Transplant or CAR T-cell Therapy for Lymphoma? How to Make the Choice

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Transplant or CAR T-cell Therapy: How to Make the Choice

October 24, 2023

Presenter: Daniel J. Landsburg, MD, Associate Professor of Clinical Medicine, Hospital of the University of Pennsylvania

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

Many thanks to Kite, A Gilead Company, for their support of this webinar.

Summary: An autologous stem cell transplant and CAR T-cell therapy are both options available to treat patients with diffuse large B-cell lymphoma (DLBCL), high grade B-cell lymphoma (HGBL), follicular lymphoma and mantle cell lymphoma. Learn what's involved in undergoing each type of therapy, who is a good candidate and the short- and long-term risks of each.

Highlights:

• 50% of patients with diffuse large B-cell lymphoma (DLBCL) or high-grade B-cell lymphoma (HGBL) who undergo an autologous stem cell transplant remain in remission for five years or longer. 30-40% of patients who undergo CAR T-cell therapy are in remission at least 5 years after treatment.
• Approximately 50% of patients with follicular lymphoma who undergo an autologous stem cell transplant remain in remission 15 years or more after treatment. 70-80% of patients who undergo CAR T-cell therapy remain in remission at least one year after treatment.
• Approximately 80% of patients with mantle cell lymphoma remain in remission after an autologous stem cell transplant that is followed by Rituxan® maintenance. 50% of patients who undergo CAR T-cell therapy remain in remission at least three years after treatment.

Key Points:

(07:04): Patient age, organ dysfunction and lymphoma in the bone marrow may dictate whether an autologous stem cell transplant or CAR T-cell therapy is the better treatment option.

(08:54): An autologous stem cell transplant may be preferred over CAR T-cell therapy if the patient has poor social support, such as no caregiver at home.

(13:59): The typical “road map” for patients undergoing an autologous transplant includes collecting stem cells for transplant, admission to the hospital for high-dose chemotherapy, reinfusion of stem cells and discharge home to finish recovery.

 (17:36):  Common side effects after an autologous stem cell transplant include gastrointestinal problems, fever, low blood count and significant fatigue.

(20:51): Recovery at home after an autologous transplant can take two or three months. Long-term side effects are uncommon but can include low blood counts, infertility, decreased antibody production, and rarely organ damage.

(23:45): The typical “road map” for patients undergoing CAR T-cell therapy includes collecting the patient’s T-cells, modifying the cells to become CAR T-cells, and infusion of the CAR T-cell into the patient.

(27:00): The two major complications from CAR T-cell therapy are cytokine release syndrome and neurotoxicity (also called ICANS).

(28:45): CAR T-cell patients must live within two hours of their medical center for 30 days after discharge from the hospital, have a 24/7 caregiver to assist them, and cannot drive for 60 days after CAR T-cell therapy.

(38:06): There are treatment options available for patients who do not remain in remission after an autologous stem cell transplant or CAR T-cell therapy. 

Transcript of Presentation:

(00:02): [Susan Stewart]: Introduction. Welcome to the workshop, Transplant or CAR T-cell Therapy for Lymphoma: How to Make the Choice. My name is Sue Stewart and I'm the founder and the executive director of BMT InfoNet. I'll be your moderator for this workshop.

(00:19): Before we begin, I'd like to thank Kite, a Gilead Company, for their support of this online seminar.

(00:26): So, there are a lot of exciting therapies being talked about for people who have some form of lymphoma, and CAR T-cell therapy is certainly one of them. But there's also a lot of confusion about who's eligible for CAR T-cell therapy, how well it works, who's a good candidate, who should be choosing transplant versus CAR T, et cetera. So we've invited our guest speaker today, Dr. Daniel Landsburg, to help clarify answers to those questions so folks can make clear decisions about their treatment options.

(01:02): It's now my pleasure to introduce to you Dr. Daniel Landsburg. Dr. Landsburg is an Associate Professor of Clinical Medicine in the Division of Hematology and Oncology at the Perelman School of Medicine at the University of Pennsylvania. His clinical practice focuses on lymphoma, with a particular interest in treatment of patients with aggressive B-cell lymphomas. Dr. Landsburg's research interests involve the use of molecular testing to predict outcomes and guide treatment decisions for people diagnosed with aggressive B-cell lymphomas. Please join me in welcoming Dr. Landsburg.

(01:47): [Dr. Daniel Landsburg]:  Overview of Talk. Thank you, Sue, and thank you, everyone, for attending, and please feel free to add questions to the chat so I can try to answer them when the presentation is over. So as Sue said, I'm Dan Landsburg, I'm one of the faculty at the hospital of the University of Pennsylvania. My areas of interest are lymphoma and cellular therapy, and today I'm going to be talking about transplant or CAR T therapy, how to make the choice.

(02:14): Before we start, I want to make sure that the learning objectives of this lecture are clear. So at the end of the workshop, I'm hoping you'll all understand:

• the criteria used to determine whether a stem cell transplant or CAR T-cell therapy is the best treatment option for a patient with lymphoma;
• the steps involved in preparing for, undergoing, and recovering from a stem cell transplant as compared to CAR T therapy;
• potential short and long-term side effects of a stem cell transplant as compared to CAR T therapy;
• likelihood of cure;
• quality of life following a stem cell transplant as compared to CAR T-cell therapy.
• And finally, some treatment options if a patient does not achieve or remain in remission following a stem cell transplant or CAR T therapy.

(03:02): What are the different types of transplant and CAR T-cell therapy available to patients?  I'm going to start with a few introductory slides and definitions. So first, I want to be clear on the different types of transplant and CAR T therapies so we all share the same understanding as the presentation continues.

(03:17): Autologous stem cell transplant, or autotransplant as I'll typically refer to it, is a reinfusion of previously collected stem cells from the patient in order to aid in recovery of blood cell production after treatment with high dose chemotherapy.

(03:32): Chimeric antigen receptor-modified T cells, or CAR T-cells, are those collected from a patient that are genetically modified to express a marker on the surface which is directed at a specific target. And in the case of B-cell lymphomas, the most common target is CD19.

(03:49): And finally, we won't get into a discussion about allogeneic hematopoietic cell transplant, although if you have questions about it, I'm happy to try to answer, but this is an infusion of donor stem cells to induce a graft versus tumor effect and aid in the recovery of blood cell production following treatment with chemotherapy.

(04:09): Which types of lymphoma that can be treated with an autologous stem or CAR T-cell therapy. Also, I want to provide some definitions on the different types of lymphoma that can be treated with autotransplant or CAR T in the standard of care setting. So the first is diffuse large B-cell lymphoma and high-grade B-cell lymphoma, which I'm combining into one category because they are similar lymphomas in terms of how they behave and how they're managed. These are aggressive B-cell lymphomas. They can be cured with chemotherapy. However, relapses are often fatal unless treated effectively.

