TRANSCEND FL is a global trial assessing the efficacy and safety of the CAR T cell therapy lisocabtagene maraleucel in patients with relapsed or refractory follicular lymphoma. Join Dr. Kamdar, the lead investigator for this trial at University of Colorado Cancer Center, for this podcast to learn more. Feel free to email me with thoughts or questions on this podcast at hannah@healthtree.org.

 

For additional CAR T resources, see below.

HealthTree University:

• What is CAR-T therapy and how is this drug class used to treat follicular lymphoma? 
• What is some of the most promising research being done for follicular lymphoma?
• What are my options for treating follicular lymphoma?                

News Articles:

• Liso-cel CAR T-Cell Therapy
• CAR T-cell Therapy for Follicular Lymphoma 

101 Pages:

• What are the Treatments for Follicular Lymphoma?

Hannah Loosle (00:12)
Hi everyone, welcome to today's episode of the HealthTree podcast for follicular lymphoma, where we connect patients with lymphoma to the research and information they need to know about. If you've been with us before, welcome back. If this is your first time joining us, welcome. We're so happy to have you join our follicular lymphoma community. My name is Hannah Loosle. I'm your host and the lymphoma education manager here at HealthTree Foundation.

If you aren't aware of our other educational programs, make sure to check out our website and see the other ways we can help you navigate your disease and connect you to resources. The goal of this podcast is to make research and new information coming out about disease easy to understand and easily accessible. If you've ever found yourself overwhelmed by clinicaltrial.gov or medical abstract, we are here to change that.

Stick around until the end of the episode when I'll be back to share my final thoughts on today's interview as well as some additional resources you can dive into related to today's topic. The topic of today's podcast is updates from the Transcend Follicular Lymphoma Trial. We are going to be joined in just a few minutes by Dr. Manali Kamdar, a researcher on the study I just mentioned. Before we bring her on, I want to give you all a little introduction.

Dr. Kamdar completed her medical school training in Mumbai, India and attended East Carolina University for her internal medicine residency and her hematology oncology fellowship.

She then completed another fellowship in blood and marrow transplantation at Stanford University. In November 2014, she joined the division of hematology at the University of Colorado and is currently the clinical director of lymphoma services. She is a clinical researcher in malignant hematology with a focus on lymphomas and autologous transplantation. She conducts clinical trials with novel agents and chemotherapy with the hope of improving outcomes in the field of lymphoproliferative malignancies.

I chose Dr. Kamdar and the topic for today's episode because CAR T shows very promising results for relapsed refractory follicular lymphoma and this trial is looking to address some of the unmet needs that exist in the relapsed refractory follicular lymphoma space. I'm very excited to hear from Dr. Kamdar about this study. So now without further ado, let's bring her on.

Hannah Loosle (02:16)
Welcome, Dr. Kamdar. Thank you so much for joining us today. I'm really excited to dig into your research today. But first, before we jump into the study, I like to start by setting the scene for our audience. So let's start with the why behind your research. What problem or issue did you see in the lymphoma space that you are hoping to fill with your research?

Manali Kamdar (02:35)
Yeah, so I think it's important for our audience just to set the stage to generally be aware that lymphomas are a heterogeneous group of diseases. And they're really divided into nearly 85 And thus, each unique subtype has a nuanced approach, management, and thus has clinical issues which fuel researchers like me to hopefully improve the outcomes for patients where they have a suboptimal response to treatment. So since this podcast today is primarily featuring follicular lymphoma, I can say that what drove me to doing more research in patients with a subtype of lymphoma called follicular lymphoma was its unique biology. It is predominantly a chronic lymphoma, meaning patients diagnosed with it are typically going to continue to live with it. A majority of patients are able to get on what we call watch and wait or active surveillance. Some patients need antibody treatments. But then I think there are some patients who may actually benefit from starting treatment. And in those patients, it's been for me as a researcher to see varied responses. There are patients who initially get started on chemotherapy-based combination approaches and have an exceptional response, but then there are a few that actually don't enjoy a long-term remission. with chemo treatments. Then there are patients who, you know, although have achieved remission, these remissions are not long lasting, which means they have to be at the receipt of multiple treatments over and over again. Every time they have to experience a relapse. So my basic fuel for research in follicular lymphoma emerged from the hope that with research studies, maybe we could get our patients to receive a kind of treatment which is novel, which is more immunotherapy based, where we are not really just giving more patients more toxic chemo treatments, with the hope that maybe we can just trigger their own immune function to be able to destroy lymphoma cells. And so far we have had some remarkable outcomes with immunotherapy based approaches. And that is why I have been so interested in developing more novel products, treatments for patients, especially with relapsed refractory follicular lymphomas. where there remains a significant unmet need.

