Management of Diffuse Large B-Cell Lymphoma

DR LOVE: Good afternoon, everyone. I’m Neil Love from Research To Practice, and welcome to What I Tell My Patients. This is the second part of a 2-part webinar series, a follow up to the ONS Congress, and today we’re going to be talking about the management of Hodgkin and non-Hodgkin lymphoma. We have a great faculty: Dr Chris Flowers from the MD Anderson Cancer Center in Houston, and Ms Robin Klebig from the Mayo Clinic in Rochester.

As always, if you have any questions or cases you’d like to run by the faculty, just type them into the chat room. We’ll talk about as many of these as we have time.

If you’re into audio programs, check out our podcast series, Oncology Today, including a recent program we did with Dr Lunning on the management of lymphomas. We actually had — we’d never worked with Dr Lunning live until 10 days ago at ASCO when he joined us, and he has a pretty colorful approach to using slides talking about mantle cell lymphoma. I just thought I’d put that in there because I always appreciate it when people use creativity. But we’ll get into some of the wild things that happened in mantle cell at the ASCO Meeting 10 days ago.

We do webinars all the time. On Thursday we’re doing a program with Dr Johnson on targeted therapy of non-small cell beyond EGFR. We have a whole EGFR series separately. Next week we’ll be launching a series on ovarian cancer a series on ovarian cancer with Dr Flowers’ colleagues at MD Anderson, Dr Westin. Then we’re going to be doing a program on upper GI cancer. So much going on with Dr Shah. We’ll talk about that. And the PARP Inhibitors in the Management of Prostate Cancer. That all changed so much in the last few months. We’ll be doing a webinar on that on June the 23^rd. And then we’ll be starting a series with another one of Dr Flowers’ colleagues, Dr Cortes, talking about CML. That should be interesting. And then we’re going to start our EGFR series with Dr Neal on June the 30^th.

Lots going on in oncology and a lot going on for an oncology nurse to absorb, and today we’re going to focus on non-Hodgkin lymphoma and Hodgkin lymphoma. We’ve always, in our ONS programs, always emphasize the triad of the oncologist, the oncology nurse, and the patient in trying to bring these 3 entities together on the same page. That’s one of the main purposes of our work for nurses.

This is the first time we were at ONS. We’ve been going to ONS for 14 years. The last 2 years, of course, we were not able to do it. we were so happy to be back there again seeing people live. It was actually the first live meeting I’ve done since the beginning of the pandemic, and it was just a great experience for everybody.

But we couldn’t — we didn’t have enough time. We did 10 programs there. We didn’t have a slot for this one, so we’re going to do it online here today. And as we often do, we’ve asked the nurse on the program, Ms Klebig, to present some real cases from her practice that we’ll kind of use as a base to really get into the issue of what’s new in these field — this field, and particularly what are some of the new clinical research data that are leading to changes in the management, and in particular how does the oncologist sort through their own experience, the clinical research that they read about, and try to make a recommendation to the patient, and then how can the nurse assist in really explaining that to the patient.

So one of the reasons we want to present real patients is to get into the idea of why was it different to take care of this patient than somebody else with the same disease. So we’re going to start out with diffuse large B-cell lymphoma and this 77-year-old man. Maybe you could talk a little bit, Robin, about how he initially presented. It looked like he — I always separate things into pre or post vaccine. I remember how panicked everybody was in September 2020 because it wasn’t until the beginning of ’21 when we got the vaccine. So he gets diagnosed with advanced diffuse large B cell at the height of the pandemic. What was your first meeting with him like, Robin?

MS KLEBIG: Well, my first meeting with him was after he had started treatment, but exactly as you say. He was very panicked. Imagine being told that you have a disease that you have to have treatment that’s going to make you even more immunosuppressed. And he was a very take-charge individual, and to complicate it he lived 6 hours from us.

So I think, as I mentioned, he was trying to take charge of managing his own response to COVID. He was basically shopping around for a vaccine when they barely became available, and it was kind of frustrating because he expected us to be able to give it to him. But if you remember the early days, we really had no control over where they could get the vaccine or who could even get it. But eventually he made it through without COVID, so…

DR LOVE: Let’s — just to take a step back before we get into some of the new things, Chris, in terms of diffuse — and there are a lot of new things in this very common lymphoma, I’m just curious how you explain to patients what diffuse large B-cell lymphoma is and what the goals of therapy are, and in a situation like this, an older man, but it seems like he’s in pretty good condition, what to expect from the next 6 months, year, or couple years? Generally, what are some of the things you’re trying to communicate to patients?

DR FLOWERS: Yeah. Those are really great questions, Neil, and really key for a patient like this. When we think about diffuse large B-cell lymphoma the average age of onset is in the late 60s and early 70s, and so this gentleman is pretty typical of the kind of patient that you would commonly see. Oftentimes they may have other comorbidities that are involved, and so those are important to consider at that age.

I think one thing that’s important to consider about this gentleman is he lives 6 hours from Mayo Clinic and is a farmer, and so he lives in a rural population. I think some of the new things that came from ASCO that were interesting is that rural patients with cancer were those patients that were least likely to have access to telemedicine, which is probably the patient population that most needs telemedicine as part of their care, and some of the data that we’ve shown is that rural patients actually have worse outcomes with lymphoma in general, and so I think we need to take into account all those social determinants of health when we talk about the care plan as well.

