Advances in CAR T-Cell Therapy for Diffuse Large B-Cell Lymphoma (DLBCL) and Other Lymphomas — Jonathan W Friedberg, MD, MMSc

DR FRIEDBERG: Thank you so much, Neil. And I’m going to be covering some advances in CAR T cell therapy for diffuse large B-cell lymphoma as well as introduce the potential role of CAR T in other lymphomas. I’ll just briefly remind everybody how CAR T cell therapy works. A patient with active lymphoma has blood collected through pheresis, and then that blood is sent to a laboratory, done at a really commercial laboratory, although some institutions are doing this on their own, where T-cells are genetically engineered to fight cancer through insertion of a chimeric antigen receptor. These T-cells then need to be grown, and there’s a variable period of time that it takes for those T-cells to be grown, minimum of about 2 weeks. Subsequently, a product is made after numerous assurances of sterilization and quality of the product and it's infused into the patient, where, very quickly, the CAR T cell recognizes appropriate antigens on the tumor cells, in this case lymphoma, and cause cell death.

It's important to think about this process when I compare the various products because certainly, this step in the process of manufactured growth of the CAR T cells is somewhat variable. And particularly for patients with aggressive lymphomas, that has major implications on potential outcome as well as the number of patients that ultimately are successful at receiving an infusion.

There are 3 main CD19 CAR T cell products that have had extensive studies in the literature. There are numerous other homegrown products that have many similarities. The first CAR T cell product to be approved is axicabtagene ciloleucel. This CAR T cell product came out of the National Cancer Institute laboratories. These other 2 CAR T cell products are newer, and they have many similarities, but I’ll point out the differences that the costimulatory molecule with axicabtagene ciloleucel is CD28, and with the others it's 4-1BB. And there are toxicity differences among these CAR T cells as well a potentially small efficacy differences that are probably due in part to the different constructs.

Moving forward, there will be new opportunities to continue to build upon these constructs to try to limit toxicity.

These are the 3 FDA-approved products. There are other products that are close to reaching approval, axicabtagene ciloleucel or so-called axi-cel, is approved for treatment of adult patients with relapsed/refractory large B-cell lymphoma after 2 or more lines of systemic therapy. Tisagenlecleucel is approved for both ALL in the pediatric setting as well as a similar approval as axicabtagene ciloleucel, although listing out transformation from follicular lymphoma as well as high-grade B-cell lymphoma. And the newest approval just over the last few weeks is from brexucabtagene autoleucel. It's a very similar product to axicabtagene ciloleucel, although there are some manufacturing differences. And this product is now approved for the treatment of adult patients with relapsed/refractory mantle cell lymphoma.

Now, there’s a lot of interest in trying to compare these various products and to say which is better, or which should I choose for my patient, and I’m just putting this slide up to show you some of the challenge of comparing CAR T cell products. And this is from an excellent review that was written by Caron Jacobson with a reference at the bottom of the slide. But this just compares 2 of the trials, the ZUMA1 trial, which used axicabtagene ciloleucel, and the JULIET trial, which used tisagenlecleucel.

And I’ll point out, for example, that both of these trials started out with a number of patients getting pheresed, in other words their cells were collected. But if you look at this category where it says number never treated, 9% of patients on the axi-cel study, were not able to be treated because either their disease progressed, or they had an adverse event, or the product couldn’t be manufactured. Thirty-one percent of patients on the Tis-cel study were not able to be collected. That's, in part, because the manufacturing time is longer on that.

So, if you take a look at the intent-to-treat analysis, there are differences in outcome as compared to, if you look at the overall response rates.

So, it’s important to consider these differences, and this is part why it’s very difficult to compare one study against another. And until there are randomized studies, which were not currently planned, we’re going to have to derive this information looking very critically at the populations of patients that were accrued to the trials as well as some of these important statistics.

I’ll point out this other category called bridging treatment. That's between collection and infusion, sometimes additional chemotherapy or radiation therapy is given to keep the lymphoma under control while the cells are being manufactured. No patients were allowed to get bridging treatment in the axi-cel study where almost every patient got some type of bridging treatment in the other trial. And, again, how important that is to the ultimate outcome is not so clear, but it does give a little bit of a difference in the way these patients are managed.

A final global comment before I get to some of the specific trials involves the two major toxicities associated with CAR T cell therapy, specifically neurotoxicity and cytokine release syndrome.

Cytokine release syndrome is, we have probably the best understanding of, and that involves a number of cytokines that get released in the presence of expansion of the CAR T cells as well as when the CAR T cells are attacking the tumors. And often times, this occurs early in the course of CAR T cell infusion between, say, day 3 and day 7. At low grade levels, it consists of fever. In high grade levels the patients can get a septic picture with a capillary leak type of phenomenon and become critically ill requiring pressers and other treatments.

Our understanding of management of this syndrome has greatly improved. And a number of treatments now are often employed, including corticosteroid therapy at certain times as well as IL6 blockade and other types of interventions.

Less clear, although we’re starting to understand a mix of cytokines that are contributing to the neurotoxicity associated with CAR T cell therapy. I’ll point out that this is really typical of anti-CD19 CAR T cells and many of the other CAR T cell products that are under investigation for other diseases do not have neurotoxicity.

Grade 3 and Grade 4 neurotoxicity does appear to be somewhat dependent upon the product, and I’ll try to point that out, and appreciate that, although Grade 5 events are quite uncommon, this neurotoxicity can result in intensive care unit stays and is one of the big risks associated with this treatment.

So with that introduction, I’m going to begin to describe some of the most recent up-to-date information that we have now that some of these trials have really matured and we have longer-term results. And as I previously mentioned, axicabtagene ciloleucel was the first product approved. This is a manuscript that was published last year that presented what they're calling long-term results, but you can see they’re kind of intermediate term results. There’s now a median follow up of about 2 years. The median progression-free survival was about 6 months. But I think the important point to make on this slide, which accrued only patients with relapsed/refractory diffuse large B-cell lymphoma or transformed follicular lymphoma, that after about month 6 there are very few progression events, meaning that there seems to be significant durability to the subset of patients that obtained a complete remission. And this subset of patients may in fact be cured.

I’ll point out, if you look at the details of this article, that if you reach a complete remission at 3 months, 72% of those patients remained free of disease at 24 months. So that's one of the biggest predictors as to the long-term efficacy. And also, despite the fact this being now the median follow-up of over 2 years, the median overall survival has not been reached, really emphasizing that this may be definitively curing a subset of patients.

Now if you try to ask for more information on who is more likely to be a long-term responder, there is a correlation between the number of circulating T-cells that you can measure, the CAR T cells, and prolonged response. That's shown on this slide and you can see that there’s statistical differences between these groups, where almost all patients who have ongoing responses have higher numbers of circulating CAR T cells than those patients who did not obtain a response.

This is important because there are potential strategies to enhance survival of CAR T cells. People are suggesting, for example, checkpoint blockade or other types of immuno-stimulatory treatment. And this information would support those types of hypotheses.

So, the other major product that has been approved is tisagenlecleucel. This is a product that has shorter follow up, and, in fact, the initial manuscript remains the manuscript that describes the experience of this. Here, the median follow-up is only 14 months. I put up these 2 curves to make two points. One is that the shape of the first curve looks very similar to the previous trial where most of the events are happening within the first 3 months and, after that, there seems to be very few events. The other point to make is that the subset of patients who obtained complete response have much better outcomes, again similar to what was observed with the axi-cel treatment.

Now, this curve — sorry, this diagram is really to show you that one of the remarkable things about CAR T cell therapy is that lymphomas that, under other circumstances, have higher risk of disease — of poor outcome still can respond quite well to CAR T cell therapy. So, for example, activated B-cell lymphomas and germinal center B-cell lymphomas have similar outcomes with CAR T cell therapy.

Patients with older age and younger age have similar outcomes with CAR T cell therapy. Patients with double- or triple-hit lymphomas, although there were small numbers in each of these studies, also had similar outcomes to patients who did not have double- and triple-hit disease.

So this really suggests that the CAR T cell therapy does not have the same intrinsic resistance mechanisms as would be the case with chemotherapy or antibody type treatment.

The one predictor of outcome of CAR T cell therapy that has been observed across the various studies is tumor bulk. And patients with smaller tumor bulk tend to have better responses than patients who have larger tumor bulk.

The third product, which has not been approved, but it's expected to be approved over the next few months is the lisocabtagene maraleucel product. This product appears to have a slightly improved safety profile as compared to the other two products. But again, this tells the story that in this study that was just recently published, 344 patients underwent pheresis or collection of the CAR T cells, and only 294 ultimately received the chemotherapy and CAR T cell treatment.

Additionally, 25 were infused with a non-conforming product, meaning it did not quite meet the standards that would be approved for the study. So the evaluable patients are only 74% of the original enrolled patient population. And what happened between leukapheresis and the chemotherapy is that of the 50 patients who did not receive CAR T cells, 33 of them had died, just suggesting the high risk nature of this disease. And then a number of other toxicities and complications ensued that prevented CAR T cell infusion.

This does speak to the importance of trying to — being able to move quickly, and does speak to a limitation in that the time of manufacture of these products is critically important. And I do believe that right now, for the commercial products, the axi-cel is able to be made faster than the other 2 products.

The progression-free survival, if you just focus on the red, which is the total, what you can see is again a curve that looks very similar to other 2 curves I showed, where the magic number overall survival 3 months and if you’re in a complete response at 3 months you can see there are few events that occur after that time. That's shown in the blue curve at the top. And the shape of this curve, although, again, median follow-up is not quite as long as the axi-cel, this is with a median follow-up of 18 months. Looks similar.

I should point out the converse of course, that if you only achieve a partial response as your best response or certainly stable disease, those patients, very quickly, have progression events and many of those patients die very quickly.

Now in addition to the clinical trials, there have been real-world experiences, and these are collections of patients from academic institutions that were treated with the commercial axi-cel product. These 2 manuscripts were published back-to-back last year in the Journal of Clinical Oncology and came to very similar conclusions. Interestingly, the response rates that were observed in the real-world population were very similar to those that were described in the clinical trials. The Grade 3 toxicities were also similar, with about a third of patients developing severe neurotoxicity and somewhat lower number developing cytokine release syndrome. Some of the reason why cytokine release syndrome is lower is that we’re better at managing and preventing it.

And the two conclusions, in bold on the slide, really suggest that at least in the setting of academic medical centers that are experienced at giving CAR T cells, that in the commercial product real-world experience the outcomes, so far, have been quite similar to what was described in the clinical trials.

Now I think a very important question is are CAR T cells curative? We don’t really have long enough follow up of the clinical trials that I mentioned to say for sure that patients are cured, although we may be getting close with that axi-cel long-term follow up, a median follow-up of 27 months.

The original axi-cel construct was made at the National Cancer Institute. And online now in JCO is a manuscript that looks at a median follow-up now of 42 months of patients that were treated at the National Cancer Institute. Interestingly, of the patients who reached a complete remission, 76% of those complete remissions are ongoing at a median follow-up of 42 months. And, about half of their CAR T cell treatments resulted in duration of response that exceeded 3 years.

So, I think that this is the most robust evidence we have to date that these CAR T cells maybe curing a fraction of patients. And that does have implications on the types of patients that we choose for this treatment as well as when we decide to use this treatment in the course of a patients’ disease.

Now moving on to mantle cell lymphoma. Because of the interest in and the experience of the CAR T cell treatments in diffuse large B-cell lymphoma, there is rapid interest in mantle cell lymphoma, which, of course, is generally considered an incurable disease with most of our standard treatment. Now early on, it was discovered that using the axi-cel product would not work well for mantle cell lymphoma. This is a disease that often has a very high circulating burden and there was concern over potentially genetically engineering the tumor cells as well.

So, because of that, the manufacturing process had to be modified, although the construct of the CAR T cell — of the chimeric antigen receptor is very similar to axi-cel and that's why there’s a different product.

So recently published in the New England Journal was the ZUMA trial, as a study in brexucabtagene autoleucel, in patients with relapsed/refractory mantle cell lymphoma. I’ll emphasize that all of these patients that had prior BTK inhibition therapy and most of these patients were relapsing or refractory to the BTK inhibitor therapy.

They enrolled 74 patients and were able to successfully manufacture the CAR T cell in 71 patients and administered it to 68 patients. So that's, again, similar to what was observed in the diffuse large B-cell lymphoma study: Over 90% of patients were actually infused. The outcomes were quite favorable with early follow-up, 85% response rate, 59% CR rate, two Grade 5 events. And the early progression-free survival curve with a median follow-up of about a year is beginning to look somewhat similar to what we’ve seen with diffuse large B-cell lymphoma, although, perhaps slightly more events between month 6 and month 10.

The median progression-free survival has not been reached, and at some level these outcomes actually look a bit better than what was seen in diffuse large B-cell lymphoma.

Another histology where CAR T cell is under investigation is follicular lymphoma. And the ZUMA-5 trial has not been published, however, the results have been presented at ASCO several months ago. And this study enrolled patients with high-risk indolent lymphoma, mainly follicular lymphoma, but a cohort of patients with other indolent histologies as well.

Patients had to have at least 2 lines of prior therapy. About two thirds of these patients had experienced the so-called POD24, or the early progression of follicular lymphoma that is associated with poor overall survival after initial therapy. And 73% of these patients were refractory to their last treatment.

The overall response rate after the CAR T cell infusion was 95%. And 68% of these patients had ongoing responses at the time of the abstract.

Neurologic toxicity and cytokine release syndrome was similar to what was observed with the setting of diffuse large B-cell lymphoma.

And because of this experience, a supplemental biologics license application has been submitted to the FDA to expand the indication of axicabtagene ciloleucel. And I expect that this will occur. I think the challenge, of course, in follicular lymphoma is really understanding which patient should undergo this treatment because there is significant toxicity, two Grade 5 events on the trial, and you don’t want to overtreat this, although, at the same time this could represent a cure for follicular lymphoma which has been elusive with other standard treatments. So I look forward to more studies that help us understand exactly where to use this treatment.

I’ll also mention in this trial there was another cohort that was enrolling other indolent lymphomas like marginal zone lymphoma, and that cohort continues to enroll, obviously, those patients are less common, and we will be getting therefore some experience with CAR T cell in those diseases.

And finally, as far as new histologies, I will mention that there has just recently been a publication in JCO online of an anti-CD30 CAR T cell treatment that has been studied in relapsed/refractory Hodgkin lymphoma. So this was a group of patients that had a median of 7 lines of prior therapy, including checkpoint inhibitors, brentuximab, both autologous and allogeneic transplants. And what they saw with this initial experience was low-grade cytokine release syndrome, no neurologic toxicity at all, but a skin rash that was common, interestingly, after the infusion, and that may be to a homing of some of these T-cells to the cutaneous space.

They had an overall response rate of 72%, with a CR of 59% in evaluable patients. The 1-year progression-free survival is a little lower than what’s been observed, but, again, this is a small number of patients and really, a pilot experience.

And given the relatively modest toxicity profile compared to the CD19 CAR T cells, I think there will be enthusiasm of looking at this further in various subsets of patients with Hodgkin lymphoma, particularly if we’re able to show durability of these responses.

This, of course, could be used in various T-cell lymphomas, as well, that express CD30, and there’s some early experience with that.

I’ll conclude by just thinking a little bit for the practicing oncologist, how to identify patients and refer patients appropriately for CAR T cell therapy. And I think if there’s one message it would be that early referral is really most important, particularly in the aggressive lymphomas like refractory diffuse large B-cell lymphoma. You can almost view this as a ticking timebomb and you only have a relatively small window of opportunity to consent the patient, to arrange all the insurance procedures, line up the pheresis times for the collections.

There’s a lot of steps involved in all those processes. You collect the cells and then you have to wait at least 3 weeks, often 6 or more weeks, until the product comes back and gets infused. And during that entire time, you have to somehow control the disease. There may be some bridging types of treatments you can give. But the earlier the patient can be at least evaluated and spoken with about the CAR T cell therapy, I think the more likely the patient’s ultimately able to get that treatment.

There are some other considerations that I put on this slide. I want to emphasize that these considerations, although as part of a consensus conference, as per the reference on this slide here, these are just guidelines because we don’t have robust studies. But I think many of us would prefer to avoid extensive lympho-toxic therapy in patients that ultimately are going to get CAR T cell treatment. So, in the relapse setting, you may want to avoid things like purine analogs and bendamustine.

Additionally, you should try to avoid immunosuppressive therapy, including aggressive dosing of steroids; although, short-term bursts of steroid therapy or pulses of steroid therapy are probably fine.

And I think a big question mark is the new drug that was approved for diffuse large B-cell lymphoma, tafasitamab, targets CD19. And the question is if you target CD19 prior to CAR T cells, is there going to be competition or are you going to decrease the efficacy of CAR T cells?

It is a different epitope that is targeted, so there are arguments that there may not be a problem. However, at this point, until we have further data, I would certainly advise that if you’re planning to give CAR T cells to a patient, I would avoid tafasitamab and use another alternative for bridging therapy.

And then specifically for diffuse large B-cell lymphoma, I would definitely consider referring the patient before starting salvage therapy. I’ll show you in a minute, there are a number of trials that are evaluating CAR T cell versus autologous transplant, and patients may not need salvage therapy if they’re going right to CAR T cell.

The other issue is the toxicity of these products is clearly formidable in the short term. In the long term it seems less so. But new products may allow treatment of older individuals and people that have comorbidities and frailty. So that's another reason to send more patients for evaluation.

And again, the real-world experiences are variable, but are demonstrating to us that the outcome seems similar to what had been published in the trials.

A quick summary on the types of studies going on in CAR T cell therapy. For most of the products that I mentioned there have been randomized trials, either completed or nearly complete, that are directly comparing head-to-head CAR T cell therapy to salvage and autologous transplant for patients with relapsed diffuse large B-cell lymphoma. Most of these trials selected for high-risk patients, those patients with refractory disease or early relapse. And of course, in order to go on to autologous transplant you need to respond to salvage therapy, so that's all taken in to account in this head-to-head, intent-to-treat comparison.

I think we’re all eager to see these results. We participated in some of these trials, and I can say that our local experience was that these were high-risk patients that really struggled to do well on both sides of this. So I think that we will hopefully learn whether CAR T cell therapy may represent a more curative option than autologous transplant. And I think those are the most awaited trials in the CAR T cell field.