Hannah Loosle (05:47)
Absolutely, thank you for providing us with that context. And like you said, follicular lymphoma is definitely a unique blood cancer, you know, sometimes treated more like a chronic disease and a lot of patients when they're on watch and wait have a lot of anxiety. So it's great that you see this unmet need and all of novel therapies and treatment options. So I really appreciate the research that you're doing in this space.

And now we can move on to the Transcend follicular lymphoma trial. So we'll start a high level overview of this trial. So can you give us a brief description of this study?

Manali Kamdar (06:21)
Sure, so the Transcend Follicular Lymphoma Study investigates CAR T cell therapy called lisocabtagene maraleucel So as many in the audience may already be familiar with, but CAR T cell therapy is a form of cell-based immunotherapy in which a patient's own T cells are extracted and then in a lab are engineered to target lymphoma cells here would be CD19 positive lymphoma cells. They are further expanded and then infused back into the patient. This technology has revolutionized lymphoma treatments and lisocabtagene maraleucel has been at the forefront of this effort with regards to all the exceptional results it has already generated in other subtypes of lymphomas. For example, lisocabtagene maraleucel is approved for patients with a very aggressive form of lymphoma called diffuse large B cell lymphoma in patients who have previously progressed after receiving two lines of treatment or in patients who have progressed with lymphoma after receiving one line of treatment.

And it has really displaced auto transplant in this subset of high risk diffuse large B cell lymphomas. Number two, it has also been approved in patients with mantle cell lymphoma. Mantle cell lymphoma that has previously failed to respond to two or more lines of treatment. And thus, I think it is very important to test this construct which is not only efficacious, but really very manageable from a safety standpoint in patients with relapsed refractory follicular lymphoma. So what is the Transcend study? The Transcend study is testing or investigating lisocabtagene maraleucel in patients with relapsed refractory follicular lymphoma. The big question is, you know, not all relapses are created equal. And thus, it's very important to test a novel construct in a true unmet need scenario. And overall, based on data, we do know that patients who have a relapsed refractory follicular lymphoma, who have received more than two prior lines of systemic treatment, or patients who have received one line of prior chemotherapy based treatment and have progressed within 24 months after initial chemotherapy are known to be very high risk for future relapses. And thus this study primarily tests patients with follicular lymphoma that has relapsed after three lines of treatment and patients who have relapsed with follicular lymphoma after one line of chemoimmunotherapy with high risk disease features such as patients who relapse within the first 24 months after receiving chemoimmunotherapy or patients who have relapsed after one line of chemoimmunotherapy but they have high risk disease features, high risk disease features such as bulky tumors, high risk disease features such as low blood counts, or patients who have a lot of B symptoms such as drenching night sweats, unintentional weight loss and fevers, patients who present with third spacing of fluids such as Asiates and pleural effusion. We know that these patients need something else. So this is a study that was set to test patients with relapsed refractory follicular lymphoma in third line plus as well as second line provided they had high risk features. They had to have histologically confirmed follicular lymphoma. They had to have a PET that showed positive disease, which was bright on PET as well as patients who had measurable disease on PET. So those were some of the inclusion criteria for these patients. To be able to enroll onto the study, they had to have progressed with follicular lymphoma after having received two or more prior lines of treatment or after having received one prior line of chemotherapy based treatment and either progressed within 24 months or progressed with high risk features that I alluded to. Patients had to be in excellent functional status to be able to enroll on this study and they had to have adequate kidney function, liver function, organ function in general. So this is a phase two study. It was a multi-center study that was a global study that was open across United States as well as European countries. And within this study, the primary endpoint, which is what we were primarily testing, was the overall response rate based on an independent review committee by PET scan. The secondary endpoints that we were also looking at was complete response rate, duration of remission or response, as well as progression free survival, the safety of the product, particularly from the standpoint of unique side effects of CAR-T cell therapy, such as cytokine release syndrome, neurotoxicity. We were also measuring overall survival of patients as well as a very unique variable that is beginning to gain a lot of precedent in research in follicular lymphoma is the quality of life. You know, we want everybody to succeed. We want our patients to have the best outcomes, but in the process, we want our patients quality of life to be absolutely maintained. So that is a variable that was also being tested.