But some important clinical considerations that I discuss with the patient — and when we think about this lymphoma it’s the most common subtype of non-Hodgkin lymphoma and most common type of lymphoma overall. In fact, there’s more diffuse large B-cell lymphoma that happens in the United States than multiple myeloma as a disease entity. And the goal of treatment is cure for the vast majority of these patients, and patients can be cured with standard regimens like this, the R-CHOP regimen, where the vast majority of patients are cured. We saw, when R-CHOP was first developed in 2002, that regimen had a 2-year progression-free survival rate of about 50% to 60%. Now, when we look at the most recent trials, and we’ll talk about some of the data with R-CHOP itself, that 2-year progression-free survival rate is up to about 71%. And so even with the standard supportive care that we use for therapy a patient like this can be cured with standard approaches like R-CHOP.

During those first few months I tell most people they should expect to lose their hair during that 6-month period. They may feel more tired and more rundown, but that usually recovers in that next 6 months so that they’re back to doing their usual activities, and for those who are working, back to performing work and usual duties.

DR LOVE: So this is going to be a prime example of how emerging clinical research may or may not affect clinical decisions. And interesting, Robin, one of the things we talked about going through — when we do the ONS thing it actually becomes an integrated course, not just about the specific topics. And one of the themes we talked about was really for all the terrible things that have happened in the last couple years, I almost feel like people don’t even talk about it much, there’s been a revolution in medicine in terms of the introduction of telemedicine. So maybe we’ll get into that.

But I’m just kind of curious how you evaluate it, you mentioned here that he has a wife with depression and dementia, kind of how — what your take was on what it was doing to be like to try to get him through R-CHOP.

MS KLEBIG: It was really difficult because he didn’t have anybody to help him because he was trying to take care of himself and trying to take care of his wife. And he had friends that he would rely on for rides and things, but that did make it really challenging. Talking about telemedicine, we weren’t able to do telemedicine, but we at least had the portal that he was able to communicate with us, and he used that quite a bit. He would often send multiple messages during the day, and he would actually take photographs and send us photographs. And so in some ways that was to his benefit.

DR LOVE: So this man unfortunately is among the minority of people who wasn’t cured by R-CHOP, and we’ll talk in a second about a new trial that attempted to improve the cure rate, but this man ended up having relapsed disease. You can see a big white spot there on the left side of the neck with adenopathy. Anything else you want to say about his scans in the relapse, Robin? Where was the disease?

MS KLEBIG: Yeah. You can see on that bottom picture, that orange part. So he actually presented at this time, it was just 6 months after completing, thinking he was in remission, and he developed some chest pain. So he went in for a CT scan to rule out a PE, and it found this mass, so unfortunately it demonstrated that he had relapsed just 6 months later, which is not a good thing.

DR LOVE: So we’ll talk a little bit about the management of relapsed diffuse large B cell. This man kind of went down the course of people not eligible for intensive therapy, like transplant and CAR T, but we’re going to talk about those as options for people who are younger and in better condition.

He went down the other route, which now has 4 options, and maybe more coming in the near future, and he actually started out on one of the common initial therapies people use in this situation, tafasitamab/lenalidomide. We’ll talk a little bit about what happened. He had some issues, as a lot of people do, with the lenalidomide. It seems like he did respond but then again had progression. Not unusual in that situation.

I love your — I don’t know if that’s a refrigerator magnet or whatever, but I love the Plan B and your idea. And he got another 1 of the 4 options that’s often given, the antibody-drug conjugate polatuzumab along with BR chemotherapy/rituximab, and now — you can see he had some complications, we’ll talk about that, but now is in CR.

So just to take a step back, Chris, first let’s just talk about the route that this patient took. Maybe I’ll ask Robin, in general, was transplant — autologous transplant traditionally has been a common approach for first relapse, CAR T now, we’re going to talk about in a second, is coming up strong, maybe going to — maybe even before transplant. What was it that led you all to believe that maybe he wasn’t really going to be a candidate for that type and really needed to go down the other route, Robin?

MS KLEBIG: Mostly age for the transplant question, with him being 77. And at that time we knew that CAR T would probably be an option, but it wasn’t used as early. Like right now we would consider it much earlier than we would have back a year and a half or so ago. So it’s probably still on the table if we need it in the future.

DR LOVE: So we’re seeing more and more antibody-drug conjugates coming into oncology, Chris. We had a webinar the other day in breast cancer, where there are 2 antibody drug conjugates just for HER2-positive breast cancer. There are 2 approved antibody-drug conjugates in metastatic bladder cancer. So we’re seeing a lot of that. And here we have 2 antibody-drug conjugates in the relapsed setting, polatuzumab, as I mentioned, with BR, but also a loncastuximab, which is also an antibody-drug conjugate. We’ll talk more about the other options. We mentioned tafa/len, and now selinexor. But Chris, what’s your vision about how an antibody — what an antibody-drug conjugate is and how do you explain that to a patient?

DR FLOWERS: So what when we think about the antibody-drug conjugate it is a way of using antibody-directed therapy to be able to improve outcomes, and I’ll use the example of polatuzumab. Polatuzumab is an antibody against a marker that’s on the cell surface of lymphoma cells, and for diffuse large B-cell lymphoma that’s on about 95% of diffuse large B-cell lymphoma, so nearly ubiquitously expressed. And the antibody binds to that marker, to that CD79b receptor. A naked antibody like rituximab binds to that — binds to a receptor, the receptor CD20, and then it stimulates the immune system to be able to attack the lymphoma cells because of the antibody binding.

