will take years, some of them, they may not fully recover. I don't think we have a great way of predicting this. It's a hot area for research and we're still learning what to do. I want to caution though that the person doesn't need to have completely normal, pristine blood counts to be alive and healthy. Some patients will walk around with low blood counts. They have no infections, they're healthy and they're doing fine. I wouldn't agonize about the abnormal blood count unless it's severe enough or if it's causing infection problems.

(44:58): [Michala O’Brien]: Thank you. Well, on behalf of BMT InfoNet and our partners I want to thank Dr. William for a very helpful presentation. And I also wanted to mention to the audience that BMT InfoNet offers a great resource, we have a database for medical centers that provide CAR T-cell therapy and you can access that database by going to Please contact BMT InfoNet if we can help you.

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