So with that, in terms of overall about 139 patients ended up with leukapheresis. So 139 patients ended up making sure that they get their T cells extracted. That's called apheresis, leukapheresis. And of the 139 patients, 25 patients had high risk second line follicular lymphoma and 114 patients had follicular lymphoma that had progressed after three lines or more. So more than two lines of treatment. Overall, the primary analysis, which was presented last year, actually showed that at a median follow-up of one and a half year, 18 months to be precise, liso-cel or lisocabtagene maraleucel showed an overall response rate of 97%.

And of these responders, majority, meaning 94 % of patients had a complete response. With regards to safety, it was absolutely safe in patients. And this was demonstrated by the fact that cytokine release syndrome was seen in mild grade. 58 % of patients had some sort of cytokine release syndrome. But when we look at grades, severe grade would be grade three or higher. Grade three or higher only had been seen in 1 % of patients. On the other hand, neurological events on neurotoxicity, also called ICANs, was seen in 15 % of patients. Again, high grade neurological events, which would be grade three or higher, were only seen in 2 % of patients. So it was an absolutely manageable profile in terms of toxicity follow-up. And thus, at the most recent American Society of Hematology meeting, there was a follow-up of this study because as we mentioned, follicular lymphoma is a chronic disease. So we want to know if patients responded, how durable were these responses? And this was a two-year follow-up that was presented on this clinical trial.

And needless to say, we were quite happy with seeing that after approximately two years of follow-up, liso cell continued to demonstrate durable responses with very high rates of patients who remained in remission, patients who were surviving and living well, not just in third line follicular lymphoma, meaning patients who had failed two or more lines of treatment but also in patients who were in second line high risk. So this cohort of follicular lymphoma called POD24, meaning patients who receive frontline chemoimmunotherapy and then have a relapse within 24 months, this is the cohort that also showed exceptional responses. Just to talk about specifics, I can say that with regards to duration of response, so

If the patient achieved a response, how durable was it? So at the two year mark, if you look at patients in third line, follicular lymphoma, the 24 month duration of response was 75%. And in the second line setting, the 24 month duration of response was 86%. This is truly remarkable. And then when it comes to progression free survival, meaning how many patients were able to live without having the follicular lymphoma come back. So that's called progression free survival. And it is a variable that gets a lot of importance in follicular lymphoma because patients usually have a good survival, but it's very important to us as researchers to make sure that the survival is not living with follicular lymphoma getting treatments. So progression free survival.

With regards to the two-year follow-up, in the third line setting, 73 % of patients were progression-free two years after receiving liso-cel And in the second line setting, 83 % of patients were progression-free at the two-year follow-up. Now with regards to overall survival, it was exceptional. In the second line setting in patients who had POD24, 96 % of patients are still alive. And then in the third line follicular space, 89 % of patients had a 2-year overall survival was 88.2%. Now with regards to safety, there were no new safety signals that were seen. So that's another point that I think I do want to emphasize that as a function of CAR T-cell therapy because CARs basically just unleash on the tumor. So we expect patients to have cytokine release syndrome, which is essentially patients have fevers or shortness of breath, or they might have low blood pressure. And based on whether we see one feature, two or more, we grade them.