When we tried that with CD79b that did not work, and it did not work because when that antibody binds to the cell surface marker it gets internalized by the cell and brought in. And so CD79b — polatuzumab is an antibody-drug conjugate that has both a CD79b antibody, but then tied onto the back of it is MMAE, which is a microtubule inhibitor. And so when the CD79b gets pulled into the cell that drug, the MMAE, inhibits microtubules and then kills those particular lymphoma cells. And so I think that’s where antibody-drug conjugates really play very nicely in this spectrum. Likewise loncastuximab tesirine, or lonca-T, is an antibody-drug conjugate against a different marker on the cell surface, CD19, which is also broadly expressed on B cells.

DR LOVE: So any comments, Chris, about selinexor? We know that’s a drug that’s used in multiple myeloma. It kind of has a reputation of being a little bit challenging to use in terms of toxicity. When and how is it used in diffuse large B-cell lymphoma?

DR FLOWERS: It is a drug that is approved in relapsed diffuse large B-cell lymphoma. It’s an oral medication. It’s what’s called a SINE inhibitor or an inhibitor of XPO1. It is one that I think with the dosing regimens that we typically use has been a challenging one, that it’s associated with profound fatigue, asthenia, and kind of feeling bad all over. And you can see the response rates shown there. It’s available, but I would say is much less commonly used, and it’s typically used in the later lines of therapy for patients with diffuse large B-cell lymphoma.

DR LOVE: So I’m curious how this patient — when we ask people — our way of finding out how people are taking patients, we’ll ask like 20 or 30 docs, and sometimes they all say the same thing and other times you see a lot of differences. In general, when we — when we ask people what they usually start with a common answer that not everybody, but a lot of people, will bring up, tafa/len, because it “seems to be well tolerated” and people can stay on it a long time.

How did he do on the tafa/len? That was his first-line therapy in this situation.

MS KLEBIG: Right. And we’ve used it quite a bit. And you’re right, people tolerate it well, so we thought this would be a good option for him. So generally both are started on day 1.

With this gentleman it took a little bit longer for the lenalidomide to arrive, so we actually started him on tafa. So he had 2 doses of that first, tolerated it well; started him then on the lenalidomide at full dose, and after 2 days, or 2 doses of it, he developed intolerable pruritus of his scalp and a rash, and it was driving him crazy. He couldn’t sleep. This was when he was sending in pictures of his scalp. And he had called in, I think, over the weekend at night. He was using like topical steroids, topical diphenhydramine. Somebody had called in prednisone 20 mg for him. So he, on his own, just stopped it rather than resuming at a smaller dose. He’s just like no, I’m not taking anymore.

So he came in for the second cycle, and we kind of talked him into okay, you’ve got all this onboard, you can have the steroids, just try it again because this is really an important drug. Again, he took 2 days of it, came back, he’s like I am not taking this anymore.

And then after that — as our typical practice after 2 cycles we typically will reimage, but he ended up not taking the tafa/len for a very long period of time.

DR LOVE: So and of course the whole issue of giving lenalidomide in general is a challenge. Obviously, multiple myeloma patients get it for years and years, and you hear of all kinds of ways to deal with the various kinds of toxicities that can evolve. Chris, any comments on your experience with lenalidomide and some of the more problematic issues you run into?

DR FLOWERS: Rash is a problematic one and one that can lead to difficulty with patients tolerating it. Typically what I do is to give patients a little bit of a break and then restart at a lower dose. The more common things that you see with the dosing of lenalidomide, particularly at the higher doses, are problems with cytopenias, and oftentimes those may require lower dosing of lenalidomide for people to tolerate it.

DR LOVE: So this is actually tafasitamab that we’ve been talking about. And this is the L-MIND study that really is the basis for the use of this strategy. And you can see a significant number of patients respond, even complete responses, and side effects and toxicity seem a lot related to the lenalidomide and the challenge there.

What about lonca-T, Chris? This is another antibody-drug conjugate, but this is targeting CD19, also the target of the CAR T therapies. How dose lonca-T work, and what’s your experience with it, Chris?

DR FLOWERS: So it really works in much the same way that I described for polatuzumab. It’s an antibody-drug conjugate that binds to the cell surface and then releases a drug toxin inside of the cell. It’s a regimen or approach that is reasonably well tolerated. It’s produced meaningful responses in the relapsed setting for diffuse large B-cell lymphoma.

The primary results here that led to its approval is from this LOTIS-2 clinical trial, which showed meaningful response rates and tolerability. And you can see there that the main adverse events that are predominantly Grade 1/2 adverse events, with cytopenias being the most common Grade 3/4 adverse events.

DR LOVE: Robin, any experience with lonca-T? And what have you seen in terms of tolerability and efficacy?

MS KLEBIG: We’re just starting to use it here. I did have a patient several months ago that we had on this, and it actually was very well tolerated. We really didn’t know what to expect, because as you can see on that slide you were showing I believe a moment ago, one of the possible side effects is like fluid retention, whether peripheral edema or even pleural effusions and things like that. And another thing that you have to watch out for is skin toxicities like rash or severe photosensitivity.

The patient that I had on it tolerated it quite well. He was again a gentleman from a distance. He just didn’t like having to drive to Rochester, and it wasn’t like — it was only every 3 weeks or so, but otherwise he tolerated it fantastically well and did go into remission.

