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Peter Martin, MD: Hello. I'm Dr Peter Martin from the lymphoma program at Weill Cornell Medicine and the Meyer Cancer Center in New York City. Welcome to Medscape's InDiscussion series on mantle cell lymphoma. Today, we're going to be discussing CAR T cells and immunotherapy in mantle cell lymphoma. First, I'd like to introduce my guest, Dr Michael Wang, professor in the department of lymphoma and myeloma and the department of stem cell transplant at MD Anderson. Michael, welcome to InDiscussion.
Michael Wang, MD: My pleasure, and thank you for inviting me.
Martin: It's hard to talk about mantle cell lymphoma without your name coming up. You've been involved in the development of "R-squared" ibrutinib, acalabrutinib, and a whole bunch of other drugs currently in development that we may see in the future. You also have a tremendous amount of clinical experience in CAR T-cell therapies, which we will talk about today. Despite all of that, you run a lab. I have been asking my guests what it was that motivated them to work in the field of mantle cell lymphoma. And of course, I'll ask you that. But I also wanted to ask you how you've managed to be so successful in mantle cell lymphoma.
Wang: Well, I'm not a very smart guy, but I work really hard. I was educated in China and the United States. Both countries invested a lot into my education. Eventually, I found my niche in mantle cell lymphoma. This is the area in which I can see a lot of patients and contribute to the field. Life is like this — eventually you find your niche, and you will not let it go because it is the best way to contribute, pay back society, and pay back what people invest into you.
Martin: Today, we're going to focus on immunotherapies and CAR T-cell therapies. You were involved in the ZUMA-2 trial that helped to get brexucabtagene autoleucel approved in mantle cell lymphoma. Can you help us understand what the difference is between that and axicabtagene ciloleucel, and update us on any recent data from the ZUMA-2 trial?
Wang: Yes. So the way they prepare the CD4 and CD8 cells is that they prepare them and put them together as a single infusion. But in the ZUMA-2 trials, CD4 and CD8 are prepared separately and infused separately. And with the infusion into the patient, the proportion of these two is different. They would infuse whatever CD4 count cells and CD8 cells they got. They did not have to require a 1 to 1 ratio. The major difference is that T cells in axicabtagene ciloleucel are prepared together and infused together, and in the ZUMA-2 trials, they are infused separately at a new set ratio.
Martin: Great. We saw when ZUMA-2 was published that the response rates were quite high — like 90%, with a complete response rate in the sixties, right?
Wang: In the original data published in The New England Journal of Medicine, the overall response rate was 93% and the complete response (CR) was 67%. After two more years of follow-up, we reported at the American Society of Clinical Oncology last year in 2022 at 3 years of follow up that the overall response rate was 91%. The CR was slightly up from 67% and now 68%. So, the ratio is holding up. In a recent real-world study containing 95 patients who received brexucabtagene autoleucel, the response rate was very similar, and the real-world data confirmed the ZUMA-2 trial data.
Martin: Is that your impression as well from the patients you have treated on and off trial?
Wang: Yes. Remarkably, all of those patients who would not be eligible for the ZUMA-2 trial in the real-world study, including our patients at MD Anderson, all showed a similar pattern. Even if they were sicker than the ZUMA-2 trial population, they have all the ineligibilities, such as renal disease, which are comorbidities, but they were treated in a real-world tertiary center setting. The response rate is similar, and the CR rate is even higher, at over 80%.
Martin: In the ZUMA-2 trial, I think everybody was required to have prior Bruton tyrosine kinase (BTK) inhibitor therapy, right? But in the FDA label, it doesn't really mention that. Are you currently using CAR T cells outside of a population that hasn't received BTK inhibitors? Where does that fit in?
Wang: You're absolutely right, Peter. In the ZUMA-2 trial, the entrance eligibility criteria require prior BTK exposure. In the real-world data presented by Dr Yucai Wang and their colleague Michael Jain, there's still 72% of people who received prior BTK Inhibitors. In my practice, I rarely use brexucabtagene autoleucel without prior BTK inhibitor exposure. But I did use it in several patients because they were really high risk — although they did not receive prior BTK inhibitors, they have primary refractory disease. They have high expression of Ki-67 p53 mutations, some have a complex karyotype, and some have blastoid pleomorphic origin not responding to therapy. So any BTK combination would not last very long in those patients. I had the opportunity, so I used brexucabtagene without prior BTK exposure in these cases.