And it was really remarkable to see with this product the cytokine release syndrome, as I mentioned, high grade, which was three and over, which is anything that may put somebody in the ICU or anything that may make patients be on high level of oxygen need was only 1%. And then with regards to neurogenic toxicity or neurotoxicity, also called ICANs, it was also remarkably low with a high grade neurotoxicity at only 2%.

A function of CAR is that patients can have low counts. That's called cytopenias. And some patients may actually have prolonged cytopenias. Prolonged cytopenias would be cytopenias that happen beyond three months of having received CAR T cell therapy. And for patients on this clinical study, only 13 % of patients had prolonged cytopenias. Also, of the nine patients, patients who had not recovered by one year, by one year were extremely few. So I do believe that with regards to safety, this was also an exceptionally safe product. There were obviously cellular kinetics that were done on this study, and that was also quite assuring to see that the persistence of CAR T cell therapy was actually detected up to 30 months in both cohorts of patients, whether they were second line or whether they were third line follicular, and the follow up is still ongoing. I talked about a unique variable that we are studying in all lymphoma studies now, which is called the patient reported outcomes. And it was heartening to see that the patient reported outcomes actually showed durable improvement across all lymphoma specific, as well as the general quality of life domains for most patients. So this product has secured an approval in the United States. lisocabtagene maraleucel is now approved in the United States for patients with relapsed follicular lymphoma if they have progressed after two or more lines of treatment. And this forms the basis for what we have started doing in our clinics. I do believe that CAR T cell therapy is uniquely specific to patients with relapsed refractory follicular lymphoma. It seems like a high upfront commitment, but it's a one and done treatment. So patients don't have to keep coming back to the cancer center all the time after the initial 30 day commitment.

So I am actually looking forward to continuing to treat patients with follicular lymphoma now that it is on label with lisocabtagene maraleucel for my patients with relapsed refractory follicular lymphoma.

Hannah Loosle (21:37)
Thank you so much for that wonderful overview of the study. It's so important to do that we have this research of relapsed refactory treatment options for follicular lymphoma, especially for patients that have progression of disease within 24 months or have lines of therapy. And I also loved that you touched on the quality of life for this treatment. There's lots of treatments that exist that maybe extend a patient's life, but they don't give patients the quality of life that they hope.

So this is really important. And like you said, they're not tied to coming to the hospital because it's a one and done treatment. And safety is also something that's very important for patients. I know that that's something patients sometimes worry about with clinical trials and things like that. So it's fantastic that the research of liso-cel has focused on safety. And the results so far from the study are very promising, which is super exciting.

How can you see the results of this study changing the future of follicular lymphoma treatment?

Manali Kamdar (22:33)
Long term, potentially, at least right now, we do know that a couple of years of where they don't really have to get started on any treatment. It's quite rare to find treatments in patients who have had multiple relapses with follicular lymphoma where it is time limited. It's very rare to have any treatments where patients are not continuing to be bound to a cancer center. So I think in the third line setting where it is currently approved, I think it gives the unique opportunity for patients to be able to get in remission, to stay off treatments, to stay off of a cancer center. And if these follow-up results are, you know, anything that I can see from the follow-up results is that the durability of these remissions. So of course, you know, we will be presenting follow-up data at the three-year mark and at the five-year mark, but my hope for every follicular lymphoma patient eventually is a cure. It seems quite lofty right now, but I truly believe that it's the cellular therapies that are going to eventually get us there.

I feel very, very encouraged by the existing response that liso-cel has shown.

Hannah Loosle (23:52)
Thank you for that response. I really liked that you talked about how some of these treatments may lead to a cure for follicular lymphoma down the road, which is so exciting for patients.

Another question that patients have regarding participation in a clinical trial is what their daily life will look like during the trial. 

Manali Kamdar (24:09)
Yeah. In this clinical trial, think right now, this clinical trial is open for patients who have relapsed with follicular lymphoma after having received one line of chemoimmunotherapy. The chemotherapy immunotherapy could be bendamustine rituximab, bendamustine gazaiva, could be CVP, could be CHOP, antibody backbone could be rituximab or gazaiva. They could have been on maintenance, but they could not have received one additional line of treatment because the product is now generated and approved for third line. We know that can be provided in the community, but it's very important to understand that this construct is not available yet on label for patients who have relapsed after one line of treatment.