(04:40): Follicular lymphoma is an indolent B-cell lymphoma not typically cured with chemotherapy. However, many patients will survive multiple relapses and potentially not die as a result of their lymphoma.

(04:54): Mantle cell lymphoma is technically an indolent B-cell lymphoma, but behaves aggressively, also not typically cured with chemotherapy, and relapses are often fatal unless treated effectively.

(05:07): Chart showing indications for an autologous stem cell transplant or CAR T-cell therapy.  This chart here is perhaps a little oversimplified, but I tried to list the indications for autotransplant or CAR T-cells based on the different diseases.

(05:17) What is the appropriate therapy for patients with diffuse large B-cell lymphoma (DLBCL) or high grade B-cell lymphoma (HGBL)? For DLBCL and HGBL, , autotransplant is typically given as a second line therapy in patients who achieve a response to salvage immunochemotherapy.

(05:28): CART19 has a few indications [for DLBCL and HGBL]. So, it can be used as a second line therapy if the patient were to relapse less than one year after completion of first line therapy. And that indication is for two products, Yescarta® and Breyanzi®.

(05:42): Additionally, if a patient is unfit for autotransplant, they can receive Breyanzi® as a second line therapy. Three products, Yescarta®, Kymriah®, and Breyanzi® are approved as a third line or greater therapy.

(05:54): What is the appropriate therapy for patients with follicular lymphoma? For follicular lymphoma (FL), autotransplant is used typically in patients with relapsed disease who are responding to immunochemotherapy. CART19 is approved as a third line or greater therapy, with Yescarta and Kymriah being the products that have that label.

(06:10): What is the appropriate therapy for patients with mantle cell lymphoma? And finally, for mantle cell lymphoma (MCL), autotransplant is typically used as consolidation in first line or after first line immunochemotherapy for patients who are responding. CART19 is listed for relapsed or refractory mantle cell lymphoma. You can interpret it as perhaps the second or third line of therapy. The product that has approval for mantle cell is Tecartus®.

(06:36): The Food and Drug Administration (FDA) has specific guidelines about which patients are eligible to receive CAR T-cell therapy. So, what are some practical considerations for autotransplant versus CART19? I think the most practical consideration is what does the FDA allow patients to receive, at least in the United States. As you can see from the slide before, the FDA has very specific indications for the products, based on the lymphoma subtype. I would not say the FDA has been particularly clear about the use of autotransplant, although it is given in specific situations as I mentioned before.

(07:04): Patient age may dictate whether an autologous transplant or CAR T-cell therapy is the better treatment option. Patient age is a factor. There are different cutoffs for age for autotransplant in the literature and what's done in clinical practice. I would say at Penn, we typically do not offer autotransplant for lymphoma in patients who are 75 years or older, although that's perhaps a soft cutoff and we definitely have transplanted patients who are older than 75. But I think if you're in your mid- to late-70s, or certainly early 80s, CART19 is a better option than autotransplant because of the more favorable side effect profile.

(07:36): Significant organ dysfunction may make CAR T-cell therapy the more favorable treatment option. If you have significant organ dysfunction, maybe a major heart or lung or kidney disease, typically we'd favor CART19 as long as that comorbidity or disease is not so severe because, again, the toxicity profile is a little bit more favorable.

(07:53): If you had, or have lymphoma in your bone marrow, we would typically favor CART19. This is because autologous stem cells live within the bone marrow that also contains lymphoma. If you were to take a sample of autologous stem cells out and then re-infuse them after chemotherapy, as done in an autotransplant, the autologous stem cells may be contaminated with lymphoma and then you'd be reintroducing lymphoma back into the patient with the stem cell reinfusion and that might lead to an early relapse. So, in that case, we'd probably favor CART19.

(08:24): If the patient cannot collect autologous stem cells, then we can't do an autotransplant and would favor CART19.

(08:31): Risks of CAR T-cell therapy for patients with autoimmune diseases or who received a solid organ transplant are not well known.  If the patient has an autoimmune disease or has received a solid organ transplant, it's not that you can't do CART19 for these patients. Patients with these comorbidities were not included in the original clinical trials and so the data are more sparse to support doing so, but we do worry about the activity of T-cells in patients with these comorbidities and may favor an autotransplant.

(08:54): An autologous stem cell transplant may be preferred over CAR T-cell therapy if the patient has poor social support. And finally, if a patient has poor social support or there are some concerns about compliance, you might favor autotransplant because the therapy is delivered in the hospital and the recovery happens in the hospital for the most part. At least at our center, there's really not much follow-up that's needed afterward, while CAR T, as I'll show you, has a lot of moving parts to it and requires support for the patient from family and loved ones that may not be possible for some.

(09:22): There are several common dilemmas that arise in choosing between autotransplants or CAR T therapy. So, here are some clinical dilemmas about recommending autotransplant versus CART19. If people have additional questions about certain situations, I'm happy to try to answer them, but these are the ones that I face in my practice with some frequency.

(09:35): For diffuse large B-cell lymphoma and high-grade B-cell lymphoma, if you have an older patient - 75, 76, 77 - who's had a relapse greater than one year after the completion of their initial therapy, for a variety of reasons autotransplant is probably the more effective therapy at that point. But the patient may be too old or unfit for an autotransplant. And so, it's sort of a complicated discussion about whether the patient would prefer autotransplant or CAR T.

(10:02): Similarly, if you have a patient of any age who took salvage immunochemotherapy, or second line immunochemotherapy and had a partial response, that patient could go on to receive an autotransplant, although the outcomes following the transplant may not be as good as someone who achieved a complete response to that salvage therapy. You may instead want to offer the patient CART19. That debate has come up in my practice not infrequently.

(10:26): For follicular lymphoma, we really don't do a lot of autotransplants at Penn. I have to admit it's still done at other centers. There are a variety of reasons why we don't do it here, although the data for it are quite good in some cases. But if I've had some sicker follicular lymphoma patients who have taken salvage therapy and if they can respond well, you could think about offering them an autotransplant, but they may also be eligible for CART19.

(10:52): Finally, mantle cell lymphoma is one of the more interesting dilemmas nowadays. There are some data that came out recently that suggest that patients don't necessarily benefit from having an autotransplant after initial immunochemotherapy if the patient also received a BTK inhibitor with their initial therapy, and then after their initial therapy and maintenance. And so, if you have a younger patient who's not particularly sick, who may actually want to avoid chemotherapy altogether or certainly avoid a transplant, you might not offer an autotransplant anymore based on those data I've mentioned, and knowing the CAR T-cells would be available at the time of relapse and have some very favorable data. I think that dilemma has to play out a little bit more than some of the others I mentioned.

(11:37): So, let's talk a little bit about the process of autotransplant and CART19 and then some side effects that patients may experience.