DR LOVE: So another issue I want to briefly mention, in younger patients who are able to go for intensive therapy, in the past the traditional approach has been autologous stem cell transplant with high-dose chemotherapy. We’ve seen really encouraging results from the use of CAR T therapy with all 3 of these different products after transplant. And Chris, in December at the big ASH Meeting we saw trials actually looking at CAR T before autologous transplant, and 2 of the trials were quite positive. This seems to be a strategy that people are interested in doing. Maybe you can even get people to go to CAR T who maybe couldn’t get autologous transplant.

How do you see this affecting clinical practice, Chris? Do you see this maybe moving CAR T up before transplant?

DR FLOWERS: Yeah. So I think this is 1 of the 2 things that we’ll talk about in diffuse large B cell that will revolutionize and change clinical practice. The other is the front-line trial that maybe I’ll comment on as well. In the relapse setting I think one of the important things to think about is younger is in the eye of the beholder. So the definition that I use of younger is younger than the age of the oldest practicing clinician in our group, and in our case that’s 85 these days.

So while patients up to the age of 77, like the patient Robin presented, would not typically be eligible for autologous stem cell transplantation, there are many of those patients who still would be eligible for CAR T. I just came off the CAR T service here at MD Anderson, and we had 3 patients in the range of 80 or older who were on the service during that time, and so there are many patients that are able to tolerate that, even up into that age range.

The other thing that’s important to think about the patient that Robin presented was the early relapse. And I think for patients who relapse within 12 months the likelihood of responding to more chemotherapy when they’ve already demonstrated that they’re chemotherapy refractory and moving onto stem cell transplantation is probably limited, probably even more limited than we fully appreciated in the past, in at least to 20% or less range, and maybe even in the 10% range. And so I think those are patients where CAR T therapy for the 2 newly approved agents in the early relapse setting are going to be meaningful therapies.

The third change in practice is this trial. This is one that I presented — I was involved in and the US lead for, is the use of polatuzumab in the up-front setting for diffuse large B-cell lymphoma, where we’ve now shown in this trial that the substitution of vincristine using polatuzumab in the R-CHP regimen compared in a blinded randomized fashion to R-CHOP met its primary endpoint with an improvement in progression-free survival, and that that hopefully will be something that gets approved in the future. It was just recently approved in Europe just in the last several weeks.

DR LOVE: And we talked about a lot of new trials at ONS, and as is often the case right now you see a delay or decreased recurrence, progression-free survival, but we’ll have to see long term whether it actually affects survival. Everybody who’s not relapsing is avoiding autologous transplant or CAR T, if you think about it, so that in and of itself where you don’t really — they’re not reporting increased toxicity, so you’re kind of buying decreased — 1 in 4 relapses is being avoided.

Just to finish out on this, just getting back to CAR T, Robin, I’m curious what you say to people with diffuse large B cell in a relapsed situation, where they’re able to receive CAR T, in terms of what to expect in terms of tolerability issues that they’re going to face, and in terms of efficacy because we’re seeing people now who are going 2, 3, 4, 5 years later and still in CR, hopefully cured. What are some of the things you bring up to them who are going for CAR T?

MS KLEBIG: I think a lot of patients are aware of it because they’ve been hopeful if they need it. It is intense treatment, but it’s not quite, I would say, as intense as a stem cell, but it’s kind of 1 therapy. But there are definitely some side effects that you have to prepare them for. For instance, the CRS, the reactions, and also the neurotoxicity, just to be able to prepare them for that.

And as long as you can educate that so that they’re not maybe as nervous or just prepared. And then get them to look at the long view of this is what the potential gain is, why we’re recommending this, and you may have to go to hell before you get to heaven, but it can be worth it in the end.

DR LOVE: So speaking of that, I thought maybe you’d find interesting a video we showed 10 days ago at ASCO. We rarely repeat videos, but to me this case is so memorable I wanted to get some more input on it. We did — I think you both know that we have this thing where we present — we have docs in practice who present cases. And we had an 88-year-old patient with a lot of comorbidities who was a patient of a general medical oncologist in West Redding, Pennsylvania, Dr Rupard.

And I was thinking about when we did ONS last year, and I interviewed I think 25 nurses, including Robin, and I started asking them do people ask you isn’t it depressing to be in oncology. And I started to see that every single person was saying yes, and it got to be kind of interesting to ask people how they respond when they are asked that question. And I think maybe this case has a message that maybe includes the answer. I’m just curious what the 2 of you think about this case. Here’s Dr Rupard.

DR RUPARD: I walked into the room and her entire family, literally, kids, sister, grandkids, all in the room waiting for me.

And she had 40 pounds of weight loss and some fevers and chills. And her primary care doctor had ordered a CT scan which showed lots of relatively bulky lymphadenopathy, so a biopsy showed a diffuse large B-cell lymphoma.

I had a very difficult discussion with the family, Neil. She had a cardiac history. Had a lot of comorbidities as most 88 year olds do. But she did have a decent PS2 performance status.

We sort of jointly agreed to give her a dose of R-CHOP with a 50% dose reduction of the doxorubicin. And then if she tolerated that well, that we would go up to a full dose and see if we could cure her.

So I gave her the treatment. And literally 3 days later, she was in the ICU with a bilateral pneumonia. And after a couple days of struggle, the family chose to withdraw the tube, to withdraw the care, and to no longer pursue any antineoplastic treatment for her. And they were very gracious and thanked me for the attempt. And very, very generous to me about this crummy situation.

She was extubated, but she survived and went home on hospice.

Didn’t think much of the case, until 6 months later when a hospice nurse from that hospice called me and said, hey, I’ve been seeing this patient a couple times a week for the past 6 months and since the first month was over she’s been up and walking around and doing her thing and feeling fine. So is it okay if we discontinue hospice at this point?

