Paolo Strati:

Hello to everybody, and welcome to this VJHemOnc discussion in lymphoma. Today’s discussion will be focused on large B-cell lymphoma, and we will try, with the help of my colleagues and friends that I will let soon introduce themselves, to discuss more how to select between CAR-T and autologous stem cell transplant for large B-cell lymphoma patients who relapse and require a second line or beyond.

My name is Paolo Strati. I’m an associate professor in the Department of Lymphoma and Myeloma at MD Anderson Cancer Center in Houston, Texas. And I’m very excited to have the possibility today to have this discussion with my colleagues and friends, as I mentioned before, Dr. Evandro Bezerra and Dr. Andrew Jallouk. I will you introduce yourself. Dr. Bezerra?

Evandro Bezerra:

Thanks for having me here, Paolo. I’m Evandro Bezerra. I’m a faculty at the Cleveland Clinic in the Lymphoma and Cellular Group, with focus on transplant and cell therapy.

Paolo Strati:

Thank you. Dr. Jallouk?

Andrew Jallouk:

Hi, thank you again for the invitation. I’m Andrew Jallouk. I’m an assistant professor at Vanderbilt University, with a clinical focus on lymphoma, cellular therapies and transplant.

Paolo Strati:

Thank you. Thank you both, Evandro and Andrew, for joining today. I’m sincerely very excited. I think the next half an hour will be a very productive discussion.

So I’m going to very briefly just go ahead and set up the stage for the discussion that we’re going to have today. As a reminder for our audience, CAR T-cells, autologous CAR T-cells targeting CD19 have been formally approved by the FDA for the first time in 2017. At that time, for patients with large B-cell lymphoma who require a third line and beyond, but then very quickly they’ve been able to move up to second line, and maybe this will be the earlier lines in the near future. But since CAR-T moved to second line, they started challenging what used to be the standard at that time; there was platinum-based chemo, followed by high-dose chemo, followed by autologous stem cell transplant, and that is going to be really the main conversation for today. So before we dive into more details and before we learn more about your clinical practice and your opinions, why don’t we maybe summarize for our audience the main findings from the two pivotal trials that brought to FDA approval in second line, TRANSFORM and ZUMA-7. Andrew, would you maybe like to remind us the main findings and what your opinions are about those two trials?

Andrew Jallouk:

Yes, absolutely. So the two trials that we’re talking about, ZUMA-7 and TRANSFORM, are very similar in design. They were testing two different CAR-T products; one was axi-cel and one was liso-cel. And so the idea behind these was to recruit a chemoresistant population, so that’s going to be important for our future discussions, so both trials required that patients either have primary refractory disease or disease that had relapsed within 12 months of frontline therapy. So those inclusion criteria were the same in both trials, and then those patients were randomized to standard of care, which is, as you said, Dr. Strati, a salvage chemotherapy with an autologous transplant, or the experimental arm, which was the CAR-T therapy, either axi-cel or liso-cel. And in both studies there was a very clear progression-free survival benefit for the CAR-T arm, and in the ZUMA-7 trial that’s converted into an overall survival benefit for axi-cel compared to standard of care. Now, there were some minor differences in trial design. For example, in the ZUMA-7 trial there was no built-in crossover, so a large number of those patients, I think half or something, did end up getting CAR-T, those had progressed to the standard of care arm. In the liso-cel trial, the TRANSFORM trial, the crossover was built in. But overall, very clear progression-free survival benefit, and possibly an overall survival benefit as well, at least in the ZUMA-7 trial.

Some nuances there that I think are really important to point out when talking about these trials is that a large number of patients who received the salvage chemotherapy did not end up having a response that allowed them to go to autotransplant. So if you look at these trials, the number of patients that actually got an autotransplant was much less than the number of patients randomized. And I think this is really important because what this is basically telling you is not if you have somebody who has a great response to salvage chemo, CAR-T is better. What it’s saying is that if you have somebody who comes to you with no other information, if you do salvage chemo, there is a reasonable chance that they will progress on that, and if that is going to happen, then all-comers, you are better off going with CAR-T to begin with.

So I think this is a key discussion point that we should have later on, which is if you have somebody who has demonstrated chemosensitivity even though they meet the criteria for these trials, what should you do with them? But to summarize, basically if you have a patient who comes to you, no other information, you are better off from a progression-free survival, and potentially an overall survival going with CAR-T right off the bat.