(11:44): Both transplant and CAR T-cell therapy require advance testing for exposure to viruses, heart and lung health, and in some cases, dental health and cancer screening. So, some things are in common for both therapies. There's some pre autotransplant and CART19 testing that needs to occur. This is based on insurance or Medicare recommendations as well. Patients need to be tested for exposure to hepatitis B and C and HIV. They need to have a heart function evaluation, which is typically an echocardiogram, and they need to have a lung function evaluation, which is typically pulmonary function tests.

(12:11): Some insurance companies may require other testing such as a dental evaluation and updated age-appropriate cancer screening. Abnormal testing may prompt referral to a specialist like a cardiologist or pulmonologist, although it doesn't necessarily preclude the patient from proceeding with transplant or CART19.

(12:31): The medical team following a patient for lymphoma may be the same or different than the team that manages the patient during transplant or CAR T-cell therapy.  Let's talk a little bit about the team members. This is done differently at every center so I'll just explain what happens here at Penn. At Penn, the lymphoma physicians, like me, actually follow the patients when they receive an autotransplant or CART19. We don't follow them when they receive an allotransplant, but at different centers, you may be referred from your lymphoma provider to what you would call a transplanter or a cellular therapy specialist who only does the transplant or the CART19, and then the patient may be referred back to their lymphoma specialist afterwards. But we "keep the patient", so to speak, here at Penn.

(13:10): However, when our patients are admitted to the hospital for treatment or complications, we don't necessarily follow them in the hospital and provide day-to-day care, although we do see them and visit them. There's an inpatient team that's expert in managing the therapy and the complications of therapy.

(13:27): We have wonderful cell therapy nurse coordinators that help with both autotransplant and CART19 and really work with the patients, as well as other team members, to coordinate all the logistics prior to the patient receiving cell therapy.

(13:39): We have social workers that do a wonderful job and the financial team. I think many of you probably know this therapy is not cheap and it should be covered by insurance. We want that process to go well. So, we have a whole financial team here at Penn, and I know at other centers, to make sure the reimbursements go through and all the approvals go through.

(13:59): The typical “road map” for patients undergoing an autologous transplant includes collecting stem cells for transplant, admission to the hospital for high-dose chemotherapy, reinfusion of stem cells and discharge home to finish recovery. So now, we'll talk a little bit about just autotransplant. This is a sort of map of the process that we created a couple of years ago and I think still holds true. Some steps may be slightly different for different patients, but essentially at the top left, the patient is treated with some sort of therapy. Once it's determined the patient is responding, or based on that therapy is a candidate for transplant, the stem cells are removed and I'll explain that more in a minute.

(14:26): The patient's admitted to the hospital. The patient is then given high-dose chemotherapy and sometimes radiation, although rarely in this case. Shortly after that's finished, the stem cells are re-infused. The patient remains in the hospital probably for about three weeks total. It can be longer or can be shorter depending on the disease and the transplant type.

(14:45): Then the patient goes home and finishes recovery at home. Usually by about three months after the whole process, the patient is largely feeling back to normal with not a fully restored immune system, but a better immune system than they had three months prior.

(15:03): Stem cells are moved or “mobilized” from the bone marrow into the bloodstream where they are collected for an autologous transplant. Stem cell collection for autotransplant is typically done through the peripheral blood. It is rare nowadays that patients would receive aspirations of their bone marrow to collect the stem cells right from the bone marrow. But the stem cells do live in the bone marrow and therefore need to be what we call "mobilized" into the blood so that they can be collected from the blood through the process called apheresis.

(15:27): Apheresis is essentially a filtration circuit. If you're familiar with kidney dialysis, it's a very similar process. Essentially the patient needs to have a catheter placed in their neck with two lines or lumens. One line is the line out from the patient where the blood goes into the circuit, the circuit pulls out the stem cells and then returns the filtered blood back to the patient through the other line and essentially completes a circuit that continues.

(15:54): As I mentioned, you need to be able to mobilize the stem cells from the bone marrow because they don't normally live in the peripheral blood but you want them to end up in the blood to collect them. There are a couple of different ways to do it that I've listed here. Essentially there are techniques to do this and it is possible to collect all the stem cells needed prior to an autotransplant in one day. The average is usually two or three days and some patients can take longer and even go into a second week. But overall, it's usually about one-to-three days to collect all the stem cells needed.

(16:27): Patients are typically admitted to the hospital for high-dose chemotherapy over several days, followed by a reinfusion of their stem cells. When the patient is admitted to the hospital for autotransplant, the initial days look like this: The patient would receive, at least in our institution, five-to-six days of high dose chemotherapy. It's given, I wouldn't say continuously, but through most of the periods of the days that it's being given and patients can feel okay,. They might experience some GI symptoms like nausea or diarrhea, but generally they are doing okay.

(16:51): And then, we give a day of rest after the chemotherapy is done and re-infuse the stem cells a day later. This is typically done at the bedside. Stem cells are brought up frozen from our stem cell lab. They're thawed in a hot water bath and then pulled up with a syringe and re-infused through a port or a PICC line. There are a couple of people in the room when this happens just to make sure that the process goes okay. And for what it's worth, there's an odor, at least from the preservative we use, that can permeate in the room and through the patient for the next couple of days.

(17:24): So then, what happens in the following two weeks or so that the patient remains in the hospital? So that's when patients are most likely to experience side effects. I've tried to categorize them in a few buckets.

(17:36):  Gastrointestinal side effects are common in the first few weeks after transplant.  There are GI side effects listed here. Some of them are mild, most often they're a little bit more severe and require some supportive care like IV fluids or IV anti-nausea medications.

 (17:46): If people get severe mucositis, particularly mouth irritation, and are also having other GI side effects, they may not be eating very well or it may be painful to eat. And so, at Penn, we've been very proactive in the last few years in offering patients total parenteral nutrition, which is essentially IV nutrition designed to give the patients all the calories that they need for a given day so they don't feel compelled to eat. We often do that for about five-to-seven days, when the symptoms are at their worst, so patients don't end up losing a significant amount of weight or become nutritionally deficient while they're undergoing their transplant.

(18:25): Some patients experience fevers after an autologous transplant. Fevers happen not to everybody, and if they do happen they're not necessarily due to an infection. Often when they do happen, the blood counts are low and we give IV antibiotics just to protect the patient in case there is a bloodstream or some other sort of bacterial infection.

(18:40): Low blood counts happen to everybody after an autologous transplant. Almost all patients need transfusions of red blood cells or platelets. I've never seen a lymphoma patient make it through without at least needing platelets once, and that's a pretty routine practice. Your blood counts are checked in the morning and then your transfusions for the day are decided upon based on that result.

