I want to thank all of you. It's been a really great and informative discussion. We've covered the waterfront of relapsed and refractory large cell lymphoma. Before we finish up, I want to give you each a chance to give us a quick take home message for practitioners taking care of patients with large cell lymphoma, and I'll start with Nathan, then Matt, and then Kami. Nathan?

 In the past 5 years, we've seen a huge change in the outcome of patients who are failing auto transplant. To me, that's the biggest take home message of what’s happened in the last several years; patients who fail transplant—in the past, I was trying to do everything I could to find something just to prolong outcomes— now have curative regimens that are curing a significant portion of them and there are even better versions of those coming out in the next couple of years.

It's a great time to refer patients to clinical trials because some of the cellular therapies look very active and so it's a wonderful time for patients. Not that it's ever good time to have relapsed large cell lymphoma, but the outcomes and the available options are like nothing we've seen in generations.

 I don't want the perception to be that cellular therapy for is all, rather a discussion on cellular therapy for all is reasonable. Many patients may not go on to get cellular therapy and, as we pointed out in this discussion, there are a lot of new compounds being studied and some that will make it into the commercial use. But at the end, thinking about large cell lymphoma even from a diagnosis, it’s important to determine what your strategy is going to be and you hope that you're in that bucket of 75% that may be long-term survivors. You know that you have to prepare for the quarter that are not. That's where the game really gets tough and you need a strategy. You need a team to have the strategy in relapsed/refractory large cell lymphoma and a lot of times, it helps to have a cellular therapy institution in your corner.

I agree with Nathan that it's an exciting time in relapsed/refractory large cell lymphoma with the approval of agents such as CAR T [chimeric antigen receptor T-cell] therapies, polatuzumab, the excitement of potentially tafasitamab and lenalidomide. These are providing options to patients who previously didn't have options. We are curing more patients with CAR T therapy and hopefully we just get better as far as outcomes from those therapies as we improve the constructs and decrease toxicity.

I think that, moving forward, places that we can continue to do better are increasing the rate of cure in those patients with high risk disease from the beginning. In patients who are not candidates or who progress after both auto [autologous stem cell transplant] and CAR T, we can work towards having more effective options, possibly in some of the immunotherapies like bispecifics.

 I think large cell lymphoma is getting more complicated despite our profiling data has not translated into improved outcomes. People are used to kind of giving everybody R-CHOP [rituximab, cyclophosphamide, doxorubicin hydrochloride (hydroxy daunomycin), vincristine sulfate (Oncovin) prednisone] upfront and crossing their fingers but I think the relapse setting is becoming more and more complex. Probably, before long, we’ll need more sophistication in how we approach these patients. Hopefully, that means we're using them more effectively and have more tools at our disposable.

Thank you all again. I want to thank our audience for joining us today as well. We hope you found this 

 discussion to be useful and informative. Thank you.

Videos

Closing Thoughts on Treatment of R/R DLBCL

Nathan, 1 of the things I'm struck by is how all of these things going to improve outcomes for patients. One of the things that is pretty clear to me from our discussion is that we really don't have any molecular predictors of who should get what for any of these therapies. It's really a clinical decision: you have refractory large cell lymphoma, you can get a CAR T [chimeric antigen receptor T cell], you get it. You want an oral therapy? Okay, maybe you'll get selinexor. You want a chronic therapy that's well-tolerated? Okay, maybe you'll get tafasitamab /lenalidomide. Or maybe you're not a stem cell or an aggressive chemo candidate, maybe you'll get polatuzumab. It doesn't address relapse setting. I guess we would argue we have the most data, though limited with CAR T-cells.

Beyond that, we have no molecular predictor, biomarker, profiling, any of these things that tells us what to do, other than what we've talked about today, which is your impression of the drug, your impression of your patient, and what seems to fit what they want to do. Whether or not it's let's go for the long-term remission and cure with 1 set of agents or palliation with another set of agents, how do you think we can move this forward in a reasonable way?

 This is something we see across the cancer space, especially in lymphoma, and something that we have been talking about for more than 20 years in large cell lymphoma. It started off with ABC [activated B-cell] vs germinal center B-cell subtype, and there are more refined systems to cluster patients into different groups that came out from Margaret Shipp, MD, and Louis Staudt, MD, PhD. I think there was a recent paper in 

 looking at trying to cluster patients into different groups based upon their genomics.

To date, I have not seen any of these systems used to select treatment. That's the next step—to identify these biologic subsets of large cell lymphoma and treat them differently based upon some hypothesis that that biology can be treated by some targeted agent or some immunotherapy. These things are desperately needed. There are multiple groups that are performing these analyses, dividing groups of patients by their biological characteristics either using some marker or multiplex imaging or genomics. We really need to define the biology by some assay and then using that as a way to put patients into different treatment groups. That’s the holy grail because the one-size-fits-all approach can only move the bar so much in large cell lymphoma. CAR T-cells, which are incredibly exciting, still only have 30% or 35% of patients with long-term benefit. We don't know why that is, so we treat 100% of patients to get that 30% outcome. That's a long answer to your short question but biologic predictors are what we desperately need for this disease.

Before we wrap up, I just want to ask, Matt and Kami, your thoughts about cost and how that affects your patients. We've alluded to it a little bit but, Matt, are you having trouble with getting approvals for the drugs you want to treat your patients with? Are they coming back and saying their co-pay is too high? How often does that come up?

 It comes up more than it used to. I'm doing many more peer to peer discussions explaining why I'm going down a course that I am. If you think about our highest cost therapeutics right now, it probably is CAR T, unless you are on an oral therapy that is a continuous therapy that's priced out month per month. Then if you're getting to 2 years on some of those drugs, they can be expensive. That's great if you're on an oral therapy for 2 years from a relapse/refractory large cell standpoint.

One of the ways to drive down cost that isn't the cost of the product from a cellular therapy is if they're not in the hospital. If you can decrease the in-hospital cost—I guess in MD Anderson [Cancer Center],no patient was to be sitting in the hospital unnecessarily—I think that that would be one of the avenues to do some cost savings as a total bundled price. There was a lot of cost CAR T-cell data at EHA [European Hematology Association Annual Congress] just released, trying to look at modeling around this.

Different countries have different cost structures; I saw a French and a Canadian. I know that were trying to do our own certain analyses here, but I think it will factor into it. I don't know where things will be priced out in these newer IV [intravenous]and oral drugs, but I can imagine is going to be part of the discussion also.

Cost is becoming something that I have to talk about frequently and it can be very frustrating and uncomfortable. We have all these oral therapies, while they are available, can be very expensive. There are patients that may have a co-pay of nothing where there's patients that have a co-pay of a couple thousand dollars a month or a 1-time co-pay of $5000 and that they get it for the rest of the year free. Those are significant costs to patients and it's frustrating to have to tell somebody we have this therapy that can help them but it's just not affordable for them or its it's going to make them go broke. To Matt's point, with cellular therapy, you can get it approved by your insurance company for the therapy, but then you have to still negotiate the cost of the hospitalization and the supportive care, like tocilizumab and those things. It can become prohibitive even if you get coverage for the product. We need to find ways to make these more cost-effective. We have to do better for people in that respect.

Improving Outcomes in Patients With R/R DLBCL

I want to move towards, in our last few minutes, talking about other agents. We've talked about a couple that are either approved or farther along in the regulatory review process. I remain struck by the number of agents that continue to be studied. You might think that we've reached our limit, so to speak, in immunotherapies and antibody-based therapies, but there a number of bispecific antibodies and there are versions of bispecific antibodies where different companies have engineered their own version of a bispecific or a new type of antibody. We have antibody drug conjugates. We have the bispecific T-cell engager [BiTE], blinatumomab, approved in certain settings. What do you think about—before we get to other categories of drugs that you're excited about—these novel immunotherapies, for lack of a better term?

