Loretta, please share your thoughts on the 

 [Journal of Clinical Oncology] publication 2 weeks ago. What are the predictors of how patients did on simple things such as LDH.

: When you have this available in your toolkit, you’re going to start to apply it in [populations that are] sicker, frailer….And so, 43% of patients would not have met the eligibility criteria in ZUMA-1 [NCT02348216]. Despite that, the safety looks good. When we try to predict who did best, meaning who had the best outcomes, LDH at lymphocyte depletion and ECOG performance status were very robust clinical prognostic factors, which tease out those patients [who] have highly proliferative tumors that you don’t have the luxury of time or a cellular therapy that you’re manufacturing from an autoproduct.

: David has a blood test for performance status, don’t you, David? Do you want to tell us about that?

: We don’t have a blood test for performance status. One has often said that I never get much below 2. But we do have a blood test looking at the tumor burden, which is another part of this discussion of how much disease somebody has. There was work produced by Dr Matthew Frank in our group and Dr Fredrick Locke and at ASH [American Society of Hematology], where we looked at circulating tumor DNA using the soluble DNA in the plasma blood using the clonoSEQ (assay) from the company Adaptive Biotechnologies. In that 80-patient study, it was highly informative, both looking at the amount of tumor going in, much like LDH pre-LD-amount of tumor, or some of the diameters of the tumor, or I hear metabolic tumor volume at Dr Locke’s group now. There [are] a lot of ways to read out how much patients [with tumors] have going in. And then, of course, it tells a lot about modality of when patients are losing the benefit of the CAR T, which is the most important thing about this frequent measurement, because we could see in that analysis that everybody was hitting the nadir of tumor at 21 to 28 days, arguing that, what you said, Steve, hitting them hard up front might be a very important thing for axi-cel [axicabtagene ciloleucel]. It may be different in other CAR T-cell therapies. But with axi-cel, you needed to get the big bang up front.

: Going back to something Loretta said, too, that it’s important that a good number, if not half of these patients would not have met the criteria. And we’re still seeing efficacy. And even in the patients who had poor prognostic factors, patients still did benefit. The question of selecting patients, at least in my opinion, it’s more about an optimization question than an exclusion, they’re acting on the considerations in terms of how are we paying for these therapies. But benefit was seen across the board. And I don’t think there was a specific population that uniformly did horribly 100% of the time.

: Quite frankly, Matt, the toxicity in the real world is lower than the toxicity in the clinical trials. What does that mean? It means history is important. We’ve learned something over the years. And the patient selection, as Caron can tell us, the patients had very poor characteristics in relatively speaking to the clinical trial patients. And yet toxicities were lower than expected. Maybe in the real world, doctors don’t see toxicities and report them.

: I don’t even know that we’re just improving toxicity. If we take a look at some of the real-world data, we may even be improving in efficacy, as well, because when you do tease out the patients [who] were eligible versus ineligible for clinical trials, the group that’s eligible is actually lifting as a whole, they’re the same. But when you tease it out by 2 different groups, the group that was eligible is actually lifting up the curve, or it’s looking better in multiple series now, compared [with] the pivotal clinical trials. To Matt’s point, we’re not only getting better at toxicity, we can treat people with more comorbidities, but we’re also getting better at selecting the patients and getting patients in faster, which I think is a really important point…to meet these patients earlier in their disease course, earlier in their relapse, so that we can get them in and get their cells faster when they’re in the best position to respond.

: Three studies showed that [women] who are over 65 or 70 do the best. Isn’t that something?

That may be, as we were saying earlier, a niche that autotransplant couldn’t serve, which is you’re talking about not only does CAR T-cell [therapy] save some patients [who] relapse after autotransplant, but now you’re talking about niches of patients [who] might not be eligible that you can treat. Clearly, and the real-world data are showing this. I’m waiting for Caron’s abstract next year. I want to see if this holds up in the telehealth world, whether we get these same good results.