Other things that are being discussed or looked at are post-CAR T cell treatment interventions, particularly for patients maybe who don’t achieve a CR, to try to accelerate the CAR T cells. I mentioned that at the beginning of the talk. And immune checkpoint inhibitors or immunomodulators are all being studied in various ways.

I also mention novel histologies that are being looked at, certainly within the lymphomas. But, of course, this technology could be used for other antigens as well. And there have been some early studies in various solid tumors, particularly thyroid cancer and renal cell cancers, where there have been some antigens identified. Of course, these are very early experiences.

And finally, I think we all look forward to new constructs of CAR T cells that allow outpatient therapy and minimize toxicity. And it may be that the CD19 antigen is particularly problematic for neurotoxicity, but even in that setting, the liso-cel product seems to have lower risk of neurotoxicity. And, in fact, they have an open trial that's enrolling for patients that are older and considered inappropriate for autologous transplant. And I think we’ll get some experience as to whether that may be a gentler form of CAR T cell therapy for more vulnerable patients.

DR LOVE: One thing I was trying to think about, are there any CD19 antibody drug conjugates?

DR FRIEDBERG: Yes. There are several of those in development. And, of course, there’s blinatumomab that is being used in ALL. So, whether or not — and in fact, with those ADCs, you also have the risk of neurotoxicity. There was ocular toxicity with some of those treatments. So, that's further credence to the fact that there may be something unique about CD19. There are some people who think that ultimately a very good effective antibody drug conjugate against CD19 could replace CAR T cells. And, obviously, that would be off the shelf. But, thus far, the results are really too premature to know what the durability of that's going to be.

DR LOVE: Right. Yeah, this thing is coming up with myeloma nowadays because they have an antibody drug conjugate just approved, belamaf and CAR T. And I guess the thinking is that the patients will still respond to CAR T after —

DR FRIEDBERG: Yeah, and I think it's going to be up to us to try to really help formulate what the appropriate sequence is. I think one of the challenges of the antibody drug conjugates is that unlike CAR T that's really a living drug and is able to sustain for months, if not longer, in the circulation, that's not the case with the antibody drug conjugates. And how important it is and how long you need exposure is not clear. But from 30,000 feet it feels like the CAR T cells are more likely to give that durability as compared to the drug conjugates that are given for a fixed duration.

DR LOVE: Absolutely. And clinically, I think, that's what you see for sure.

Just kind of curious, I never really asked anybody this. Do you ever see TLS with CAR T?

DR FRIEDBERG: So it's interesting. My second case had very severe cytokine release syndrome and whether a component of that was almost a tumor lysis syndrome is not clear. Because a lot of the syndrome that you see, some renal insufficiency, some hypotension, the need for fluids and poor urine output, can be across both sides. That's the closest that I’ve seen.

I think that many investigators now are — first of all, I’ll remind you that prior to CAR T cells, you’re giving some lymphodepleting chemotherapy that does include cyclophosphamide. And often, in this setting of that lymphodepleting chemotherapy, there is some impact on tumor bulk which probably limits a little bit — it's almost like a pre-phase treatment prior to the CAR T. And also, I think many investigators now have given some bridging therapy to try to limit bulk of disease.

So it's not been commonly described, but I wonder if some of the cytokine release syndromes, severe cases, may have a component of TLS.

DR LOVE: That's a good point. Also, I was going to ask you about bridging therapy because I wasn’t clear how much of that is just keeping the disease from exploding and how much of it is trying to shrink the disease so you’ll get better results with CAR T. How much bulk makes you want to shrink it just because of the CAR T?

DR FRIEDBERG: We’ve moved a little bit, I mean, our institution predominately has used the axi-cel product. And that one, we’re able to get a reliable turnaround in about 3 weeks. So the number of patients that need bridging therapy have been somewhat limited.

One thing we’ve tried in a couple of patients, and we’re actually in the process of designing a trial on this, and other institutions have looked at this, too — this isn’t just our idea — is radiation therapy as a bridge. There is some data that suggests that when you give radiation therapy, you’re exposing a lot of antigen and you may be manipulating the microenvironment to enhance CAR T cell effects. It's also not more systemic treatment. It doesn’t really beat the patient down and put them at risk for infections and things like chemotherapy might. So that's a strategy that we’ve used in some cases as a bridge that has worked quite well.

DR LOVE: That's wild, like abscopal CAR T, sort of.

DR FRIEDBERG: Yeah. And in fact, MD Anderson recently published a small series suggesting this and the patients who got the radiation seemed to have very robust CAR T cell responses. Again, this is something that needs to be looked at in more detail.

DR LOVE: But you’re saying that from the time you pheresed the patient to the time you give the axi-cel is like 3 weeks?

DR FRIEDBERG: Yes.

DR LOVE: Wow.

DR FRIEDBERG: Exactly. The turnaround time —

DR LOVE: Is that the way it was in the trial?

DR FRIEDBERG: In the trial, that's why none of those patients got bridging. They average between 17 and 21 days in the trial.

DR LOVE: Really interesting.

You put up a really interesting slide about some of the mechanism involved with cytokine release and neurologic, and I’m curious, because you don’t hear too much about the pathophysiology of the neurologic syndrome. Has anything more been learned? You’re referring to new cytokines or something?

DR FRIEDBERG: So we have a few facts about the neurologic, but I would say that is, overall, poorly understood. So, one fact, for example, is you can find CAR T cells in the spinal fluid if you look. Now, it turns out those CAR T cells may be there in patients who don’t get neurologic toxicity either. We haven’t really looked robustly because we haven’t done LPs on everybody. But that's just an observation that the cells are there and potentially mediating things.

It is also clear that there are correlations between tumor bulk and onset and severity of neurologic toxicity. There are correlations as well on some cytokine levels in the observation of cytokine toxicity. Those cytokine levels are in the serum.

So the hypotheses are certainly that it's a complex interaction that occurs. Why it's so specific to CD19 must be some type of trafficking issue as far as maybe the cells going into the CNS in a way that doesn’t happen with the other antigens. And how to prevent neurotoxicity is not so clear. The only big preventative that we’ve seen is to try to limit the bulk of the tumor going into CAR T cell treatment, sometimes that's not possible.

DR LOVE: So, wow, that stuff on CAR T and Hodgkin, incredible. I was not aware of that. That is super interesting. And any thoughts about immunology of what’s going on? And also, why it looks like they have less CRs? I mean when you think about the whole immune system in Hodgkin, I have not a clue how that ties into CAR T. But any thoughts?

DR FRIEDBERG: Yes. So, good questions. I do think that the population of patients with highly relapsed Hodgkin lymphoma are almost a unique patient population. They tend to be very young, so they’re different in many respects from the patients we usually treat. That said, they're also, in general I think highly immunosuppressed. We’ve seen, for example, that allogeneic transplant outcomes are disproportionally poor in patients with Hodgkin lymphoma compared to other diseases and you wonder why. These patients are in their thirties often, and yet, they have very high risks of death. So I do think that the underlying immune system, the ability to make and respond to cytokines, is probably somewhat different in this group of patients with heavily relapsed Hodgkin lymphoma that have been exposed often to things like checkpoint inhibition, autologous transplant, which changes your baseline immune response. Some of them had even allogenic transplants.

That said, it could be that the product itself is less immunogenic. Whether that's concerning for durability or not, we’ll have to see in larger studies.

DR LOVE: That's interesting about immune suppression. I don’t know whether most people associate that with Hodgkin. I mean you don’t see weird infections, right?

DR FRIEDBERG: Oh, no you do. I’m not talking necessarily about upfront Hodgkin’s, but you certainly can see pneumocystis in many studies of patients with Hodgkin’s. I think if you were to measure CD4 counts in patients with relapsed Hodgkin’s lymphoma, many of them would be quite low. And it may be slightly different now because of earlier use of checkpoint inhibitors. But keep in mind that our population of relapsed of Hodgkin lymphoma have often been through intensive ABVD type therapy, ICE, autotransplant, brentuximab, and then additional chemotherapy strategies sometimes, and allotransplants. I mean it takes its toll.

DR LOVE: So, the information’s come out recently on mantle cell is also really amazing and striking. Can you talk a little bit about, I think you were referring to the issue of why the product had to be different with mantle cell?

DR FRIEDBERG: The problem was, when you do a pheresis collection, you’re collecting lymphocytes. And of course, a subset of those lymphocytes are the T-cells that are eventually going to be genetically engineered and, in most patients, you have a small number of circulating B cells as well.

In mantle cell lymphoma, which often, by the time a patient is refractory, is really in leukemic phase and patients can present with very high levels of circulating B-cells. The ability to make the product was challenging because they didn’t initially build in specific T-cell selection when they were doing the genetic engineering. So a lot of it was around that. And now the manufacturing process has been adjusted where there’s a phase where the T-cells are initially selected, and then those are the ones that that subset are genetically engineered. That was not built into the initial diffuse large B-cell lymphoma trial because circulating cells are limited.

This is also an issue in ALL. So, they essentially use the ALL manufacturing process as compared to the diffuse large B-cell lymphoma manufacturing process.

DR LOVE: Interesting. What about CLL?

DR FRIEDBERG: It would be similar there.

There are CAR T cell studies going on in CLL. Interestingly, and in fact I think we all remember the first clinical publications of CAR T cell were in 3 patients with CLL from the University of Pennsylvania. So there’s certainly a long history of interest in that area.

I think the challenge in CLL, similar to what I described in follicular lymphoma will be to know which patients are the right ones to choose, particularly in the context of all the novel agents that we have in CLL.

We’ve had some of the trials open here for CAR T cell in CLL. And we’ve enrolled very few patients because it's just very few patients that are kind of the right ones, that pretty much have been through BTK inhibitors and venetoclax and are still in good enough shape and don’t have the comorbidities that would make them good candidates to go ahead with this.

DR LOVE: There was another question I had for you, which is, in terms of performance status, age in CAR T, and I’ve kind of had the feeling — of course I guess it depends on which product, which disease, and a lot of other stuff— but I’ve kind of had the feeling in general that the bar’s a little bit lower than, for example, say, autologous transplant, that you could take an older, more comorbidities. Is that the case?

DR FRIEDBERG: I think we’re all learning. And I think your sense is correct, that we had a 78-year-old patient here, who we never like to have an absolute age cap, but for autologous transplant for diffuse large B-cell lymphoma it would be very uncommon for us to take a patient of that age. And he actually went through the commercial axi-cel and he did okay. He’s done quite well, in fact, now, with a seemingly durable response. So that's just a sign that there are some patients that we’re starting to push the window on.

I think we’re also participating in some of the clinical trials that are targeting these patients, particularly with the liso-cel product, which may be thought to be a little bit safer.

If you ask me, when I care for this patients on the inpatient service, I think during the CAR T cell treatment the patients with CAR T, when they get sick, are certainly sicker than patients who undergo an autologous transplant. That said, it's a short period of time with a fairly stereotyped course and management strategy. So, for some reason, I think we're a little more comfortable than with autologous transplant, where, sometimes, the toxicities are for a much longer period of time.

DR LOVE: How often do you see patients cruise through CAR T? Like, really almost nothing?

DR FRIEDBERG: It's interesting. When we first — I’d say with the first 10 or 15 patients, we had a sense that if patients were cruising through CAR T it wasn’t going to work. But that's the case. In fact, the first case that I’ll present is somebody who basically cruised through the procedure. She had one fever. It was very transient, but we kind of were a little concerned about CRS in that situation. And after that, nothing happened, and she sat in the hospital for about 2 weeks without even knowing anything had happened.

So I would say, again this is ballpark, of just the patients that I’ve rounded on when I’ve done inpatient time, it may be about 20%.

DR LOVE: Interesting. Let’s take a look at your cases.

DR FRIEDBERG: The first case is a patient who was referred to me. She was 70 years old. And she had a history of transformed follicular lymphoma that also was like a double-hit transformation. So, what I consider a very high risk scenario.

Just to give a little bit context around her history. She was treated outside of our institution, initially in 2007 after a period of observation with fludarabine and rituximab. And then that was repeated in 2012.

She first came to our attention in 2013 when she had this double-hit transformation. We treated her with 4 cycles of R-CHOP. She went into a complete remission at that time, and then we did an autologous transplant. And she went into a complete remission. And then, interestingly, 4 years later she recurred, and the biopsy again showed transformed follicular lymphoma, not indolent histology. She got additional R-CHOP at that time. Started lenalidomide. And then shortly after the approval of the axi-cel product, we gave her the axicabtagene ciloleucel product.

And again, she had a low-grade fever, but otherwise tolerated things well. And just to give you a sense, at the time of the infusion — this was right before lymphodepleting chemotherapy, she still had a fairly sizeable FDG-avid abdominal mass, perhaps most apparent on the right side of the slide there. And then 3 months after CAR T cell therapy, that mass is still there, but you can see there’s no FDG-avidity at all.

And I just saw her about 2 weeks ago in clinical. She’s feeling great. She’s now on like a every 6-month follow up plan, feeling very well. And she was, at the time, somebody we were a little worried about. She was in her seventies. She had had an autologous transplant. And to answer your question, she was somebody who cruised through this treatment. She also had a lot of high-risk features with the double-hit cytogenetics and yet, responded quite well.

So I think she’s illustrative of how well CAR T cell can work. And in a subset of patients, how well it could be tolerated.

DR LOVE: So, kind of a follow-up question. One of the things that's been interesting to hear, again from the myeloma people, and of course, myeloma is a different disease, but one of the things they’ve been telling me, and they don't really see necessarily, at this point, the same kind of long-term responses, but one of the things they brought up that they feel was a benefit of therapy, even if they do relapse — and it seems like maybe in a year, year and a half — is that they're not on any treatment. And of course, myeloma, the patients are always on some treatment. And from a quality-of-life point of view, these patients just love not having any treatment. Of course, nowadays, COVID, etc, people want to get away from the clinics even more.

I don’t know if that's the same phenomena you see with lymphomas. Is it?

DR FRIEDBERG: Well, I think many of our patients are less — they’re not chronically treated. But that said, I think that lymphoma doctors really prefer an attempt to treatment that we think is definitive. And that's the enthusiasm for this in a disease like follicular lymphoma or mantle cell lymphoma, where, sure, you might be able to nurse things along with lenalidomide and ibrutinib and you go through all of the different treatments, but knowing that each one of those may have a progression-free survival or about 2 years. I think many patients ultimately would choose, despite some higher upfront risk, to do this, particularly if we thought this was curative. And that's why I think the long-term follow up is going to be so important.

DR LOVE: Let’s do the second case.

DR FRIEDBERG: This is a very dear patient to me, a 55-year-old physician at our institution, who had mantle cell lymphoma. He was treated for what was found to be p53 deleted mantle cell lymphoma, with the NORDIC regimen upfront that included, of course, an autologous transplant. And he finished that in September of 2016. He then was put on maintenance rituximab as per that protocol. And interestingly, that's when he moved to Rochester and I met him. And he, shortly thereafter, experienced some evidence of disease progression just on surveillance imaging.

So we started acalabrutinib at that time. And initially, you’d be thinking about an allogeneic transplant I think at that point. Fortunately, we had the ZUMA-2 trial open. And when he progressed on acalabrutinib about a year later, he got the axicabtagene ciloleucel — actually, it was the mantle cell product that he got.

He had very severe neurologic toxicity requiring a prolonged intensive care unit stay. Really became quite ill, but he did have a complete response. And to just explain one of the challenges with mantle cell lymphoma, this is what his PET scan looked like prior to the CAR T cell infusion. And he initially had just presented with basically some right axillary adenopathy and supraclavicular adenopathy. And within literally a few weeks, this disease really just exploded. And that's something that you can see in patients that are becoming refractory to BTK inhibition, both in CLL and in mantle cell lymphoma. And I think it speaks to the fact that you really need to give things quickly. Because he was on the trial, he couldn’t get any bridging therapy. I think knowing what we know now we would have given him some venetoclax or something to try to keep this under better control prior to his infusion.

But his repeat scan looks very, very good.

DR LOVE: I’m going to save that one. Incredible. Wow, that's awesome. I never saw anything like that.

DR FRIEDBERG: And that's really been my experience with CAR T. I mean when I first read about the CLL series I, of course, was cynical and I said, well, they were getting chemotherapy too, and some of these patients do well. But you have a few patients like this who care for that you know was looking at death within weeks and you see this degree of response so quickly, it's really incredible.

That said, I don’t want people to think that this is curing everybody. I’ll emphasize those progression-free survival curves have reproducibly shown that the majority of patients are not having these durable responses. And therefore, there’s still work to be done and for us to understand it. But since we’re so early in this, I think the eventual outcomes are only going to improve and that's why I find it so exciting.

DR LOVE: How did the neurotoxicity in this patient manifest itself? What neurologic symptoms did he have?

DR FRIEDBERG: So, as part of our standard practice, it's amazing how quickly they come on. Just to give you a sense, as part of our standard of practice, we do mental status evaluation, like a mini-mental status every day, and it involves having patients write a sentence and doing things. And for him, he would always get, of course, all 30 points or whatever. I mean he was a practicing physician. In the morning, he missed 1 question, which was a little bit atypical, so we noticed that, and by 4:00 o’clock in the afternoon he couldn’t write a sentence or do anything. It came on that quickly. He actually had some seizure activity. And ended up having to be paralyzed and intubated, in part for airway protection. And as I said, he was intubated for close to 2 weeks. And we were quite concerned that there would be some permanent sequelae of that, and I have to say our intensivists did a phenomenal job at making sure that other things didn’t happen to him when people are so vulnerable in that situation. And in the end, he needed to go to rehab for a short time after discharge because he was weak, and he basically had some intensive care unit neuropathy. But within about 2 months he was back at work.

DR LOVE: Wow. Wow. What a story. Do you see, or did you see with him, or do you see anything focal? I’ve heard about problems with speech? Anything in particular?

DR FRIEDBERG: Yes, we’ve seen a few patients — I had another patient who similarly had rather severe neurotoxicity, and one of the first manifestations was that he just stopped talking. And you could tell, just couldn’t. It was too complicated to take thoughts and put them into words. Very distressing for family members to be sitting there and to see your loved one not being able to communicate. We put a lot of energy prior to admitting patients to CAR T to warn people this can happen. It's something we watch for. It's transient and all of that. But even despite all those warnings, it's probably the most disturbing thing for family when mental status is off.