I'll ask Matt to go first, and then Kami and Nathan, and share your thoughts on where these fit. Some of them have data, both the antibody-drug conjugates and the bispecifics, that are approaching or even better than some of the things we talked about today. So Matt, your thoughts.

 Some of the bispecifics, like glofitamab, which has 2 different binding domains; CD20 that then engage CD3. You have—it's always fun trying to learn the new names—epcoritamab, which is a subcutaneous injection going after the same space. It's going to be generating data but not a lot of the data will follow CAR T. We’re going to get response rates and PFS, but they aren't going to be in the population where you enter the playing field.

It's great to have the data because if you don't have data there, you're not going to want to go into those populations. I'm excited about seeing those drugs get a longer follow-up. We've got the overall response rates and CR rates, but we need durability.

There's still some good data out there. There are 3 CD19 ADCs that have been developed, all showing pretty similar responses, however 2 are not going to be further developed due to toxicity. The third one had good responses that don't last long and is probably going to have to be in combination—kind of like some of the other agents we talked about today—to really get good remissions. I think the bispecifics are interesting. A few of those have been looked at in the post-CAR T setting and have activity there, which is probably one of the highest unmet needs of those patients who are post CAR T.

 Mosunetuzumab had a couple of post-CAR T patients on it, if I remember the data correctly.

Yes, that one and then the Regeneron Pharmaceuticals one just recently put out data with some responses post CAR T. We have potential therapies, like selinexor, to offer those patients.

 At least it shows that they're listening to us because a lot of trials have been trying to write off patients by not allowing prior exposure to CD19 CARs. Why are you doing that? That's exactly who we should be studying. Yes, create an expansion cohort for all you want and analyze the data differently, but we need to understand that population.

Nathan, your thoughts on some of these new drugs?

 I will echo what everyone said already. When we were looking at the BiTE molecules a couple of years ago, there was some sense that they would maybe displace CAR Ts. But a lot of the data that were seeing now is immature. I don't think that the durable CR rate appears to be at the same level that we're seeing with CAR T-cells, at least in large cell lymphoma. So I don't see these replacing CAR Ts, but I agree with Kami and Matt that they will probably follow CAR T as a salvage for these patients.

The other thing I thought at this most recent ASCO, there was a nice abstract on AlloCAR T and it would be very interesting to develop an off-the-shelf strategy for CAR T where we you would have something that's sitting in your blood bank and able to be given to patients when they relapse. Those studies are still very small, but that would be something we should consider more.

Matt, you've talked about the access and applicability of CAR T. It strikes me that there's a large percentage of people who could benefit from CAR T that are not getting them. It also strikes me that having new agents around is going to make that number of patients getting CAR T even smaller because there will be alternatives. Whether or not they're appropriate, it's good for patients to have alternatives.

The fact is people will be more inclined to say “You got to go get CAR T.” And now the discussion will be, “You should get CAR T but you could get this or that.” How do you think that's going to change the big picture?

 I still have a lot of hair to pull out in my career, but I think it just comes back to being a resource to have those discussions about who in this population is appropriate to go to CAR T cell and who isn't. It's great that we're getting all of these new classes, more drugs to have the discussions about. It's a chess match against large cell lymphoma and knowing what piece to play next; You may be moving 1 piece to make a move 3 times down the road and that may be CAR-T-cell because that's what the data shows. 

We have to continue to encourage that if you're doing a CAR T-cell study, you should be able to get a CD19 BiTE or you should be able to get a CD19 antibody for the CAR T cell so that we know and can inform the patients about this. We want to not exclude the patients from the studies so that they can't get a CAR T-cell or the next generation CAR T-cell because that may be the patient population that does derive benefit.

So Kami, you at Ohio State University Medical Center clearly have lots of access to CAR T, yet you’ve been participating in a variety of different trials, including some of the agents we've talked about today, which in some ways tells me that you see excitement and promise in some of the things that are not CAR Ts that we've talked about, that they're fulfilling or potentially filling a need for your patience. Why do you think that is, from the standpoint of just ease and toxicity?

I’m putting you on the spot here but I just want to see how people in practice should think about this. Clearly, going on a trial with tafasitamab offered something to those patients that was attractive. So how do you think about it because I think it's the same way people are going to have to think about it in practice.

When looking at your patient, you need to know what are they able to tolerate if something is very well-tolerated and they can get a good response from it. Regarding access, they have to come to us for the trial, but just in general, Ohio serves a big population. There's a lot of land here for a small amount of people so we serve a number of states. When you're looking at making recommendations for therapy, not everybody can have access to the big center; not everybody can wait to have their CAR T sent off, manufactured, and returned and not get therapy in between that time. Sometimes it's still an insurance issue or a financial issue; you have to have the coverage and pay what isn’t covered. You have to stay within a certain closeness to Ohio State for a certain amount of time after you leave the hospital. All those represent challenges for our population in this area.

Emerging Therapies for R/R DLBCL

I want to move to another drug that is undergoing regulatory review for relapsed and refractory diffuse large B-cell lymphoma and that is selinexor. This is an agent that has a somewhat different mechanism of action and is already approved in some myeloma subsets so the audience may be familiar with it. Nathan, tell us why selinexor might be a reasonable agent for this patient population and the data supporting its potential use.

This is a new class of drugs and it's not anything that we have for large cell lymphoma or any other cancers. It's called a SINE [selective inhibitor of nuclear export] and it targets certain proteins that are exported out of the nucleus that gives cells a pro-survival advantage. It is not necessarily specific to large cell lymphoma, but it targets the mechanism that large cell lymphoma probably uses to keep itself alive and potentially resistant.

The drug is oral. It's a single agent. It's associated with some unique effects– a lot of which are GI and we've seen now some fairly decent size phase 2 trials targeting patients that have large cell lymphoma. In this trial [phase 2b SADAL trial] looked at a fairly difficult population. Most of these patients had at least 2 prior lines of therapy, some patients were failing transplant, and some patients were double-hit patients. In that study, they saw almost 30% overall response rate with a complete remission rate of around 10%. If you think about CAR T-cell data and others, it's not quite as good. It's a single drug so it’s fairly easy to give. It is effective in a subset of patients that have pretty difficult-to-treat large cell lymphoma, including patients that have double-hit lymphoma.

One thing I really thought was interesting with the drug is that in the responders, we saw pretty good long-term responses. In fact, if you look at patients that have PR or better, the duration of response is over 2 years. There is a select group of patients that do achieve durable benefit with the drug.

I want to ask Matt and then Kami your experiences with the drug if you've used it, and/or your take on reading the literature about it from the standpoint of efficacy as well as the safety profile. So Matt, your thoughts.

 I have not used the drug in lymphoma. We do have it available in myeloma, as you pointed out, and use it in a clinical and a research setting. My read of the initial paper that was published is it went on an adventure of dose-escalation, dose-finding, and schedule-finding driven mostly by GI toxicity, as was pointed out. How could you get enough drug in the subjects that allow them to respond and want to stay on it? Over time, if it takes a while, where's the enthusiasm for continued use?

If this drug is going to continue to be used, it may have to be with other drugs, if it can be playing in the sandbox together. We have these other novel agents, like tafasitamab and some other oral lenalidomides, where you're seeing longevity in this population. We also should be studying patients are who are responding, even if it’s a small piece of the pie, so we can know who it's worth potentially having those toxicities. Those toxicities can be manageable over time, per the paper. We really need to identify those patients.