: It is shifting our transplant practice. When you look at the patients who are having what we would now consider suboptimal responses or partial responses following salvage therapy, we’re thinking about those patients differently now in the world of CAR T. The trials don’t necessarily reflect that, and some of the randomized studies that’ll be coming out and the phase 3 studies. But overall, moving forward, we are shifting the needle in terms of transplant versus CAR T in this population, just knowing the burden of treatment and taking a patient who may still have chemorefractory disease.

: I’m eagerly awaiting the results of the randomized studies in second line, because for some of these patients [who] we don’t think are transplant-eligible, right now, the label makes us treat them with a second line of chemotherapy, and it would be nice to be able to take those patients directly to CAR T cells. We have 3 randomized studies looking in the second line, and I think that those will be important to further this along.

: I agree 100% with Caron. I agree because I’m a convert to this opinion that you just expressed. I totally thought this would just get rid of autotransplant completely. I was so impressed with how well we were doing with CAR T cells nowadays, and how poorly our outcomes have become in the rituximab era with autotransplant. And most of our patients are progressing in a year, and they do terrible, but guess what? Okay, so we’re expressing opinions. I’m going to share observations. These come from my practice. I have patients in my practice [who] were part of 1 such trial, who progressed after getting CAR T second line and went on for salvage by transplant. And I have early [University of Pennsylvania] data on that exact situation, progressing and failing CAR T cells despite expansion, and then having a splenectomy and go. Because this particular patient, that was probably 1 of the reasons he was failing. And getting an autotransplant, he’s 5 years in remission now. And then the converse is the patients [who] have an autotransplant and stay in remission. When you do this randomized study, I think we need these studies to be done, because there is going to be a subpopulation of patients [who] will still benefit from transplant, even autotransplant, as primitive as it sounds. And…I know for a fact that it will even salvage some CAR failures. So we’ll wait and see.

: I think we’ve all had those. Whether you resensitize a tumor to chemotherapy following CAR or whatever the different selection pressures are, we’ve all probably taken a couple patients to allo[transplant] following a CAR T failure once you’re able to get the patient back into remission. And there are people who are still walking around doing that.

: But I’m talking auto, not allo, Matt. And in this particular case, the CAR T-cells were probably being sequestered in a massive spleen. And taking the spleen out was the key.

: The point is, keeping score is very important. Sponsor randomized trials are very powerful. But having real-world data and CIBMTR [Center for International Blood and Marrow Transplant Research] registry data going forward where we can track the people who were on those trials, who went on to another trial, and [then] went on to another trial. We’ve been talking in our own center about the problem of competing risks. This is a good problem to have. In the old days, competing risk was if the therapy didn’t work, and you died of something, we blamed the therapy. Now…we’re becoming multiple myeloma docs, right? We have multiple therapies, and patients are benefiting, living longer. Good news for the patients.

: This is also going to be a paradigm for multiple myeloma. We’ve all seen the patients who are getting to the CAR T therapies with BCMA [B-cell maturation antigen] and other antigens. They receive average 5, 6, 7 lines of myeloma therapy. Just like we can with patients prior to going to CAR T with lymphoma, we can do the same thing in myeloma. And if it does hold true, that we do get durable responses in myeloma eventually, moving it up in earlier lines is only going to benefit patients.

: It’s pretty difficult to think of 11 lines of therapy for lymphoma. But I agree with what you said.

Videos

LDH and ECOG Performance Tests

: We’ve talked a lot about axi-cel (axicabtagene ciloleucel). Tisagenlecleucel is the 4-1BB-driven CAR (chimeric antigen receptor ) developed at Penn [University of Pennsylvania], and we’ve played a major role in its clinical development. We have data now that have been presented at 1 year, which was about one-third of patients who were responders [and] were still in remission at 1 year. I can tell you that that hasn’t changed at 2 years, although I’m not sure that that’s yet appeared in abstract form. But again, this is the same construct that was licensed from Penn to Novartis. We have follow-up in large-cell lymphoma now, median follow-up that’s 5 years. These responses are durable. At Penn, we received better than one-third. We were actually between 40% and 50% still in remission at 5 years, not because our vector was better at Penn, the one that was licensed to Novartis, or we made it better. It’s because in every single study, there [are] differences among patients, selections, and centers. There are so many variables that can influence the outcome, and I’m only comfortable saying it’s between 30% and 40% for any of these products in terms of durable remission. There are too many variables to sit down and compare studies side by side.