Paolo Strati:

Thank you, Dr. Jallouk. I’m going to put a pin on that. I think it’s extremely interesting you brought up the intent that both trials had in both arms and trying to clarify whether the intent was being able to get to transplant or not, but majority of patients actually in the transplant arm didn’t, and so one [inaudible 00:05:39] chemosensitivity. So I’m going to put a pin on that and discuss a little bit more in a second and ask you more questions.

But before we talk about that, I was thinking, Dr. Bezerra, if you could maybe share with us what your thoughts are instead regarding the third study, the BELINDA study, that of the three was the only one that was negative, and because of that currently, as we all know, tisa-cel or Kymriah, remains approved by the FDA for large B-cell lymphoma only in third line, but not in second line. Can maybe summarize for our audience what the study design and main findings are and why, in your opinion, the study was negative as compared to TRANSFORM and ZUMA-7?

Evandro Bezerra:

I think the BELINDA trial, that trial has a very similar design to TRANSFORM trial, both 4-1BB CAR-T-19 product, and both allow bridging chemotherapy in the patients randomized to the CAR-T while on ZUMA-7, the key difference, they only allow these steroids as bridging therapy. The reason that the BELINDA trial CAR-T arm did not outperform the salvage platinum-based chemotherapy followed by stem cell transplant in response, I think there are several hypotheses to speculate why there’s difference. One could be the CAR-T product. Another important difference is the time for manufacture. The median time for manufacture for tisa-cel was significant longer, I think, to the time from apheresis to infusion is about 52 days in tis-cel, while significant shorter in the liso-cel and also in the axi-cel.

Also, the primary endpoint definition, in both ZUMA-7 and TRANSFORM, they use EFS, and the time point for EFS in the TRANSFORM was nine weeks. And if the patient requires second type of salvage therapy in the stem cell transplant arm, that would consider an event. While in the BELINDA trial, it was a 12-week time point, and if the patient have not respond to the first salvage therapy in the stem cell transplant arm, they have a second type of salvage, that would not be considered event. And also, the lack of initial response if you have stable or refractive disease or progressive disease by 12 in the CAR-T arm was considered event. While in the other studies, we require a disease progression. And we both know that in CAR-T field, there is patients that have delayed response; at the initial reassessment of disease, they don’t see a clear response. It’s sometimes because of the CAR-T traffic to the disease site, and then later they can have a delayed response. So it’s hard to pinpoint their reason this trial was not positive, but that is the most popular possible explanations that we suspect that this trial did not show that CAR-T outperformed to the salvage-based chemotherapy followed by stem cell transplant.

Paolo Strati:

Thank you, and thank you for bringing that up, Dr. Bezerra. I feel like the common denominator as we try to highlight overall strengths and weaknesses of these three trials is really trying to better understand and define the overall concept of chemosensitivity. And I feel like there are really two levels of chemosensitivity; one, for eligibility, in this case for the trial, so chemosensitivity or resistance to frontline chemo, to an anthracycline-based chemo; that also has translated for axi-cel and liso-cel into an FDA label; but also the definition of chemosensitivity when it comes for those patients who received the platinum-based salvage chemo.

So I’m going to maybe ask you more questions about that, and I’m going to go back to Dr. Jallouk. So as we mentioned, currently in the FDA label, Yescarta can be utilized for patients who are primary chemo refractory in second line, and there’s a very arbitrary cutoff of 12 months within which the relapse happens. Of course, I think we all agree it’s very easy to define what’s really primary refractory, so the very rare, aggressive lymphoma patients who don’t respond at all to frontline or CHOP or EPOCH. But can you tell us more, in your opinion, what should be considered chemosensitive in terms of relapse after frontline anthracycline chemo? What are your biological and clinical thoughts, and what has been your practice beyond the FDA label?