I've had experience with the drug in a few different ways. We were involved in the phase 1 study, and as mentioned, there was this toxicity, weight loss, and fatigue, and those seem to be problematic. However, once they were able to address these effects by looking at appetite stimulants and scheduled antiemetics, we have a phase 2 study in combination with ibrutinib and it seems to be much better tolerated with the use of these agents now that it's recognized that there are side effects.

It's an oral therapy that can be given to high risk patients so it does provide an option for those patients. When you look at the overall responses, I think that Matt and Nathan are right, that it's probably best used in combination with another therapy to get the best bang for your buck.

We participated in some trials and now that the dose level is better settled as you cited, it does seem to be better tolerated. It's going to be important for people—when they have access to it and are considering using it—to really think about the toxicity in the context of the dose they're using rather than the up-and-down doses that were studied.

We have also had a study looking at it in combination with RICE [rituximab, ifosfamide, carboplatin, etoposide] chemotherapy in relapsed large cell lymphoma. Interestingly, it may be tolerable and can be given with chemotherapy, with support from a randomized trial, and that’s what you're seeing with your ibrutinib study.

Nathan, as you look at this, if you have this available as a single agent and you had a patient with large cell lymphoma, where do you see this used relative to CAR T-cells, tafasitamab, and other kind of standard chemotherapy drugs? The nice thing about it is it's an oral regimen that is relatively easy from the perspective of administration for patients to take. Who do you think would be the patient getting single agent, assuming you have access to it and had a patient population?

When I think about patients that are failing CAR T, and that's going to be at least half, maybe more of those patients, I don't have good options for those patients. Generally, I'm thinking about clinical trials. We talked about a Revlimid-containing regimen, but we’re still grasping those patients. We often do things like radiation to limited sites, but they don't have a lot of great options that could give them a durable remission.

What I really liked about this is that in those patients who responded, they've got over 2-year PFS. So that suggests that it's an active drug. I don't think this is going to replace auto [autologous stem cell transplantation] or CAR T. In patients that are failing those kind of approaches, we don't have a lot and we can do Revlimid and Revlimid plus a CD19. Post-CAR T-cell failure patients or patients that would not qualify, and are not near a center are the obvious population.

Kami and Matt, your thoughts, anything different?

Safety and Efficacy of Oral Agents in R/R DLBCL

So Kami, in a world where you have a relapsed large cell lymphoma patient who has not had a good response to second line chemotherapy and is not a great candidate for it, you now might have tafasitamab and lenalidomide as an option and you have CAR T-cells as an option. In the assumption that both are available in a clinical setting, how would you think about approaching those? Clearly and outpatient regimen that's easy to give relatively speaking versus CAR T-cells that are more complex but also for the effective in refractory patients, how do you think about that decision as you would move forward?

As I mentioned regarding the population of patients treated on that trial and as Matt also mentioned that with some other differences, the one downside to the population of patients is they weren’t heavily pretreated. They weren't primary refractory and they weren't double hit patients. We know that those patients do better with CAR T and I would be hesitant to use this combination in somebody who had access to a CAR T center and was in that population of patients that hadn't been studied in this study.

For patients who fit these criteria and both are available, they both have similar responses, similar CR [complete response] and durability is very good with tafa [tafasitamab] len [lenalidomide] also. It's much less toxic, it's much easier to access and it could be given at any center across the country as opposed to sending a patient to a CAR T center. If a patient was not a candidate for CAR T, I would definitely offer the tafa len.I think if it's a patient who had a good response to chemo and is on the board for something, that's a patient I would offer tafa len to if they couldn't get access to a CAR T center. For some of the higher-risk patients, I think we need more information on tafa len and if that really works in those patients like CAR T does.

Matt, you alluded to some of these key questions but if tomorrow you had access to one and you have a patient who says they could do either one of these things and would like to try the tafa first, because it's less involved and outpatient and everything else, and do the CAR T if that doesn't work or they relapse. Speaking to the CD19-directed approach, how would you answer that and what would you advise that patient as to the best strategy?

 We have an access issue in relapsed refractory large cell lymphoma anyway. I would be thrilled to be part of the discussion about when to use tafa len versus CAR T cell. If it has to be in the Covid-19 era over telehealth, I think that is still worth the time to have laid the roadmap from that because the data is showing us tafasitamab lenalidomide, in the appropriate patient population. It wasn't just a flash one abstract wonder, it's held over time in that patient population. If you’re going to use it first before CAR T cell, there has to be a strategy and you have to be looking to make sure that, just like large cell lymphoma, they are not progressing fast enough. You can't caught on your heels not thinking about CAR T-cell­ therapy right after that. What are you using otherwise, pola-BR [polatuzumab vedotin plus bendamustine/rituximab]? Polatuzumab single-agent or lenalidomide already, ibrutinib maybe?

There is a period of time where you're seeing that you want to go to CAR T-cell [therapy] and you can't or it's going to take long because of logistic reasons. I’ve spoken to this whole mysterious time when you want to do CAR T cell and it's just taking forever to get to apheresis for numerous reasons, tafa len seems to be reasonable, as Dr. Maddocks pointed out, because of the toxicity profile. I'd like to get experience with the drug but to take those patients out of the running for CAR T-cell. If it takes a couple of weeks to get them to their apheresis and then another 3 weeks to get them there, maybe tafa is the best option because it's 8 weekly doses early on. You're getting drug exposure and then you give them the intent to go to CAR or they could say no, and you haven't lost anything if they're responding.

The one concern people have is just sequencing the CD19 therapy, like Matt touched on a little bit ago, and really does that, using that tafa len as a bridging therapy to CAR T, make the CAR T less effective? We just don't have enough information to say that. There was one patient that's been reported on the L-MIND study that responded to tafa len, progressed after, went on to CAR T and has over a year remission.

But that is an N of one and you can't base anything on one patient. As Matt said, there is preclinical data on treating cells with both the CD19 and that doesn't affect the CAR T effector function. As this becomes available to people, we'll hopefully know more about if there is an effect on the CAR T efficacy.

 I think it's important, as we've looked both in the polatuzumab BR coming out and the tafasitamab lenalidomide coming out, that each dose of tafa that's delivered is likely a CAR T-cell patient somewhere in your region. Are you able to and are you having those conversations? Do you have a network established that can say let's work together to decide what the next steps are. And if that next step is tafa len or pola-BR or some other combination therapy that that doesn't include CAR T-cells, so be it. Then we've at least checked that box on the discussion in large cell lymphoma that we should be having with patients out there in this disease state.

I just want to ask if there's any data on collecting CAR Ts, having had a patient of mine with mantle cell who recently couldn't get CAR Ts collected because they weren't enough T cells. I know that doesn't come out very often but it’s certainly a consideration. Do we have any data of collecting T cells after lenalidomide? And that might be a good thing. It might be a bad thing. I don't know. Any data on that? Is that an issue?

 I have not seen any but I bet you there will be data coming out because of the R2 [lenalidomide (Revlimid) and rituximab] CHOP [cyclophosphamide, doxorubicin hydrochloride (hydroxydaunorubicin), vincristine sulfate (Oncovin), and prednisone] versus CHOP studies that were done. There were patients that were refractory they are. If I had to go back and look at that question, I would key in on that population and see what their outcomes were to second line and how many of them got CAR T-cells. The problem is that they're all going to have gotten another light of therapy that kind of tackles those T cells. It's going to be hard to interpret, unless you're coming off of some of the lenalidomide. There was the Spanish data looking at len plus R-GDP [rituximab plus gemcitabine, dexamethasone, and cisplatin] but that was a transplant ineligible population. The data is out there but it's just kind of just made somebody's ASCO abstract for 2021.

There you go. It's out there for whoever wants to tackle that one. There's a study looking at tafasitamab up front. I don't know, Kami, if you’ve been involved in that study or have any insights into that. I don't know if it's open and accruing yet.