So was shocked to hear that she was still alive. I was shocked to hear that she was doing well. And I saw her in clinic a week later and there she was. She looked well. She looked like an 88-year-old, but like a healthy, functioning 88-year-old.

So I sent her for a CT scan and she had no lymphadenopathy anywhere.

DR LOVE: Wow.

DR RUPARD: And I’ve seen this a couple of times, but this was the most dramatic of these cases. My question to your investigators is how many cycles of R-CHOP are actually necessary to cure a patient?

DR LOVE: So Chris, it’s not so much the medical message here, maybe the spiritual message. Any thoughts about this case?

DR FLOWERS: Yeah. I mean this is really awe inspiring. I mean maybe going back to your original question, my answer to that question about isn’t it depressing, I would say no. I mean functioning as an oncologist is the most rewarding career I can possibly imagine. I mean there are so many potential situations like this that come to mind when you bring up this particular case that I’ve seen in my practice throughout the years, including some that are exactly like that.

And then even in situations where you’re not able to ultimately cure the patient, as they described at the beginning, which is where I thought the case was going, there are ways that you can make a meaningful difference in patients and families lives that really matter to them both. And so really everybody that walks in the door you’re intervening in their life at a time when it matters most, and that’s what makes oncology so rewarding.

DR LOVE: And actually, Robin, we had another case over the weekend of a patient with a GI cancer who was basically in the hospital dying, and the hospitalist wanted to send the patient to hospice, the hospital didn’t want to pay for chemo and an IO. The doc talked them into doing it. And they didn’t cure the patient, but all the symptoms went away, and the patient had excellent palliation. So any thoughts about the case, Robin?

MS KLEBIG: About this 88-year-old with lymphoma or the GI?

DR LOVE: Yeah.

MS KLEBIG: Yeah. I think, yeah, the question that he asked, like how much therapy does it take. We see this a lot when people are so sick with their lymphoma, no matter what age they are, but as soon as you treat the lymphoma it’s like they’re a different person. And so that’s one of the reasons that I think we maintain so much hope. It would have been tempting, I think, to just talk to the family and say hey, let’s not — let’s not give up. Let’s just give her a little time and see if — see how she does after a month or so. But then in the end did she really even need any more treatment if you would have tried to give her some more. Good question.

DR LOVE: So —

DR FLOWERS: I’ll give you 2 other quick comments. Yeah, 2 other quick comments —

DR LOVE: Go ahead.

DR FLOWERS: — here, Neil. One is I think as we start to explore more in diffuse large B-cell lymphoma we’re learning more about the disease and the ways that we can treat it. So my colleague Jason Westin, as you know, had this trial where he’s not giving chemotherapy in the first 2 cycles to patients with diffuse large B-cell lymphoma, and we even have 1 patient who never received chemotherapy, received a combination of targeted therapy, and now is 3 years out. So I think as we learn more we may eventually have individuals like that.

My favorite personal story is actually a physician who was in his 60s who had CNS involvement of his lymphoma when it relapsed, and we did radiation. We saw that the tumor grew, and we did PD-1 inhibitors and didn’t really see a response, and then sent him home to hospice and told him he had 6 months left to live.

And for whatever reason he had scheduled an appointment on my clinic schedule that was like a year and a half out because he traveled to come see me. And so a year and a half later he had that appointment. He came in and saw me and said you told me I had 6 months left to live, is that still true now? No, 2 years later you’re no longer still have 6 months left to live. You should go about living your life. And fortunately he had actually been living his life as if he had 6 months to live. He’d had some incredible experiences over that last 2 years.

Caring for Patients with Hodgkin Lymphoma

DR LOVE: So we’re actually starting out with 2 situations where you can see cure with systemic therapy in Hodgkin lymphoma. We’ve known that for a long time. We’re going to talk about another step forward that occurred in Hodgkin lymphoma in the first-line setting and particularly from the point of view of, again, this what does it take to see something come into practice. And actually this is a patient who really benefitted by that because just like we talked about substituting an antibody-drug conjugate, polatuzumab, in diffuse large B cell, this is another similar strategy doing another antibody-drug conjugate, which is kind of like chemotherapy but more targeted, but this is brentuximab vedotin that was added to the AVD regimen.

Before Robin talks about the case can you kind of talk a little bit about the historical evolution of first-line therapy, Chris? Again, I think Hodgkin was maybe the first disease that was cured with systemic therapy. Where were we before the ECHELON-1 study, and then what did ECHELON-1 look at, and how did it change practice?

DR FLOWERS: Yeah. In a lot of ways Hodgkin lymphoma really set the standard for the way that modern chemotherapy has been developed. So really the first chemotherapy regimen that was ever developed was the MOPP chemotherapy regimen. There was a combination of 4 drugs of chemotherapy. And the second chemotherapy regimen was ABVD, and ABVD was really the second regimen because it was a combination of the 4 chemotherapy drugs that were available but were not in MOPP. And so that’s how long that regimen has been around historically.

And what we’ve seen kind of gradually over time, or with additional tries in approaches to improve upon ABVD, that there have been a series of failures that were really no better than ABVD despite changing around different chemotherapy regimens. And so this really stood as the standard of care that produced response rates and cure rates in nearly 80% of patients with Hodgkin lymphoma.