DR LOVE: Do you see anything on imaging? I remember there were some reports of cerebral edema. I mean do you see anything in the brain?

DR FRIEDBERG: There can be some cerebral edema that is seen. And one of the reasons to do imaging is because in a couple of cases there had to be — there have been reports of the need to do decompression. That said, otherwise there really isn’t a whole lot that's seen. And in fact, as part of the clinical trials we did MRIs. We did lumbar punctures. We did a full evaluation. Sometimes you can see a bit of a pleocytosis in the CSF, but it's like a picture of an aseptic meningitis. But other than that, there aren’t a lot of diagnostic signs on imaging. And in fact, you rule out things like stroke or anything focal if somebody is having mental status issues. And we haven’t ever really seen an MRI be positive in that setting.

Evolving Treatment Paradigms for Patients with DLBCL — Ann S LaCasce, MD, MMSc

DR LaCASCE: I’ll be talking today on evolving treatment paradigms for patients with diffuse large B-cell lymphoma. So we’ll start with a case. This is a 77-year-old patient of mine who initially presented with Stage IV nongerminal center subtype of diffuse large B-cell lymphoma. She had extensive symptomatic disease above and below the diaphragm, with splenic and multifocal bone disease. Her IPI was a 5. She was treated with 6 cycles of R-CHOP with systemic high-dose methotrexate for CNS prophylaxis and achieved a complete remission.

Unfortunately, however, she developed recurrent disease about 6 months later, and at that time was in her mid 70s so was felt to be an appropriate potential candidate for transplant. She then received 2 cycles of R-ICE and had improvement, but her PET did show some residual disease in the abdomen. So we therefore planned to take her to CAR T-cell therapy. She underwent T-cell pheresis followed by lymphodepletion and received her CAR T cells. She did quite well. She had some Grade 2 cytokine release syndrome, but otherwise had a relatively uncomplicated course.

Unfortunately, 1 year later, after achieving a complete remission after CAR T she developed biopsy-proven recurrent disease involving the left thigh. She went on a clinical trial with a bispecific antibody and did very well and achieved a near-complete remission. Towards the end of her therapy on that trial she did develop some Grade 1 neurotoxicity and came off. She then, however, had very rapid progression of significantly symptomatic disease. You can see here on her PET scan she had a very large thigh mass with disease in the abdomen and had significant lower extremity swelling.

So today I’m going to talk about polatuzumab vedotin. This is an antibody drug conjugate that targets CD79b and is conjugated to MMAE. This is the Phase I data from a trial in relapsed/refractory B-cell lymphoma and CLL.

And you can see in terms of the adverse events the most commonly seen adverse events of importance were neutropenia, Grade 3 and 4, as you can see 24% and 16% respectively. This is similar to what we may see with brentuximab vedotin, so it may be an MMAE-driven issue, potentially. Also peripheral neuropathy, though the majority of adverse events were Grade 1 and 2. So a relatively well-tolerated drug.

And you can see from the waterfall plots on the right the single-agent activity is really quite impressive here, including indolent non-Hodgkin lymphoma on the top, diffuse large B-cell lymphoma in the middle, and mantle cell. And the R denotes refractory disease to the last therapy. So really a very promising Phase I study.

So this then led to this randomized Phase II study in patients with relapsed and refractory diffuse large B-cell lymphoma combining polatuzumab with bendamustine plus rituximab compared to bendamustine plus rituximab alone. And if you look at the patient population here, the median number of prior therapies was 2, but almost 50% of patients had had 3 or more prior therapies. The overall response rate was about 63%, with half the patients achieving a complete remission. And if you look at the progression-free survival curves here, you can see really a significant benefit to adding polatuzumab, and the median progression-free survival on this study was about a year.

And you can see there is potentially a tail on this curve, though the follow up of this study was relatively short. So we need longer follow up. But very, very encouraging data.

So in addition to looking in the relapse and refractory setting, polatuzumab was moved up front, and in a Phase II study was combined with R-CHP, so leaving out the vincristine, given the overlapping toxicity with the MMAE.

So you can see in this study of patients with diffuse large B-cell lymphoma the overall response rate is nearly 90%, with a complete remission rate of 77%. As you look across the various subtypes, ABC and GCB, the response rates really look very favorable, including in the double expressor, though maybe slightly lower in that subset.

In terms of toxicity, again peripheral neuropathy was seen, but mostly low grade. Febrile neutropenia was common, as one might expect with a combination with R-CHP. And you can see the progression-free survival here, for a Phase II selected-patient population looked very, very favorable.

And this then led to the POLARIX study, which is a large international study randomizing nearly 900 patients with IPI 2 to 5 diffuse large B-cell lymphoma to pola/R-CHP versus R-CHOP chemotherapy. This study has completed accrual, and we are eagerly awaiting the readout. Hopefully this will be coming out sometime during 2021 and may actually change the up-front therapy of diffuse large B-cell lymphoma. This would be the first time since the introduction of rituximab now a long time ago.

So going back to my patient, she was treated with polatuzumab plus rituximab. We withheld the bendamustine given she had some baseline cytopenias, which we see very commonly after CAR T-cell therapy, particularly in older patients who’ve had significant prior therapies. And she achieved a metabolic complete remission with essentially no toxicity. Her response was very rapid, and she remains in remission now about 9 months out. So really quite a favorable response.

So going on to another case, this has some similarities, but we’ll use it to discuss some other novel combinations. This is a woman who was in her mid 70s when she initially presented with left-sided pleuritic chest pain. She had a chest CT scan that revealed diffuse lymphadenopathy. She underwent an excisional biopsy that showed, again, a nongerminal center diffuse large B-cell lymphoma. She had a relatively high Ki-67 fraction at 80%. She had this PET scan, which showed really extensive disease above and below the diaphragm, including involvement of the right kidney and hydronephrosis on that side. She had pleural effusions, and her IPI was a 5.

She received 6 cycles of R-CHOP. I recommended and administered high-dose methotrexate, given her CNS IPI was a 6. She declined the last cycle of systemic methotrexate. She was just tired of being in the hospital. And she did achieve a complete remission, but again had an early recurrence at about 9 months after completing her initial therapy.

So what options might we consider in this setting? So selinexor is a novel oral drug that is approved for use also in multiple myeloma. It is an XPO1, or exportin inhibitor. This is a protein that’s been shown to be overexpressed in diffuse large B-cell lymphoma and correlates with a poor prognosis. And what this protein does is that it exports tumor suppressors out of the nucleus, so by blocking this you keep things like p53 and Iκβ in the nucleus where it can exert an antitumor effect. And the other mechanism of action here is it decreases the production of oncoproteins in the cytosol, including MYC and antiapoptotic proteins like BCL2 and BCL6.

So in this Phase II in patients with relapsed and refractory diffuse large B-cell lymphoma the dose was 60 mg twice a week, and this was given in this way because this was the tolerable dose. This drug is associated with some significant GI toxicity, which is mitigated by giving it less frequently. It’s important to note the key eligibility here. So patients who were refractory to their most recent systemic therapy needed to wait 98 days before enrolling on therapy. Patients who had had a complete or partial remission waited 60 days.

If you look at the prior therapies, about 60% of patients had had 2 prior treatments, and 72% of patients were refractory to their most recent line of treatment, suggesting this really selected from a less aggressive group of patients with diffuse large B-cell lymphoma. A typical patient we see has disease that is progressing rapidly in the refractory setting.

So in terms of the activity of this drug, it was about 20%, with complete remission rate of about 12%. And you can see in terms of the adverse events, the Grade 3/4 toxicities were low. However, Grade 1 to 2 nausea, weight loss and vomiting were significant, and given that this is a drug that’s taken over long periods of time, potentially, if a patient is responding, it may have significant impact on quality of life.

However, there may be patients for whom this is a good option, and this led to the FDA granting of accelerated approval in June in patients with relapsed and refractory large cell lymphoma, including those who have transformed follicular lymphoma after 2 prior systemic therapies.

So tafasitamab is a novel engineered anti-CD19 monoclonal antibody which is designed to enhance ADCC and antibody-dependent cell-mediated phagocytosis with macrophages. As a single agent this drug has a response rate in the 25% range in diffuse large B-cell lymphoma. So this drug is given with lenalidomide, which has a similar response rate as a single agent, but the idea here is that perhaps the lenalidomide would enhance NK cell function to have better ADCC. And this was shown in in vitro models.

So this led to the study of tafasitamab plus lenalidomide, and this was in relapsed and refractory diffuse large B-cell lymphoma. The tafasitamab is given weekly during the first 3 cycles and then every other week until progression. Lenalidomide is 25 mg for 12 cycles. The patient population, here you can see, was an older patient population, median age of about 70. And about half of the patients had had 1 prior therapy. You can see about half of patients entered the study with an elevated LDH. A small percentage of patients had had prior stem cell transplant, as again, this was an older patient population.

As you can see on the left here, the complete remission rate was quite favorable at 43%, with 60% of patients responding. One of the major toxicities here was presumably related to the lenalidomide, and nearly half of patients required dose reduction of lenalidomide. 25 mg would be a significant dose in a pretreated patient who’s older with this disease. 22% of patients permanently discontinued the lenalidomide. About 60% of patients received the full course of 1 year of both agents.

These progression-free survival curves look similar to the polatuzumab/bendamustine/rituximab with a median PFS of about a year. You can see in the lower curve, however, those patients who achieved a complete remission had very favorable outcomes. Though again, the follow up is relatively short, and there’re a small number of patients who are in that group. But I think this is intriguing, and when we look at other toxicities, neutropenia, myelosuppression is common, and other adverse events were typical to what we would expect in this patient population.

So this combination was granted accelerated approval in relapsed and refractory large cell lymphoma and also targeted for patients who are not eligible for stem cell transplant, but may be used in subsequent line of therapies for other patients with large cell lymphoma. So we’re seeing a lot of new trials coming out with this combination for salvage and even we’ll be seeing this coming up front. But interesting drug and combination.

Mosunetuzumab. This is a bispecific antibody targeting CD20 and CD3, and as you can see this is a full-length antibody which is favorable in terms of pharmacokinetics, so it doesn’t have to be given as a continuous infusion like the BiTEs. This binds to the CD20-expressing tumor cell and then brings the CD3-positive T-cell in conjunction, leading to tumor cell death. There are a number of these bispecific antibodies currently in clinical trials.

This was data presented last year at ASH in the plenary session, and you can see the drug during cycle 1 is given weekly, and then on day 1 of a 21-day cycle for the subsequent rounds. For this Phase I study, patients who achieved a complete remission got a total of 8 cycles, and those who had partial or stable disease could receive up to 17 cycles. And retreatment was allowed for patients who achieved a CR and then relapsed.

As one might expect, we did see some cytokine release syndrome and neurotoxicity with this bispecific antibody, but the majority of the CRS was about 30%, but mostly low-grade and reversible. The neurotoxicity was about 45%, but again the vast majority of cases were low grade and reversible. And you can see in the right-hand box there were 30 patients who had had prior CAR T-cell, and their neurotoxicity rates look similar to the entire patient population.

In terms of the efficacy here, it’s broken down by subsets. So for patients with aggressive lymphoma the overall response rate is about 40%, with about 20% of patients achieving a complete remission. And this is obviously a heavily pretreated group of patients. For those patients who were evaluable after CAR T-cell therapy, about 40% response rate and again 20% complete remission rate. I would point out, however, 4 of these patients were follicular lymphoma patients after CAR, and they had overall response rates of 100%, which is what we’re seeing. These bispecific antibodies seem to be very, very active in follicular lymphoma as well.

And you can see in this study for the indolent lymphoma patients, again heavily pretreated, these are patients who are refractory to PI3-kinase inhibitors, and this group was enriched for patients who progressed early, and the overall response rate there is about 63%, 40% complete remission rate.

So for my patient, unfortunately she had presented prior to the availability of any of these agents, and when she relapsed she did not want to have infusional chemotherapy. She was on the borderline to being an auto candidate if she had wanted that. So we opted at that time to pursue a BTK inhibitor therapy. She was a nongerminal center subtype, and some of her cells were CD5 positive. There was a delay in getting her this oral therapy, and ultimately when she started she progressed relatively rapidly. And this was the scan at the time she progressed after BTK inhibitor.

So we opted to try polatuzumab, but for her, she was really quite ill by the time we started that, so she didn’t do well. But had she presented even a year later, our options would have been quite different, which is really, we’re in an interesting place in this disease.

So in summary, we have multiple novel drugs recently approved for patients with diffuse large B-cell lymphoma. Polatuzumab, bendamustine, and rituximab is an active regimen. It’s appropriate for elderly patients. The cytopenias can be managed with dose reductions or holding bendamustine, and obviously with the use of growth factors.

We’re looking forward to the POLARIX study. Hopefully that will read out soon and would be really exciting to have a new front-line option for patients with large cell lymphoma.

Selinexor has a novel, very interesting mechanism of action. It’s activity is modest, and it does have some low-grade GI toxicity. It may be appropriate for patients who have less aggressive disease who prefer an oral regimen twice a week. It’s really easy in terms of patient compliance.

Tafasitamab and lenalidomide looks very favorable as well, particularly in those patients who achieve a complete remission. The dose of lenalidomide is quite high, so many patients will require dose reduction. It is a relatively intensive option, given that patients come in weekly, initially even an extra dose on day 4 of cycle 1, and then they’re coming in every other week for infusion. But this is a good option for our older patients. You want to keep an eye on them. They’re coming in frequently. So we’re excited about this combination.

And then mosunetuzumab is one of a number of bispecific antibodies targeting CD20 and CD3, and I think we’re going to see a lot of these drugs moving forward. There are a number of things being presented at ASH with these agents. And we look forward to seeing how this is going to play out. I think we’ll also see these moved up earlier in the course of treatment, and there’re ongoing studies in the front-line setting.

DR LOVE: Great. So the first case, the patient did not have a transplant, correct?

DR LaCASCE: That’s right. She got R-ICE. We had planned to take her to transplant. She was right on the age cutoff, but she did not achieve a complete remission. And in those patients I much prefer to take them to CAR T-cell because I think they don’t do well with transplant.

DR LOVE: And other than that, in the patient who has a good remission, how do you choose, I mean theoretically, how would you choose, I know there’re trials looking at this, between CAR T and transplant?

DR LaCASCE: So for now we cannot get CAR T approved unless patients have failed 2 prior lines of therapy. So we’re looking forward to these studies in the high-risk patient population because she would have fit into those studies. And I suspect we’ll see good results there because this is a patient population when the relapse early they’re chemorefractory, and we see time and time again when you give them salvage they don’t achieve a complete remission.

DR LOVE: So another question, in terms of sending a patient to CAR T, do we know anything about whether or not CAR T works in people who’ve had prior anti-CD19-directed therapy, for example tafasitamab?

DR LaCASCE: I think it’s a big question. I think we really don’t know the answer. And I think it’s giving some people pause, as now there are studies coming out looking at adding this in the salvage or front-line setting. So we’re going to have to see whether you do see any loss of CD19, but hopefully not.

DR LOVE: What about lenalidomide alone or R-squared in diffuse large B-cell lymphoma, in relapsed disease? Do you use that? And what kind of efficacy have you observed?

DR LaCASCE: So I think in the past we have used that, before we had some of these other options available, either single agent or in combination with rituximab. Often these patients have had lots of rituximab, so we may just use a single agent. And I’ve had a few patients who’ve responded well, but honestly I’ve been underwhelmed by the activity as a single agent.

DR LOVE: Any thoughts about how mosunetuzumab is going to shake out related to CAR T? Do you think that it’s going to end up being used instead of it? Before it? Where do you think it’s heading?

DR LaCASCE: I think it’s heading further up front. I think there are these studies combining it with R-CHOP or with polatuzumab. So I think other strategies might be to use it as consolidation after initial R-CHOP chemotherapy, maybe in patients who had high-risk disease. Maybe we’ll be looking at using MRD, circulating tumor DNA, or other strategies to try to identify patients who are high risk. So I think we’re going to see it move further up front, whether it will ever be compared head-to-head to CAR T? Hard to say. But I think these drugs are very promising. They look really good in indolent lymphoma. I think they’re going to make a big impact there.

DR LOVE: So where do you think we’ll be in 2 or 3 years? Any predictions?

DR LaCASCE: So I’m hoping we’ll be using a novel up-front regimen, hopefully the POLARIX study will be positive. I think that would be really exciting because irrespective of cell origin hopefully we can cure more patients up front. And I suspect that CAR T will look good in the early relapsers and be a better option, I think those 3 studies looking at the 3 CAR T constructs, hopefully those will be positive studies, so that may be our second line for patients. And then hopefully we’ll be doing fewer stem cell transplants.

DR LOVE: I’m curious about some of the questions you get from your fellows or general medical oncologists in practice about diffuse large B-cell in general, including relapsed disease. Any things that you see in patients that you’re seeing for second opinions who’ve been managed previously by other docs, things that they do that maybe you wouldn’t do?

DR LaCASCE: So I think there’s a temptation to try to intensify therapy for diffuse large B-cell lymphoma, particularly the double-protein expressors, where there’s really no evidence that anything is better than R-CHOP. We know R-CHOP is not great, but there have been multiple randomized studies. Those studies are limited by the fact that the sickest patients often are not on those studies, so one could say maybe that’s why they’re negative studies.

But sometimes you’ll see people will add in lenalidomide or add in ibrutinib or give dose adjusted R-EPOCH to a patient who’s not a double-hit lymphoma patient. And I think we really shouldn’t be doing that because the data doesn’t support it. There’s a lot of significant potential toxicity, and now that we have much better options for relapsed and refractory patients, I think hopefully that practice will go away. It’s relatively infrequent that you see that, but I think there’s this sense “Oh, I know this is a really bad lymphoma, I need to do something other than R-CHOP.”