There is a phase 1 study open at a small number of centers. We're not involved but it's actually looking at R-CHOP plus tafa and then R-CHOP plus tafa and len. That's ongoing with a planned phase 3 study with R-CHOP and then R-CHOP plus len plus tafa.

 I think it's going to be interesting because I've looked at eligibility for that. It does exclude double hits. It does allow I think it's IPI 2 to 5. There are competing randomized trials in the higher risk groups so maybe it's a good thing to have multiple upfront trials going after what cell lymphoma in different groups. Maybe if we do different things, then there will be a positive trial against R-CHOP instead of all negative trials.

Treatment of R/R DLBCL: CD19-Directed Therapy vs CAR T

As we move toward other emerging options for relapsed and refractory diffuse large B-cell lymphoma, we have a number of new potential agents that are out there.

One that is undergoing regulatory review right now is the anti-CD19 antibody tafasitamab [tafa]. It's been studied primarily in combination with other agents, including lenalidomide [len]. I know, Kami, you have led some of the trials around tafasitamab. Can you tell us a little bit about what it is first from the audience that may be unfamiliar and some of the initial studies that have been on primarily in relapsed and refractory large cell lymphoma with this agent in combination, particularly lenalidomide?

Tafasitamab is actually a CD19 monoclonal antibody. The Fc portion has been enhanced to increase ADCC [antibody-dependent cell-mediated cytotoxicity] and ADCP [antibody-dependent cellular phagocytosis]. There was a single arm study that looked at the monoclonal antibody tafasitamab alone in relapsed refractory non-Hodgkin lymphoma and they saw some responses in diffuse large B-cell lymphoma but notably there was a handful of patients who achieved a complete remission. The median duration of response in those patients was over 20 months, signaling that there might be some activity in this agent with large cell lymphoma.

The combination of tafasitamab and lenalidomide was evaluated in a phase 2 study that combined the 2 drugs for 12 months. The antibody is given once a week for the first 3 months and then every other week for months 4 through 12. Lenalidomide was given at a dose of 25 mg. After a year of therapy, patients were allowed to continue on tafasitamab maintenance. The further rationale of this trial is that the lenalidomide activates NK [natural killer] cells and that brings more cells for tafasitamab to act on.

The phase 2 trial of the combination showed pretty high response rates. It showed a 60% overall response with a little over 40% of those patients achieving a complete remission. The patient population in the study was allowed to go on trial with relapsed/refractory disease with a median prior therapy of 1 to 3; the population had median prior therapy of 2. These weren't extensively or very heavily pretreated patients.

It was really targeted at those patients who relapsed after their initial therapy or maybe received a first salvage and then are not candidates for autologous stem cell transplant. The therapy was pretty well-tolerated with toxicity mainly being hematologic, fatigue and diarrhea. Really when you look at the toxicities after the first year of treatment, the majority of them resolved, really suggesting that the toxicities that were seen with the combination were primarily what you see with lenalidomide alone. There were very few infusion related reactions. About three quarters of the patients were able to stay on a lenalidomide dose of 20 mg or higher.

Matt, I want to ask you your take on this agent. We just talked about CAR [chimeric antigen receptor] T cell data with and we’ll come back to whatever comparisons we can draw. How does this compare with either lenalidomide alone or anti-CD20 alone? Are these patients characteristic of this population? Are they the same people were seeing with CAR T cells? I know that the RE-MIND study tried to make some comparisons, obviously with different cohorts. How do you interpret this phase 2 data regarding this combination in light of the patient population that we may want to apply this combination to in the future?

 Dr. Maddocks, correct me if I'm wrong here, but I was just waiting and waiting and waiting for the publication and I think it came out recently in 

 because some of the methodology of the study, too, is that the patients couldn't have double-hit or triple-hit biology. My understanding is that you couldn't have been primary refractory to your first line of therapy. If you were refractory to R-CHOP [rituximab cyclophosphamide, doxorubicin hydrochloride (hydroxydaunorubicin), vincristine sulfate (Oncovin), and prednisone]—or any CD20-targeted monoclonal antibody—or dose-adjusted EPOCH [etoposide, doxorubicin, and cyclophosphamide with vincristine, prednisone], you couldn't be in the study also.

There are some differences there because we've seen on CAR T-cell therapy those patients, double-hit, CAR T-cell appears to be as agnostic. It doesn't care that you're a double-hit. You can still respond and have durability. The same thing is that if you're primary refractory, you're still going to CAR T-cell likely double refractory with a lot of disease and those people have gone chemotherapy jumping from one to the next.

I think there is certainly a population difference between ZUMA-1, JULIET, and likely TRANSCEND compared to the L-MIND. Now don't get me wrong. The data that tafa and lenalidomide is putting out is impressive, 40% response rates. I think at EHA [European Hematology Association], they just looked at the duration of remission in those people at 2 years. There's definitely some synergy here because lenalidomide alone is not putting up those numbers in relapsed/refractory large cell lymphoma. Your PFSs is around 3 to 4 months.

That's even in combination with rituximab, where you'd say lenalidomide re-sensitizes rituximab. I guess of the one thing that I would have been looking at in the RE-MIND study is in R2 [[lenalidomide (Revlimid) and rituximab] arm compared with the lenalidomide alone arm, I mean they went a lot of patients looking for lenalidomide monotherapy patients that met the criteria for the L-MIND to compare 1 to 1. I think another thing that would've been interesting is, you kind of hinted at that Dr Maddocks, is the GCB [germinal center B-cell] or ABC [activated B-cell] with lenalidomide where we've seen data from other groups, at least retrospectively that maybe there may be some GCB patients that do respond. 

With the follicular lymphoma data with R2 that GCB, there has to be some people out there that would respond in that setting also. But the data is impressive. I do have concerns about what is CD19 manipulation or perturbation going to do a CAR T-cell? There is some preclinical data with tafa and looking at cell lines, and that it does engage the same CD19 antigen that you'd expect that the CAR T cell would go after but at least in cell lines, it didn't appear to affect CAR T-cell.

That needs to be bore out in reality because I think we're going to see, if this drug does get a label or is in use, a lot of it getting use because it is an IV therapy, given weekly for a lot of doses up front and an oral therapy that people are very comfortable with using in lymphoma and multiple myeloma. We'll get a lot of use and I think we're going to have to be very, very on top of our game as CAR T-cell lymphoma doctors to really capture the data of those patients who are previously tafa-len­ exposed that don't respond or get a PR [partial response] and go to CAR T-cell therapy to see what the true durability is. That's only going to come out real-world experience data rather than a commercially funded experience.

I'm going to ask both of you, Kami and Matt, in a second if you had both of those approaches available, how would you think about it? But first, I want to ask Nathan, Nathan you’ve been very involved with lenalidomide studies in several different contexts. The RE-MIND study took a historical group of patients treated with lenalidomide alone and then the prospective treated with a combination of tafasitamab and lenalidomide and try to combine them.

We have to be careful about retrospective vs. prospective comparisons, etc, but what's your take on the logic and at least the biology of why lenalidomide might work with this drug, and your take on this combination in this particular setting?

Matt said it very well. The thought is with lenalidomide, at least in the lymphoma space, is that there is augmentation of antibody response that's possibly due to change antigen recognition, increasing NK cell activity in T cells. That would make a lot of sense, combining a drug like that with a monoclonal antibody is going to make that monoclonal antibody better. That has a lot of people scratching their head; why is CD19 so much better than CD20 when you add lenalidomide?