DR LOVE: So Robin, we’ll get to your patient in a second, but this study, which now was just updated at the ASCO Meeting and I think’s going to be presented also in the EHA meeting, now looks with more follow up — and initially, like we were just saying for the pola approach first line, you see progression-free survival advantage without survival advantage, but what you’re really looking for in the long run — and we do now, we’re out — with 5-year follow up of ECHELON-1, and we do see a difference in survival, Chris, in terms of when we switch and take out bleomycin, which is nobody’s favorite to start with, and put in brentuximab. We do see, even though it doesn’t look that impressive on the actual curve, the way it’s plotted right here a significant difference.

We talked a lot in the ONS meeting, and we always have, about the issue of hazard rate, and if you look down there where the 2 things come together you see hazard ratio of 0.59. And what you do is subtract from 100, and what you see is the difference between these 2 curves is actually 41% fewer recurrences — I’m sorry, deaths, this is death, at any given time. And of course we already had seen progression-free survival benefit.

I’m curious, Chris, how you think this affected — we already know that the big intergroup study that’s going to look at the next form of therapy used this strategy as their control, so they felt like it was going to be the strategy of the future. But a lot of docs in practice were not really picking up on it. They wanted to see survival. They were only using it in high-risk people. Now that you have these data out there how do you see it? Do you see this now being kind of accepted as first-line therapy, Chris?

DR FLOWERS: Yeah. So I think the short answer is yes for any patient who would be eligible for this study. What it does summarize was about the 40-year-history of the development of therapy in Hodgkin lymphoma, but what is interesting now is really kind of the 2-year history of this trial.

When the trial was first presented it was presented with an endpoint that’s not really a standard endpoint for clinical trials, a modified progression-free survival. It’s probably maybe a little bit better called event-free survival. But because it was a nonstandard endpoint when the trial was first presented as a positive trial I think the uptake was not so great.

And then eventually they presented the progression-free survival benefit that was seen in this trial, and that showed the hazard ratio that was really preserved in those curves that you just showed. And now with more follow up we now see a benefit in overall survival, and that clearly demonstrates the advantage of giving brentuximab vedotin in combination with chemotherapy up front. And that for these higher-risk patients that were eligible for this trial this is improving not only their likelihood of relapse but their likelihood of survival with Hodgkin lymphoma.

DR LOVE: And Robin, your colleague at Mayo Clinic, Dr Ansell, actually ran this and presented it. When you, in the past or even now, were preparing a patient to get ABVD, which is going to include bleomycin, what are some of the things that you discuss with patients? And then how does that compare to when you’re preparing a patient to receive BV-AVD?

MS KLEBIG: I think the main difference, certainly, with the ABVD compared to the BV-AVD is, as we kind of discussed, the pulmonary toxicity. Of course we always talk about the cytopenias that they might see, or the hair loss, nausea, vomiting. But really when they were getting bleomycin we would have them do pulmonary function tests ahead of time to make sure their pulmonary status could withstand it, and we were watching them like a hawk for those first couple of cycles looking for any early evidence of any pulmonary toxicity because the saddest thing is when you’ve cured somebody from their Hodgkin lymphoma, and they end up dying from pulmonary toxicity. So it was very nice when the RATHL study came out and allowed you to drop the bleo after 2 cycles if they were in a CR, but now it’s nice that you don’t have to have that.

The other thing about that is that when we were giving bleo we were not giving pegfilgrastim with it, granulocyte colony-stimulating factor, because of the enhancement of the potential pulmonary toxicity. So now that we have BV-AVD we just routinely often will give the pegfilgrastim.

DR LOVE: And of course this patient had a lot of problems during treatment, but in talking to you it seemed like a lot of them were from her comorbidities. She has heart disease, atrial fibrillation, multiple cardiac meds, chronic diarrhea. And Chris, typically when you think about Hodgkin you think about younger patients who are in good condition, but you do see a second peak in older people, and there’s been a lot of debate. You still want to try to cure somebody if you can, but now you’ve got an older patient with a lot of comorbidities.

They managed to get her through this therapy. She still now — just completing it now. But what are some of the strategies that have been looked at in these older people, Chris, who — where the thinking is maybe they’re not going to be able to get through chemotherapy? Can you give them BV alone? There have been other checkpoint inhibitors that are very effective in Hodgkin lymphoma. What are some of the creative approaches that are taken in these older patients, Chris?

DR FLOWERS: Yeah. You hit the nail on the head, is that you really need to think about approaches that will help to debulk the tumor and help patients to get through the therapy. And what we found is that the most critical time is really that first cycle of therapy, or those first few cycles of therapy, and so an approach like this one that was shown, giving BV for 2 cycles before giving the chemotherapy, is helpful. Giving reduced chemotherapy, so giving the BV plus dacarbazine, has been an approach.

And the other one that my colleague Pam Allen has led clinical trials on from when I was at Emory, is the approach of using PD-1 inhibitors up front as a way of helping to reduce the tumor burden before adding in the chemotherapy. And so I think all of these are promising approaches that hopefully we will see move forward for older patients with Hodgkin lymphoma.

DR LOVE: And certainly Hodgkin is one of the diseases that’s most sensitive to checkpoint inhibitors. You would think there’s going to be a future up front. It’s just a question of figuring it out.

So Chris, I call this the year of the antibody-drug conjugate. So many wild trials came out. We had an approval in cancer of the cervix. We had this huge trial that was just reported at ASCO, HER2-low breast cancer. It’s half of all breast cancer. They’re seeing responses to an antibody-drug conjugate. Belantamab mafodotin, multiple myeloma, a very important antibody-drug conjugate.