And that one line of treatment has to be chemoimmunotherapy. And then patients either have to relapse within 24 months of the receipt of chemoimmunotherapy or patients needed to have the high risk features such as disease bulk or symptoms or low blood counts. So that's basically what the clinical trial currently is looking for because we are hoping that if liso-cel can show such a great response in third line, and second line that it hopefully gets approved even for second line so that our patients can get the benefit of it. To answer your question about what it actually means for a patient, know, clinical trials are done with very cautious eyes, which means it's another different village in any academic center that gets activated to make sure that everything gets done appropriately, seamlessly, and making sure that our patients are taken well cared for.

So with that said, usually it typically entails a couple of visits prior to apheresis. Those visits are to get some additional blood work, maybe a scan, maybe a biopsy. If a biopsy has not been done to confirm that we are still looking at follicular lymphoma. And then subsequently they have to come back to clinic for what we call apheresis That's a one day commitment.

After apheresis, it depends on the cadence of the disease. Now the cells take about three, three and a half weeks to manufacture. During that time, what do we do in terms of making sure that we keep the follicular lymphoma stable is certainly something that every center is quite different. So if I have a patient where the disease cadence is relatively slow, I make sure that they are checked on by phone calls and make sure that they don't have any new issues.

However, if patients have proliferative disease, meaning a disease that is quite fast growing and we need to do something in the middle, I think we may use certain bridging treatments. These bridging treatments could be low dose chemo. These bridging treatments could be radiation therapy. And where I practice, I have patients coming from a couple of states besides just Colorado. So I have patients coming from far away. So frequently we try to keep it less cumbersome for our patients, make sure that maybe their primary oncologist from where they are referred to could take care of the bridging treatments. And then that way they don't have to keep coming back to the local site. After the bridging treatments are done, there's usually one more assessment because in order to get back on the clinical study or get the product that is being manufactured, we want to make sure that the PET still shows disease. So that's one PET that we typically have to do.

And then after that, we get the process started. This, I would tell my patients, tell my audience here on the call that it is give and take a 30 day commitment to the academic center. If the patient's fitness is good, if they are able to have a good caregiver with them, if they stay close by, or we have been able to finagle housing for them close by, it's really easy for us to do all of it outpatient.

However, there are times that my patients are older or they don't have adequate caregiver support, in which case scenario I have admitted those patients for the whole process. So what does it entail? It basically entails the first step, which is call lympho-depleting chemo treatments. It goes over a few days where you get two chemos which are very low and low intensity chemo. It's basically to make space in the marrow.

so that the CARs that have been manufactured when infused can home in the marrow and then start doing the job that they have been scheduled to do. So the few days of chemo initially are usually quite manageable. Patients, if they live close by, can go back and forth to their home and come back to the cancer center. And then afterwards is what we call the day zero, which is the day of the CAR infusion.

I will say that it is a very normal day. Patients typically don't have any reactions to the infusion or anything like that. They basically get the CAR infusion and after that starts a very vigilant monitoring period for a total of 14 days because this is the first two weeks after CAR infusion that we typically see the unique effects of CARs which can manifest initially as cytokine release syndrome and then maybe as neuro-toxicity. After 14 days, it's quite rare for patients to have any of these unique toxicities, but at our academic center and majority of the academic sites, we typically continue to follow patients locally for additional 14 days. So that's why I basically said give and take, it's a one month commitment. But after the 30 day mark, the visits go down. Patients are typically seen in clinic maybe once a month.

They can obviously be seen more frequently. If they continue to have low blood counts, they might need transfusion support or they might need an occasional white blood cell shot. But majority of the patients are able to return home around day 30. So yes, it's an upfront undertaking so as to speak, but it is something that we try our best to make it less onerous on our patients, to make it more quality of life friendly.