I think the other thing that we see a lot of is this whole notion of CNS prophylaxis. I think we still don’t know the answer to whether that A) is it effective to give systemic methotrexate? What’s the optimal timing? We still do it. I did notice there’s an oral presentation at ASH looking at this, a retrospective analysis, that I’ll be looking forward to seeing, suggesting that perhaps we’re really not impacting on risk of recurrence by using systemic methotrexate. It’s expensive. People have to come in the hospital. Sometimes they get renal failure. I think intrathecal chemo for diffuse large B-cell lymphoma is not useful. Most people have parenchymal recurrences, and the intrathecal just doesn’t penetrate. So I don’t think it’s worth doing that. But it would be nice to know whether we’re really just treating ourselves when we give systemic methotrexate prophylaxis.

DR LOVE: Well the other thing I’ve heard brought up is the issue of, in some instances, the methotrexate compromises your ability, you get cytopenias, whatever, to give the R-CHOP. Do you see that happening much?

DR LaCASCE: Not usually. We have given it typically around day 14, as their counts have recovered. Usually the white count has recovered, and I have not personally encountered that issue. But it is a big issue if you have a double-hit lymphoma patient. Those patients who are high risk for CNS disease, it’s really very, very difficult to give intercalated systemic methotrexate, so patients often get IT, and then sometimes get methotrexate outback. It can be problematic.

DR LOVE: So I notice that your first patient had CNS prophylaxis. What was the indication there? In general today what are your indications to treat? And how did the patient do with the methotrexate?

DR LaCASCE: So she had a high CNS IPI. Her IPI was 5. So for patients with 4 to 6, so it’s the IPI risk factors plus renal or adrenal involvement. And she had multifocal bony disease. So she was otherwise a healthy person who presented with a normal performance status. And interestingly, she had been treated in the community, and I saw her late in her course, so we decided to add the methotrexate at the very end and just admitted her every other week for 3 cycles. And she did extremely well, cleared it beautifully, and then had a systemic relapse. So that’s what happened with both of these patients, and maybe that’s telling me something. If they didn’t have a CNS relapse did we prevent that with the methotrexate, or is this just a high-risk patient who’s not going to do well?

Optimal Management of Newly Diagnosed and Relapsed/Refractory Follicular Lymphoma — John P Leonard, MD

DR LEONARD: Well it’s great to be here and to be part of this program, and I’m sorry we’re not together in person, but I’ve always enjoyed being part of the Research To Practice symposia, so again, even though we’re virtual, great to be here.

We’re going to talk about follicular lymphoma here. And I think the audience really knows that this is one of the areas where there’s a lot of the art of practice in choosing therapy for follicular lymphoma patients, whether it’s at diagnosis or relapse.

What you’re thinking about is really what the indications for therapy are, how the patient is doing, why you’re starting treatment, how much disease they have, their comorbid conditions. I think in follicular lymphoma there’s a lot of concern about toxicity for the patient and what they’re willing to put up with or not put up with, preferences around chemotherapy, no chemotherapy.

And then the other big area is really the risk of transformation. And so high SUV on PET scan to some degree correlates with risk of transformation, although that’s imperfect. But clearly if a patient has high LDH, rapid progression, we want to think about that because obviously we’re going to approach the patient differently. And I typically treat patients Grade 1, 2, 3a very similarly, and then 3b more like diffuse large B-cell lymphoma.

So bendamustine/rituximab has been around now for over 5 years, probably longer altogether, and the net for follicular lymphoma is that the efficacy is at least similar. In this study it looked better with regard to PFS. This is the StiL study from Rummel, but no difference in overall survival. And so you have a regimen that is similar or better in effectiveness to R-CHOP and similar overall survival, better toxicity profile, less — generally less infections, less alopecia, less cardiac toxicity. So BR has really been a standard regimen for some years now.

We know that from the PRIMA study that maintenance rituximab after R-CHOP or R-CVP improves progression-free survival but not overall survival. Some people have said now we’ll give maintenance rituximab because, again, this blue curve looks pretty good, a long PFS. On the other hand, in the absence of an overall survival benefit, skipping the maintenance rituximab, retreating the patient at the time of progression is another option. And I would say that I’d talk about both of these with most of my patients and consider either one of these an appropriate regimen; no maintenance or maintenance.

We have less data, comparatively, with maintenance rituximab after BR. So the GALLIUM study, which has been available now for the past 3 years or so, when it was presented at ASH, I think, in 2016, the ASH Meeting, so coming up on 4 years. Took patients with untreated follicular lymphoma, 1,400 patients, gave them obinutuzumab or G or rituximab with CHOP or CVP or bendamustine. Everyone on this study had maintenance rituximab or obinutuzumab based on the arm that they were assigned to. And the primary endpoint was progression-free survival.

You can see that there is a modest difference in progression-free survival here, somewhere in between 5% and 10%. But similar to the PRIMA study, no difference in overall survival. And so again, I think it’s, to some degree, the same conclusion. You can use the newer drug obinutuzumab for a benefit in PFS, but again, since there’s no difference in overall survival, rituximab again remains a reasonable choice.

So this benefit for obinutuzumab seems to be present regardless of the chemotherapy backbone, bendamustine/CHOP/CVP, all of which were improved a bit in regard to PFS. You can see the hazard ratios here if you used obinutuzumab versus rituximab. So it doesn’t seem to be dependent upon the chemotherapy backbone.

Now there was more toxicity with obinutuzumab, more infectious toxicities, you can see, and a few more infectious deaths with obinutuzumab versus rituximab, particularly with bendamustine-based therapy. And so this concern, as this plot outlines Grade 5 adverse events, had led some to be a little more concerned about using obinutuzumab with bendamustine because of this slight increase in severe and life-threatening infections. So that’s something else to keep in mind as you think about using this regimen.

On the other hand, the efficacy has been something that at least is supported in part by some surrogate endpoints. In particular, MRD negativity at the end of the induction treatment was higher, slightly higher, in the group of patients that were treated with obinutuzumab. So some have argued that this might result in a longer-term benefit even in the absence of an overall survival benefit. And you can see the — R/chemo-based patients versus the G/chemo-based patients who are MRD negative. Again, a little bit better with obinutuzumab.

And I want to go back here and just point out something here at the bottom, that to the extent that POD24, or progression of 24 months, correlates with long-term outcome. There was a slightly better POD24 rate in the obinutuzumab-containing arm versus the rituximab-containing arm, and these absolute percentages were 12% versus 18%. So about a 6% difference, or 6 out of 100 patients achieved POD24 without progression with the use of obinutuzumab. Again, will this translate to longer-term benefit I think remains to be seen. So far it has not, but again, to the extent that this is a surrogate for outcome, one might argue is an advantage of obinutuzumab.

Now the other strategy here has been the “chemo-free” regimens, and this has been best and most extensively studied in the RELEVANCE trial, lenalidomide/rituximab (R-squared) versus R-chemo. You see the schema here where patients received about a year and a half of R-squared, followed by another 4 weeks of rituximab versus R-chemo followed by rituximab, again, a total duration of treatment just over 2 years. So asking the question was R-squared better than R-chemo? The primary endpoint here was focused on superiority.

You can see that the overall response rate was similar between the 2 arms, the CR/CRu rate at 120 weeks was also similar between the 2 arms. The progression-free survival also similar between the 2 arms. So that really tells you that it was a negative study because the target here was superiority, but the fact is that these curves and these outcomes are quite similar between the 2 arms, and one might argue that R-squared and R-chemo are quite similar in outcome, even though that wasn’t the primary endpoint of the study. The primary endpoint was really looking at superiority rather than equivalence.

And so I think about this with patients really with a focus on the safety and that R-chemo had a little more Grade 4 neutropenia, although it was shorter, a little more febrile neutropenia, a little more in the rate of Grade 3 or 4 infections, a little less rash. So the toxicities are summarized here, R-chemo more febrile neutropenia, growth factors, nausea, vomiting, neuropathy, alopecia, more chemo-related toxicities versus R-squared having more rash, tumor flare, and GI toxicity with regard to diarrhea. So your patient may prefer one or the other. In the end the efficacy is quite comparable.

So I think for the up-front setting that really leaves us with a couple of different options. In the low tumor burden patients, I think single-agent rituximab is still there. In the higher tumor-burden patients who need more treatment, R-chemo, obinutuzumab/chemo, and R-squared all being similar with respect to long-term efficacy, slightly different in PFS, slightly different in toxicity profile.

DR LOVE: So I’m just kind of curious how this all fits into your non-protocol treatment approach. First of all, in terms of R-squared, do you generally bring it up as an option? And do you present it to patients as an option? And if so, how do you present it to them?

DR LEONARD: Well, I do present R-squared as an option for patients. I think that the toxicity profile’s a little bit different. I think many people do like a non-chemotherapy, or the concept of a non-chemotherapy-based approach, although obviously there is toxicity there. It’s a different toxicity. I think that the downside of an R-squared approach is that you’re kind of committing yourself to maintenance. If you just give a patient — or a longer-term therapy. If you’re following the RELEVANCE study, it’s 2 years of treatment versus some patients say I’ll take BR. I’ll do no maintenance if I go into a CR, and I can do well for 5 years or longer with just 6 months of therapy. So I think that’s kind of the tradeoff there.

Can you get away with less longer — shorter, I should say, duration of treatment if you use R-squared? Sure. But if you’re really basing it on something like the RELEVANCE data, it’s 2 years’ worth of treatment, which is obviously a lot longer than doing 6 months of BR as an example.

DR LOVE: So when patients — if any patient were to bring up with you quality of life and kind of what it’s going to be like, what kind of input do you provide to them? It’s interesting, the lymphoma people bring up a lot of issues with lenalidomide toxicity, and the myeloma people go hey, we use that like water all the time, what are they talking about? But anyhow, I’m just curious how you see it and how you present it really from a quality of life point of view.

DR LEONARD: Yeah. I think it’s a good point. I think it depends on the options the patient has. It also depends a bit on if they’re a front-line patient versus a relapse patient. And I think the situation in myeloma is that myeloma patients tend to be much sicker, and so they put up with more nagging toxicities a little bit more than a follicular lymphoma patient who maybe has been on watch and wait, just getting ready to start a treatment. And that toxicity profile’s a little bit different.

I would say that the quality of life is probably a little bit better. My take, my perception is that it’s probably a little easier with R-squared than a chemotherapy-based approach. But there are — the thing is there are always exceptions, right? You get the one person who gets the bad rash with lenalidomide. You get the one person who gets the bad nausea with bendamustine. And it’s really — those are the extremes of the 2 scenarios. The average person, I don’t think it’s going to be hugely different.

I think it really comes down to diarrhea and rash are more of an issue, I would say with lenalidomide, a little more fatigue with bendamustine, a little more nausea, and a little more stomach upset, and obviously the infection risk. And people tend to be a little more worried about infection risk. And certainly these days with the COVID picture and everything else, that dominates peoples’ concerns, as well.

DR LOVE: That’s a good point. What about obinutuzumab? You presented those data. How do you use it clinically in FL?

DR LEONARD: I would say obinutuzumab’s a little bit more infusions. There’re a couple more infusions at the beginning of the treatment. There’s a little more in the way of infusion reaction. I would say that there are occasional patients where I use it up front. We’re going to get to in a few minutes the relapse setting, and I think there — I tend to use it more in the relapse setting because I think the value is a little more clear in the relapse setting.

So if a patient comes to me in second opinion, and their doctor’s planned obinutuzumab, I’m fine with that. I think it’s okay. But I tend to use more rituximab up front because I’m less convinced that there’s a huge difference in the up-front setting. And also, I often have patients who don’t want to do maintenance therapy, and so if you’re using obinutuzumab and you’re basing it on the GALLIUM study, you really — to follow that regimen to the letter you’re — you’re essentially saying I’m going to give maintenance there.

DR LOVE: What about patients who up front have some issue that makes you think a little bit about whether or not you’re dealing with transformed or large cell disease, either high SUV or high grade? How do you approach those patients?

DR LEONARD: Well, those are patients where I would, again, do my best to try to biopsy that to demonstrate that. Occasionally there are patients that have double hit, they go from follicular lymphoma to double-hit lymphoma. I’ve had patients that have been on watch and wait and suddenly progress and are transformed and have double hit. So that’s a scenario where I would try to do a biopsy and look for that because that occasionally happens, and clearly that’s a bad prognostic sign.

But in those patients, I would tend to use a CHOP-based regimen, and I think obinutuzumab/CHOP, rituximab/CHOP, both of those are reasonable choices for that person who I’m more concerned about transformation in.

DR LOVE: What about single-agent rituximab, particularly the 4-dose approach that’s often used? And how do you decide when to use that? And do you use maintenance in any situation there, which of course the RESORT trial suggested wasn’t going to be beneficial?

DR LEONARD: Yeah, I tend to use maintenance rituximab a reasonable amount. It tends to be in those watch and wait patients that just kind of cross the threshold into — to needing treatment. It tends to be the person with a relatively low tumor burden disease who has some cosmetic issue, maybe they have a swollen leg, a little bit of a swollen leg, they’re a little more tired, their counts are becoming more of an issue. That’s something I think is very reasonable. I mean 4 doses is pretty easy to do, and I don’t think you lose a whole lot.

I don’t do it in bulky disease patients who are — patients where I’m concerned about transformation. But I would tell the patient let’s try it, let’s see how it goes. I tend not to use maintenance. And if that person — because I have some people who’ve had 5-year remissions with 4 doses of rituximab. But if somebody that comes back 6 months later — 6 months later, 8 months later with progression after 4 doses of rituximab, I’m probably going to move to a chemotherapy-based approach at that point.

DR LOVE: Interesting. Well let’s go on and talk about recurrent disease. Incidentally, in that situation you just described, would you include a CD20 antibody? And which one?

DR LEONARD: In a patient who had a relatively short remission, and I think it may come up in one of our cases, in a relatively short remission I’d probably change the antibody.

DR LOVE: All right. Let’s talk about recurrent disease then.

DR LEONARD: Okay. So when I look at a patient with a recurrent follicular lymphoma, many of the considerations are quite similar to the up-front setting. The benefit is that I have some sense of how the patient did. How did they tolerate the last treatment? How — how well did it work? Because then I’m going to either do the same thing or something similar if it went well, and obviously do something different if it didn’t go well.

So I’m still thinking about transformation. The patient may or may not need treatment, and the psychology around observation in the up-front setting versus observation in the relapse setting is always interesting. Sometimes patients are more hesitant to observe or less excited or comfortable with observing because they’ve kind of been through things and gotten used to the fact that they have this lymphoma.

Clearly the duration of prior response and what they achieved it with is important, as well as, of course, the age and the comorbidities.

So a chemotherapy-based approach is a reasonable-based approach, obviously depending on what the patient had before. In the GADOLIN study, which was specifically in rituximab-refractory patients, and largely chemorefractory patients, bendamustine alone versus bendamustine/obinutuzumab showed a benefit in PFS and overall survival in this group of patients. So this isn’t every scenario because these are bendamustine-naïve patients, and they are rituximab-refractory patients. But at least in this scenario, so a patient who had R-CHOP and had recurrent disease, bendamustine/obinutuzumab may be a reasonable choice, depending on the durability and the risk of transformation in that scenario.

And I would say that somebody who had single-agent rituximab, I would consider bendamustine/obinutuzumab, as an example, in part based on these data, although not exactly the same scenario. A short remission, I would change the antibody around, given that there’s evidence that obinutuzumab can be useful in somebody who is relatively resistant or refractory to rituximab.

We now have a number of other choices. The AUGMENT study was not in the refractory patient group as far as rituximab, but in the relapse group of patients. This study took patients with relapsed and refractory follicular and marginal zone had disease that relapsed after typically either rituximab or chemo/rituximab, randomized patients to rituximab with placebo. And you can see the schedule and the schema were R-squared (lenalidomide/rituximab) over the course of a year of lenalidomide in this course, a shorter course of rituximab, as you see. Similar in both arms. The primary endpoint was PFS.

And you can see that the PFS was clearly better by the IRC (independent review), 39 months versus 14 months. So a pretty significant difference I would say. And in fact, in the follicular lymphoma subset of patients there was actually an overall survival benefit, so suggesting, again, more reason for the benefit. The response rate was improved with the addition of lenalidomide. You see here roughly 78% versus 53% in the independent review, a higher CR rate, a higher duration of response. And again, this shows you the follicular lymphoma subgroup of patients where there was an overall survival benefit.

So again, this argues, to me, that if you’re thinking about single-agent rituximab you may want to think about lenalidomide added to it because clearly a different PFS, clearly a different response rate, clearly, I think, an overall survival benefit as well. I may, in someone who had a long response maybe be less enthusiastic and try to get away with single-agent rituximab, but I think for many patients this combination offers some potential advantages and efficacy.

And interestingly, if you look at the group of patients that had POD24 versus the patients that didn’t have POD24, you see that this less favorable POD24 group of patients actually did better with regard to their — their progression-free survival.

Now the other option that patients have, including beyond lenalidomide, would be PI3-kinase inhibitors. And we now have several PI3-kinase inhibitors that are approved for follicular lymphoma patients. This slide summarizes idelalisib in patients who had rituximab- and alkylator-refractory indolent lymphoma. You can see that the overall response rate here was about 57%. A minority of patients had CRs. And this was continual therapy, 150 BID. But in patients who had disease resistant to rituximab, resistant to alkylators, this could be a very useful treatment regimen for patients to go on.

So I think this is something that is also an option for our group of patients with recurrent follicular lymphoma. Idelalisib has some immunosuppression, some low blood counts, some GI toxicities, colitis, and liver enzyme abnormalities. But again, many patients tolerate this very well, and I have some patients that have been on it for years doing well with it, although the toxicities can be significant.

This is the overall progression-free survival and overall survival from one of the pivotal studies with idelalisib, about a year PFS and a longer overall survival. And again in this early-progressor group of patients, you can see in POD24 patients still quite a good, or reasonably good, PFS and overall survival.

We also have 2 other agents that are approved, the CHRONOS-1 study looking at copanlisib. This has a different specificity for PI3-kinase. It’s given intravenously day 1, 8, and 15 of a 28-day cycle. The toxicities are a little bit different here. It’s IV, so it’s a little more inconvenient, but I have a patient right now who I’m treating who has compliance issues, and it’s good to see this patient once a week. They get the IV infusion. You have to watch blood pressure, you have to watch glucose, but generally a manageable treatment regimen. And the efficacy here, I would say, fairly similar.