I haven’t seen too many of them, other than polatuzumab, in lymphomas, but what about this camidanlumab tesirine, Chris? That’s an antibody-drug conjugate targeting CD25. What’s the idea behind this, and where do you see things heading? I know there have been some neurologic complications that have been seen.

DR FLOWERS: Sure. So CD25 is found on Hodgkin lymphoma, and it’s found on some other lymphoid malignancies. T-cell lymphomas also have that as a marker. And so it’s an approach similar to the approach that I described earlier using an antibody-drug conjugate where they antibody binds to the lymphoma cells and the conjugated drug works as a warhead that kills both the lymphoma cell that it binds to, and then also nearby cells, presuming that those nearby cells are also lymphoma cells. And so this has been looked at in a Phase I trial in Hodgkin lymphoma.

DR LOVE: And I guess it does seem to have activity, but again, in terms of — I guess the issue is going to be how well tolerated it is. They have reported some Guillain-Barre syndrome, polyradiculopathy. We never know necessarily what we’re going to get into with these new agents. Robin, any experience with this drug?

MS KLEBIG: We have had it here. I’ve seen a couple of patients with it. I didn’t see Guillain-Barre or any of those things, but as you probably can with any of the PD-1 inhibitors just weird autoimmune things like development of type 1 diabetes mellitus in an adult or nephritis, things like that.

DR LOVE: So let’s talk a little bit —

MS KLEBIG: Everybody has tolerated and responded well, but — sorry.

DR LOVE: Yeah, no. That’s always an issue, is tolerability, and a lot of times you find things that work but then can’t be tolerated, kind of your patients were examples of that.

Treatment for Follicular Lymphoma

DR LOVE: Here’s another case of yours. Interesting, this patient’s a nurse at the Mayo Clinic who’s had follicular lymphoma now since 2009, when she was diagnosed at age 53. That must have been a reach shock. I know you were taking care of her almost from the beginning, and I guess now it’s been a number of years. She initially, back in 2009, got R-CHOP, then later on got radioimmune therapy. You don’t hear too much about that, but she got it in 2013, actually did very well. And like many patients with follicular lymphoma she’s had multiple therapies. She got rituximab, and I guess most recently she’s just being observed.

Can you talk a little bit about what it’s been like to take care of her?

MS KLEBIG: Yeah. So I kind of think of her — she’s like living the life of follicular lymphoma. She’s had this for a number of years. She’s had — she’s been in either a partial or a complete remission. She’s needed treatment, we’ve treated her, she goes for a while. And especially back — this is kind of really historical, too, because if you look back at how she was treated initially that was really before we were using something like BR.

DR LOVE: Right.

MS KLEBIG: Most of us probably wouldn’t necessarily use R-CHOP, let alone 8 cycles that she got. And then also just fast-forwarding to when she did get the BR we actually sat down and had a discussion about what the options were, because we did discuss the possibility of using R2 (rituximab and lenalidomide), and she chose herself to go with BR because she just wanted to get her treatment and be done. She didn’t want it to last for a long time. So that was her choice, and it worked well for her. She went into remission, had a little bit of chemo brain, but otherwise — that just kind of made her decide to retire earlier, and she’s enjoying her life now.

But now what we have to think about moving forward is not only looking for when is the next relapse and what will the next therapy be, but we have to think about what is her life because of the risks of the long — the late effects, the late toxicity effects, things like cardiotoxicity from receiving 8 cycles of R-CHOP or secondary malignancies, skin cancers even. Or even with all of the therapy that she had, and the radioimmunotherapy, you think about therapy-related myeloid neoplasms. So thankfully she’s doing well right now, but we keep all those things in the back of our mind.

DR LOVE: And of course there’s always COVID as a consideration, particularly when you have a disease that’s — or you’re using anti-CD20 antibodies, and we’ll get to that in a second. But speaking of anti-CD20 antibodies, we saw at ASH, and we’ve seen before, some data looking at shorter infusion times, which we already have for rituximab, Chris. It looks like a kind of similar principle of being able to do this in 90 minutes is going to apply to obinutuzumab. How do you see people bringing this into their practice, Chris?

DR FLOWERS: I think this is important and useful practical data for infusions of obinutuzumab in the later dosing of therapy. With first dosing of therapy we typically will give a slow infusion to make is more tolerable. But this creates the opportunity for giving shorter duration of obinutuzumab over 90 minutes, the same way we normally would for rituximab in many clinical settings.

DR LOVE: Any comment, Robin? Of course the first dose is always a little bit tricky with obinutuzumab, but what are your thoughts about this shorter duration, particularly after people have gotten through a dose or 2?

MS KLEBIG: Yeah. Similar to rituximab. If they tolerate that first dose, and maybe even the second dose, depending on how the first one went. I can see benefits for everybody. Definitely for the patient, they don’t have to sit in the chair as long, the nurses, even the whole chemotherapy suite. You can get more patients treated during that — during that day of business.

DR LOVE: So Chris, I’m curious about your current thoughts because it seems like this question changes all the time in the last couple years in terms of COVID and let’s just say non-Hodgkin lymphoma for starters because of course we did a program on CLL a couple days ago, and we talked about that as well. But so many issues come up related to COVID, again, particularly in patients where a CD20 is a consideration. We showed the follow up now from the RESORT trial looking at how effective rituximab is in follicular lymphoma.