(18:58): Significant fatigue is common after an autologous transplant. And there is fairly significant fatigue. You see a lot of transplant patients walking around the hospital floors in their initial days and getting some exercise. Then, as they hit that maybe second week in the hospital, they become pretty tired and they just sort of lounge in the room,. There are some days when patients don't even want to get out of bed but it all improves as the next slide suggests.

(19:20): There are several criteria patients need to meet before discharge after autotransplant. So people do get discharged. And what are the criteria for discharge?

(19:25): So first, the blood counts have to increase. We typically do not send patients home who are neutropenic. We want their neutrophil count to be at a safe level so they're not in an emergent situation if they were to have a fever and concern for bacterial infection. And we tend not to send patients home until they're not requiring frequent transfusions of red blood cells or platelets because it's very tough, as an outpatient, to come back every day or every other day to get transfusions. So, we hold patients until they either don't need them anymore or they need them much less frequently.

(19:57): We keep people until their GI symptoms improve. We don't usually send patients home with IV medications or with total parenteral nutrition (TPN,) although their GI symptoms are probably not perfect when they go home.

(20:10): And finally, their energy level has to improve. They must be able to manage at home. Most people go home with a caregiver with them, some people do go home alone, but essentially you don't need very frequent assistance and you can kind of manage for yourself. So, the patient won't be perfect when he or she comes home, but they'll be doing well enough to be able to function at home. And when I'm rounding on these patients in the hospital or see my own patients right before discharge, I say, "Look, you can feel tired at home or you can feel tired in the hospital. You can have nausea at home or you can have nausea in the hospital. Which one do you want?" And most patients say, "Well if it's more minor side effects, I would just rather be home and comfortable and managing them there." And that's often what happens.

(20:51): Recovery at home after an autologous transplant can take two or three months. The recovery at home, it's about two-to-three months until patients feel largely back to normal. One thing I see in my patients is that patients get home and then start to feel even more tired than when they left the hospital and they call and they're upset and they say, "Something must be wrong. Why am I feeling more tired?" I think the reality is that they're doing more at home than they were in the hospital. You're not staying in one room the entire time like you were in the hospital. Your bathroom may not be 10 feet from your bed. Someone may not be bringing you meals to your bed every day, and so you have to do a little more for yourself at home. And I think appropriately, patients become tired as a result.

(21:28): You can return to regular activities as you tolerate them. There are lots of different recommendations about being in public and what to do, based on COVID and other things going on. So always check with your provider team about specific recommendations.

(21:42): The frequency of follow-up visits is not that often. It's usually a couple weeks or maybe 10 days after your discharge and then less frequently after that. And then, at about day 100, at least at Penn, that's when we'll repeat a PET scan or CAT scan to see what the patient's response to transplant has been.

(22:01): Long-term side effects of an autologous transplant are fairly uncommon. In terms of long-term side effects, fortunately they're fairly uncommon. It is true that patients can have slightly lower blood counts. Maybe their platelet count doesn't return to normal or their white blood cell count runs on the low side. And that's not uncommon, but typically not problematic. Patients are not at risk for bleeding or infection with slightly lower blood counts.

(22:21): Infertility can be an issue for patients who had fertility capability before transplant. They may lose it afterwards. Some people may have lost their fertility prior to transplant based on other therapies, and counseling with a reproductive specialist is always important if a patient still desires to try to have children after transplant.

(22:44): Decreased natural antibody production, or hypogammaglobulinemia, can happen and that basically is an effect of the high-dose chemotherapy killing off healthy B-cells which make these antibodies that we detect. This can be treated with intravenous immunoglobulin or IVIG to reconstitute the antibodies that the patient can't produce.

(23:05): Organ damage is rare, very low blood counts are rare. And it's worth noting that patients can develop what we call second cancers or secondary cancers, so not a relapse of their lymphoma, but a new cancer that developed in a response to healthy cells being exposed to high-dose chemotherapy. It's sometimes hard to figure out if a cancer that develops later in life is due to the chemo that the patient received with autotransplant. Typically, these cancers occur within the next couple of years and are somewhat rarer cancers that you wouldn't expect a patient to have happen. Net risk probably is about 5 to 7% over time, so it's not 0% but it is relatively low.

(23:45): The typical “road map” for patients undergoing CAR T-cell therapy includes collecting the patient’s T-cells, modifying the cells to become CAR T-cells, and infusion of the CAR T-cell into the patient. On to CART19. This is one diagram out there of the whole process of CART19 in terms of what happens to the patient's cells after they're collected and when they get them back. So,  if you follow from top left all the way around with the arrows to the top right, the patient's T-cells are collected. They are then activated through antibody-coated beads and transduced with the CAR or the virus that's been modified to be able to enter cells but bring with it the genetic material that we want to introduce into the cells. The CAR T-cells are developed. They now have a marker on the surface that targets them to the lymphoma cells. These CAR cells are expanded and then delivered back to the CAR T center. The patient then receives a little bit of low dose chemotherapy for lymphodepletion and then receives their CAR T infusion.

(24:38): The time between collection of T-cells and infusion of CAR T-cells can be a month during which patients may receive bridging therapy. What's not shown in this diagram is what happens to the patient between the time of collection and the time of the infusion, which is typically about four weeks, give or take, depending on the CAR T product and demand for CAR T production. In that period, patients may receive something called bridging therapy. I didn't address this in my presentation and I'm happy to take questions about it because there's a lot of debate about whether the patients need it or not, and what to use. But I would say that many patients receive some therapy while they're waiting for their cells to come back in order to achieve disease control or not allow their disease to progress.

(25:12): T-cells are collected from patients by apheresis, similar to how stem cells are collected for an autologous stem cell transplant.. So, the CART19 collection, or the T-cell collection, is similar to the apheresis stem cell collection I mentioned before. We do use apheresis. Patients may or may not need an apheresis catheter placed. Because the T-cell collection usually lasts for only one day, patients may be able to get away with just two IVs - usually one in each arm - to complete the circuit and give a line out and a line in. You don't necessarily need to have a semi-permanent catheter that you can use multiple days in a row.

(25:46): [Unlike with autotransplant] there's no need for mobilization. The T-cells are naturally found in the patient's blood. You don't need to use any tricks to get them out of the bone marrow and into the blood. It's typically a much briefer T-cell collection than it is for stem cells.

(26:01): The CART19 infusion may be done inpatient or may be done outpatient. There's a lot of debate about that. The FDA requires that some CAR T products have at least inpatient monitoring after the infusion, or it's strongly recommended. Patient characteristics and disease status may also dictate whether a patient is inpatient or outpatient when they receive their cells.

(26:22): All [CAR T-cell] patients should receive lympho-depleting chemotherapy a few days prior to the CART19 infusion that's designed to suppress the immune system and drive down some inflammatory chemicals that might impair the function of the CAR T-cells once they're introduced.