Andrew Jallouk:

Yeah, so that’s a great question. Like you said, with the FDA label, that provides an arbitrary, but very clear threshold of what is likely to get approved by insurance versus what is not likely to get approved. So if it’s earlier than 12 months, you have the label behind you. If it’s later than 12 months, then you don’t. I think looking at chemosensitivity, it is a biological phenomenon, but we are using clinical variables to try to interpret it. So obviously response to the initial frontline chemo is important to look at. But even in patients who are primary for refractory, like you brought up, if you look at the PARMA trial, which is where autologous transplant was initially established, about 20% of patients who were primary refractory actually ended up responding because it’s a platinum-based chemo; it’s a different kind of chemo regimen. So even then, I think there is some question as to what exactly chemosensitivity means.

I think what happens in my practice a lot is not that I’m going to be making the decision. I can tell you, if I have somebody who’s an all-comer just coming in, new second-line diagnosis, I follow the label. If they’re within 12 months, I go for a CAR-T, again because in that population, for whatever reason, we can talk about the trials, there is an event-free and an overall survival benefit. If they’re past 12 months, then I can’t get the approval anyway, and so I will try to salvage chemotherapy. But the real question is what happens if somebody comes to your practice who has already gotten chemotherapy from an outside physician? Or what are you going to do if you have delays in getting your CAR-T approved, and so you give holding therapy, and then they have a response to that? These are situations we find ourselves in all the time, and I think they’re very difficult to manage.

I will say, a lot of times what I will do is if we make the decision to start with CAR-T, we will try to get insurance approval and get them to CAR-T as fast as possible. If they need holding therapy, we will give that, and especially if we have the CAR-T ready, we will execute on the plan as planned, and so we will move forward with the CAR-T. It’s a different situation, I think, if a patient comes into your clinic having received second-line chemo from an outside provider and is in good partial or a complete response. I do practice differently there. There was a CIBMTR analysis done, as well as some other papers that were published, that showed a benefit to doing auto-transplant in these, what you would call proven chemosensitive population. So I think that that is a little bit different story, but again we’re using clinical variables to define all this. I would love if there was a laboratory or a test that we could do to define, is somebody likely to respond to chemo? Is somebody likely to respond to CAR-T? And I think that’s going to become even more important if some of these current trials, like ZUMA-23 and some of these others read out, that are looking at CAR-T in the first-line setting. So I think there’s a lot to go on there, but not ready for practice at this moment.

Paolo Strati:

No, thank you. You said it very nicely, and thank you for the second part of the question. So I think what we’re hearing is that it’s kind of a non-brainer when it comes to definition of primary refractoriness in terms of sensitivity to frontline anthracycline-based chemo because, as Dr. Jallouk said, currently, unfortunately, we have to go by FDA label. So complete lack of response to frontline anthracycline-based regimen or relapse in progression within 12 months is what we have to follow to be able to get access to second-line CAR-T, no matter how arbitrary it is from a biological or clinical perspective.

But as Andrew started to mention, and that will be my question for Evandro, the hardest part is trying to define chemosensitivity and chemo-resistance to second-line, platinum-based chemo. While we all have, I agree, different approaches to bridging therapy or holding therapy as we wait to make a decision or we wait for logistics to resolve, I would say still many academic physicians and definitely the majority of community oncologists do utilize platinum-based chemo in second line no matter what the response was to frontline anthracycline-based chemo. And Andrew mentioned the 20% response to platinum-based observed in the PARMA study in primary refractory, anthracycline refractory patients, and you started to mention the CIBMTR study. So just to summarize, and I’ll let Evandro comment more on this, there are studies demonstrating that for patients who receive a second line or beyond platinum-based treatment and they achieve a PR initially in the first study and then a CR in the second study, it’s debated whether we should use trans-autologous stem cell transplant or CAR-T. So I wonder if you could comment more on those two studies, the CIBMTR experience. What’s your opinion about those specific study designs, and what’s your practice for patients who get a second-line, platinum-based chemo and they have some degree of response, PR or CR?

Evandro Bezerra:

This is a very important studies published by Mazyar Shadman from the Fred Hutch. So the first one, as you mentioned, patients in PR, published in Blood, that showed that patient that achieved PR to salvage chemotherapy, and retrospectively compared with patient that received CAR-T versus auto stem cell transplant, at least you can say this auto stem cell transplant is not inferior to CAR-T. And then later, he also showed the same similar findings in patients that got complete remission, his publish in Blood Cancer Journal, showing that patient that got complete remission to salvage chemotherapy and then went through stem cell transplant or CAR-T, stem cell transplant was at least no inferior, and there’s possible superiority.