This is certainly a construct that can be absolutely given outpatient. It does not entail a mandatory admission unless obviously cytokine release syndrome occurs and then that puts the patient into the hospital for a couple of days until it resolves and then they are back in the outpatient setting. So, you know, I do say that, you know, it's a treatment that initially if we are willing to give it 30 days to our health based on the data.

We're beginning to see some really durable remissions. You it works for a lot of patients here that are able to go through it very successfully. Age is never a bar for giving CAR T cell therapy. I've given it to octogenarians and with a remarkable success, but a follow-up is crucial, but it's not cumbersome.

Hannah Loosle (31:28)
That's great that, like you said, this can be a mostly outpatient and give or take 30 days. It's great that it shouldn't impact clinical trial participants' daily life really, really long term. And so you mentioned that this was a phase two trial. So what are the next steps kind of looking ahead to phase three for this one?

Manali Kamdar (31:49)
Yeah, I think that is probably where it's going to intuitively go. But I don't know if it is actually something that is needed in the second line and beyond. Maybe, you know, I think the big question is, there space for cellular therapy products in earlier line setting? You know, we have an approval in the third line setting. I know it works.

The second line setting, hopefully it continues to show the same kind of responses in this clinical trial that is open. And if it is approved, that will be a great opportunity for patients. I think for me, in terms of how I think through being able to cater to patients even earlier, I think the big question is, it make sense to bring it earlier? And earlier, which patients would get the most benefit. Maybe patients where you initially treat them with frontline chemoimmunotherapy, right? Nobody wants chemotherapy. If we can avoid chemo, that would be lovely. So I do believe that that may be a route, but we'll see how the research unfolds.

Hannah Loosle (32:54)
Absolutely. I think that would be great if immunotherapy could be moved up into first and second line treatment. know, like you said, chemotherapy is not super ideal for a lot of patients. So it would be great if there were treatment options like this sooner in their sequencing. And well, this has all been so interesting. Do you have any final thoughts about the study that you would like to share with our audience today?

Manali Kamdar (33:19)
No, think I hope the audience took away some really important pivotal findings of this study. I hope that through this podcast, we could benefit patients who may be looking for options. It never hurts to ask an oncologist or your primary oncologist to connect you with an academic site that does CAR T cell therapy.

If we have a product that is currently approved or we have something that is being tested in a clinical trial, you might actually get the benefit. So I think my plea to the audience on the call is going to be that if you have a question, never hesitate to ask, always look for more treatment options that may be better, may be durable, never hurts to get a second opinion.

And we are all invested in your health. And we really want to make sure that this chronic disease called follicular lymphoma eventually finds a cure. But for now, at least we offer treatments that are not repetitive, that are not something that tie you down to a cancer center all the time. It's one and done. And so far, I think we have made some success. We obviously have miles to go.

And that's where we'll be trying to focus our efforts.

Hannah Loosle (34:37)
Absolutely. This whole interview has been so informative. So thank you so much, Dr. Kamdar, for joining us today and sharing about the incredible work you're doing in the lymphoma space. I want to thank you on behalf of HealthTree and our follicular lymphoma community.

Manali Kamdar (34:51)
Thank you so much for having me on this podcast and nice to talk to you as well.

Hannah Loosle (34:59)
This was a fantastic interview. I loved that Dr. Kamdar discussed the quality of life and safety this treatment offers to follicular lymphoma patients. Like we discussed, treatments that enhance the quality of life are so important for patients like you, so you don't have to be worried about feeling sick all the time or being tied to the hospital and can live your life as you would like.

It was also exciting to hear about the results so far from the study and the potential they have for the future of CAR-T. If you want to keep learning, we have some additional resources on CAR-T that you can look at related to today's topic. I'll link them in the episode description so you can check them out.

Thank you for joining us today on the Health Tree Podcast for Follicular Lymphoma. I hope you learned something new. I would love to hear your thoughts on today's episode. Share them with me in a comment or send them to me in an email. You can find my email in the episode description. Join us again next time to learn more about follicular lymphoma research and what it means for you.