(26:39): Post infusion monitoring can be done inpatient or outpatient. Typically, if you're getting your cells in the hospital, you stay in the hospital for about 7 to 10 days, assuming there are no complications, and then you're discharged. If you receive your cells outpatient, at least at our center, you typically remain outpatient unless there are complications which bring you into the hospital.

(27:00): The two major complications from CAR T-cell therapy are cytokine release syndrome and neurotoxicity. So, what are these complications from CART19? There are two big categories.

(27:05): Cytokine release syndrome (CRS). The first is cytokine release syndrome or CRS, which basically is an inflammatory syndrome. It looks a lot like sepsis if you're familiar with that, because the activated T cells can secrete chemicals that are similar to those that bacteria secrete when a bloodstream infection is occurring. So, you can get fever, low blood pressure, low oxygen. If it's low-grade symptoms, we may not treat them or just use Tylenol. If they become more severe, there are rescue medications like tocilizumab that can be used.

(27:38): Immune effector cell-associated neurotoxicity or ICANS is a constellation of neurologic symptoms that are also a result of an inflammatory state. It can be confusion, disorientation, and attention, and rare things like seizures or brain swelling. At least at Penn, we always treat ICANS when it develops because neurologic symptoms are scary and we want to nip them in the bud when they start. We typically use dexamethasone, which is a steroid, but there are other treatments we can use as well.

(28:11): The incidence and severity of side effects varies among CAR T-cell patients. So, what about the recovery from CART19? There are some patients that have literally no side effects. They don't get cytokine release syndrome, they don't get ICANS. They may have a little bit of generic chemo side effects from the lympho-depleting chemotherapy, but some people basically feel fine every day.

(28:29): People who do develop CRS and ICANS may need just a few days to recover, or they may need longer. The recovery time really depends on whether the patient develops any side effects and how long they last and how severe they are.

(28:45):  There are a few rules with CAR T for the recovery. You must "live" within two hours of the medical center where you're treated for 30 days after the infusion. We at Penn actually prefer that patients are really within an hour, although we do allow one-to-two hours.

(28:59): Patients who live far away will be given temporary housing nearby. We usually house them in Philadelphia, like at an extended stay hotel. We have some other housing options for them as well. That way they can live nearby and in the event they have a complication, they're coming to our emergency room right away and not their local hospital that's far away that may not know how to manage complications of CART19.

(29:26): Patients must live with a caregiver for 30 days after infusion and a lot of patients do live with someone else already, so that's not too complicated to coordinate. There are some patients that live alone or have a caregiver that cannot travel with them to live near the infusion center, and so this is a problem for some patients. But usually, family members and friends chip in and essentially the patient's able to have someone with them.

(29:50): The reason for this requirement is in the chance that the patient may have a neurologic event. If they can’t call or communicate what's going on, we want somebody with them so that they can call our office and let us know if there's a problem so we can help out.

(30:05): The FDA says you're not supposed to drive for 60 days or two months after infusion. This, again, is with respect to neurological events that could happen. We don't want a patient to have a neurological event behind the wheel of a car because that could harm the patient or harm those on the road nearby. We do sometimes let patients drive earlier if they've had no significant side effects, but the technical length of time is 60 days.

(30:29): The follow-up for CAR T-cell patients is a little more intense than for autotransplant, particularly for the patients who are outpatient because they need to be seen somewhat regularly. Essentially, you need at least weekly visits for the first month and then less frequent visits afterwards. There is some debate on when the best time is to perform an imaging assessment after CART19. I still typically do it about 3 months or 90 days [after CAR T-cell therapy]. Some people do 30 days or some clinical trials look at 30 days, but essentially you want to look soon thereafter to see how patients are responding.

(30:59): Long-term side effects are not dissimilar to autotransplant. I would say that perhaps if CAR T remains effective for the patient and they have ongoing immune system suppression from that therapy, they might be more prone to infections long-term than an autotransplant patient. But again, there are some common things like hypogammaglobulinemia and slightly lower blood counts, but it's unlikely that there will be long-term complications.

(31:28): Finally, something I'm not going to focus too much on in this talk is vaccinations after autotransplant or CART19. Part of the reason I'm not going to focus on it is because the vaccination requirements or recommendations vary by center. This is just one list of vaccine series recommended by an infectious disease organization. And at Penn, we do not vaccinate our autotransplant or CAR T patients afterwards outside of flu, COVID, and shingles. A couple of reasons for this, but mainly we historically haven't done it. We have not seen patients develop any of the infections listed here. Typically, childhood infections are more severe infections as a result of not vaccinating them and so we don't tend to do it. My impression is most centers do vaccinate after autotransplant or CAR T and that's definitely something that you would hear about at your center.

(32:23): What about outcomes after these therapies? I'm going to show a few survival curves just to highlight some points about how patients seem to do with these therapies. These are all going to be progression-free survival curves. So essentially the curve is looking over time at the proportion of patients that remain progression-free or disease-free or in remission, however you want to frame it.

(32:47): 50% of patients with diffuse large B-cell lymphoma (DLBCL) or high grade B-cell lymphoma (HGBL) who undergo an autologous stem cell transplant remain in remission for five years or longer. We'll start with autotransplant for DLBCL and HGBL. This is one of the more widely studied outcomes for this patient population. Essentially there's probably about a 50% five-year remission rate and maybe even 50% long-term remission rate for studies that look a little bit longer. And this is independent of when the patient relapses after their first therapy.

(33:12): As I mentioned before, CAR T is now an approved and preferred therapy for patients who relapse early or within a year of completion of their first therapy. However, if you look at the curve here, the early relapsing patients on the bottom have very similar survival outcomes to the late relapsing patients on the top curve suggesting that no matter when you relapse, if you respond to second line chemotherapy and then get a transplant, your outcome should be similar regardless of time to relapse from your initial therapy.

(33:41): CART19 for DLBCL and high-grade B-cell lymphoma is also one of the more heavily studied cellular therapies and lymphoma, and there are many, many different curves I could put here including second line. What I chose to do is show the patients treated on some of the original CAR T studies in the third line or greater setting that have five-year or greater follow-up to really look at the long-term outcomes for these patients who've been followed for that period of time. Yescarta® is on the top and CTL019, which was the original name of Kymriah®, is on the bottom. This bottom study was patients treated at Penn on our original clinical trial which started in March of 2014, almost 10 years ago.

(34:24): 30-40% of patients with DLBCL or HGBL who undergo CAR T-cell therapy are in remission 5 years after treatment. As you can see, there's about a 30 to 40% five-year or long-term remission rate for CART19 regardless of the product used. You can see the curves start to flatten out after a while. Some people believe or feel that data demonstrate that Yescarta® has a better long-term response rate than Kymriah®. Happy to address that if people have specific questions. I'd say they're probably somewhat equivalent.