So it’s very hard to change… Because I think the best-quality data we have is prospective randomized trial. And looking at that in the prospective randomized trial, that when you have this patient population relapsing in the last than 12 months, I think even though you have this data retrospective showing that there is possible non-inferiority of stem cell transplant if you have remission, I think it’s very hard to based on retrospective data to not follow randomized clinical trial. I agree there’s a very heterogeneous patient population that had relapsed in less than 12 months. I don’t think everyone of the patients of primary refractory and early relapse probably are not the same disease, not that they have/share the same biological factors and may not have the same prognosis. This comes a lot from the publication from Farooq at British Journal of Hematology back in 2017 that showed a difference in the outcomes; patient have primary refractory disease and early-relapsed and late-relapsed disease.

So if a patient comes, either because I give their holding therapy or they received a holding therapy from a referring physician, and they come in for a remission, I try to explain the data available. If they fall in the category of relapsed in less than 12 months, had a remission, showed the trial data of the prospective data showing favorable outcomes of CAR T-cell over auto stem cell transplant, but also try to show the data of the retrospective data. And one thing I like to highlight is we have a lot of data of CAR-T after stem cell transplant. It’s third line. That’s how CAR-T started. But we don’t have a lot of data of stem cell transplant, auto stem cell transplant after CAR-T. And we know, like Dr. Jallouk mentioned, auto stem cell transplant, even patients with refractory disease, I was able to offer the curative treatment option for a subset of patients. And when you use the CAR-T before the stem cell transplant, are we going to be able later to use the treatment optionally down the road? So very interesting question. I have a couple cases in my clinical practice of success; you’re doing auto stem cell transplant after CAR-T. But if you look back, if you go to the data, it was very rare nowadays patients going to get auto stem cell transplant after the CAR-T.

Paolo Strati:

First of all, I really like that, the fact that you try to have a conversation with your patients just discussing data, the trial data, but then also the real-world data, and trying to make this, for patients who may be potentially eligible both for CAR-T and transplant, kind of a provider-patient discussion and having the patients engage as much as possible in the decision-making process. And I’m also very excited that as you both talk, you’re actually… And there was no agreement before we met on what we would specifically ask. They’re actually bringing up the same question that I had in mind. So clearly, in the community, we all have the same challenges and the same questions in mind.

So let me ask you a few follow-up questions, and maybe I’m going to ask both of you. And actually, let me make a comment first. As for patients who are in PR after platinum-based, second-line chemo, we did publish, our center, kind of a provocative follow-up study where we looked into TMTV, and we were able to demonstrate the answer should probably be more biological than clinical. So patients who had the low TMTV, they may speak to low tumor burden and essentially a less suppressive tumor microenvironment tended to do better with CAR-T as compared to transplant. But those who had a relatively higher TMTV, where there was more immunosuppressive microenvironment, as long as the PR was a reflection of the true chemosensitivity… Because not all PR are the same. You can have a decrease in disease from 100% to 50%, but from 100% to 10%. So there are different degrees of PR. So if the PR was a reflection of chemosensitivity, didn’t matter how big was the tumor burden, then transplant would be better.

So going back to what Andrew said, I think that with time, hopefully we’re going to develop biomarkers to make a decision. But let me ask you, again, a couple of follow-up questions for both. So we all know that in second line, Breyanzi can also be accessed for patients who are primary chemo-refractory, but overall transplant-ineligible. And while I acknowledge that definitely there’s no universal agreement on what’s CAR-T eligibility, but some agreement on what’s transplant eligibility, many times transplant eligibility is in the eye of the beholder. Could maybe both of you comment on what would be the typical transplant-ineligible patient for you? And it’s not somebody that you… But still CAR-T-eligible. Maybe you can just start with Andrew or… Yeah.

Andrew Jallouk:

Sure. Yeah, I can talk a little bit about how transplant eligibility is handled at our center. So any patient over 65 going for either an auto transplant or a CAR-T gets a formal geriatric evaluation, and those are certainly helpful for informing patient frailty considerations and things like that.