Overall response rate between 55% and 60%. Duration just under a year. So quite similar as far as that efficacy. And there are a number of ongoing trials with copanlisib that are moving forward as well that people should keep an eye out for as they’re presented.

Duvelisib, an oral PI3-kinase delta/gamma inhibitor is also approved in this patient population, and in patients who had double-refractory disease, to rituximab and chemotherapy, this is another oral agent, 129 subjects. Again, interestingly, very similar efficacy, about 50% response rate, just under a year, 10 months here. And again toxicities — cytopenias, diarrhea. But this is approved in patients also with recurrent indolent lymphoma. And there are several others in clinical trials that people should keep an eye out for as well.

And then finally in the recurrent disease setting, EZH2 inhibitors are now FDA approved, at least one of them. Tazemetostat, this is a selective oral inhibitor of EZH2. EZH2 mutations are seen in both follicular lymphoma and a subset of large cell lymphoma as well. Interestingly, the idea here is that the role functionally of EZH2 can essentially be — has a number of different effects, including immunologic effects. And that’s something we at Cornell, my colleague Ari Melnick, is very interested in studying, the idea that it may have immune effects against the tumor by inhibiting EZH2 may be of interest.

But EZH2 is relevant to both mutant and wild-type subsets of follicular lymphoma, and tazemetostat is now FDA approved. Tazemetostat has, in the EZH2-mutant cohort of patients, about a 75% response rate, and the durability here is between 8 and 10 months. And in the wild-type group of patients, lower, but still I would say meaningful response rate of about 33%, and again, the durability about a year. So tazemetostat approved both in the mutant subset and in the wild-type subset of follicular lymphoma patients who don’t have other options. Again, something that is now available, and I think people will be starting to be checking for EZH2 mutations, as well as occasionally treating patients without mutations based on what other options the patient has.

So I think this is — we’ve got a lot of new drugs. We’re still working on how to sequence them, but a lot of options now for patients with follicular lymphoma, and some things we didn’t get to, as well, including CAR T cells also out there.

DR LOVE: So actually you brought up CAR T cells. I was going to ask you about that. Where do we stand? I think there was some data presented at ASCO.

DR LEONARD: So there have been some data presented at ASCO and EHA, a single-arm study in follicular lymphoma. The response rates are quite high, in the 80% to 80-plus-percent range. This is in patients who’ve been through a number of prior therapies, often resistant to prior therapies, at least 3 prior therapies, I think, the study had. The durability, we’re still waiting to see. The follow up at this point in that study is between 1 and 2 years.

So the magic question is going to be how durable? And are you going to take your follicular lymphoma patient who’s been through 1 or 2 treatments, jump to CAR T cells? Are you going to kind of use the standard things, and then when you don’t have any other options, maybe would be thinking about a transplant, use CAR T cells instead? It’s not yet approved in that setting, but we’ll see how that moves forward in the near future.

DR LOVE: Yeah, it’s really going to be interesting to see that in terms of durability because to my simple eyes I see CD19 in diffuse large cell, great plateau, then I see BCMA targeted therapy in myeloma, not very much of a plateau, but maybe that’s because they’re getting treated later. So theoretically, I guess if it follows the disease this shouldn’t have great duration.

DR LEONARD: It’s hard to know. I would say every study in follicular lymphoma has 25% of patients with a long-term remission, radioimmunotherapy, the PI3-kinase inhibitors, lenalidomide, every study has a tail. You wonder if it’s the same people just on different studies or if it’s specific to the treatment. So wouldn’t surprise me if it turns out to be 25% long term, just like radioimmunotherapy.

DR LOVE: Yeah, it’s funny. I’ve been video recording all these cases with general oncologists. The other day I had this patient who had a CR to radioimmune therapy. I’m like woah, I didn’t know anybody was still using that. But anyhow, I don’t know why —

DR LEONARD: I have some of those patients. Yeah. I have some of those patients 5 and 10 years out. 25% long-term remission.

DR LOVE: Right. Moving back to PI3-kinase inhibitors, I’ve been hearing things about umbralisib. Any thoughts about that? Has that been looked at in follicular? I think it’s been looked at in CLL, but do you know anything about that?

DR LEONARD: It’s been looked at in follicular, and it has activity. I think it’s been looking — it’s still in clinical trials. So far, to me, I haven’t seen things that are really distinguishing from some of the others we’ve talked about. But I think it’s still being studied. Clearly an active drug, which would make sense based on its mechanism of action.

DR LOVE: Well what they’re saying in CLL, at least what I’ve heard, is that it doesn’t have as much of the diarrhea and autoimmune problems, but I don’t know if that’s true.

DR LEONARD: Yeah, I think it’s hard to know because the autoimmune — many of the bad toxicities, or the severe toxicities, came out after the drugs were approved and were given to hundreds and hundreds of people. So it’s hard to know if you don’t see it in the early studies is it going to pop up later.

DR LOVE: Right. What about tazemetostat? First of all, how do you test for EZH2? What kind of assay is it?

DR LEONARD: So there’s an assay that I think will be available pretty commonly commercially. On the other hand, many in-house panels, our panel — actually the first patient commercially that I wanted to use it in, our panel in-house at Cornell, turned out to have an EZH2 mutation.

DR LOVE: But this is IHC or what?

DR LEONARD: No, this is looking for the mutation,

DR LOVE: But what about tolerability issues?

DR LEONARD: It seems to be pretty well tolerated. There are some cytopenias. There can be some GI toxicity, but I would say in general this appears to be perhaps a little bit easier than some of the alternative drugs. So we don’t have comparative data, but it tends to be pretty manageable.

DR LOVE: So I’m thinking in terms of where right now — I don’t even know where it’s approved exactly, but where in the sequence of things in FL you’d be thinking about it? For example, before or after a PI3-kinase?

DR LEONARD: I think I would be thinking about — so the data — I would say it’s in that patient population where you’d be thinking about a PI3-kinase inhibitor. You would be thinking about tazemetostat also. In my mind, if you knew the patient had the mutation, then the efficacy being roughly 75%, I’d probably go with tazemetostat.

I think if the patient didn’t have the mutation, then the question really is the tolerability, and the tolerability profile. I think on efficacy a PI3-kinase inhibitor in wild-type EZH2, you’re talking 50%, 55% versus 35%, would lean toward the PI3-kinase inhibitor. But again, this is probably going to be a little more tolerable, so in that case where you weren’t as urgent to get a response you might think about tazemetostat there.

DR LOVE: Really. Interesting. So yeah, the response rates — what’s the presumed mechanism of why it would help people with wild type?

DR LEONARD: It’s a good question. I mean EZH2 functionally has a few different roles. It can still [with] a protein being there. It may be affecting the function. The other piece of things, which is interesting, is that — and we’ve been interested in looking at it — may have some T-cell affects. And so the concept of affecting an immune response against the tumor is something we’re looking at. There’s some theory that it could make CAR T cells work better and some other agents as far as effects on T cells, so — in the preclinical studies, got a ways to go in patients.

DR LOVE: Right. So one final question, what about the patient with the early relapse? I know there’re trials, but before 2 years. There’re trials looking at that. What are the trial concepts? And how do you handle these people clinically outside a trial setting?

DR LEONARD: So I think the early relapsing, so about 20% in various studies, 20% of patients present early — with an early relapse, meaning within 2 years. About half of those patients have transformed disease. So you have to look for transformed disease. If that patient has transformed disease, and some of these may be double hit, you need to treat them more aggressively down that line.

The other 10% of people, of the total population that is nontransformed but early progressor, I think that we don’t know what the answer is, number 1. The ongoing study led by SWOG, an intergroup study, is comparing chemotherapy, either benda/obinutuzumab or CHOP/obinutuzumab, depending on what the patient had before, versus PI3-kinase inhibitor with obinutuzumab versus lenalidomide/obinutuzumab. So it’s comparing chemo-based approach, PI3-kinase-based approach, and lenalidomide-based approach in these early progressors to see which is better.

I’d say outside of a trial, those seem to be reasonable possibilities to think about. There are also data with autotransplant. We’ll see what the CAR T-cell data look like. But I think, in my mind, the main message is don’t do the same thing, probably do something different, because if they didn’t have a long remission to chemo, probably the next chemo is not going to suddenly give them a 10-year remission. And so changing up the mechanism of action and changing up the anti-CD20 antibody, in my mind, makes sense.

DR LOVE: When I saw that trial I was thinking, I don’t know, those are kind of tame alternatives. I was expecting — because people don’t have a good prognosis, something more radical, transplant, CAR T, something like that. What was the thinking to do it this way?

DR LEONARD: Well partly it’s when the — what was available when the study came along. There are studies looking at CAR T specifically in that group of patients. I think transplant is a reasonable thing. We have series of patients treated with transplant in that setting, autotransplant, where the long-term remissions seem to be about 50%, 60%, so that seems pretty good. I think randomizing those patients to transplant is a tough thing, so that’s the main reason why transplant isn’t there, although I agree with you, it would be a reasonable thing to look at.

DR LOVE: Yeah, that’s a good point about the randomization. Let’s talk about your cases.

DR LEONARD: So this was a patient that presented about — well she presented about 2 years ago, was on watch and wait for a while. This was a lady who basically had disease going on, wasn’t that sick, but it got to the point that it was more or less a cosmetic issue. She had a few different areas of 2 cm lymph nodes. We watched it. And really wasn’t sick, but was tired of the lymph nodes being there. So this, to me, is somebody who’s a good patient for the 4 doses of single-agent rituximab. Wasn’t that sick, wasn’t bad enough to go to chemotherapy.

So this is somebody that really did well with that, but progressed 11 months later. And at this point, she had a little bit more disease, some leg swelling. She had 3-4 cm lymph nodes in her groin. The PET scan at that point showed the nodes that we knew about on exam, 2 cm nodes in her neck, 3-4 in her groin, a little bit of splenomegaly. She had some other nodes here and there. SUV was 7.3, so really not particularly dramatic. A little bit anemic. And we biopsied her because it was easy to biopsy. She had a relatively larger node in her groin. Again follicular lymphoma, Grade 1.

So it’s a lady who basically had a reasonable but not stellar response to single-agent rituximab and at a point where she needs treatment. She had a number of different options, and so in thinking about this particular patient, she decided to do bendamustine/rituximab because she had done well with the rituximab before tolerability wise with her infusions. She didn’t want a long-term therapy. She wanted 6 months of treatment, so the BR was something that appealed to her.

But obviously the things we talked about, including giving her rituximab again, maybe with maintenance, and I think we could have gotten away with that in her. I don’t think she would have had a 5-year remission based on an 11-month remission the first time. But it wouldn’t have been crazy to do that again if she really wanted to.

I think one could make a case for obinutuzumab. While she wasn’t really rituximab refractory, we could say well she didn’t have a stellar response to rituximab, what about giving her obinutuzumab? And then we could have given her R-squared. I think that would have been a reasonable choice, and I put R meaning lenalidomide with obinutuzumab would also be a choice, as well, to think about. There are some data with that.

And so this is not a crazy group of options. I think if this lady came to me having been offered these things and having her heart set on one of these, I would have been fine with them. But I think you go through the trade-offs, so the pros and cons here, and all of these, in my mind, would have been reasonable. She opted for the rituximab she had before and benda because she wanted 6 months’ worth of treatment, nothing longer than that at this point.

DR LOVE: So generally speaking, you don’t use R maintenance after BR? Or just — what caused you not to use it in this situation?

DR LEONARD: It was more of her preference. It was more of her preference. I think that given — depending on her response, we don’t know. My inclination is to give more therapy if they don’t have a great response and less therapy if they do. That may not be right. It may be that the CR patient who has responsive disease should get maintenance because they’re the people that have sensitive disease.

I think it would be fine to give her R maintenance as well. In her situation, she really wanted to cut it short at 6 months and just watch there. And I think if she goes — she’s in the middle of therapy right now. We’ll see how everything goes. But if she’s in a CR I would say she’s likely to go 5 years or longer, and if she wants to pass on the maintenance that’s fine.

DR LOVE: Why don’t we go onto your second case?

DR LEONARD: So this is an interesting case and gets into the early progressing and what do you do with an early-progressing patient outside of a trial. And this would, in an ideal world, would be a perfect patient for that clinical trial we referenced a little bit ago. I’ll tell you why he didn’t go on it in a minute.

So this is a 59-year-old male who happened to be a surgeon, and he developed diffuse adenopathy in the abdomen and pelvis, lymph nodes 4-5 cm or so. SUV was 10. Normal labs, normal LDH. Gets a biopsy, shows follicular lymphoma.

So he needed treatment. We gave him bendamustine/rituximab at that point in time. His end of treatment PET scan was negative, and he decided not to do maintenance. He, interestingly, has his own practice. He wants to avoid time off of work, and obviously is focused on maintaining his work and his functionality.

Surprisingly to both of us he progressed in about a year. And this is someone who follows the literature, is very concerned. He knew pretty quickly that early progressing was not a good thing. He felt the lymph nodes in his groin. He had normal labs except mild thrombocytopenia. He had 2-3 cm nodes, SUV 11.

Because he was an early progressor we biopsied him even though I wasn’t hugely concerned, with the SUV of 11, it could have been large cell lymphoma. But it was follicular lymphoma, and he was anxious to start treatment, in part because he — he progressed within, again, about a year’s time and knew that he wasn’t going to be sitting around doing nothing for another few years and also was very worried about this early progression. A lot of discussion about this, a lot of concern. He knew what it meant in the big picture.

So this would have been someone, again, perfect for the clinical trial we talked about, looking at a PI3-kinase with obinutuzumab, looking at lenalidomide with obinutuzumab, and you could argue CHOP plus obinutuzumab and/or heading toward a transplant would have been a reasonable thing to think about as well. He really did not want CHOP, in part — I mean he was very focused on his practice. He didn’t want to lose his hair. He’s a solo practitioner, though he operates in a hospital. And he also didn’t want neuropathy because as a surgeon he didn’t want to risk any of the fine motor skills and things that he needed there.

So he really didn’t want to go on the clinical trial because he didn’t want to get randomized to a CHOP type of regimen, although otherwise he would have gone on the study. And this is something that — this is somebody that we decided to give lenalidomide to and gave him obinutuzumab with it. Again the rationale being that while he’s not explicitly resistant to rituximab, 1 year of remission to BR has to reflect some relative rituximab resistance.

And he’s now about — now he’s about 6 months into the treatment. After 4 months he had really a negative PET scan, and everything looked good. So at this point we’re planning to treat him with the AUGMENT-type regimen of a year of therapy, although it’ll be interesting when he gets out to be a year, does he want to stay on it because he’s tolerating it so well. But clearly a CHOP type of regimen, a transplant. In the future we would think about a PI3-kinase inhibitor, an EZH2 inhibitor, but I’m hopeful that he’ll have a long remission with what he’s on here.

DR LOVE: So I’m curious what we know about the combination of lenalidomide and obinutuzumab. It seems like it makes a lot of sense. What do we know about it? And also, how did this man do with the obinutuzumab in terms of an infusion reaction?

DR LEONARD: So he did very well with obinutuzumab and did well with rituximab before. He didn’t have meaningful reactions, I would say. A little bit the first time, but nothing I would say out of the ordinary or particularly concerning. There are preclinical reasons why lenalidomide may work also well with obinutuzumab. Franck Morschhauser has presented data in relapsed patients, and Loretta Nastoupil has presented data in up-front patients. And the data look good. It’s very hard to compare across studies to know is it better than R-squared. But certainly no reason to think obinutuzumab’s worse in this setting.

DR LOVE: I was going to ask you about your first patient, how you felt about choice of anti-CD20, given she only was on rituximab for 11 months. Did you want to get really — think maybe it would be better to give obinutuzumab? And what did you say to her to expect in terms of obinutuzumab versus rituximab?

DR LEONARD: I was on the fence about it, but to be quite honest. She was very — being 67, for what that’s worth. Some people get excited and worried about infusion reactions, I mean more. So she was, again, less — I think a little more concerned about obinutuzumab. Since she had had an 11-month remission I was fine with giving her rituximab there again. And she also was not really committed to the maintenance, so if I had started her on obinutuzumab/bendamustine, did I have to give her maintenance? No, but that’s kind of what the data are based on, so you tend to want to follow the study if you can.

DR LOVE: What do you say to people who say what’s the difference between taking rituximab versus obinutuzumab for me? How’s it going to be different?

DR LEONARD: Well I think — so first of all, in CLL I think it’s clearly better in CLL, so I really don’t even offer rituximab to patients with CLL.

DR LOVE: Sure.

DR LEONARD: I think in follicular lymphoma, it’s an extra infusion or 2. That’s not a big deal, depending on how you’re giving it in the regimen. I say there’s a little bit more in the way of infusion reactions and a little more in the way of cytopenias. But generally speaking, not a huge difference.

DR LOVE: Do you say there’s a little more in terms of efficacy?

DR LEONARD: I would say that it’s slightly more in terms of efficacy, but it’s — for follicular lymphoma, I mean in an up-front patient, or in a relapsed/nonrefractory patient, my take efficacy wise is it’s close to a wash. Whereas in the relapsed patients — or the refractory patients, I should say, that’s a patient where you’re trying to squeeze out everything you can. So in a refractory patient it’s like well, we’ll change this and we’ll change that, and that’s — making a change is, I think is — you like to give people something a little different, because then they’re saying well you’re giving me the same thing, why am I doing that?

Mantle Cell Lymphoma: Currently Available and Emerging Novel Approaches — Michael E Williams, MD, ScM

DR WILLIAMS: Well thanks very much. I appreciate the opportunity to take part in this satellite symposium to discuss advances in mantle cell lymphoma. We’re going to focus on novel and emerging therapies. It’s really a very dynamic field, and I think a lot of the lessons we’ve learned, the observations we’ve made in this subtype of lymphoma actually are very helpful and informative for what’s really accounting for dramatic advances across all the subtypes of lymphoma and CLL.

So mantle cell lymphoma is one of many subtypes, as you know there are a lot of challenges, but also opportunities by understanding and optimizing treatment for this disease. It’s a very biologically and clinically heterogeneous disease, which leads to a number of different subtypes, ranging from very indolent, slow-paced disease that can be observed without treatment to patients who present with very advanced, rapidly progressive blastoid disease that need very active and immediate treatment.