Martin: I'll touch briefly on bridging therapy because I think that's something we don't read enough about. Do you use a BTK inhibitor as bridging therapy in these patients if they haven't received one before? And in patients who have had a prior BTK inhibitor, patients who get CAR T cells do better if they have less tumor bulk. Finding the right kind of bridging therapy is kind of important, right?
Wang: Yes. In most of the cases, the brexucabtagene is used as a consolidation therapy, and so we have prior bridging therapies. Before bridging therapies, we would like to have relatively good control and a bridging therapy to wipe out the majority of the disease. Like you said, very early on we realized the preinfusion tumor volume is very important for efficacy, toxicity, and a persistence or durability of the response. So in order to control that, you have to use bridging therapy. And fortunately, in the ZUMA-2 clinical trial, the bridging therapy was steroids, ibrutinib, and BTK inhibitors. That's why in 33 patients who received the bridging therapy, after the bridging therapy, imaging showed that 32 of them had a higher tumor volume. So, the bridging therapy was really weak in the ZUMA-2 trial. However, why did 95 patients in the real-world data population have an even higher CR? Because of the freedom of the usage of a prebridging therapy, Peter. And you know, in the real world, we can use anything we want — chemotherapy, BTK inhibitors, combination with venetoclax. We used everything we could to reduce the volume, and I think that's why the real-world data look like the efficacy was so good.
Martin: That's an important point. I think the degree to which mantle cell lymphoma can exist without having clear tumor bulk is undervalued or underappreciated. We can have a ton of cells in the bone marrow and the spleen, and tumor volume is maybe more difficult to measure in mantle cell lymphoma than in something like diffuse large B-cell lymphoma.
Wang: Totally agree. And they also hide in the GI tract.
Martin: Right. And this is shown by MD Anderson colleagues. I'm glad we're getting into this with your personal experience. Another personal question I'll ask you is about the populations of patients who have blastoid mantle cell lymphoma. I saw in the ZUMA-2 trial that the response rates are reported as similar between blastoid and nonblastoid patients. My personal impression is, although that might be true, I am still more anxious about people with blastoid and super proliferative tumors even when they do respond to CAR T cells. I don't know if you have any data from that trial or personal experience regarding the durability of the response.
Wang: I feel the same. In the primary analysis of the ZUMA-2 trial, there's only 60 patients, so you almost cannot make a new conclusion about this. There were only 6 patients with a TP53 mutation, but there were only a minority of patients who had a blastoid variant. So, the real answer is coming. Why? Because the real-world data with more cases are more powerful. Ninety-five patients are not even enough, but we are continuing enrolling patients for these real-world data. And when we reach 300 or 400, we will have a statistical difference in each subvariance. And if there are five or six or seven ongoing projects looking at brexucabtagene in the real world, eventually when we compare them across the board, we will find the truth. I do have patients after 5 years now with a p53 mutation with a blastoid variant with a high Ki67 with a complex case. I thought they were not going to survive very long, but surprisingly, after 5 years, they are still with me, and they live a normal life.
Martin: Yes, it's pretty impressive when it works. I have a related question to the ZUMA-2 trial — we talked a little bit about BTK inhibitors and bridging therapy. There is one graph from the ZUMA-2 trial that I thought was interesting, and it probably also applies to this limited population and limited statistical analysis you mentioned. Do you feel like there's a difference between ibrutinib and acalabrutinib prior to CAR T-cell therapy, or are there too few people to really make that kind of assessment?