(34:52): Approximately 50% of patients with follicular lymphoma who undergo an autologous stem cell transplant remain in remission 15 years or more after treatment. For follicular lymphoma and autotransplant, I mentioned we [at Penn] don't really do a lot of autotransplant for follicular lymphoma anymore. Other centers likely do, but this curve is actually fairly impressive. This is up to 20-year follow-up in this curve and you can see that at about 15 years, the progression-free survival rate is about 50%. So, it looks like very durable responses to autotransplant for follicular lymphoma.

(35:17): A couple caveats here. When you look at these long-term follow-up curves, you have to start to wonder how closely the patients are really being followed. Are they being seen once a year or just as needed? Are they just getting blood work and examined, or are they getting CAT scans or PET scans to really look for low level relapses? And so, it's possible that some of these patients long-term that appear to be in clinical remission actually have relapsed and it's just not detected.

(35:44): The other thing about follicular lymphoma in the relapse setting is some patients have very indolent courses after they relapse and will probably survive their natural lifespan no matter what you give them. And some patients have more aggressive disease and both patient groups may be contained in this curve here. So, this favorable long-term outcome may be expected for some of the patients here regardless of receiving autotransplant or not. So, I think you have to look a little critically at these data, particularly in this slide, but I do think it has a very positive outcome for some patients.

(36:15): 70-80% of patients with follicular lymphoma remain in remission at least one year after CAR T-cell therapy. CART19, currently Yescarta at the top and Kymriah [on the bottom] have been approved, and again many, many curves for this patient population. I just chose to look at the original clinical trials for both therapies and see what the longer-term follow-up looks like. The data are continuing to read out, at least in publication form, they report confidence of one-year remission rates or [progression-free survival] PFS rates, which are about 70 to 80% for both products. You can again see the Yescarta may have a higher curve than Kymriah. I still think they're pretty similar, but more favorable rates than for diffuse large B-cell lymphoma, probably because the disease behaves a little less aggressively.

(36:56): Approximately 80% of patients with mantle cell lymphoma remain in remission after an autologous stem cell transplant that is followed by Rituxan® maintenance. I mentioned that transplants are falling out of favor, but for patients who do get an autotransplant after initial therapy and Rituxan maintenance, you can see that there's a very high rate of progression-free survival. At six years it's about 80% and that curve goes on a little bit longer but eventually will drop off. For patients with mantle cell lymphoma who are willing and able to go through some very intensive therapy upfront, they can experience a very prolonged time of not needing additional therapy, which was very important several years ago when we didn't have great therapies for relapsed mantle cell lymphoma and getting a long remission the first time was worth all the effort of going through intense therapy. That's maybe a little bit more debatable now with some of the newer treatments available.

(37:40): 50% of patients with mantle cell lymphoma who undergo CAR T-cell therapy remain in remission at least three years after treatment. And finally, CART19 for mantle cell lymphoma. I mentioned Tecartus® is the approved product. We now have roughly three-year follow-up and it looks like the progression-free survival rate at about three years is 50%. The blue curve at the top is patients who achieved a complete response. They clearly do better than the patients who don't and are depicted on the bottom curves. That's some very encouraging quasi long-term follow-up for this patient group.

(38:06): There are treatment options available for patients who do not remain in remission after an autologous stem cell transplant or CAR T-cell therapy.  Finally, for the last minute or two, I'm just going to talk about some treatment options for patients after autotransplant or CART19 if those therapies are not effective.

(38:16): So, for DLBCL and HGBL, you could do the other one that you didn't do. So, if you did an autotransplant and it didn't work, then you could do CART19. If you did CART19, it didn't work, you may consider an autotransplant in some specific cases. The bispecific antibodies, epcoritamab and glofitamab, are the new hot drugs out there for patients who need third line or greater therapy with this disease.

(38:39): Similarly, for follicular lymphoma, there's a bispecific antibody approved in the third line or greater setting. Lots of other therapies for all three lymphomas I'm not going to mention today and always appropriate to consider clinical trials.

(38:52): Real quick for the bispecific antibodies, I'm happy to field any questions about those. They are sort of off-the-shelf antibodies that target T-cells and B-cells and pull the T-cells to the B-cells, which also include the lymphoma cells. Similar side effect profile to CART19, maybe a little bit more mild, and you need ongoing infusions of these therapies to be effective.

(39:13): These are just some early progression-free survival curves here, which look fairly promising for some patients . At about a year out, maybe 40% of patients are still in remission, which may be just as good as CAR T for this disease. And for follicular lymphoma, with mosunetuzumab, the survival curve looks a little bit better as does CAR T for follicular lymphoma when compared to DLBCL, so about a 60% progression-free survival in a year.

(39:40): In conclusion, I feel that both autotransplant and CART19 are excellent treatment options for patients with all three of these lymphomas. I think there are several factors which contribute to the decision about whether or not to take autotransplant or CART19, namely FDA approval, but also some very important patient and disease-related factors.

(39:59): Short-term side effects are common, long-term side effects are rare and some, but not all patients can achieve long-term remissions following autotransplant or CART19. As always, the treatment recommendation should be individualized. The data I've shown and my preferences are somewhat limited and you always need to have a good discussion with your provider team about which therapy is the right one for you. With that, I'm happy to take any questions.

Question and Answer Period

(40:29): [Susan Stewart]: Thank you Dr. Landsburg. Wow, that was a very comprehensive trip through autotransplant and CAR T in a short period of time. We really appreciate that. We have a number of questions so let's start with the first one which is "At what age is CAR T not possible to do?"

(41:05): [Dr. Daniel Landsburg:] Great question. To start off, there's a decent sized population of patients that have received CAR T in their 80s, several I've treated. I have not treated anyone in their 90s, though I think we've treated one or two people that are 90 or 91 here. Hypothetically, there's no real upper age cutoff. If the patient's healthy and has good organ function and is willing to accept the potential risks, I don't think that patients can really age out of CAR T, but I would say practically late 80s and early 90s might be a practical upper age limit unless it's a very, very healthy patient in their early 90s or higher.

(41:45): [Susan Stewart]: Okay, great. Next question, "Can you get an autotransplant or CAR T-cell therapy more than once if you had a good prior response to one of them?"

(41:56): [Dr. Daniel Landsburg]: That's another excellent question. So, in lymphoma, we typically do not do a second autotransplant. It's not that that's never happened but that sort of falls out of favor. Most of the time in lymphoma, but not always, we think that autotransplant could be curative and so if it didn't work the first time, doing the same thing over again may not help.

(42:17): I would say multiple myeloma patients can definitely have second transplants because they get a long remission from the first one and the hope is they get a long remission again, but that's a different treatment objective for the transplant.