We have better treatment endpoints that are emerging that include things like looking for evidence of measurable residual disease and directing therapy based on that. We’re learning to optimize our targeted therapeutics. That’s going to be the real focus of today’s discussion. And importantly it’s moving us toward the opportunity to have chemotherapy-free regimens that lower the toxicities in most cases compared with what we’ve had in the past. And then we’re going to consider the role of postinduction stem cell transplant versus maintenance therapy, which has been a standard, but is evolving now in important ways. Ultimately, we want to do better at curing patients with this disease.

So the B-cell receptor pathway is familiar to most of you. It’s in this somewhat simplified cartoon. The point is to show you that there are many targetable molecules within this, ranging from drugs that interfere with cyclin-dependent kinases that are critical to mantle cell persistence, but also B-cell receptor inhibitors for the Syk protein, BTK inhibitors, the PI3-kinase inhibitors, mTOR inhibitors, the proteasome inhibitors, and finally venetoclax, which is a BCL2 inhibitor that can induce apoptosis. So we’ll talk about several of these and work that’s being done to put them together in more effective ways.

So just a brief summary here of targeted non-chemo approaches for relapsed and refractory mantle cell. Some of these drugs have been around now for 10 years. Proteasome inhibitor bortezomib, lenalidomide, the combination of len and rituximab, and the PI3-kinase inhibitor idelalisib all have activity, but as you can see, in the 20% to 40% range.

We entered a new era a few years ago with the onset of BTK inhibitors, and as you can see, ibrutinib, acalabrutinib, and now zanubrutinib, the third BTK inhibitor approved for mantle cell all have activity in the 70% to 80% range. And when you compare these drugs in similar populations, meaning say only 1 prior line of treatment, the response rates are similar, but they differ in other important ways that we’ll discuss. Venetoclax, a different target, namely it hits the BCL2 molecule, and by inhibiting that can induce apoptosis. There is synergy between BTK inhibitors and venetoclax so that combinations such as ibrutinib and venetoclax are being explored now in large-scale trials.

So just to consider the BTK inhibitors, there are 3 that are FDA approved, ibrutinib, acalabrutinib, and zanubrutinib. As I said, they have similar overall responses. The response rates tend to be better when you use them early in the sequence of therapy. In general, the toxicity profile for acalabrutinib and zanubrutinib is improved over what we had with ibrutinib, primarily with less atrial fibrillation, less risk of bruising and bleeding, arthralgias. And therefore, especially with the bruising and bleeding risk, we generally prefer acala or zanubrutinib over ibrutinib if a patient is on concurrent anticoagulation or anti-platelet therapy or both. And part of the reason for this lower toxicity is felt to be due to the more targeted BTK, in addition, fewer off-target effects with acala and zanu than with ibrutinib.

Venetoclax, a very potent FDA-approved oral inhibitor of BCL2. It induces apoptosis in B-cell lymphomas. And as you can see here in the blue is the response to single-agent, heavily pretreated mantle cell lymphoma, so there is a response rate that’s modest for the single agent. Very poor responses seen in diffuse large cell, and surprisingly, and somewhat disappointingly, although follicular lymphoma overexpresses BCL2 as a characteristic of the disease, due to the 14;18 translocation, doesn’t respond all that well to single agent.

So venetoclax can give responses in patients who have failed BTK inhibitors. As a single agent, there’s limited data available, but in 1 study of about 20 patients, heavily pretreated, overall responses were about 50% with some CRs. If you combine venetoclax with an anti-CD20 you can increase that response rate. And an important, somewhat anecdotal, but I think important observation has been that you can sometimes rescue a suboptimal response to single-agent venetoclax, and we’ll go over that in the first case discussion.

So one of the lessons learned with venetoclax is that it is a very potent inhibitor of BCL2 and can induce apoptosis and rapid cell death, to the point that you can see laboratory or clinical tumor lysis syndrome. For that reason, when you’re using this drug you have to introduce it in a stepped-up dosing fashion. And this is the current schema that’s typically used, where for patients being managed, as an outpatient especially, you start with a week of 20 mg, and then you step up weekly until you get to the target dose, which is typically 400 mg, not 800.

So if a patient is a moderate to high risk for tumor lysis syndrome, we admit those patients for treatment initiation. And this means they’ve got bulky adenopathy, bulky splenomegaly. They have a leukemic phase above 20 or 25,000. Even if they have more modest disease burden, if they have underlying renal insufficiency it’s important to admit those patients, as well, because they can’t clear the release of potassium and phos and uric acid in an adequate way, and so you can get into clinical tumor lysis. So you treat with IV fluids, allopurinol or rasburicase, and monitor labs every 6 to 8 hours while they’re in.

One of the advantages in admitting a patient for venetoclax initiation is that you can ramp it up more quickly. So what we typically will do is if a patient is inhouse, we get their IV fluids going, we treat them with allopurinol and/or rasburicase if their uric acid is high at baseline, but then you can step up a little more quickly if they’re doing okay with monitoring, so daily 20/20, 50/50, then we get them to 100. And important because, especially with mantle cell lymphoma, you often don’t see responses to venetoclax until you get to 100 mg or 200 mg. So the disease can get ahead of you if you’re trying to do the slower ramp up of dosing. So it’s something to keep in mind when you’re starting the drug.

Now our lab and others have shown that there’s synergy between ibrutinib and venetoclax in preclinical models, and that’s led to a couple of studies, including this one that was published by Constantine Tam and the Australian group, as well as European collaborators, about 2 years ago. So what they did here, relapsed/refractory mantle cell. 24 patients, 1 of them had no prior treatment, but the rest relapsed/refractory. Most of them had had prior stem cell transplant and they had poor risk features, including TP53 deletion or mutation. The way they introduced the drugs were a month of standard ibrutinib at 560, and then in month 2, cycle 2, you do the ramp up that I described, and then you continue both drugs indefinitely.

And this data was published, as I said, in the New England Journal 2 years ago, but in the ASH meeting in 2019 they updated this data. And here’s what they found in terms of PFS on the left and overall survival on the right. So you’ll see that there are several patients who are resistant even to the combination and progressed on their initial treatment. The mechanisms of that resistance are now becoming better understood.

But what was important in this trial is that they followed MRD by both flow and by more sensitive PCR methodology, and you can see the achieved MRD to the latter in about a third of patients. Five (5) patients became MRD negative, stopped treatment, at an average of about a year and a half into their combined therapy. And at the time of this presentation you can see that from 6 to 18 months off treatment, 4 were remaining in remission and MRD negative. So for a relapsed/refractory very poor-risk population this combination can provide deep and durable remissions even after they’d had extensive prior therapy.

So this observation and others have led to this important international trial called SYMPATICO. This is ibrutinib with venetoclax or placebo, so it’s a Phase III, randomized, double-blind study. Initially, it was open to patients with relapsed/refractory mantle cell, but the study was revised subsequently to also include front-line treatment. So a nonchemotherapy regimen for front-line treatment. This is the safety run-in, just to give a glimpse of the study. This was presented at the Lugano meeting in 2019 by Michael Wang, who’s the study lead.

So you can see the schedule for treatment there. At 24 months, if they were not having unacceptable toxicity or progression, the venetoclax or placebo were discontinued, and they continued on ibrutinib alone. And the take home from the safety run-in were that they only saw 1 patient with laboratory TLS. That was in a high-risk patient who had a leukemic mantle cell with a count over 100,00, but clinically did fine. And so the recommendation from the run-in is that you can continue this concurrent initiation of ibrutinib, where you start the ibrutinib on day 1, and you start the ramp-up in cycle 1 as well.

Let’s switch gears and talk about PI3-kinase inhibitors. There’s much less robust data in mantle cell with these agents. They do have response rates in the 40% to perhaps 50% range, very small series. And I’ve just shown here the array of PI3-kinase inhibitors that are available. You can see that they all target the delta isoform of this enzyme, which is the subtypes that’s expressed in lymphoma. And they have other effects on other PI3-kinase inhibitors.

But umbralisib is one I wanted to mention. It’s in clinical study now. And this is a report, small numbers of patients again, just 21 with mantle cell, shown here in the red. The green are CLL patients, relapsed/refractory, umbralisib in combination with ibrutinib. And you can see that responses were achieved pretty much across the board, including complete responses in some patients with mantle cell. So this is a promising PI3-kinase inhibitor that I think we’ll hear more about in other disease subtypes in the coming months.

So this is a little bit older data at this point, but important to remember when you’re thinking about noncytotoxic regimens, and that is that the R-squared regimen, or lenalidomide and rituximab, has activity in relapsed mantle cell, as well as front line. This is a small study with very long follow up, was in the New England Journal 5 years ago and an update 2 years ago in JCO. This was from Dr Ruan and the group at Weill Cornell Medical College. But you can see the response rate’s 92% with two thirds of patients achieving a complete remission.

And in the JCO follow-up study that highlighted there in green, you can see that the 3-year PFS was 80%, the 5-year estimated PFS 64%, and 8 of the 10 patients in complete remission at 3 years remain MRD negative. Unlike the high- versus low-risk MIPI score, which can be predictive for response to chemo regimens, these both responded, these subtypes responded well, to the combination. There was no correlation with the low versus high and adverse Ki-67. So a promising regimen and one that you certainly can consider for patients, potentially older patients, especially, who aren’t good candidates for more aggressive treatments.

I wanted to mention CAR T cells, which have been an important advance in ALL and in diffuse large B-cell lymphoma, but this study was presented at ASH in 2019 and subsequently published in the New England Journal, again Michael Wang at MD Anderson led this important study. And I’ll show you the activity, but it was such that FDA approved this as the most recent CAR therapy available to treat lymphoma, in this case relapsed/refractory mantle cell.

So here’s the study design, and without going through it in detail, relapsed/refractory patients who were eligible had enrollment, they were leukapheresed. Importantly, as we know with large cell lymphoma, bridging therapy is often needed, and I’ll comment on that a little more on the next slide. There was conditioning chemo, and then the CAR Ts were administered.

Bridging therapy is very important, of course, because it takes a least 3 to 4 weeks in most cases to collect the CAR, get the CARs generated at the central laboratory facility, and then have them grown up to be reinfused then to the patient. So how you get a patient from the collection to keep the disease in check until they get the CAR is important. And I think an important aspect of this study is that they used almost exclusively targeted drugs, a BTK inhibitor, sometimes corticosteroids, or both. So you can bridge without having to give patients more toxic chemotherapy.

And here are the results. If you look at the bar graph on the upper left it shows that about 90% of patients responded, most of them with a complete remission, and you can see on the upper right duration of response, PFS, and on the lower right overall survival. So it’s encouraging that these heavily pretreated patients are showing an ongoing response out to 18 to 24 months. So it’s at least hopeful that some of these will, in fact, be long-term survivors with control of their disease.

And their conclusions are shown here from the 2 presentations. Very high rates of response. 43% remain in remission more than 2 years since their treatment. Safety profile is what we’ve seen in terms of potentially severe toxic effects from cytokine release syndrome or neurotoxicity.

So just to close, as you can tell, there’s been a lot of progress in mantle cell just in the last 2 or 3 years. We expect this is going to continue. There are a number of front-line studies and numerous studies in relapsed/refractory patients, some of which are listed here. But I wanted to specifically call out this study, which has completed accrual 4 years ago. The data analysis is now in progress, and we hope to be hearing this very soon. This was benda/ritux with or without bortezomib, and then ritux maintenance versus R-squared maintenance.

The next study, which is open now. This is for untreated patients generally that are considered not transplant eligible, and this is benda/ritux plus venetoclax that begins after cycle 3. A very important study for transplant-eligible patients, this is the ECOG 4181 trial. I won’t read through the details, but basically Arm A is the R-BAC regimen, which is rituximab, bendamustine, and then cytarabine, each of those, the BR, and then the R/cytarabine given for 3 cycles with, in Arm B, acalabrutinib added to the chemo regimen, and in Arm C there’s no high-dose cytarabine, so just BR and acala. So a very important front-line study for transplant-eligible patients.

And then we would hope that many of these patients will then go into this study looking at the role of stem cell transplant in mantle cell. This is open for any patients who’s transplant eligible getting an induction chemotherapy of your choice, then they go into screening. They have molecular testing. If they have an MRD marker then they’re enrolled. If they are MRD positive, or they just have a PR, they didn’t achieve a complete remission by PET after their induction, then they go to an autotransplant and rituximab maintenance.

If they are MRD negative, then this is the experimental part, where we’re testing whether you need an autotransplant if you’re already MRD negative. So patients get randomized to an autotransplant and maintenance versus maintenance alone. So a very important study to help us answer whether we need, or the patients benefit, from an autotransplant if they’ve already achieved a deep response.

So I’ll stop there and go through a couple of cases that are illustrative, in some ways, the sequencing of therapy, but also some of the progress that’s been made. So this is a patient I’ve taken care of for the last 5 years, a physician, presented with fatigue, symptomatic anemia, had a lymphocytosis, on exam had adenopathy and splenomegaly; mantle cell lymphoma, typical phenotype. We did a lymph node biopsy that showed the mantle zone growth pattern, which tends to be a little more indolent. His Ki-67, though, was borderline elevated.

This gentleman declined any cytotoxic treatment, so he elected to just have rituximab alone. And he did all right with this, had a partial remission, cleared his circulating cells, did okay for a couple of years, but then developed with an orbital mass and diffuse adenopathy. Started ibrutinib, which gave a prompt but partial response, but unfortunately developed a severe rash related to ibrutinib, so stopped it after 4 months. We then switched him to acala, and he had a transient improvement in his adenopathy, did not develop a recurrence of his rash. But he pretty quickly was progressing on this BTK inhibitor.

So we then bridged him over to venetoclax, got him up to 400 mg. In the first couple months he had an impressive decrease in his adenopathy and splenomegaly, but then progressed again with enlarging nodes and spleen, did not get a lymphocytosis. So we elected, rather than giving up on venetoclax, we elected, based on some early data, to add obinutuzumab with an aim of getting synergy between the 2.

And interestingly, he got his first dose of obinutuzumab, just 100 mg, we had done the standard pre-work, IV fluids, PO fluids, allopurinol. So he got just 100 mg of obinu, and I saw him back the next morning, when he was scheduled to get the 900 mg dose, and interestingly his lymph nodes were significantly smaller, as was his spleen, after just 100 mg of obinu and the venetoclax. His LDH went from, normal at our lab is about 250, which is where he started. The next morning he was at 2,000. And his phos was up. His potassium was up.

This resolved with fluids. And so after getting that stabilized the following week, we proceeded with obinutuzumab again. He had no further TLS. We continued the obinutuzumab for about the better part of a year, and then discontinued it when he developed a pneumonia. And interestingly now, since last December, he’s been on just venetoclax alone, and he remains in remission. I just saw him a couple of weeks ago. So I consider this a rescue of what looked like a venetoclax failure. I’ve not done MRD. Perhaps if I did, I’d find he was negative, and maybe he could even come off the venetoclax now. But we’ve elected to continue for the time being.

The second case is a gentleman, 70 years old, presented with a higher-risk subtype called the pleomorphic histology, higher Ki-67 score. He had Stage IV disease but with a base of tongue mass that was several centimeters. He was marrow positive. He initially elected treatment with bendamustine/rituximab, achieved a PET-negative remission, started on maintenance. But after the second dose he developed multiple subcutaneous nodules, came to see us, and we documented that this was relapsed mantle cell. And I’ll show you the PET scan in just a second.

We initiated treatment with a Phase IB/Phase II clinical trial of the PrECOG 0404, which is a combination of ibrutinib plus ixazomib, which is an oral proteasome inhibitor, essentially oral bortezomib. And that’s given as an oral dose weekly times 3 in each 4-week cycle.

So here is, on the left side that’s his preclinical trial scan showing multiple subq nodules, the largest was about a 5 cm mass on the right arm. So he got a complete remission with a PET-negative response after about 3 months. I saw him back about 6 weeks ago for regular follow up, and he had a new swelling in his left calf. An ultrasound showed a soft tissue mass. It was about 10 x 14 cm. This was after a negative PET scan just about 2 months earlier, and the biopsy of this showed pleomorphic mantle cell.

So he’s failed that regimen after a good response. There was no other signs of disease on PET scan. So what we’ve done is he’s come off the clinical trial, I’m keeping him on ibrutinib because it’s known that even with progression if you stop a BTK inhibitor patients can have more rapid progression, including more systemic disease would be a risk, so I left him on ibrutinib while he completed radiation therapy. And he’s had a good response to that. We’re now considering him for a consolidative CAR T.

So these cases are, I think, instructive in a number of ways, but helpful to see both the progress in having multiple therapeutic options for these individuals, but of course what we would like to do is to get to deeper, longer remissions up front and ultimately to cure.

DR LOVE: Awesome. That was great, Mike.

I noticed you mentioned a trial with ixazomib. What do we know about proteasome inhibitors in mantle cell?

DR WILLIAMS: Yeah, so they’ve got decent single-agent activity, bortezomib in the 35% range, something like that. So modest by themselves. They’re often given in relapsed disease. We’ll learn something about the role of combining them with bendamustine/ritux from the 1411 trial that I mentioned. But it’s been shown in the laboratory that just as ibrutinib and venetoclax have synergy, ibrutinib and proteasome inhibitors have synergy for mantle cell lymphoma. And there have been studies done, haven’t shown as much activity as we’ve seen with venetoclax, but having an oral form of bortezomib certainly is convenient for patients, rather than the weekly or twice weekly IV or subq injections.

DR LOVE: And in that regard, that trial that you mentioned with the R-squared maintenance, et cetera, that had bortezomib as part of the up-front evaluation.

DR WILLIAMS: Right.

DR LOVE: I thought that had reported already to be negative.

DR WILLIAMS: It hasn’t reported out yet.

DR LOVE: Was there another trial that reported on looking at bortezomib up front?

DR WILLIAMS: Yeah. There’s been bortezomib with CHOP, the VR-CAP regimen, that did show a benefit over CHOP alone. So in fact there was a survival advantage in that study.

DR LOVE: So another question. That case with obinutuzumab is incredible, with the venetoclax, and I’m just curious in general what we know about obinutuzumab in mantle cell. Obviously, in CLL it kind of has a different role. What about in mantle cell?