We have 2 available home runs. And we’re waiting for a third home run to come in later in this year. And that’s liso-cel, or lisocabtagene maraleucel. That is another 4-1BB-driven CAR developed by Juno and licensed to Celgene and now to BMS, [Bristol Myers Squibb], and they’re all one big happy family. Jeremy Abramson presented data at ASH [American Society of Hematology] last year, which I thought were pretty exciting, [first because of] the patient population. Every study is a little different. And just the way [it was] in follicular lymphoma, I’ll be impressed by 2 years if I know the patient characteristics; you really have to know the patient characteristics [when] comparing even large-cell studies. The data presented by Jeremy included some histologies [that] weren’t included in other aggressive lymphoma studies. For example, transformed marginal-zone lymphomas, you were allowed to have had CNS disease. That was not done for either of the other products. The data that were presented showed the CR [complete remission] rate was 40%, similar to what was shown with the other 4-1BB CAR. And one-third of those patients had ongoing CRs at 1 year. Looking like tisagenlecleucel, with a very low toxicity profile, which may be a historical artifact, because we’ve learned a lot about CRs and how to manage and prevent it. And earlier intervention leads to lower grades in the end. Not only are there patient selection characteristics, but we’re all victims of history, as well. 

: We get different outcomes based on who the patients are that we put in, and, of course, if we do clinical trials that are very stringent, we get a more stringent outcome. If we do experiences, [such as] the real-world type of experiences where you can capture consecutive patients at large centers, then we get to have increased numbers and a little bit more variety. The retrospective analysis of those multivariates becomes very interesting.

Liso-cel Therapy in R/R Large B-Cell Lymphoma

The Importance of Antigen Loss in R/R Disease

Let’s talk about axicabtagene ciloleucel, or axi-cel. That was the first approved CAR [chimeric antigen receptor] T-cell therapy for lymphoma. About 4 to 6 months before that in pediatric ALL [acute lymphoblastic leukemia], there was approval of tisagenlecleucel. Technically, that smaller market was hit first by tisagenlecleucel. But in the big market, which is lymphoma, axi-cell [axicabtagene ciloleucel] was more common. We have mature data that Fred Locke published in 

 One thing I’ll mention about this is that it’s a win for science, and it’s a win for clinical researchers, because I have patients beating on the door trying to get on these phase 1 studies, and it was something that was so novel, but it did reinvigorate our clinical research program. As you mentioned, some of the early publications were criticized based on the relatively short follow-up. The questions about whether this would be a durable treatment in a onetime therapy for patients with large-cell lymphoma. What we saw with Fred’s publication with longer follow-up, at the time he had about 27 months of median 

 follow-up. We didn’t see any new late-toxicity signals, which was incredibly important. The overall response rate, which was the best response rate, settled in at about 83%. And 58% of patients had achieved a complete response. ASH [American Society of Hematology Annual Meeting] this past year updated that with 3 years of median follow-up and shows that the overall survival had about 47% still alive at 3 years of follow-up. That starts to answer the question that yes, there is a subset of patients, approximately 40%, for whom we do think this is a definitive onetime therapy. The question remains, how can you improve outcomes for those 60% of patients where that’s not true? 

 I’ll tell you that 5 years ago, when we saw our large-cell lymphoma patients who were refractory to immunochemotherapy go into remission and not die within a year, that was very exciting. Now we’re talking about, “Wait, we didn’t cure them. What are we going to do now?” There was a time where we didn’t cure anyone. And you’re right. What’s impressive is, 40% of those patients, for 2 to 3 years are in remission. Most people, including the FDA, agree that 2 years is a pretty good benchmark. About 80% to 90% of relapses occur in large-cell lymphoma within the first 2 years anyway. These are good data. As Loretta said, 2 years is certainly a benchmark, in my opinion, for aggressive lymphomas. But Caron, would you feel as enthusiastic at 2 years for follicular lymphoma if you’re sitting on the FDA committee reviewing the new drug application?