(42:29): CART19, you could do more than once. The major issue is that commercial insurance or Medicare won't pay for a second CAR T infusion, but you could do a clinical trial for your second CAR T, which is what we've done here at Penn for the last couple of years. Or if your first CAR T happened to be on a clinical trial, then you can get a commercial CAR T after that. So, the answer is you can do two. There just are some logistical constraints to having both done.

(43:00): [Susan Stewart]: Next question, "Is IVIG typically needed long-term or just during the first months after transplant?"

(43:08): [Dr. Daniel Landsburg[: So, in general, IVIG is typically not needed early on unless the patient already had hypogammaglobulinemia from their prior therapy and we're getting IVIG up until the time of their cell therapy. In particularly CAR T, where we see it needed long-term a lot more because hopefully the CAR T-cells remain active in the patient's blood and do kill off some healthy B-cells leading to hypogammaglobulinemia. I don't always use it or see it needed for even the first 6 to 12 months after CAR T, and then the immunoglobulins start dropping off and then we start to use it.

(43:45): I have a couple patients that are over five years from CAR T, some of them are still getting IVIG. I suspect they'll need it long-term, but I think how long patients will really need it for in the long run remains to be seen. We just need longer follow-up from a lot of these patients.

(44:00): [Susan Stewart]: All right, the next question is "What are the important considerations and risks after an allogeneic transplant, that is a transplant using donor cells, after CAR T-cell therapy for a patient in their 50s who's reached a complete remission from B-cell ALL?"

(44:21): [Dr. Daniel Landsburg]: Well, maybe I'll make that question a little bit more generic to say are there any specific concerns giving CAR T-cell after allotransplant and then maybe you could flip it the other way. What if you had CAR T-cells and then receive an allotransplant?

(44:34): And for the first part, the patients after allotransplant probably should be free of graft-versus-host disease (GVHD) or not had a significant history of graft-versus-host disease before CAR T-cells, although it's not totally an exclusion criteria. And the patients who have received prior allotransplant may have lowered immune systems before they receive CAR T.

(44:55): Going the other way, which is a little more common nowadays, CAR T and then allotransplant...usually if the patient has recovered from CAR T, as long as they don't have severe hypogammaglobulinemia, you don't have to make too many modifications to their transplant regimen or the protocols that you use to follow the patients.

(45:16): [Susan Stewart]: All right, thank you for that. Next question, "Can my indolent marginal zone B-cell non-Hodgkin's lymphoma transform to any of the three lymphomas discussed today?"

(45:28): [Dr. Daniel Landsburg]: Yes. So marginal zone lymphomas can transform to diffuse large B-cell lymphoma. The risk of that per year is relatively low, but it does happen. And then, you would typically proceed with treatment as you would for de novo or newly appearing diffuse large B-cell, or high-grade B-cell lymphoma. It can transform to either one, and you can use CAR T for transformed indolent lymphomas, marginal zone, and follicular, and Waldenstrom's or lymphoplasmacytic lymphoma.

(46:00): Interestingly in one of the slides, which I can try to go back to, CAR T has been studied in marginal zone lymphoma. In this slide here, I wrote on the top for Yescarta, the blue line is the follicular patients but that bottom orange line is actually marginal zone patients that received CART19 with Yescarta who have slightly lower outcomes or less favorable outcomes, although it was a very small number. So, there is some interest and studies looking at CAR T-cell particularly for marginal cell lymphoma.

(46:32): [Susan Stewart]: Great. All right, this next question comes from someone who's 42, has refractory diffuse large B-cell lymphoma, and she wonders "Is an auto stem cell transplant an acceptable treatment after CAR T or would you need to go to an allogeneic stem cell transplant using donor cells or bispecific antibody treatment?"

(46:55): [Dr. Daniel Landsburg]: That is a great question. So, an autotransplant could be acceptable if you've never received it before CAR T. And I have been offering salvage chemo and autotransplant to patients who have relapsed after CAR T. They never had salvage chemo or an autotransplant and some have responded well. Just this morning I visited a woman who had relapsed a couple months after Yescarta who just responded to salvage chemo and got her stem cells today for her autotransplant. And so, the answer is it's an acceptable treatment.

(47:26): One of my research interests is trying to figure out who these patients are who may respond to autotransplant after CAR T. More commonly, people are getting bispecific antibodies or allotransplant or a clinical trial, but it is definitely worth discussing salvage chemo and autotransplant because I think that probably has the best cure rate if the patient responds, and then gets an autotransplant. Based on these curves I showed, they have a 50% long-term survival rate and I think that's probably better than anything else we have to offer patients right now. So, I think that discussion should happen in regard to salvage chemo and autotransplant.

(48:05): [Susan Stewart]: All right, thank you for that. Next question. "In your experience, does getting an autotransplant first and then CAR T later once you relapse result in a favorable overall outcome versus doing CAR T first then autotransplant?"

(48:22): [Dr. Daniel Landsburg]: Hard to say. Some of our data at Penn suggest that the patients who had autotransplant and then CAR T didn't have as great a response as the patients who had just CAR T with no prior auto. Well, it's a little bit tricky to tease out. I think that it really depends on where you are in the line of therapy and what's your response or how long you've responded to your initial therapy. As of this moment, I do think the patients who relapse late after their initial therapy should try an autotransplant first and then CAR T if it fails. And probably the reverse is true if the patient relapses early, within a year after finishing therapy.

(49:00): Again, along with the research interest I mentioned before, I'm trying to tease out what features molecularly may predict response to salvage chemo and autotransplant as a second treatment. So, if we knew a priori, which patients would do well with salvage chemo and autotransplant, we might offer that first and then CAR T later. Right now, we're just using the time to relapse to decide that, but I think that's a surrogate for other features that are maybe more specific to each patient.

(49:28): [Susan Stewart]: All right, the next two questions come from a couple of clinicians. The first one is "Have you seen potentially masked cognitive dysfunction become much more evident post CAR T? We've had folks almost seemingly have dementia-like symptoms really become prominent post CAR T."

(49:50): [Dr. Daniel Landsburg]: Yeah, I can think of one patient who was probably mildly demented before CAR T. He, unfortunately, had a seizure and then recovered from that fully. But his dementia had progressed significantly shortly after his CAR T infusion, and I think maybe that neurologic event had exacerbated the condition that was already there. In general, I've not seen a lot of progressive dementia in my CAR T patients. I will admit not all our patients follow up with a neurologist and my screening for neurologic issues is probably less and less as the patient does well long-term. But potentially, I would say a neurologic event during CAR T may exacerbate an underlying neurologic condition.

(50:34): [Susan Stewart]: All right, and then the next question is "Why and what type of dental clearance is needed prior to transplant?"

(50:42): Dr. Daniel Landsburg: So I haven't recently had that requested for CAR T, maybe autotransplant in the last year. It's typically something that's required before allotransplant. And so, I basically only send patients to their dentist if they have major dental issues or insurance requires clinical clearance. But essentially, I think clearance is just a good routine exam to make sure there's no possibly infected teeth, because you don't want any evidence of infection going into any of these cellular therapies if you can avoid it.