I will say, I personally don’t like the terms eligible versus ineligible. All of these things are risk-benefit discussions with the patient. If you gave me a hypothetical patient who had a 90% chance of dying during their procedure, but a 100% chance of dying without it, and they were willing to take that 10% chance of cure, that is a discussion that you have to make with them. Now this is totally hypothetical, but the point being is I think you need to weigh the options on one side and you need to weigh the options on the other.

Liso-cel is a generally pretty well-tolerated CAR-T, especially compared to some of the other options, and so that takes the risk down a little bit. And honestly, now we need to have the discussion with bispecifics as well. That’s a whole different conversation, but it is no longer that you need to have a CAR-T or an auto or you have no reasonable treatment options. I won’t say curative; that’s a different discussion. But everything should be a discussion with, what are your options, what are the risks of each option, and what are the benefits?

And so in terms of who is CAR-T-eligible, I would say that I think CAR-T is a generally lower-risk procedure, especially with liso-cel, than auto, and so I’m a little bit more flexible in terms of who I would recommend or suggest go through CAR-T. But I don’t like firm numbers or anything like that, especially when it comes to age. It really is, I think, it is a risk-benefit discussion with all the options, which include salvage chemotherapy and transplant, CAR-T, and now also bispecific and bispecific-chemo combinations.

Paolo Strati:

Thank you. And, Evandro, again, I’ll be very mindful in not utilizing the term eligibility, but could you comment more in your discussion with patient regarding transplant versus CAR-T? What are the elements that would maybe make you lean more toward one or the other?

Evandro Bezerra:

I agree with Andrew. I don’t like the term transplant eligibility. Now, challenge, it’d be very different to have a Hodgkin patient. Would be much more [inaudible 00:23:14] T-cell lymphoma patient that would require an auto stem cell transplant. Wouldn’t follow so specifically age cutoffs of 65 or 70 years, like on the pilot on the ALKALINE trial, and some comorbidities as we have the comorbidities assessment, geriatric assessment. But I think because we do have diffuse B-cell lymphoma, a very good treatment option, curative treatment option like the CAR T-cell, makes you less willing to take the risk of the stem cell transplant. So I agree, my cutoff for eligibility for stem cell transplant in diffuse B-cell lymphoma is significantly lower because I have the CAR-T option versus in other lymphomas like Hodgkin or T-cell lymphomas that we don’t have that CAR-T option.

Paolo Strati:

Perfect. As we’re running out of time, I’m going to ask maybe three final questions we’ll try to address in the next couple of minutes. So the first one… Evandro brought up a very interesting point. Let’s say for patients who may be potentially eligible for both, we have very all and long-term follow-up data clearly showing that you can use CAR-T after autologous stem cell transplant, but no vice-versa, but I think we all have developed some experience. Maybe, Andrew, have you had any experience, successful experience, in consolidating with auto in patients who relapsed after CAR-T?

Andrew Jallouk:

I will say I haven’t, but it’s probably for lack of trying more than anything else because we have so many other options. We have bispecifics now. We have a large number of trials that these patients are eligible for. So I think it’s rare to see a post-CAR-T relapse patient that we would not do these other options in but we would do chemo, and also has slow enough disease that we could do chemo and then get to an auto transplant. As you know, a lot of these post-CAR relapses, the issue is they’re explosive and it can be difficult to manage. So I’ll say that I haven’t necessarily had that experience. I certainly believe that especially if you’re using CAR-T in the second-line setting, there’s probably some proportion of patients that biologically won’t respond to CAR-T but would have been chemosensitive and would therefore respond and potentially be cured with a transplant. I just, because of all the other options, we [inaudible 00:25:27].

Paolo Strati:

Right. That’s a nice segue, and we’ll see maybe what the data will show in the near future as we develop more and more real-world experience. So follow-up question for Evandro, and then I’ll ask a final question to both. It can happen that you may have in front of you a patient is ideal candidate, both from a patient factor perspective, lymphoma-specific factors for both CAR-T and transplant. So thinking that you may have this ideal patient in front of you, is there any logistic or access-related issue that will make you lean more toward one or the other, and has the mitigation with the elimination of REMS requirements to stay around a CAR T-cell center for four weeks and decrease to two weeks in any way affect your logistical considerations?