D19 probably has some other affects within the microenvironment. We know that it's involved in signaling within the B cell. It's involved in mixed signaling. There may be something else that's different about combining CD19 with rev [Revlimid]; is it somehow affecting the microenvironment? I don't think we truly understand why at least with the data we have, we don't have anything head to head. If you look at the phase 2 studies with R2 which we did here at [The University of Texas] MD Anderson Cancer Center, the response rate and the PFS is dramatically shorter that we see with CD19 plus rev.

If you look at the duration of response in the CR [complete response] patients, it's phenomenal data that they just published in this paper. It's like 80%, 90% in patients achieved a CR. I know that's not the answer to your question. I'm not sure why the mechanism looks so different when you hit CD19 versus CD20 combined with Revlimid. Revlimid has multiple mechanisms, probably related to how they are affecting nonmalignant cells within the microenvironment, and that clearly is important with CD19.

CD19-Directed Therapies for Treatment of R/R DLBCL

 Kami and then Matt, when I look at ASCO [American Society of Clinical Oncology], what I look at ASH [American Society of Hematology], I was just looking at EHA [European Hematology Association] abstracts. It's session after session of safety of CAR [chimeric antigen receptor] T cells. My eyes glaze over as a nontransplanter. We know there's cytokine release. We know there are neurologic toxicities. We know that steroids can potentially affect efficacy. How do you package all this together in a way that tells us what to do going forward? First, Kami, your thoughts and then Matt after that.

As you mentioned, the neurotoxicity and the cytokine release are the two biggest concerns with these therapies. There is a difference in the two approved products: one has a higher rate of higher-grade neurotoxicity, one has a higher rate cytokine release syndrome. Early treatment and preventing toxicity has gotten better over time, as Matt has already mentioned.

Looking at early use of steroids was shown to be able to decrease the toxicity, although a recent abstract suggests that that maybe high dose steroids, early on in the course, has a higher rate of decreasing response. Other agents such as IL-6 receptor antagonist tocilizumab have been used to prevent or help with higher grade cytokine release syndrome. Intrathecal chemotherapy has been used to help with neurotoxicity. There is a score developed to help gauge if patients are developing neurotoxicity and the grade at which that is. Over time, certainly we been able to recognize what these toxicities are and treat them early on to prevent them from being higher grade.

 Matt, how do you look at these toxicities? Something else I'll ask you to comment on is, I think we focus on CRS [cytokine release syndrome] in neurotoxicity but there's also low immunoglobulins, infections, neutropenia, all those things that people in the community may be getting these patients back 6 months later and have to be aware of at least. So, your thoughts on those.

 We're still learning in the what I call the day 28 and before. We're absolutely still learning in the day 29 and beyond. You're absolutely right, Dr Leonard, when you send these patient back out in the community, you're having those discussions. I call it the double dip. You see the CYFLU cytopenias and then they recover. Then you see potentially cytopenias that occur again in the midday 20s that can extend to people who are transfusion dependent. They do require intermittent growth factor support for neutropenia. Sometimes, it's 1 dose. Sometimes, it's multiple doses. Over time you can see that they can improve. There has been data looking at that, that the cytopenias do improve. We don't often know when to incorporate IVIG [intravenous immunoglobulin]. I sort of use the CLL [B-cell chronic lymphocytic leukemia] principles as a sign of recurrent sinopulmonary symptoms rather than an IgG level that I would start to use IVIG, given that we have a national shortage of it from that standpoint.

I try to comfort the community physicians, saying that if this person is at day 100 and ACR [albumin‐to‐creatinine ratio] in their hemoglobin is 8.5 and their platelets are 50 and their neutrophils are 1.1, that's good because the alternative is having those same counts in progressive large cell lymphoma. The data has shown us that it's hard to get those patients post CAR T-cell [transplant] with prolonged cytopenias on a clinical trial so they are not well represented. I'll take a person in a CR1 after double refractory disease but with a persistent not grade 4 cytopenias but grade 2 to 3 cytopenias.

 Just briefly, are you doing outpatient administration at University of Nebraska Medical Center? I know that there are been some data presented at ASCO around outpatient and readmissions and other things. What's your take on that at your center?

 We do outpatient autos. We are set up to do outpatient CAR-T. We were ready to do it on TRANSCEND but then accrual was held. We have not done it in an axi-cel product to date. I think that it would require substantial outpatient but a floor above us in the hospital type of approaches to outpatient. I do think the data, which is the pilot study with liso-cel as well as some other experiences and TRANSCEND, was looking at where there was outpatient administration. If you have later onset of CRS and neurotoxicity, you may be able to get several days beyond infusion before they may need to be brought into the hospital. For a fair number of people, when you start off in the outpatient, the general expectation is that you're going to spend some of your CAR T cell in inpatient. You may get away with doing it completely as an outpatient in a small percentage. But the safety profile is going to matter.

 To close our discussion with on CAR Ts, I want to ask Nathan just to remind the audience, from your perspective, of patient selection because for many people in the community, they're not going to be administering. They might be, but for most people it's going to be referring the patients. We want to be sure that people at least know who to refer to for a consultation and a discussion. Any kind of guidelines you would give people as to who to send as far as the disease, the timing, the age, CNS involvement from your perspective?

 A good rule of thumb is if you have a patient that is not eligible for a transplant, for example due to age, but has a good heart—meaning good ejection fraction—and normal kidney function, that's a great patient to send for a CAR T cell. There is now, again a couple of retrospective looks looking at patients that are elderly that would not qualify for transplant and do quite well. I've referred patients and have given CAR T cell to patients all the way up to age 86 and many of them have done quite well. That's transplant ineligible but otherwise have good organ function. The other large group of patients, are transplant failures. Those patients should be evaluated for CAR T cell. It's the most appropriate and the most effective option for those kind of folks.

I think those are the two big buckets. Generally, chemo refractoriness means that patients don't do too well with auto transplants. To Matt's point, in patients who have refractory disease, even before they fail their second line, I'm already thinking about CAR T cell. So those are patients that are not in the FDA label yet but the majority of patients that are primary refractory are going to end up a CAR T cell. The sooner you start thinking about them, the better.

 Kami, I think the unmet needs around CAR T cell are very similar to where we started this discussion around R-CHOP, more effective therapy, less toxic therapy, easier to do. Are there any other unmet needs that you would throw into the CAR T-cell scenario? Clearly, there are a number of new drugs that are being combined. The question is will they make it more effective or less toxic?

You're exactly right. There are studies looking at improving upon CAR T, so using different constructs, adding other medications, either pre-or post-infusion to try to improve the efficacy, and then all of the areas that you mentioned.

 John, something you mentioned and I didn't talk about is relapsed large cell lymphoma in the brain. There is some data with CNS lymphomas. Now that I think about it, that is another population, relapsed large cell, that I would consider for in the brain.

 We've seen some small studies at ASCO and otherwise that have suggested that responses can be seen and potential value in that setting.

CAR T in R/R DLBCL: Safety and Patient Selection

 Nathan, in a minute I'm going to ask you about the long-term follow-up and reality for older patients but I want to ask Matt quickly about a couple of abstracts presented at ASCO [American Society of Clinical Oncology]that are fairly preliminary but intriguing at least. One abstract addresses re-treating patients and the other addresses moving towards a second line. How do you see all of that emerging?

 If there is a second product that's made and a patient relapses at 12 months and had a CR [complete response], I would determine if they're an allo [allogenic stem cell transplant] candidate to know that you could go to allo and they won’t have high-grade toxicity. The data shows for patients that have a response without much toxicity, CAR T cells, compared with chemotherapy in a double- or triple-refractory patient, have good odds to get you into remission. 

I would try to consolidate and use the CAR-T cell as a bridge to a different form of cellular therapy, allogenic stem cell transplant – which we have been using for much longer than CAR-T cell therapy –if they are able to. In a person who I can't bridge to something, I'd be looking for a CAR-T cell plus a novel combination or not doing it at all if it was too cost prohibitive.