(51:15): [Susan Stewart]: All right, next question. "Are people considered immunocompromised after transplant or CAR T forever?"

(51:23): [Dr. Daniel Landsburg]: I don't think so. I think for autotransplant, after a while the immune system can pretty fully recover. I think for CAR T, it's a little bit harder to know because the patients that respond well and have low levels of CAR T-cells in their blood probably do have somewhat of an ongoing immunocompromised state. Their healthy B-cells will be targeted and damaged and they won't make normal antibodies. So maybe it's more likely for a CAR T patient who's doing well to have an ongoing immunocompromised state. But I think that they might be functionally immunocompromised but hopefully can return to a pretty normal day-to-day activity and maybe just avoid situations in which the infection risk is very high.

(52:08): [Susan Stewart]: All right, the next question is a little lengthy. "I was diagnosed with mantle cell lymphoma in 2020. I received chemo. Following that, I received an autotransplant in 2021. My mantle cell lymphoma was almost exclusively in the bone marrow. I'm concerned that you said this could mean that I have contaminated cells back in my body. So what now? Should I be getting blood tests every time to look for these issues every few months? All my numbers are good except IGs, which are now low due to rituximab maintenance that I finished six months ago. And secondly, would it be good to go to a second like treatment like CAR T-cell therapy now? And does CAR T mean cure for mantle cell lymphoma?"

(53:04): [Dr. Daniel Landsburg]: Oh, great question. So, my concern about taking stem cells from a patient who has marrow or had bone marrow involvement by their lymphoma is a little bit hypothetical. I mean, the stem cells are sort of washed. They should be potentially free of lymphoma when they're given back to the patient. And mantle cell, although I don't do it myself, there is some data out there on minimal residual disease testing. So you can actually look at the patient's blood or bone marrow right before the transplant and understand to a very small degree if there is active lymphoma left. But the other thing is that most patients with mantle cell lymphoma do have involvement in their bone marrow prior to their diagnosis. And so, it's very common that this would be the scenario and then you would transplant the patient. And as I showed in the data in the figure, many patients can have prolonged responses.

(53:57): So essentially, if the patient's doing well, even with that history, I typically just monitor their blood counts and scans and hope and expect they'll get that very nice long-term progression-free survival. Most patients with mantle cell will relapse though and will need additional therapy and CAR T is the next therapy that's possible. In some cases, the BTK inhibitors are very good, but it's hard to think about changing follow up, just Rituxan maintenance for someone who's doing very well, because any new therapies can add toxicity and it's not clear that the patient would benefit them at that point in time. So, I guess I usually just monitor the patient with blood work and scans and so forth. And if they're doing fine, I leave them on their current plan and then we switch the plan when there's evidence of relapse.

(54:49): ]Susan Stewart]: Great. Okay, next question. "What does "often fatal unless treated appropriately" mean as it relates to mantle cell lymphoma? I see many people surviving multiple relapses."

(55:02): [Dr. Daniel Landsburg]: Yeah, that's a good point. And the outcomes for patients with mantle cell lymphoma have been much better in more recent times, recent years, particularly with the BTK inhibitors like ibrutinib and acalabrutinib than they were before. I think the key with mantle cell is some of the relapses can be very severe and depending on which therapies the patient has seen in the past, or which are available to them in the future, the relapses can be very challenging to manage.

(55:31): I do think that mantle cell lymphoma is a chronic disease. I do hope that CAR T can cure some patients with mantle cell. We just don't have long enough follow-up to really say that. But I do think it's a disease where patients relapse very frequently or have multiple relapses over time. They may not be able to survive all of them, much like diffuse large B-cell lymphoma. But the more drugs you have out there that are good, and again I didn't mention many of them for both diseases in my talk, you could potentially manage both lymphomas as chronic diseases for a long period of time, even if you can't cure these lymphomas with cell therapies or other treatments.

(56:07): [Susan Stewart]: All right, we have time just for a few more questions. "If you already had an allogeneic stem cell transplant - a transplant using donor cells - and currently have graft-versus-host disease (GVHD), is it possible to have CAR T-cell therapy if you're 65 years old and your cancer returns?"

(56:29): [Dr. Daniel Landsburg]: You probably should not receive CAR T therapy with active graft-versus-host disease (GVHD) for a couple of reasons. If you have active GVHD, you probably need to be on immunosuppression to control it and then you would have to stop the immunosuppression to get CAR T and that might lead to an exacerbation of the graft-versus-host disease. The immunosuppression is typically suppressing the donor T-cells and you need to have T-cells available to collect for CAR T. So that's a problem. It's often a problem to treat patients that have active lymphoma or leukemia and active graft-versus-host disease, but I would say I would not offer that patient CAR T-cells at that time. But if the graft-versus-host disease can be controlled, then I think it's reasonable to do that.

(57:19): [Susan Stewart]: All right. "Have you experienced autotransplant patients having the long-term side effect of extremely low IgA levels and what are the issues and precautions to be aware of with non-existent IgA levels?"

(57:34): [Dr. Daniel Landsburg]: I haven't, outside of also having other lowered immunoglobulin levels. I mean, it's possible that patients can have immunodeficiencies before they're ever diagnosed and treated for lymphoma. Sometimes we're better than others at picking that up ahead of time. Lowered IgA levels are not something that IVIG will treat, so we can't really make that number go up with IVIG. We can make the immunoglobulin G number go up. And I have to admit, I don't recall specifically which infections the IgA deficient patients are prone to, but I would say if you are hypergammaglobulinemic and have a lowered immune system, you do generally want to be careful and avoid situations in which the risk of infection is high.

(58:19): [Susan Stewart]: Great. This will have to be our last question. "Can you ever be a blood donor after an autologous stem cell transplant or CAR T therapy or is that permanently contraindicated?"

(58:30): [Dr. Daniel Landsburg]: The answer is, at least in the United States, to the best of my knowledge, it is contraindicated and it doesn't have to do with receiving therapy or your response to therapy. It has to do with ever being diagnosed with cancer or at least a blood cancer. So, the answer is once you've been diagnosed with a B-cell lymphoma, you cannot be a blood donor in the United States.

(58:51): [Susan Stewart]: Closing. Excellent. So, with that, we will need to close the session today. I want to thank Dr. Landsburg for an excellent presentation and very helpful responses to the many questions that we had. And I want to thank the audience for some terrific questions. This presentation was recorded. It will be available on BMT InfoNet's website sometime next week, complete with Dr. Landsburg's slides as well as a transcript. We will send you an email when the presentation is available for viewing. In the meantime, if you have any questions, please contact us by email or give us a call and let us know how we can help you in any way. Thank you everyone and have a wonderful afternoon.