Evandro Bezerra:

I think from the logistical standpoint and access standpoint, the CAR T-cell is more accessible than this auto stem cell transplant. We have much more… And time-consuming as well. The stem cell transplant’s much more time-consuming. Patients need to have the mobilization, they freeze for the collection of stem cell transplant. That’s similar to the CAR-T, how the freeze the collection of the T cells. And then in the transplant itself, patients needs to be under the care of the transplant center a longer period of time than CAR-T, especially now with the flexibility of the REMS criteria.

So for me, most of the times I see my patients discussing about the two options be more inclined to the CAR-T option because it’s the less time-consuming and much more flexible than the stem cell transplant. It’s hard for me to think a patient that from logistic standpoint would be able to do the stem cell transplant and not be able to do the CAR-T. I cannot think it.

Paolo Strati:

Yeah. Agree. Agree. And definitely, as I mentioned before also with mitigation of REMS requirements, that makes for sure CAR-T a preferable option from a logistical perspective for patients who would be otherwise, I’m not going to say eligible, but a good fit for both.

So very final question. I think it’s important for our audience to be aware that when it comes to CAR-T prescription in the US, most of centers will defer the prescription to transplanters and other centers to cellular therapists who are not necessarily transplanters. And I’m very happy now that today there’s representation of both, with Evandro having more transplant training, having been born as a transplanter and then doing cellular therapy, and Andrew being more a non-transplant cellular therapist. And I wonder… Well, I think that we all agree that since people don’t try on third line and then in second line, there’s been a meaningful decline in the prescription of transplant… whether you feel that based on the setup of the center where you work, so being the prescription or CAR-T and defer to transplanter or cellular therapist, there could be a difference in the frequency of prescription of CAR. Has that been your experience? Let’s say, Evandro, you’re more of a transplanter. You were born as a transplanter. Do you feel like there’s a difference based on the setup of the academic center where you work?

Evandro Bezerra:

I’m not sure specifically where I work, but definitely I think there is who is transplant training, like more experiencing patient-successful cases of auto transplant, and also seeing the very low toxicity of auto transplant. It’s very, very rare to have a case of non-relapse mortality, very, very rare to a patient after auto stem cell transplant go to the ICU. So having that experience makes you more flexible and consider that therapy option than someone that doesn’t have the experience dealing with the complications of the stem cell transplant. I think that definitely may play a factor, who is the provider that’s prescribing the therapy experience both therapies, seeing the… Because we always say that our stem cell transplant have a higher risk of complication than CAR-T, but is that true? I question that. I think the ICU transfers, if you look at ICU transfer patient getting CAR-T and auto, I’m trying to say there’s more frequent ICU transfer if patient’s getting CAR-T than auto stem cell transplant.

Paolo Strati:

And as a cellular therapist, non-transplanter, hearing what you just said, it’s actually really powerful. So I’d to conclude hearing from Andrew what his thoughts are.

Andrew Jallouk:

Yeah, I completely agree with Evandro. So at our center right now, a patient is referred, and then the transplant and cell therapy groups very closely overlap, and so it’s usually kind of a joint decision by the group which one to go with. So I do think that puts them a little bit more on an equal footing in the sense that the groups who are making these decisions are familiar doing both and they can take a little bit more of an objective balance of which one is right. I think anytime, this is true even beyond lymphoma, anytime anybody can do one procedure but would have to refer out for another procedure, that very much creates a barrier, and it tends to favor whatever procedure can be done in-house or in-department. But I will say, the current practice model I’m in I think works very well, and we don’t run into that that much.

Paolo Strati:

Well, thank you. Thank you so much. I think our time is over. This has been a very dynamic and insightful conversation. Thank you to VJHemOnc for supporting this conversation. Thank you to Dr. Jallouk, Dr. Bezerra, Andrew, Evandro, for joining us today, and thank you to our audience for listening.

Paolo Strati: PS is a consultant for Roche-Genentech, Abbvie-Genmab, Beigene, Ipsen, Kite/Gilead, Novartis, AstraZeneca-Acerta, ADC Therapeutics, Sobi, and Incyte; he has received research funds from Sobi, AstraZeneca-Acerta, ALX Oncology, Kite Gilead and ADC Therapeutics.

Evandro Bezerra: Consultancy to Novartis, Kite, Kyverna and Alexion

Andrew Jallouk: Consulting: Kite/Gilead, Allogene, Autolus