DR WILLIAMS: Yeah, fascinating. So obinutuzumab, as you know, is a Type 2 anti-CD20, rituximab being a Type 1. There’s more direct cell kill of CLL and lymphoma cells with obinutuzumab. One of the mechanisms of resistance to venetoclax is upregulation of the alternative NF-κB pathway, or by mutations or deletions in a gene complex called SWI/SNF. It’s a chromatin-modulating set of enzymes that also upregulate BCL-XL as does the NF-κB pathway.

As it turns out, obinutuzumab can downregulate BCL-XL, which can mediate resistance to venetoclax. So there’s preclinical logic to combining those 2, and other mantle cell investigators have also observed really pretty dramatic synergy between obinu and venetoclax, even more so than we see with ritux/veneto. So I think it’s a very promising agent, and I’m hopeful that we’ll have an obinu approval for mantle cell at some point.

DR LOVE: What do you see with obinu alone, and what about in the leukemic mantle cell?

DR WILLIAMS: Yeah, so obinu alone does have activity. I’ve used in the patients with leukemic phase, again, who were not eligible for or didn’t want other therapies. And so you can certainly, as with CLL, you can pretty promptly clear circulating cells, and you can get decent responses in node and spleen, but they just aren’t all that durable by themselves, even if you’re doing ongoing maintenance. So they need a partner, in general.

DR LOVE: Also I’m curious about umbralisib. What do we know in terms of monotherapy with umbralisib? Or is it just being looked at in combination?

DR WILLIAMS: Yeah, so I don’t know, certainly in mantle cell, what the responses are as a single agent. In marginal zone lymphomas umbralisib does show pretty impressive activity, so I think it’s going to find utility in at least some areas of lymphomas and CLL potentially.

DR LOVE: So you mentioned TP53, and I’m curious, any therapeutic implications of that?

DR WILLIAMS: Yeah. It’s a good question. So p53 is commonly mutated in the pleomorphic and blastoid variants of mantle cell. And curiously, in the very indolent subtype of mantle cell that often looks like CLL, they have a leukemic phase, they have a big spleen, but little in the way of adenopathy, about 40% of those will also have a p53 mutation, but it doesn’t necessarily correlate with rapid progression.

That said, if you have p53 mutation it’s very much like CLL. You don’t respond well to cytotoxic therapy. Some have suggested that perhaps if you have a p53 mutation you should not go to an autotransplant for mantle cell and that you should be certainly considering targeted drugs, BTK inhibitors and/or venetoclax up front rather than a traditional chemotherapy approach.

DR LOVE: So I was getting a bunch of cases from general medical oncologists the other day and somebody presented to me a patient who got R-squared up front, doing great, about 3 years. Do you think that’s a reasonable non-protocol option right now for first-line therapy?

DR WILLIAMS: Well I do. I mean we don’t have prospective comparative data, but we’ve got long follow up. All oncologists these days are awfully used to navigating R-squared or lenalidomide in a number of different diseases. And the data that’s been discussed in other sessions that you’ve had with looking at R-squared in follicular lymphoma, either front line or relapsed, has shown responses that are equivalent to R/chemo. So I think it is a legitimate option for patients who are either not eligible for more aggressive therapy or are not interested in pursuing that.

One of the things that would be important is, for the patient such as you described, who’s good after 3 years, that perhaps you can stop therapy at some point and follow, and then restart.

DR LOVE: What about the combination of a BTK inhibitor, ibrutinib, with venetoclax outside a trial setting?

DR WILLIAMS: Yeah. I’d say for right now that’s still a clinical study regimen, but one that is being studied, as you know, and has the preclinical rationale that we talked about a few minutes ago. But that, I think, has special promise and potential to really allow us to do a time-limited therapy. You hit the disease in several directions and very likely, in the majority of patients, you’ll get MRD negativity that can then be followed for molecular relapse and then reinitiation of treatment. It’s an expensive regimen, and toxicities need to be a little more fully defined, but I think it’s certainly of interest for a clinical study.

DR LOVE: So you of course discussed the exciting data with CAR T. I’m curious right now when you start thinking about CAR T in a mantle cell patient, and generally when you think it’s appropriate to cycle it in.

DR WILLIAMS: Right. So I think if we’re considering it here, and I think most centers are for patients who’ve relapsed after at least a couple of lines of therapy. That’s going to include younger patients, meaning under the age of 70, who have progressed after an autotransplant, or patients that have front-line failure of treatment. So we’re looking at it in those individuals now.

And patients like the one I showed, who really would not be an autotransplant, or an allotransplant candidate, the second gentleman with that progression through the clinical trial therapy, I think a CAR is a very good option for him. And he’s going to have, hopefully, a very low burden of disease at the time he would be treated. And so we’d like to think he’ll be in that group of people, the 40% or 50%, who are still in remission out beyond 2 years.

DR LOVE: Do you think a patient needs to be in a similar condition and performance status to get CAR T as say autologous transplant, or maybe can be older and more frail?

DR WILLIAMS: Well, I think in general that’s probably a good barometer that they have similar function status to be eligible. That said, there are patients who are older for whom they might be able to get an auto, but it’s not likely to help them because they’ve failed a couple of other lines of therapy. So I think it’s going to find a role in some older patients. We’ve got folks that are into their mid 70s but very functional that are also being evaluated now for a potential CAR.

Selection and Sequencing of Therapies for Patients with Hodgkin Lymphoma — John Kuruvilla, MD

DR KURUVILLA: So our topic today is selection and sequencing of therapies for patients with Hodgkin lymphoma. And by way of introduction we’ve seen lots of change in the field of Hodgkin lymphoma over the last 5 years or so, with lots of great new data looking at incorporating novel agents. And so what we’re going to talk about through the course of this presentation highlights a lot of those issues.

And so firstly we’ll look at some of the longer-term follow up data from the ECHELON-1 clinical trial, which evaluated brentuximab vedotin in front-line therapy of Hodgkin lymphoma. We’ll look at how that data may influence outcomes in patients looking at potential risk factors based on disease characteristics, as you can see. We’ll talk a little bit about the Phase II studies looking at the role of brentuximab in elderly patients as well, beyond the elderly subset that was described in ECHELON-1.

And continuing on the theme of looking at brentuximab vedotin and combination therapies, what may we do in other patients in the curative setting when we’re looking at patients in the second line, a potentially transplant eligible setting as well.

We’ll then shift gears to look a little bit at the newest Phase III data. So KEYNOTE-204 was a trial comparing the anti-PD-1 pembrolizumab versus brentuximab vedotin in a nontransplant-eligible or relapsed post-transplant population, and how those data are informing clinical practice, because that is the most recent data set for us to look at.

And lastly, we’ll close with some of the data looking at these novel combinations, as well as other promising strategies that we may see moving forward in the next few years in this very interesting disease.

So with that, let’s get to the data. And so here is the 4-year update of ECHELON-1 as presented by Nancy Bartlett last year at the ASH Meeting. And you’ll also be seeing some updates from this data set coming up shortly, as well, through the meeting. As a way of reminding you of this, here’s the schema slide. So this was an open-label, international, randomized, non-PET-adapted Phase III trial in which the control arm was standard ABVD for 6 cycles, as you can see 670 patients in that arm, versus AVD, so the bleomycin was removed, with the addition of brentuximab vedotin, again for 6 cycles as well.

You can see the dosing with BV was a 1.2 mg/kg per combination cycle with chemotherapy, given on days 1 and day 15. There was a PET scan that was done through the treatment, but people did not have to act on that unless it showed clear disease progression. And at the end of treatment there was a CT/PET scan as well, then follow up as you can see.

Looking into the data, so this was the 4-year follow up by intention to treat. And as you can see, the top line, the blue line, is the experimental arm of brentuximab in combination with AVD, still showing a significant improvement. So the hazard ratio there of 0.61, statistically significant p-value, as you can see, 0.003, highlighting the improvement, again, in progression-free survival with this regimen.

When you look at the landmark PFS here, so as you can see they’ve now published, or presented, 2-year, 3-year, and 4-year follow up data, showing, again, statistically significant improvements at all of those timepoints. And again, the experimental arm, as you can see, remaining at about 82% versus 75% for conventional ABVD, now with a follow up of 4 years. So very consistent over the lifetime of this trial, and again, we’ll look forward to the 5-year follow up.

And important to note this was progression-free survival not the modified progression-free survival, which was the primary endpoint and slightly controversial because it did include some other events, which I think clinicians would normally agree as being quite important, including the initialization of additional treatment for patients, though they may not have constituted a formal progression event under standard definitions.

Now to highlight specific subgroups, so this is the forest plot that looks at a number of prespecified subgroups in this clinical trial, and you can see, looking at the important ones there. So it is important to highlight that the second variable of age, when you look at the patients aged 60 or greater, that is a smaller proportion of the patients on this study. But you can see this crosses 1, the hazard ratio, and thus it isn’t statistically significant in that predefined subset.

Interestingly, again, investigators have published the significant benefit that we’ve seen in the North American cohort, and you do see there was a bit of variation based on the geographic region in terms of the patients being enrolled from. Looking at prognostic score, you can see the majority of all of those, whether they had statistically significance or not, all favoring the experimental arm, stage favoring the experimental arm, extranodal sites as well, though you start to see we lose a bit of statistical power in terms of the interpretation. And those are really the main highlights in terms of looking at the risk factors, as you can see.

Looking now at progression-free survival and highlight 2 key points, so PET2 and age, both in the ITT population. So firstly, we all struggle with the implication of that interim PET scan following 2 cycles of chemotherapy because we know that portends for poorer outcome. We know the data that exists from retrospective series made the progression-free survival look very poor, in the range of about 20% or so. And we know from the clinical data that’s available from other studies, including the RATHL trial in the UK and the SWOG trial that was done in this setting, where the switch was from ABVD to escalated BEACOPP. We see with that switch that the benefit, in terms of progression-free survival, is around 65%.

What do we see here? The control arm is quite important because when you look at the PET2-positive population you can see the PFS there is about 44.5%. And so that’s better than what was historically reported based on retrospective data sets.

When you look at the combination with brentuximab you can see the PFS there is around 60%. And so maybe not quite as good as what we see with escalated BEACOPP, but important because even in those patients that were PET-positive their outcome does seem better with the addition of BV to chemotherapy.

The important point to highlight on this, though, is when you also look at age over 60 that’s where we start to see the importance of age, and the concern here being we see less benefit for the patients receiving BV in combination with AVD. And I’ll show you a little more data about that when we look at the specific poster that looked at this population in a little more detail.

DR KURUVILLA: So these are data that Andy Evens presented at ASH 2018 and looked at the subset of patients who are age 60 or above from the ECHELON-1 clinical trial. And as you can see, this is modified progression-free survival, and the 2 arms, both the experimental and the control arm, are overlapping. And thus, there appears to be no benefit in terms of modified progression-free survival in the older population.

When you look at the 2-year event rates, they look very similar. So the experimental arm 70.3% and ABVD 71.4%. Looking at Stage IV, as well, that’s the other group of patients that are presented in the table, you can again see no difference between the 2 groups.

Why is this important? So we don’t see the benefit, but we also see the potential for increased toxicity with the experimental combination in patients above the age of 60. And so just highlight a couple of key points here, the proportion of Grade 3 or greater adverse events, again, looked a bit higher, so 88% versus 80%. Fatal adverse events between both arms were similar at about 4% or 5%. But we see the rate of neutropenia’s more significant, 70% versus 59%.

We see a much higher rate of any-grade febrile neutropenia, so 37% versus 17%. And that 17% is important because, again, that doesn’t typically meet the level of febrile neutropenia that most guidelines would recommend febrile neutropenia prophylaxis, that being above 20%. But many people have taken to not using GCSF commonly in this patient population because of the potential interactions with bleomycin for pulmonary toxicity and the understanding that typically in the younger population that the rate of febrile neutropenia’s quite low and thus routine GCSF support isn’t really needed.

What was realized through the conduct of the trial, and as well from investigator experience, was that GCSF can certainly improve this. And what you see, in the older patients, if they were receiving primary GCSF prophylaxis, a much lower rate of neutropenia, so 4% versus 57%, a much lower rate of febrile neutropenia either in cycle 1 or in general. So again, nothing surprising. GCSF can help manage this toxicity, but the content in this clinical trial, the data really show that this is a higher-risk population to see this toxicity, and so thus caution. And the investigators learned through the conduct of the trial that GCSF does need to be given. And this has been included in the label for the use of BV in combination with AVD.

Now to switch gears, so that’s a large, randomized control trial. Now what else do we know and what other brentuximab-based approaches can we use in patients with older Hodgkin lymphoma? So here I’ve just highlighted a couple of the data sets that speak to this. And so unfortunately we don’t have large data sets that have looked at these novel combinations, but we do see some interesting data that I think may help us understand how to use this drug more effectively.

At the top, again, is a study that was led by Andy Evens, published in the JCO a couple years ago. In a little under 50 patients, this looked at sequential use of BV, then followed by subsequently then consolidated with single-agent BV. And what you can see is a very good response rate, a very high CR rate for an elderly population, and an excellent 2-year progression-free survival of about 84%, with generally reasonable toxicity. We know that we see a fair amount of toxicity in this older patient population, as some of these other studies also speak to. So that 2% non-relapsed mortality must be taken in context.

The second study was published by Jonathan Friedberg and as well a series from Forero-Torres, both in Blood, that looked at BV either as a monotherapy or potentially in combination with dacarbazine, so the D from ABVD or potentially the combination with bendamustine, where again, our group with Owen O’Connor helped do the initial Phase I work. And what you can see here, smaller series, all under 30 patients, but again great activity in terms of response rates, 90% or better, excellent CR rates. But you can see the progression-free survival is not what we typically would see for a Hodgkin population, between 10 to 18 months.

Significant Grade 3 peripheral neuropathy, 30% of patients. And the combination with BV and bendamustine, which we know is quite tolerable in younger patients, was ultimately closed because the non-relapsed mortality in the elderly population ultimately reached about 10%.

There are some additional series, so BV at a lower dose, instead of the traditional 1.8 mg/kg, so at 1.2 mg/kg in combination with benda, a European study showing good activity, a CR rate of 65%, favorable progression-free survival without the non-relapsed mortality that was seen in the higher dose from the previously published experience. And also to highlight some data from the German Hodgkin Study Group, where they added BV to essentially CHOP, so CAP being cyclophosphamide, doxorubicin, prednisone without the vinca, as the BV does have that MMAE component. And you can see, again, a respectable overall response and CR rate. Progression-free survival reported early at 12 months, but 94%, and looking very feasible, and in 50 patients roughly, 2 patients discontinuing for infection and 1 treatment-related death.

So the take-home message here is that these combinations or sequential strategies look effective and may be more easily managed than the combination of BV with AVD based on the pivotal ECHELON-1 data when looking at the older population.

Now to turn our attention to strategies in the younger, typically pretransplant eligible population, there are a number of different approaches that have been taken. And so the first one here was to look at sequential approach, where patients start on conventional brentuximab at its standard dose as a single agent, and if you achieve a CR then you can move on to your transplant, or if you didn’t, the opportunity to receive some sort of salvage therapy would be the next maneuver. So the goal might be to avoid platinum-containing chemotherapy in this patient population if they respond to the single agent.

And so what you can see is that about a third of patients, you see a CR rate of 27% to 35% in these 2 series, are able to move on, with a complete remission from the single agent of BV, and then go on to a transplant. Where then in the remaining two thirds of patients they go on to get chemotherapy. And at the end of both packages, you can see potentially two thirds of these patients in complete remission by PET before they go on to a transplant. That generally leads to excellent 2-year event- or progression-free survival.

And the toxicity from single-agent BV in this setting we know to be very manageable for patients. I’ll say philosophically this makes sense if you’re trying to avoid beating up patients before their transplants. I think the concern though is we’re ultimately consolidating these patients with high-dose therapy, so we’re not truly doing this in a chemo-free or avoiding-toxicity perspective. But minimizing the toxicity of 1 component is a very reasonable strategy. And there were no issues with peripheral blood stem cell mobilization, and certainly no downside with the transplant procedure itself in terms of toxicity.

Another approach, and this one I think many groups are more interested in, was to look at the combination of chemotherapy with brentuximab vedotin with the goal of using 1 regimen to try and drive the CR rate into very high ranges. And what you can see here, a variety of experiences, both from industry-led studies, as well as cooperative group-led studies where the combination of BV with bendamustine or multiple platinum-containing regimens, including ESHAP, DHAP, or ICE, leading to exceptionally high overall response rates. As you can see, all over 90%. The CR rates better than 70% or 80%. And with early data, excellent progression-free survival, although we’ll need to see more follow up from these studies.

The toxicities of the combination, not surprisingly higher rates of neutropenia and febrile neutropenia. And an interesting point from the combination of BV and bendamustine, they did see more drug-related infusion reactions, but this was managed effectively with the introduction of some corticosteroid premedication during the drug infusion period. But again, the concept of BV in combination with a salvage regimen before transplant showing very, very high levels of activity.

Certainly the other thing we’d be all quite interested in is can we look at a combination of novel agents, such as a checkpoint inhibitor with brentuximab, as well. And so here we have earlier data, but again great combinations looking at nivolumab in combination with brentuximab, Catherine Diefenbach’s study looking at nivolumab in combination with brentuximab and potentially in combination with ipilimumab, and then there’s a sequential study that came out of City of Hope looking at nivolumab followed by ICE if there wasn’t a complete response to nivolumab.

And what you can see, again, in all of these trials, smaller numbers, but very encouraging CR rates above 65% for all of them, excellent 2-year progression-free survival where that’s been reported, or median progression-free survival not reached in the ECOG trial. But we do see a smattering of different toxicities, given the incorporation of an immunotherapy agent. So we see all of those unusual itises. You do see a case of Guillain-Barre there. You see immune colitis, and you see some implication here in terms of toxicity. So these are regimens that still remain, I’d say, a little earlier in development that some of the other things you’ve seen, but lots of experience coming, and I think very encouraging as we see the incorporation of novel agents into the curative setting.