 Kami, what do you think about second-line therapy? There was data presented at ASCO suggesting that the PR [partial response] patients still do well with an auto transplant. We have randomized trials looking at second line CAR T versus chemotherapy and transplant. What are your thoughts on that at this point? Is there a patient in practice, assuming you have access, where you made choices in that? Or do you pretty much give everybody the second-line chemotherapy at this point?

At this point, if there was a trial with 1 of the products and now there's a second trial looking at those early progressives or those patients who were refractory, and if I can get them on the trial for a potential for the CAR T therapy as opposed to just giving them chemotherapy, that's great. Otherwise, I will give them just chemotherapy. We are going to see a benefit to giving CAR T to refractory patients as opposed to just giving them platinum salvage and auto transplant.

As far as a patient's response to chemotherapy, that depends on how you define the PR. If somebody gets only a partial response and still has a ton of disease versus if somebody hasn’t achieved a CR but they have very minimal disease activity, there is probably more benefit to proceeding to transplant in that second population. I think the one area of interest is patients who are not candidates for auto transplant but maybe they are candidate for CAR T. There is no real definition the candidacy for CAR T, but it is typically somebody with at least reasonable performance status, good cardiac function or lung function. In that group of patients, there was an ASCO abstract that showed being able to infuse CAR T and that group of patients who were considered transit candidates for transplant is a great group to target for this therapy also.

 Nathan, [The University of Texas] MD Anderson [Cancer Center] has been involved, as has Ohio State University Medical Center and University of Nebraska Medical Center with some of the earlier trials. What's your experience with the long-term follow-up of patients treated with CAR T in relation to data presented at ASCO? I tend to tell people it's 3 thirds; a third of people have a long remission, a third have a short remission and transient benefit, and a third get 0. Is that what you tell people or how do you look at it?

 We've seen long-term follow-up along with real-life experience with two of the big CAR T cell products. You hit the nail on the head. Matt's analogy of apples to apples to apples applies here. Although the response rates and the CR rates are a little different, the long-term durable remissions across all 3 of these products is in the mid-30s to the low 40s with most of these patients. That tends to be confirmed with not only long-term follow-up but the real-life experience with a lot of these trials. We've also seen the outcome of elderly patients. There was an abstract in this recent ASCO suggesting that elderly patients also do fairly well with CAR T cells, slightly less well but still you're looking at 20%, 30% of patients that are probably going to be cured in the elderly population.

ASCO 2020 Data: CAR T in R/R DLBCL

We would all argue that a patient who is a transplant candidate is going to get a second line chemotherapy regimen, whether it’s RICE [rituximab, ifosfamide, carboplatin, etoposide], RGDP [rituximab, gemcitabine, dexamethasone, cisplatin] or 1 of the other platinum-containing regimens. Certainly if I have a CR [complete response], they’re going to go on to get an autotransplant as of today. There were some data presented at ASCO [American Society of Clinical Oncology Annual Meeting] suggesting that even if they had just a PR [partial response], they could do well with an autotransplant. That’s an area where there has been some uncertainty, and we’ll come back to that in a few minutes.

Patients who get autotransplant and relapse or are multiple refractory CAR [chimeric antigen receptor] T cell have become the standard approach, assuming the patient is a candidate. I’m going to ask you, Matt, to give us a brief summary of the 3 leading agents in the setting and how you think about them. We will come back to some of the new data presented at ASCO and otherwise. How do you think about CAR T cell, Matt?

 When I see that primary progressive or primary refractory patient in the frontline setting who is transplant eligible, I’m already starting to discuss CAR T-cell therapy at their initial visit. While they can go on second-line platinum-containing regimens, I still think there is a high probability that they’re not going to have chemotherapy-sensitive disease and that I’m going to want to take them down the path of a consolidated transplant.

CAR T cell is such a complex process. Just wait until 2 to 3 cycles of second-line therapy, then drop that discussion and it can leave their heads spinning. There are a lot of logistics to do a CAR T cell, like there are a lot to get into doing a transplant. Having already started that process or having people aware that you could go down this road, when that PET [positron emission tomography] scan occurs that doesn’t show that a response is amenable to consolidated transplant, you can quickly pivot to CAR T cell. That’s the important part that we’re all preparing for, both in the commercial setting and previously in the clinical trials. Right now, there are 2 commercially available CD19-directed CAR T cells: axi-cel [axicabtagene ciloleucel] and tisagenlecleucel. They both had single-arm data, both with the ZUMA-1 as well as JULIET. Liso-cel [lisocabtagene maraleucel] is in late-stage development and has been presented multiple times, yet it is to be published from the TRANSCEND [NHL 001] data. I described them as all 3 apples. They’re not apples and oranges, but they’re 3 different types of apples. They could be Fuji apples, Red Delicious, and Granny Smith apples. They do have subtleties to them, just as each apple may taste a little different, but they’re still apples. The overall response rates are, on average, 70% to 80%, their CR rates are anywhere from 40% to 50%, and their PFS [progression-free survival] actually lines up at around 6 months.

There are still a lot of patients post CAR T cell who are progressing. But on the flip side, there appears to be durability. If you can get to CR in 6 months, 30% to 40% of the patients may derive benefit to the point where you’re just starting to discuss that this is now 3 chances to cure diffuse large B-cell lymphoma up front after an autotransplant and potentially after CAR T. For those double-refractory patient populations, if you have your ducks in a row, you could get that narrow window of disease stability and go to a CAR T cell. You have to be previously treated with 2 lines of therapy to get a commercially available CAR T. I still think there is room for improvement in clinical trials in CAR T from that standpoint.

From the available or close-to-available agents, what’s your quick-and-dirty bottom line? I know there are a lot of researchers, a lot of studies trying to compare apples and oranges. To me, it seems like they’re more similar than they are different, but what are the key distinctions from a clinical perspective?

 I try to get the CAR T cell that I know, when I perform apheresis, will be coming back and I can infuse it. We’ve gotten better over the last 5 to 6 years that we’ve been trying to manage toxicities. We’ve gotten better at managing toxicities, and we’re looking at strategies to manage toxicities better to try to prevent those grade 3, 4 CRS [cytokine release syndrome] and neurological events but being mindful that you don’t want to affect the efficacy of the therapy by the risk-mitigation strategies you’re using.

Getting it out and getting it back in the shortest period of time is key because large-cell lymphoma doesn’t care that the coronavirus [pandemic] is going on or that it’s the weekend or a holiday; it’s going to grow. What the data are showing us is that ALK matters. LDH matters. You don’t want to perform apheresis and not infuse.

Role of CAR T-cell Therapy in R/R DLBCL

I want to get into stem cell and CAR [chimeric antigen receptor] T [cell] and more aggressive approaches in a minute. Before we get to that, I’m going to ask for Kami’s thoughts on the less aggressive approaches or the nontransplant approaches. Let’s say a patient who had R-CHOP [rituximab, cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone] is in their late 70s, relapses 2 years later and is not a transplant candidate. What’s the chemotherapy approach for that patient? And we now have the CD79B antibody-drug conjugate polatuzumab. How do you think about the approach to the nontransplant candidate at this point?

Typically a patient who is a nontransplant candidate, if they’ve had a prior response to chemotherapy, the first thing I’m going to offer them is R-GemOx [rituximab, gemcitabine, oxaliplatin]. About half the patients or a little better than half will get a response, although it’s usually less than half who have received prior rituximab again, which is going to be everybody we see anymore. In less than 6 months, patients will get a response.