 I don’t think we can say anything about it being a definitive therapy for follicular lymphoma after 2 years. But if you think about the way it’s been tested in the third line and beyond, median 

 duration of responses to other available agents in that setting are under a year. If we continue to see more than half of patients maintain their response at 2 years, that’s a meaningful opportunity for patients with follicular lymphoma. I cannot say it’s definitive, though.

 No, you are spot-on. It really depends on the patient population, right? As we were saying before this conference in our informal discussion, there are those who we know early on have a terrible prognosis, 

 chance of being dead at 2 years. That’s within the first 5 years, rather. You’ll know quickly. At the other end, for patients you’ve been following for 10 to 15 years, us old doctors, we know when they get to the end, what the survival is like when their remission duration becomes very short to the existing agents, under 12 months in most cases. That’s a group of bad actors. If you look at those patients, I would be impressed with 2 years in some of those. There are a group of patients with follicular lymphoma, despite the fact that it’s “indolent,” that I would be impressed with 2-year data. They’re the patients Caron described. There’s a subset of bad actors. It really depends on the eligibility criteria.

R/R Large B-Cell Therapy in Managing Various Lymphomas

 We’re talking about finding a potentially curative regimen for people who failed a therapy that was potentially going to cure their lymphoma. There are a lot of lymphomas that we don’t have conventional cures for. And when we get to the second- and third-line treatments for those lymphomas, even though they have generally longer natural histories, response durations are short and people relapse, and we start to see decreased life expectancy. What we’ve already seen for mantle cell lymphoma, knowing that patients who relapse after BTK [Bruton tyrosine kinase] inhibitors have a short survival, on the order of months, has been impressive. Some data were presented in indolent lymphomas as well, especially late lines of therapy.

 A lot of that will be your data, and they are very important data. For indolent lymphomas, people are less impressed. There is a business of progression of disease within 2 years as a subset, maybe 20% or so of patients have a bad indolent lymphoma. But having been in practice for 40 years, I’ll say that when you’ve taken care of these patients for 10 to 15 years, and they’ve been through a number of treatments, guess what? They’re not progressing within 2 years. It’s a bad disease. And Caron’s right. We need something for those patients too. It’s just not captured the same way, because we’re looking at patients with much shorter follow-up. At the other end of the indolent lymphoma natural history, it gets bad.

 It’s important to remind the audience that we’re the gateway drug, right? We’re the gateway drug to cellular immunotherapies for the nonblood cancers or the diseases that need alternative therapies beyond chemotherapy. The lessons we learn in lymphoma, leukemia, mantle cell, and myeloma, like everything that’s ever happened in hematology, will be important guides for how you combine therapies, how you target. We’re the gateway drug.

 You’re right. Rituximab taught us that patients can respond to immunotherapy when they’re resistant to chemotherapy. You hit an external target with immunotherapy, and you can get a response in a disease that is resistant to all kinds of toxic substances that kill cells by getting into them. We saw that with Rituxan, but then there were Rituxan failures or Rituxan chemotherapy. Now we’re at the cellular end of immunotherapy, as opposed to serotherapy, and we’re seeing the same thing again. Patients who are resistant to those drugs that kill cells internally—like chemotherapy, small molecules—can respond to immunotherapy. And those are unresponsive to intracellular agents and rituximab or anti-CD20s. You can get at them with a T-cell–based therapy, another extracellular agent.

 We were trying to do a GVL [graft versus leukemia] and allogeneic transplant to a much larger degree with a shorter period of toxicity and fewer toxicities. It’s less of a bazooka approach of an allogeneic transplant and more targeted.