Wang: It is always my belief that targeted therapies are not separable from immunotherapies. Targeted agents such as ibrutinib have immune boosting properties, and immunotherapy is often signaling through targeted pathways. There's much evidence in the lab saying that the BTK inhibitors would enhance the CAR T-cell expansion, proliferation, and even persistence. However, the real data in the patients in the original ZUMA-2 manuscript presentation showed there are three groups: an ibrutinib exposure alone group, a no BTK and acalabrutinib alone group, and an acalabrutinib plus ibrutinib group. Whoever received ibrutinib, whether in combination with acalabrutinib or not, had a four-fold higher CAR T-cell expansion than the acalabrutinib alone group. So I do believe that ibrutinib is superior to acalabrutinib based on the preliminary data. And of course, we need to see more data. This is just one study, but this study showed us statistical significance.
Martin: We're going to get back to the toxicity in a second. One other quick question: Prior to CAR T cells, what is the impact of bendamustine?
Wang: In the long-term, 3-year analysis, we have two groups. Those who received the bendamustine within 6 months had really poor CAR T-cell expansion, and within 6 months of bendamustine, the two groups showed statistical difference. If the patients received bendamustine but it was more than 6 months ago, there's a trend we see that those with a prior exposure of bendamustine have a shorter peak of CAR T cells. So, their CAR T-cell expansion is not as good, but it showed no statistical difference — only a trend. So the real significant difference is receiving bendamustine within 6 months.
Martin: Okay, so you've got all of this experience and these insider tips. Does this information impact the way you manage patients with respect to when you might use bendamustine, which BTK inhibitor you might use, and how you sequence everything with CAR T cells?
Wang: Absolutely. When I do bridging therapies, I try not to use bendamustine. If the patient has received bendamustine, I may give them a bridging therapy to space the bendamustine. So, that is more than 6 months. If I know the patient is going to get CAR T cells and not only bendamustine in the future, I think fludarabine and other drugs may have similar properties, right? So, I would use a combination with targeted therapy and with radiation as a bridging therapy, and I try to avoid chemotherapy if I can.
Martin: Okay. You brought up some of the side effects to CAR T cells. Really, we're talking about cytokine release syndrome (CRS) and neurotoxicity or ICANS (immune effector cell-associated neurotoxicity), and it seems to me like people taking brexucabtagene autoleucel have a fairly high risk for both CRS and ICANS. That gives me some pause when I'm thinking about using CAR T cells. Informed consent is part of it but also patient selection. I'm wondering what your interpretation of those data are. Do they impact who you might offer CAR T cells to, in particular?
Wang: First of all, you know the percentage of patients with CRS grade 3 or 4 toxicity was 15% in the ZUMA-2 trial, which is pretty high compared with other CAR T cells or the same CAR T cell used in different histologies. And grade 3 or 4 neurotoxicity was seen in 31% of patients. So to this date, each time I walk into a situation with a patient transferred to the ICU who is not able to talk and not able to respond, it always puts me on my toes. It makes me really think about whether the patient is going to survive or not, Of course, almost everybody survives, but it's still always a scary experience. I would be very careful giving the patient CAR T cells. I usually have a family conference to tell them the risks and what will happen — 20% of patients go to ICU, 3% or 4% or 5% get intubation, and 2% of people don't survive. I explain to the patient and their family that this is a toxic therapy. Number two, I usually ask my patients to do gym training for 2 months. This means hire a trainer, go to the gym, and make themselves physically fit. This is very important. It's always the elderly, frail patients who don't exercise and live a solitary lifestyle — those people are always at a higher risk for toxicities and sometimes severe toxicities. That's why treating lymphoma is difficult. There are so many factors — the patient choices, the prior therapies, the genetics, the morphology. That is why that we really need people super specialized in diseases to guide the rest. Like you and me guiding a lot of other people for better outcomes in patients.
Martin: I agree. I've heard a lot of your stories about pulling out all of the stops to help people who have experienced neurotoxicity. And you've got some pretty remarkable ones. Do you think that neurotoxicity is preventable? And are there ways we can reduce the incidence of it, or is it just something we have to be prepared for?