We do now have this CD79B antibody-drug conjugate polatuzumab available in combination with bendamustine or rituximab chemotherapy. In the United States this is approved as third-line therapy, although it sometimes can be given in the second-line setting. It’s approval is after a patient will have failed another treatment at relapse. This approval was based on a randomized study that compared it with BR [bendamustine, rituximab].

I’ll be honest, the responses to bendamustine-rituximab, while it is active in large cell, are very short lived. The trial showed that adding the polatuzumab to BR significantly improved the rate of overall response, complete remission, and the progression-free survival close to a year. This is an option I offer patients who are candidates for treatment for the chemotherapy because it includes BR.

The downsides are that it does cause more cytopenias—and that can be a problem when patients received prior chemotherapy—and the neuropathy. For most of the patients in the study, their neuropathy improved or resolves, but neuropathy is often a problem in patients who have had R-CHOP [rituximab, cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone] and have had a vinca alkaloid before. Those are the challenges with having that in mind.

It sounds like your approach is a chemotherapy for the nontransplant candidate, a chemotherapy-based approach as a second line, and then going to polatuzumab as part of the third line. Is that more typical? Nathan I’m going to ask your approach in a second as well.

Other options for patients are the oral therapies lenalidomide and ibrutinib, and both have shown to have activity in nontransplant patients. Ibrutinib’s activity tends to be limited to the non–GC [germinal cancer] patients, whereas lenalidomide’s activity is unclear but suggested for those patients. I’ll offer ibrutinib in some of the non-GC patients, and I’ll offer R-len [rituximab, lenalidomide] in some of the patients if I feel that’s a reasonable approach.

I’ll mention because we touched on polatuzumab that there are randomized trials as part of up-front therapy comparing the R-CHOP R-CHP-POLA [rituximab, cyclophosphamide, doxorubicin, prednisone, polatuzumab vedotin] vs. R-CHOP, as well as studies using R-GemOx. Nathan, in your approach in the nontransplant candidate, do you also use chemotherapy, polatuzumab, chemotherapy, novel agents? What’s your general approach there?

There are a couple ways to talk about it. In patients who are not transplant eligible, long-term remission from any chemotherapy-based regimen is only about 15% of patients. If you’re not transplant eligible and you have a relapsed large-cell lymphoma, everything is palliative. We are, in general, trying to hold this thing in base.

I know you can try a lot of different things, but if I have something a patient who is at very high risk of dying of this disease, then I really have to think about the toxicity of any salvage regimen because we want to ensure that we maintain as much quality of life as possible. It’s very different in patients who have a localized relapse because I’ll radiate if I’m not going to transplant. If they are older and have a lot of systemic disease, I’ve seen a lot of good responses with R2 [lenalidomide, rituximab].

We’re seeing some very interesting outcomes in elderly patients with CAR T-cell therapy, so trying to get them into some type of cellular therapy or clinical trial is a great option. Polatuzumab—I do use this. I’m not that impressed with bendamustine as a drug for salvage relapsed large cell lymphoma.

Treatment in Transplant-ineligible R/R DLBCL

Nathan, we have people who relapse after frontline therapy and, to some degree, lack-of-cure meeting relapse is the biggest unmet need that we more or less decided. Patients are either refractory or relapsed, so in your experience, how does that break out from some patients in the double-hit group who progress in the middle of their treatment or soon thereafter, who tend to relapse? How do you shake out the relapse setting as far as patients who have relapsed disease and their presentation and the timing of such?

Those are 2 very different populations, John. Patients who are refractory, meaning they’re progressing during treatment and soon thereafter, and patients who progressed after some interval, somewhere around 18 months to 2 years. Patients who are primary refractory often do very poorly regardless of outcome with regard to standard treatment option. That’s been seen again and again in different types of trials, patients who are either primary refractory or progressing very early. Unfortunately, they do poorly with standard treatment, and that brings up questions. Is this a population for whom we should be thinking of alternative approaches, either some type of cellular therapy or enrollment in a clinical trial? Those are the patients for whom I’m really thinking of novel approaches before trial referral, patients who are refractory to their first line of treatment. I’ve talked to Wyndham Wilson MD, PhD and he’ll tell you patients who are refractory to EPOCH [etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin] in the frontline setting do poorly, which is not surprising since it’s a pretty aggressive regimen. That in my mind makes up somewhere around 10% to 15% of all patients. The other 20% to 25% of patients who relapse 2 to 5 or 6 years later I consider re-exposing to chemotherapy with stem cell transplant as consolidation, assuming that with standard frontline therapy there will be long-term remissions around 60%. There are a lot of data to suggest that those patients actually do well. You can cure about 50% of patients who have a late relapse that you can get into remission and go to transplant. Those are the 2 big buckets. In general, even in those early relapses, I will re-expose them to chemotherapy. The outcomes are much worse than patients who have an interval that’s significant without disease.

How can we identify those patients de novo? That’s a much more difficult question. Are there prognostic markers? Are there genomic findings that can uniformly predict these early relapsed patients? I don’t think so. We talk about double hit, MYC, ABC [activated B cell-like], GC [germinal center B cell-like], and other kinds of prognostic systems coming out of multiple places on the East Coast. Even within those systems, there are groups of patients who do well, such as double-hit patients who do well with CHOP [cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone] and EPOCH. I don’t think we have a uniform way to identify those patients with biological markers de novo. Is there a scoring system that tells me I should have treated this patient differently in the frontline? To me, no. As Kami and Matt mentioned, double hit is probably the only thing I use routinely to stratify patients in the different treatment groups. And that would be something like EPOCH.

Kami, when you see a relapse DLBCL [diffuse large B-cell lymphoma] patient, what are the things that come to your mind as to prognosis in that setting and how you’re going to approach the patient?

Two things come to mind. One, are they primary refractory, or did they get some response to their initial chemotherapy? Second, are they in good shape, and how old are they? What are they going to be a candidate for moving forward with treatment? The first thing I think about at this time is bad outcomes for patients if they’re primary refractory, although we don’t necessarily have, outside clinical trials, any great answer other than giving them more chemotherapy and trying to get them to transplant.

Our randomized studies are ongoing. Look at the use of cellular therapy with chimeric antigen receptor CAR T cells right now, but that’s not something available in the second-line setting. The biggest decision is if they’re a candidate for more aggressive chemotherapy, to try to get them to transplant. Or if the patient is not a candidate for more aggressive therapy, even because of their age, their intolerability to R-CHOP [rituximab, cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone] or R-EPOCH [rituximab, etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin] and their other medical comorbidities, or if the patient is just not interested in that kind of aggressive approach.

Most of the time, regardless of whether a patient is a candidate for transplant, they’ll be offered a second-line chemotherapy-immunotherapy regimen. We know in patients who are refractory to the first-line regimen they don’t respond very well to that chemotherapy. We also know that even patients who respond to the chemotherapy get much less of a response if they have had previous rituximab, which in this era is pretty much going to be every patient.

We’re going to get into the run-of-the-mill patients and how we standardly approach them. But I want to ask you, Matt, are there any patients you would re-treat with R-CHOP [rituximab, cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone] or give a second-line regimen and not transplant them, even if they’re a candidate? I’ve had a couple of people recently who’ve had more or less 7- or 8-year remissions to R-CHOP and have relapsed with large-cell lymphoma again. It crosses my mind, should I just treat them again and not transplant them? Assuming they’re a candidate for transplant, is there any case in which you would try to get away with a less aggressive approach?

If the intent is curative, I would have difficulty not going down a second-line platinum-based regimen and trying to consolidate with an autotransplant. You have to go back to the R-CHOP question and you’re looking at doxorubicin at about 300 mg/m2 of cumulative dosing with 6 cycles of R-CHOP. I can’t say I’ve come across a situation where I’ve said I’m going to give you a second time of R-CHOP.