And so with that, again we’ll shift gears, and we’ll talk a little bit about now one of the most recent publications. So this is a Phase III trial that we reported initially at ASCO. So this is the confirmatory registrational trial for pembrolizumab in relapsed/refractory classical Hodgkin lymphoma, KEYNOTE-204. So the patient population here are those with relapsed or refractory classical Hodgkin lymphoma that had relapsed post-transplant or ineligible for autologous transplant, having had a least 1 prior line of therapy, good performance status.

Important to note that it was possible that a patient could have been exposed to brentuximab as part of primary treatment or as salvage before getting onto this clinical trial. The randomization was 1:1 for the experimental arm of pembrolizumab given at one of the standard doses, 200 mg intravenously every 3 weeks for up to 35 cycles, whereas the control arm was standard dose BV 1.8 mg/kg every 3 weeks. And they kept symmetry in this design, allowing up to 35 cycles of BV to be administered. Important to know the registrational trial with BV was only up to 16 cycles, and so most of us would not tend to give BV for that long, either because of cumulative toxicity or potentially due to eventual disease progression. But the study was kept very clean and symmetrical in terms of the treatment that was administered.

The stratification factors were prior transplant yes or no and time to relapse after primary treatment. Important to note the primary endpoints here were dual, and so that included progression-free survival by blinded independent central review using 2007 International Working Group criteria, including all of the patients, whether they were to go on to a transplant after being on this study and responding or not, as well as overall survival as the coprimary endpoint. Secondary endpoints included progression-free survival, again by blinded independent central review, but excluding the patients that then went on to have a transplant. They also included traditional other endpoints, including PFS per investigator review, duration of response, overall response rate, and safety.

Now just to highlight a couple of points quickly in terms of the patient characteristics. So 300 patients again ultimately randomized. About 35% to 40% of the patients had had a prior transplant, so the majority of these patients had actually not been able to go to transplant either due to age and comorbidity or refractoriness of disease. The red box highlighted in the right column shows that a lot of these patients were refractory or relapsed very early. So you can see more than two thirds in both arms were primary refractory or relapsed within 12 months, suggesting, again, this was a very high-risk patient population.

As you’d expect, given the randomization, there was only a small number of patients, though this was imbalanced because it wasn’t a stratification factor, that had been exposed to BV, 5 in the pembro arm and 10 in the BV arm.

Just to highlight this here, in terms of the medial number of prior therapies, the range was broad, 1-10 or 1-11, and it is important to note there is a numeric difference there, so the median number was 2 in the pembro arm though 3 in the BV arm. And then looking at subsequent stem cell transplant in terms of what happened with these patients, so you can see ultimately 20% in both arms went on to have an autotransplant, a smaller number went on to have an allotransplant. Days on therapy significantly favored the pembrolizumab group, 305 versus a little under 150. And in terms of what proportion could complete the 2-year package, about 17% in the pembrolizumab arm and only 2% for the BV arm, but again that’s not particularly surprising. And only a small number of patients at the time of this initial analysis were still on treatment.

So here’s the primary endpoint, progression-free survival by blinded independent central review, including all of the patients. So you can see the hazard ratio there is 0.65, very statistically significant, met the predefined level of statistical significance for the trial. Looking at the medians, 13.2 for pembrolizumab versus 8.3 months for brentuximab. The 1-year point estimates 54% versus 36%, so showing meaningful clinical benefit there as well.

Looking at key subgroups just very quickly. The presence of prior transplant or not, the refractoriness of the disease, and that question about prior BV exposure. None of those things mattered in terms of the benefit being extended broadly across the patient population for pembrolizumab. Though again, in certain groups you lose statistical power just due to the size of the trial being only 300 patients.

Looking at treatment-related adverse events, this is just to highlight a little bit of the detail. We didn’t see anything that was surprising for either agent, and both drugs, having different mechanisms, having slightly different AE profiles. You can see in the green the pembrolizumab toxicities were largely all Grade 1 or Grade 2 here, and typically things you tend to see with checkpoint inhibitors, thyroid dysfunction, bit of fever, itch, fatigue. Whereas the contrast what we know about an ADC like brentuximab with the MMAE payload, again we see peripheral sensory neuropathy and peripheral neuropathy as common toxicities. Again, most commonly Grade 1 or Grade 2, as you can see.

In terms of immune-mediated adverse events, again this is where you see a higher proportion of immune-mediated events for an immunotherapy such as pembrolizumab, but the more common one being hypothyroidism. It is important to know that pneumonitis is an important toxicity in this patient population. So in all grades, 10.8%, and you can see that’s equally split between Grade 1 or 2, being 5.4%, and the more significant Grade 3 or 4 toxicity in 5.4%. So again, this was largely managed very effectively by the investigators, with discontinuation, institution of steroids for higher-grade toxicity, and resolution in more than 75% of the patients at the time of reporting. And you can see the smattering of uncommon toxicities that we see from an immune perspective with BV.

Now to look a little more forward, what are some of the novel strategies that we’re seeing here moving forward in terms of relapsed/refractory classical Hodgkin lymphoma, and here I’ve just highlighted a couple of things that we’ve seen in publications or in abstract form. So certainly one of the most interesting compounds we’re seeing is AFM13 bispecific antibody which targets CD30 on the Hodgkin Reed-Sternberg cell and CD16a on the NK cell. So the idea here, can we bring in a different type of immune effector, an NK cell, to the tumor microenvironment to try to deal with Hodgkin lymphoma.

And so the paper published back 5 years ago now in Blood in a small number of patients did show some preliminary signs of activity, with a 12% response rate. And at a higher dose level, not just the whole dosing in the cohorts, you can see a response rate of 23%, and really proof of concept that this does have activity.

A more recent paper published by Nancy Bartlett and colleagues looked at the combination of AFM13 with pembrolizumab, where again, we know the single-agent activity there is in the range of 65%. And we see what looked like additive effect there, 83% response rate, a CR rate of 37%. Safety was demonstrated in that clinical trial, so it looks like a very interesting doublet that hopefully we’ll see more data from moving forward.

And lastly, just to highlight very quickly the experience from the Baylor College of Medicine, as well as the University of North Carolina, looking at CAR T cells targeting CD30, where again the proof of concept here, in a small number of patients, there is activity. There are CRs. And again, there are plans moving forward for a registrational trial.

And so having taken that tour through some of the more recent data and highlighting some of the challenges in these patient populations I’ll just present you a couple of cases where we can think a little bit about how we approach making decisions in the clinic, given what we know. And so the first one here is a patient that I think would be familiar to many of you, a 25-year-old, in this case a young man, with newly diagnosed Stage IV classical Hodgkin lymphoma. No other major medical history, but his Hasenclever Index is 4 because he has Stage IV disease, he’s male, he has a high white cell count and an absolute lymphocyte count of 0.5.

So thankfully, the high-risk patient here is infrequent when looking at advanced Hodgkin lymphoma, but these represent some of our most difficult patients in terms of how to approach treatment. And so I’ve just outlined a few of the options I think about in the clinic at Princess Margaret. Many patients might be considered for a PET-adapted ABVD-based approach such as from the UK RATHL study. The appeal there is that we know a lot and feel very comfortable in North America with an ABVD-based approach. We know the concern with this, though, is that in a high-risk patient you may be very likely to have to do escalated BEACOPP after those 2 cycles if that PET remains positive.

Initially the data from the German Hodgkin Study Group had shown an overall survival advantage for escalated BEACOPP and its approach, based on older trials, HD9 being the first to show the survival advantage. Now with PET-adapted strategies the most recent German Hodgkin Study Group trials show that PET2 is really not informative as a biomarker anymore, but you can use PET2 to minimize the exposure to escalated BEACOPP. Why is this important? It allows you to minimize the toxicity, both acute and delayed, of such a complex and potentially toxic regimen. And so one strategy might be to start with escalated BEACOPP and continue for 4 cycles, and if the PET scan remains positive after 2 to go to 6, based on the most recent German data.

A trial that I’m a fan of, as well, comes from the French, AHL2011, where they start with escalated BEACOPP and subsequently deescalate to ABVD in the majority of patients that are PET negative after 2 cycles of treatment with that approach. And so again, these approaches in the PET-adapted era have not been compared head-to-head to know which one is better. And so this involves careful discussion with the patient in terms of risks, including things like infertility, the tradeoffs of complexity of giving these types of regimens.

And having just shown you the data from ECHELON-1 with the incorporation of brentuximab, what do we think as clinicians about adding a novel agent. Can we think more like we do in DLBCL where we’ve added rituximab in the front-line setting to our algorithm for many years now? Can we do the same with BV with a positive front-line trial? Or do we even depart a little bit from the data and say since we have different data sets to pick from could we use a PET-adapted approach where we incorporate BV potentially on demand? Or in a less evidence-based approach, admittedly, can we start with AVD-BV, and if people are PET negative deescalate to AVD even?

So I’ve presented those options. I think, in our practice currently at Princess Margaret, we’d be most likely starting with a BEACOPP-based approach in this patient population, which is a bit of a departure from what we’ve traditionally done, starting with ABVD. But I accept that this is a complex discussion, and there are many tradeoffs in terms of what we need to do.

The second case I’m going to show you is a contrast and highlights the approach of management of the patient that has received multiple attempts at curative therapy and has ultimately relapsed. So here a primary refractory case, now 32 years old, who had a CR to second-line chemotherapy, went on to have an autologous transplant, but experiences early treatment failure 3 months post-transplant.

And now we know that there are many choices that could be made. BV monotherapy based on the older registrational trial has been our mainstay for a long time. The patient progressed fairly early and may not have been considered a candidate for BV maintenance because of the CR to second-line chemotherapy. We know that there are now comparative data showing the benefit for pembrolizumab monotherapy versus BV in this setting.

The combination of BV and nivo, we had talked a bit about the study looking at this regimen, particularly pre stem cell transplant in the second-line setting. But there is a trial called CheckMate 812, which is currently ongoing and much like KEYNOTE-204, is the confirmatory registrational trial for nivolumab in relapsed/refractory classical Hodgkin lymphoma and looks at the doublet of nivo and BV versus BV alone. So the design is similar to KEYNOTE-204.

And then the last one I add down there as an option is any one of these other things to induce remission, but do we consolidate with an allogeneic stem cell transplant. And this is where I’d say there’s clearly Level 1 evidence to say that the checkpoint inhibitor pembrolizumab would be preferred over BV in this setting and that looking forward one would hope that a combination approach, when we see the data from CheckMate 812, might ultimately be superior to either monotherapy approach. But important to know how long term that disease control may be, and if there is a potential for cure, because then we get into a question of combination versus sequential approaches and how best to palliate patients.

And the last thing I’ll conclude with, I think a lot of us are now a little more tempered in the approach to allogeneic transplants in this population because we have a lot of these other options. We have checkpoint combinations in development. We have CAR T coming down the road. We have these novel combination approaches. And I think for most groups, if you have access to these types of therapy, we’re saving a more potentially-toxic regimen like an allogeneic transplant for patients that have at least had 1 attempt at this type of an approach, which is low in toxicity and likely to have big dividends in terms of disease control.

DR LOVE: That was really awesome, John. If I could, I’d like to just ask you a few follow up questions.

DR KURUVILLA: Yeah, of course.

DR LOVE: So just to go back to that first patient, could you tell me again exactly what you said?

You said you did BV or what did you do?

DR KURUVILLA: I did escalated BEACOPP, and I used the AHL2011 clinical trial approach from the French, which was you start with escalated BEACOPP, you do the interim PET scan following 2 cycles of chemotherapy. And the majority of those patients with that interim PET scan are PET-negative after 2 cycles. And their data shows you can successfully deescalate to ABVD and thus avoid needing to continue with longer course BEACOPP. And that was at a time where in Canada we still did not have funding and approval for BV. And I guess that would be one of the options available to physicians in other jurisdictions as another option.

DR LOVE: So I was going to ask you, you brought up the issue of BV-AVD. I didn’t realize it wasn’t available. If it were available would you have used it, or would you still have taken the other approach?

DR KURUVILLA: Yeah, I think the challenging thing for us still, when you look at comparing these approaches, and this is one we struggle with in the clinic for sure, is how do you interpret the ECHELON-1 data in comparison to your routine clinical practice, where we’ve all largely adopted using PET-adaptive approaches? And so I’ll admit I’m a believer in targeted therapy and novel approaches in Hodgkin lymphoma, that was the appeal of participating in the trial, but reconciling that and applying it to my patient population remains the challenge.

So for me, when I see someone with that high-risk factor profile, as the case that I presented, that high IPS score, I have to admit our group has agreed to start with an escalated BEACOPP-based approach. And I think that will remain our standard until we can better understand how that plays out using an interim PET-adapted approach over time with BV.

DR LOVE: So is there any clinical scenario right now up front where you would use BV-AVD?

DR KURUVILLA: Yeah, so I think where the data make the most sense, the patients that you felt very comfortable giving ABVD with, and so to me that would definitely be the IPS 0 to 3 patients, you’re going to improve their outcome by giving them BV. And the interim PET scan, I think, in that population typically is less likely to be positive after 2 cycles anyway. And their outcome look very good in the clinical trial.

Where I struggle with BV would be if that population was over the age of 60. And as I showed you in that data set, those are the patient where they saw no efficacy benefit. Admittedly, it’s retrospective subgroup analysis, and there as much more toxicity as well. And so I would only be doing this in patients under the age of 60.

DR LOVE: Well just to be clear, because I think there was like 50 patients over 60. I think I saw that.

DR KURUVILLA: Yeah, you’re exactly right. And again, the same issue in terms of its retrospective data. And I think the other point to really highlight is the importance of knowing now that these people don’t run into issues as long as you give them GCSF. And so I think that colors that interpretation for the older population. I think though, with the older population, when you looked at the next data, where I showed you those 3 or 4 different studies looking at different approaches, I have to admit I think Andy Evens data that looked at sequential BV followed by again a smaller data set, unfortunately, but that to me looked like the most encouraging signal in older patients with classical Hodgkin lymphoma that I’ve seen in a long time.

DR LOVE: Well just to clarify though, I mean theoretically it seems like you’d want to look at older patients that got treated in North America. And if you start out with 50, I imagine that’s less than 50.

DR KURUVILLA: You’re right.

DR LOVE: Just kind of bringing that up. Because I guess the issue would be, I would assume this is about toxicity and not really antitumor effect, or do you think the antitumor effect would be different?

DR KURUVILLA: Well, it’s a great question, Neil, because I think the biology in those populations with the disease is not well known. We submitted data to ASH last year from our center that really showed that in older patients, even if you use a cut point of 60 or 70, a major difference in outcome with standard treatment with ABVD. And to me it spoke more about the biology. It wasn’t driven by stage. It wasn’t driven by anything else. And so I think those older patients probably need approaches that are a little different that just generalizing what we do in a 35-year-old.

DR LOVE: Could you explain more, I guess this is classic oncology, but why you can’t use GCSF with bleo.

DR KURUVILLA: Yes. So there are a couple of data sets that have looked at bleomycin pulmonary toxicity. And again, the Mayo published a big series back in the early 2000s, I think in JCO, we had a similar experience at PMH, that showed that there was an interaction and that you saw more bleomycin pulmonary toxicity in patients that had GCSF exposure. And it’s interesting, that’s a place where my practice has changed from when I started as a fellow to now, in that there’re data that have surfaced over the past 10 of 15 years that show in younger patients you don’t need to give GCSF at all, right? Like you can treat them with low neutrophil counts. They don’t get infected. They don’t get fever.

And so I think the population that you need to think about giving GCSF in, outside of those when you’re giving BV, are the patients above the age of 60 because the FN rate is higher. It didn’t hit 20% in ECHELON-1 in the control arm over 60, but that’s that group. And I think that’s that group we’re also a little keen to look for reasons to stop bleomycin pulmonary toxicity as well, or the risk of it. And so with the RATHL data showing when your PET2 is negative you can stop bleo after 2 cycles, that’s the majority, I think there’s a nice way that you can build in the use of some GCSF in the people that you’re worried about and still avoid meaningful risk with bleomycin pulmonary toxicity.

DR LOVE: Okay. All right. And then the pembro versus BV study, I’m curious, were you expecting to see these results?

DR KURUVILLA: Yeah, that’s a good one. So when you look at the Phase II data with BV, right, from the pivotal trial, which was all post-transplant, the median PFS there was about 6 months, right? And when you look at the Phase II pembro study that led to the approval, the PFS was about 12 or 13 months. So I just remember thinking if one was going to bet on a clinical trial with that difference I would bet on that clinical trial. And when you look at the comparison here, so the control arm outperformed a little. It ended up being about 8 months, and the experimental arm was about 13 months. So pretty close. So it kind of went much like I think the investigators and the sponsor would have expected.

DR LOVE: So another question about that trial. You might have presented it, but treatment discontinuation because of toxicity in the 2 arms?

DR KURUVILLA: It wasn’t a major problem in both, but you did see discontinuations in BV for the usual things like neuropathy, again not common. And the discontinuations in the pembro arm were for the rare immune-related events. And so you didn’t see enough of them add up that it meaningfully impacted the outcome of the trial.

DR LOVE: And then AFM13, I’m kind of curious, do you see cytokine release and neurotox? I’m still trying to figure out bispecific and whether they all cause that. Does this one cause it?

DR KURUVILLA: So it doesn’t appear to, yeah. And so it looks like because your recruiting NK cells and they’re not as revved up as those T cells are to have all that cytokine release, that it doesn’t seem to happen the same way. And I think the other thing that’s kind of interesting there, Neil, and we’ll have to see how this plays out over time, right? So a tumor that has much more microenvironment, much less actual tumor cell expressing CD30, there’s maybe just less antigen to present to then lead to all this immune activation. So I think there’s probably both the effector cell and the target antigen are both reasons that you see less of the toxicity.

DR LOVE: I’m kind of curious, I only recently became aware of the CAR T data. In terms of, again, cytokine release neurotoxicity in Hodgkin patients, is there a lot? A little? How does it compare to what’s seen with lymphomas? I know it’s a different product, but I’m just curious how much of a problem they have.

DR KURUVILLA: It’s early days, I think. And so one of the unknowns, is that that initial experience from Baylor and UNC, they also looked at 3 different ways of lymphodepleting the patient, as well. And so at this point there are too many variables to kind of really be able to tease out if there’s going to be a difference or not. Again, my guess is going to be I think you’re probably going to see a little less toxicity, in all honesty.