 What do you think? Is allogenic going to disappear, Matt?

 It depends on the disease, the context, and whom you talk to. There are going to be a subset of patients once we can risk stratify. I think there are going to be various clinical characteristics or drug characteristics or product characteristics in terms of persistence, and what may be important for 1 disease in terms of persistence may not be the same for another. Depending on what we see and how we risk stratify, I can see a world where we have low-risk AML [acute myeloid leukemia] that you can cure with consolidation therapy, and a low-risk lymphoma or leukemia that you don’t need a transplant for. For others, you may want to transplant at 3 to 6 months.

 There’s an important point to make here, though, and that is that the lymphocytes that give rise to lymphoma are long-lived cells. They’re far beyond the hematopoietic stem cell stage, sometimes a lifetime’s worth, whereas the cell contributing to AML and MDS, myeloproliferative disorders, that’s about 14 days down the pipeline. We are continually going to be facing the problem that the patient needs not only a cellular therapy, for AML or myeloproliferative disorder, but a lot of repair.

 Loretta is going to tell us about AlloCAR T therapies. There’s always going to be AlloCAR T if you believe in CARs. We’re not addressing stem cell diseases. We’re taking care of neoplasms of mature cells. There always will be diseases where we have to replace stem cells. The only way I can think of is CAR. I’m sure with the way technology is moving, we’ll be differentiating our skin cells. You’re going to need different stem cells, not your own, for certain diseases. It’s never going to disappear, in my opinion. And you know I believe very much in CAR T-cell therapy.

CAR T-Cell Therapy in Managing Various Lymphomas

 I’m Steve Schuster from Abramson Cancer Center at the University of Pennsylvania in Philadelphia. Joining me today for a lively discussion are my friends and colleagues Dr Matthew Frigault from the MGH [Massachusetts General Hospital] in Boston, Dr Caron Jacobson from Dana-Farber Cancer Institute in Boston, Dr David Miklos from Stanford University Medical Center in Stanford, California, and Dr Loretta Nastoupil from The University of Texas MD Anderson Cancer Center in Houston, Texas.

Today we’re discussing a number of topics related to the use of CAR [chimeric antigen receptor] T cells in patients with lymphoma. We’ll be making reference to ALL [acute lymphoblastic leukemia] as well, because that was the earliest data. Most of us have some experience. But we are primarily treating lymphoma patients right now. We’ll talk about the latest information that’s out there, some of which was presented in December at the American Society of Hematology Annual Meeting, and most recently at the meeting that just happened, which is ASCO [American Society of Clinical Oncology Annual Meeting].

Let’s begin with lymphoma and possibly discuss leukemia. Some of the leukemia data will come out as we discuss lymphoma, and we can compare and contrast diseases that are treated with the same agent but with different outcomes.

What is the rationale for CAR T-cell therapy? We know it’s approved for diffuse large B-cell lymphoma. There must have been a need if the FDA approved it. What do you think is the rationale for further development of diffuse large B-cell lymphoma? There will be new developments. Who wants to weigh in?

 It’s 1 of the first therapies we’ve brought to the market that’s a cellular gene therapy, and we’ve overcome barriers in terms of technology and regulatory hurdles. And we’ve seen it only accelerate. As remarkable as the responses have been, there’s still room to improve the technology, whether it’s in efficacy or toxicity or just having more access to patients.

 I agree. What you’re seeing right now are the first-generation cars, the Model Ts. It’s going to get better and better, and every manufacturer is going to say that they make the best car. That’s what happens in Detroit and everywhere else, right?

 If we consider what happens when the patient has progression and relapse after R-CHOP [rituximab, cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone], chemotherapy and other things that we call salvage on a goal toward going to a high-dose stem cell transplant with, at best, a 50% response to salvage and 50% durable responses after autotransplant. We can help many patients by bringing an effective immunotherapy forward, if for no other reason than what they endure going through mobilization, salvage chemotherapy, and an autotransplant. If you add it up, that is 5 months of their lives right there, let alone the problem of median 

time to survival of patients who have relapsed, since refractory chemotherapy-resistant lymphoma is only 5 to 6 months. 