Wang: Maybe in the future when we really study the cerebrospinal fluid and study some samples, and when we have enough information, we will be able to predict. So far, we cannot predict. I have this one patient who was a 58-year-old lawyer. I said, you know, in 2 months, your tumor has grown to 3 centimeters. And because you relapsed three or four times, I would like to use the CAR T cells. I asked him to go to the gym. And he did that every day for 60 days. He came back with a lot of strong muscles, and he was looking different. So I put him on the CAR T-cell infusion. About 6 hours after CAR T-cell infusion, he started spiking fevers. We did everything — tocilizumab, steroids, siltuximab, everything. Three or four days later he went into severe, severe neurotoxicity with the MRI showing brain edema. If the MRI shows cerebral edema, the chances for a patient to survive is almost zero. We did a lot of stuff — we did an intrathecal injection of steroids to kill the CAR T cells attacking the brain. We gave mannitol; we gave high-dose methylprednisolone sodium succinate 1 gram every 12 hours. And then we drilled a hole. We did a ventriculostomy to let the pressure go. Finally, we gave rabbit ATG. The ATG dramatically reversed the course. So, these days many people have started using ATG. But that patient was in the ordeal for half a year — rehab and all of that. Now he's totally normal. Practicing law. For 5 years now.
Martin: What a story. In the last couple of minutes, I want to change the topic a little bit to bispecific antibodies. We've seen some data with glofitamab, and these data are pretty exciting. Are you optimistic about the role they'll have in mantle cell lymphoma? Do you have any concerns about where they'll fit in?
Wang: Yes. So bispecific or trispecific antibodies could be used in the community. But CAR T cells are only limited to certain centers. The bispecific antibody is a huge advantage. I think they are coming to the market. You are seeing more and more trials. And also in the laboratory — if you want to do a CAR T cell, you have to make the antibody construct, right? So the antibody is the key step in both the antibody immunotherapy and the CAR T cells. It's much easier to make antibodies than, depending on the complexity — generally speaking — the CAR T cells. At the recent American Society of Hematology meeting, Dr Tycel Phillips presented 30-something patients with a glofitamab trial. The response rate was 83%, the CR was 73%, and the CRS was 15% at grade 3 or 4 — they still have a severe CRS, right? But there's no grade 3 or 4 neurotoxicity. So this much-improved response rate is good, and the follow-up is still short. But with the longer follow-up, glofitamab might be approved for mantle cell lymphoma. There is another subcutaneous CD20xCD3 epcoritamab. There's a European study that is the pivotal study enrolling mantle cell lymphoma patients, and I enrolled quite a few patients on that trial. We cannot talk about the results, but I think the data are coming. Mosunetuzumab has also been studied with polatuzumab in mantle cell lymphoma. And the data are going to come out. I think we're going to see a lot of these data. My concern is that we repeatedly tap on the T cells of our body. So you do one CAR T-cell infusion and you have already exhausted the T cells in the patient's body, then you give them another CAR T cell infusion or then you give them the bispecific antibodies, and the T cells are exhausted. That will lead to lower responses, shorter responses, and maybe more infections. That is my really deep concern in the current paradigm of immunotherapy.
Martin: We're touching on the tip of the iceberg when it comes to immunotherapies in this era of history. I was talking with Dr Chris Flowers from MD Anderson, and he was telling me they were recently looking at all of their clinical trial enrollments, and 60% of your patients are treated on clinical trials, which is absolutely amazing. So, the mantle cell lymphoma community as a whole owes you a debt of gratitude for that. I wanted to thank you for being part of our series and for joining us today. I'll list a couple of takeaways for our audience. One is that CAR T cells clearly have a role in mantle cell lymphoma, but there are a lot of nuances with respect to how we use them, both with respect to the bridging therapy, the therapies that come before harvesting the T cells, and some of the surveillance for toxicities and management of toxicities. The other takeaway is that bispecific antibodies are showing promise, and they're clearly on the way. Thanks to everybody for tuning in. If you haven't done so already, take a moment to download the Medscape app and listen and subscribe to this podcast series on mantle cell lymphoma. This is Dr Peter Martin for InDiscussion.
Resources
KTE-X19 CAR T-Cell Therapy in Relapsed or Refractory Mantle-Cell Lymphoma
Frequency of Gastrointestinal Involvement and Its Clinical Significance in Mantle Cell Lymphoma
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Cite this: CAR T Cells and Immunotherapy in Mantle Cell Lymphoma: Bridging Therapy, Toxicities, and Bispecific Antibodies - Medscape - Mar 30, 2023.
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