From that standpoint, the unique ones are the localized relapses that have long durability. If people don’t want to take chemotherapy or don’t want to do a transplant, are you then trying to find some other short-course therapy you could consolidate with radiotherapy? I don’t think that that’s necessarily standard, but everybody on the screen here has always seen those cases that just don’t fit the textbooks.

And they’re trying to figure out some way or some data to explain why you didn’t go down the platinum and transplant route in what would otherwise be perceived on paper as a person who could go to transplant. If you’re in those situations, you’re documenting very heavily what your discussions were and rationalizing why you chose the course you went down. Because anything short of that, unless data show us in the second line CAR T-cell setting, I’m not sure I’m having a curative intent discussion in that setting.

I’m just wondering, John, is there a patient where you think they could have a second large-cell lymphoma, not a relapse, for whatever that risk was that led to the initial large cell? Is there a select group of patients where the relapse is long enough to weed treatments that it’s a new clone? This is something I struggle with, and we hear about these cases in tumor board. In our setting, I’ve treated these patients a couple of times with CHOP and if they’re at 300 mg/m², I’ll do 2 or 3 cycles of CHOP and then 2 or 3 cycles of COP [cyclophosphamide, vincristine, prednisone]. Whether that’s right or wrong, everything is anecdotal because some of them do well and some of them don’t.

You really have to go searching to pathology reports to pull those out. The first was CD5 positive, then relapse, CD10 positive. And then that asks you, do you spend the money proving that the first and the second clones were different? Even in those situations, that clone that’s arising, you have to think it has seen anthracycline and it’s ontogeny of development of the second large cell. Would you even then you re-expose them to it an anthracycline-containing regimen?

Prognosis of R/R DLBCL

® titled “Improving Outcomes in Relapsed/Refractory Diffuse Large B-Cell Lymphoma.” I am Dr John Leonard from Weill Cornell Medical Center/New York-Presbyterian Hospital in New York, New York. Joining me today in this discussion are my colleagues: Dr Nathan Fowler, from The University of Texas MD Anderson Cancer Center in Houston, Texas; Dr Kami Maddocks, from The Ohio State University Comprehensive Cancer Center in Columbus, Ohio; and Dr Matthew Lunning, from the University of Nebraska Medical Center in Omaha, Nebraska.

This is a great lineup of speakers, and I’m really excited to be talking to all of you today. We’re going to focus our discussion on a number of topics pertaining to the use of novel agents in relapsed and refractory diffuse large B-cell lymphoma. We’ll discuss newly available agents, the latest research in the field, the impact of clinical trial, and other aspects of decision-making as we choose therapy for patients with diffuse large B-cell lymphoma. Let’s get started on our first topic.

I wanted to introduce our discussion by highlighting some of the current approaches and unmet needs in diffuse large B-cell lymphoma. As this audience knows, R-CHOP [rituximab, cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone] chemotherapy is the standard therapy for most patients with DLBCL [diffuse large B-cell lymphoma]. We do have different subsets of DLBCL that we may at times treat differently than with R-CHOP. In some cases—for instance, primary mediastinal lymphoma and double-hit lymphomas—we may choose R-EPOCH [rituximab, etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin]. But for most patients, we stick with R-CHOP. One exception is the mini R-CHOP regimen, or a dose-reduced version of R-CHOP in cases of patients who are older and have comorbidities, and may not be able to tolerate standard R-CHOP. I’m going to ask our panel, and I’ll start with Dr Lunning. Are there any other patients besides what I mentioned that you might treat with other regimens? If so, what else is out there that you commonly use for DLBCL patients? Or is my summary pretty much in line with what is described?

 I agree. The double-hit population is always interesting. EPOCH [etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin] is commonly used and we have the results of the CALGB-50302 trial, which had some of those patients in it and randomized dose-adjusted EPOCH vs. R-CHOP. One of the things I often think about when I’ve seen these patients in the second line—because I have either relapsed the disease or pride every progressive—is whether they were dose-adjusted during their EPOCH. That’s in the CALGB study, where the median number of dose-increase or dose-adjustment was 3 mg/m2. For those, if you’re not dose-adjusting and looking at twice weekly CBCs [complete blood counts] to either dose reduce—because sometimes the regimen may be too toxic at the current doses—or consider going up on the dose if they meet parameters because that’s how it was initially studied. The first publication was in 1993, so we’re over 2 decades of using EPOCH in diffuse large B-cell lymphoma. We should try to stick to how the recipe was made if you’re going to use it.

Nathan, what about MD Anderson’s approach? When I visited there some time ago, there were patients receiving infusional doxorubicin. It’s a place that’s been on the cutting edge. What is new there? What are people doing in practice for large cell lymphoma up front?

 is a tough word because it suggests we treat everybody with a similar frontline regimen—CHOP [cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone]–based approaches with rituximab, as Matt pointed out, are the standard of care. We tweak those, for example, in patients who are maybe a little bit older. We, almost universally, use infusional doxorubicin over 24 to 48 hours, still outpatient, but we often send patients with a pump.

As Matt pointed out, double-hit patients pretty much all get R-EPOCH [rituximab, etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin]. There is this gray zone, no pun intended, for patients who don’t have double-hit histology but present with a very aggressive large-cell lymphoma. For these patients with a really high Ki-67, the pathologist comes back and says it’s an aggressive-looking disease under the microscope and maybe the PET [positron emission tomography] scan is really high or they have a lot of high symptoms or high LDH [low-density lipoprotein].

For those patients a lot of my colleagues will lean towards R-EPOCH. This is gestalt; these patients may not have a positive MYC, but they have something else driving this tumor to behave more aggressively. Those are the 2 scenarios in patients who are chemotherapy eligible. That’s a different conversation, and I’d sure might be interested to hear what other people do in patients that won’t tolerate chemotherapy.

Kami, for your approach with higher-risk patients, is there anything different you do as far as prognostic scores or other high-risk features that cause you to deviate from R-CHOP?

 The only thing I would add in this, in adding to R-CHOP, is looking at patients who are at high risk for CNS [central nervous system] progression or relapse and there’s a CNS-IPI [International Prognostic Index] score in calculating that. In patients who are high risk, we’ll add methotrexate for prophylaxis, either as IT or IV. Typically we would do 4 intrathecal treatments or 3 intravenous treatments of methotrexate and also do this in the double-hit patients to whom we give dose-adjusted R-EPOCH. Otherwise, I approach it similarly to everyone here.

I would like to summarize the unmet needs, and I’m going to ask all of you to put your thoughts in on this. It seems like the main unmet need is obviously to cure more patients. We cure the majority of patients, but we certainly want to cure those patients, whether they’re identified by prognostic scores or pathology or other features. We want to improve tolerability of treatment as well. Certainly getting R-CHOP is manageable for most people, but we would like to do something better.

To some degree, we’d like to get away from chemotherapy. It would be nice at some point, if it was better tolerated, to have an approach that didn’t include chemotherapy, cured more patients, was easier to tolerate, and was hopefully affordable. Those are some of the key things. Any other thoughts on unmet needs as you approach it? Matt, what are your thoughts beyond that?

 It’s about trying to get more of the IPI 3 to 5s into the up-front clinical trials in diffuse large B-cell lymphoma, and finding mechanisms to do that as we’ve spent a lot of resources. The CALGB study was a multiyear study. As we move into the next generation of the Alliance for Clinical Trials in Oncology study, for instance, which is looking at that really high-risk population, it is about finding novel strategies to really capture those patients, so the data we see at the end is reflective of the real-world experience in large-cell lymphoma. We are really trying to work on novel strategies to get those patients into the randomized clinical trials.

Matthew A. Lunning, DO, FACP, University of Nebraska Medical Center

Articles