 Just to reiterate, because they’re really important points. There are patients who would not be candidates for autotransplant who are candidates for CAR T. This relates to patients who are older and have comorbidities, because it’s a lot easier on patients, as we’ve learned, than high-dose chemotherapy. This is a benefit for those patients. We’ll wait for additional studies to see if we can move it to second-line for some groups of patients that are not transplant eligible. Also, our ability to salvage patients with autotransplant in the immunochemotherapy era has dropped significantly. I remember when we first started doing autotransplants in the late 1980s, prior to rituximab. And 50% of the patients were fixed, OK? In the current era, with rituximab and particularly those who fail within the first year of receiving a rituximab-containing induction regimen, the outcome with second-line chemotherapy and autotransplants is kind of abysmal. That’s the other big niche for CAR T in aggressive lymphomas.

Rationale for Further Development of CAR T-Cell therapy

David Miklos, MD, associate professor of medicine, Blood and Marrow Transplantation, and clinical director of Cancer Cell Therapy at Stanford University Medical Center, discusses the process of developing KTE-X19 and the ZUMA-2 trial in mantle cell lymphoma (MCL).

The pharmaceutical company Kite Pharma, a subsidiary of Gilead Sciences, introduced axicabtagene ciloleucel (axi-cel; Yescarta) to the treatment paradigm for diffuse large b-cell lymphoma, says Miklos. Using the same construct of targeting CD19 with a CD28 costimulatory domain as axi-cel, KTE-X19 was produced; however, it is important to note the difference that they are isolating T-cells using CD4-positive/CD8-positive infinity isolation and then making products that are specific to T-cells. This was the conversion; it was the important process of evolution for the ZUMA-2 trial in patients with MCL who had failed 2 prior lines of therapy and were either ibrutinib (Imbruvica)-refractory or ibrutinib-intolerant, adds Miklos.

At the 2019 ASH Annual Meeting and the 2020 TCT Meetings, Michael Wang, MD, of The University of Texas MD Anderson Cancer Center, who is the lead author on the study, shared data from ZUMA-2. At Stanford University, investigators were very enthusiastic to bring these patients forward. This is a challenging patient population because once ibrutinib fails them, venetoclax (Venclexta) and other therapies are available, but no long-term remissions are observed, concludes Miklos.

David Miklos, MD, discusses the process of developing KTE-X19 and the ZUMA-2 trial in mantle cell lymphoma.

Dr. Miklos on Development Process for KTE-X19 in MCL

David Miklos, MD, associate professor of medicine, Blood and Marrow Transplantation, and clinical director of Cancer Cell Therapy at Stanford University Medical Center, discusses alternative options to the investigational CAR T-cell therapy KTE-X19 for patients with relapsed/refractory mantle cell lymphoma (MCL), while awaiting a regulatory decision from the FDA.

In February 2020, the FDA granted a priority review designation to a biologics license application (BLA) for KTE-X19 as a treatment in adult patients with relapsed/refractory MCL based on data from the phase 2 ZUMA-2 trial.

While awaiting the FDA’s decision regarding indication, price, etc., an expanded access trial is open at the same centers that in which the ZUMA-2 trial was conducted. Patients can be referred to those centers at this time and they will then be treated on a trial with close data acquisition for both clinical and adverse event collection, says Miklos. While awaiting the FDA’s decision, there is a bridge to help patients who are intolerant or refractory to BTK inhibition. Very few options are currently available to this patient population, concludes Miklos.

David Miklos, MD, discusses alternative options to the investigational CAR T-cell therapy KTE-X19 for patients with relapsed/refractory mantle cell lymphoma, while awaiting a regulatory decision from the FDA.

Dr. Miklos on Alternative Options to KTE-X19 in MCL, While Awaiting FDA Decision

David Miklos, MD, associate professor of medicine, Blood and Marrow Transplantation, and clinical director of Cancer Cell Therapy at Stanford University Medical Center, discusses anticipated sequencing challenges with the investigational CAR T-cell therapy KTE-X19 in mantle cell lymphoma (MCL).

In February 2020, the FDA granted a priority review designation to a biologics license application (BLA) for KTE-X19 as a treatment for adult patients with relapsed/refractory MCL based on data from the phase 2 ZUMA-2 trial.

Where the therapeutic modality will best fit into the paradigm has yet to be determined, says Miklos.

The treatment paradigm in MCL includes platinum-based therapies, ibrutinib (Imbruvica)-based therapies, rituximab (Rituxan), autologous stem cell transplant, and venetoclax (Venclexta). As such, it can be difficult to introduce another novel agent into an already crowded armamentarium, explains Miklos.

Additionally, the role of ibrutinib is expanding, and the agent is being tested in many clinical trials, says Miklos.

Though there are other potential settings where this agent could have efficacy, the current BLA submission is for adult patients with relapsed/refractory disease, concludes Miklos.

David Miklos, MD, discusses anticipated sequencing challenges with the investigational CAR T-cell therapy KTE-X19 in mantle cell lymphoma.

Dr. Miklos on Anticipated Sequencing Challenges With KTE-X19 in MCL

David Miklos, MD, associate professor of medicine, Blood and Marrow Transplantation, and clinical director of Cancer Cell Therapy at Stanford University Medical Center, discusses the safety profile of KTE-X19 in mantle cell lymphoma (MCL).

In February 2020, the FDA granted a priority review designation to a biologics license application for the investigational CAR T-cell therapy KTE-X19 in patients with relapsed/refractory MCL, based on data from the phase II ZUMA-2 trial.

The toxicities experienced by those who received KTE-X19 in ZUMA-2 were as significant as the toxicities observed in the ZUMA-1 trial, says Miklos; these events included grade ≥3 neurotoxicity and similar levels of grade 2 cytokine release syndrome (CRS), which was reported in at least 50% of patients, adds Miklos. Additionally, cytopenias and low blood cell counts developed in approximately half of the patients at day 28 or beyond.

Three known toxicities commonly associated with CD19-directed CAR T-cell therapies include CRS, neurotoxicity, and cytopenias, and these adverse events (AEs) continue to complicate the treatment of this patient population; however, these AEs are not any worse than those that have already been experienced in this space, says Miklos. An experienced transplant CAR T-cell therapy center will find these toxicities to be very manageable. However, even at these experienced centers, KTE-X19 will be an in-patient therapy that requires an “all-hands-on-deck” attitude to deliver favorable outcomes to patients, concludes Miklos.

David Miklos, MD, discusses the safety profile of KTE-X19 in mantle cell lymphoma.

Dr. Miklos on the Safety Profile of KTE-X19 in MCL

David Miklos, MD, associate professor of medicine, and clinical director of Cancer Cell Therapy at Stanford University Medical Center, discusses the results of the phase II ZUMA-2 trial with KTE-X19 in mantle cell lymphoma (MCL).

In the trial, patients with relapsed/refractory MCL were treated with KTE-X19, an investigational CAR T-cell product. After a single infusion of the product, the best objective response via independent radiologic central review among 60 evaluable patients was 93%, with 67% of patients having achieved a complete response, says Miklos. The patients who had been followed for at least 2 years are showing durable disease responses, adds Miklos.

In MCL, where leukemic phase serves as a very important measurable aspect of the lymphoma, blood next-generation sequencing technologies can be applied to detect the number of cancer cells down to 1 in 1 million, says Miklos. Forty percent of patients who were tested in that manner were found to have achieved undetectable minimal residual disease, according to Miklos.

Notably, these are still early data so additional long-term follow-up is needed to determine the durability of these responses; however, the data seen thus far are very promising, concludes Miklos.

David Miklos, MD, discusses the results of the phase II ZUMA-2 trial with KTE-X19 in mantle cell lymphoma.

David Miklos, MD, Stanford University

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