Everything’s changed. Like every 2, 3 months it seems like, Chris, this whole situation changes. I’m curious from both of you what your current approach is in terms of prevention, vaccines, antibodies, and also what you do when people get it and are asymptomatic. Chris?

DR FLOWERS: Yeah. So with regard to CD20 antibodies, I think these are important data. (1) The data from the RESORT trial that you flashed through that showed that there is a benefit to the maintenance arm in terms of keeping disease away longer and reducing the — or increasing the time before somebody gets an additional therapy.

Likewise, we know from the front-line trials, like the PRIMA trial, that there’s a benefit to rituximab maintenance in terms of progression-free survival. However, in none of those settings is there a clear demonstration of overall survival benefit. And so I think one of the things that the COVID-19 pandemic has called into play is the role that maintenance plays when there is no overall survival benefit for it, and only a progression-free survival or time to treatment benefit.

We’ve seen from data from — Lee Greenberger actually did a nice study utilizing patients from the Leukemia & Lymphoma Society, really kind of a patient group — internet group and collected samples to be able to know how effective their vaccine therapy was. And those who were on an anti-CD20 antibody did not have effective levels of antibodies at that timepoint. And so I think because of that and because of what we’ve seen clinically in terms of COVID infections in those patient populations, I and many others have dropped the use of maintenance rituximab in our clinical practices during this timeframe.

Now we need to continue to monitor as the pandemic goes along, as people are increasingly vaccinated, which we encourage all of our patients to do, to see kind of over time is there a timepoint where we should start to readopt the therapy of maintenance rituximab for those progression-free survival and time-to-treatment benefits in the future.

DR LOVE: So Robin, any comments? And also how are you approaching the use of Evusheld and other preventive antibodies?

MS KLEBIG: I was just going to say. So definitely we’re doing the same thing as Chris, really backing off on rituximab maintenance. There have been a few patients who really strongly want it, and we might — we might do it in that case, but even those patients, we’ve seen them get COVID, and it doesn’t always end well. So definitely we very much encourage the vaccination, the fourth booster, and we definitely also arrange for Evusheld and recommend that.

And people tolerate the Evusheld very well. Some people have difficulty with the vaccine, but it’s certainly a lot better than getting COVID because we’ve seen too many people die from it.

DR LOVE: So let’s go back to new developments in lymphoma. And Chris, in follicular lymphoma we have a targeted therapy that’s captured a lot of peoples’ imagination, an EZH2 inhibitor, tazemetostat. What is EZH2? And how does tazemetostat fit into the management of FL?

DR FLOWERS: Yeah. So EZH2 is a gene that is an epigenetic regulator that affects both the lymphoma cells and may also affect the microenvironment. And what we know is that tazemetostat is an inhibitor of EZH2, an inhibitor that works both in patients who have wild type EZH2 and in those patients who have mutations of the gene EZH2. What we do know is from the biology, is that those patients who have EZH2 mutations that the response rates are higher in that setting.

And that’s shown nicely here with a waterfall plot, where you can see those below the line are the ones that had — or below zero, are the ones that had reduction in their tumor burden. And those who are above the line of zero had an increase in their tumor burden with therapy. And you can see for the EZH2 mutation population that the majority of those patients were responders, with an overall response rate of 69%, meaning that had more than 50% reduction in their tumor burden.

We also saw responses in the EZH2 wild type, as shown on the right, with an overall response rate of 35% in that population.

DR LOVE: And I’ve heard oncologists say since they can give it under the approval, whether they’re wild type or not, that they don’t even do the test because it looks like the wild type does pretty well anyhow. So everybody, theoretically, would benefit. That’s the thinking.

What do you see, Robin, with tazemetostat, both in efficacy and also tolerability? I kind of haven’t heard anything major in terms of tolerability, but what’s your experience?

MS KLEBIG: Honestly, I haven’t seen a lot of it. I maybe have seen 1 patient 1 time filling in for a colleague. I recall that it was tolerated well, but that’s a pretty short picture. I apologize.

DR LOVE: So — well that’s the way it is nowadays. We have the agents coming out, and so many new things, that even investigators aren’t — can’t use them all. I hear that all the time. And it is also challenging, Chris, when you hear about drugs that are in development, not approved, when to get excited or not. Oncologists — I think I’m generally optimistic. I’m always thinking positive, so I try to kind of tone myself down.

But these bispecifics sound super exciting. It sounds to me like maybe these are going to come into the clinic like soon. What’s your take on this, particularly in follicular lymphoma, mosunetuzumab, glofitamab is another one, and I think that’s been looked at with other lymphomas, diffuse large B cell. Chris, it kind of seems like CAR T but can be done as an outpatient and not as many tolerability issues. And it seems like most people respond. I mean what’s your take on where this is heading?

DR FLOWERS: Yeah. I would say these are exciting agents and look for more to come even beyond this. So these are bispecific antibodies in lymphoma against lymphoma targets, with CD20 being the major area of use with mosunetuzumab, glofitamab, odronextamab, epcoritamab, as kind of the agents in that area. But we will see these in other areas of oncology, with CD3 being that marker against the T cells. So a bispecific antibody is binding the lymphoma cell with the CD20 and with CD3 bringing T cells into there for that immune response. And so we will see other markers replacing CD20 to bind to other kinds of tumors in other ways.

In the lymphomas I would expect that we may see approvals of some of these agents or more in the relatively near future and look to see meaningful responses in both follicular lymphoma and diffuse large B-cell lymphoma.

DR LOVE: So I’m curious, Robin, of course one of the things you see with CAR T, you see with cellular therapy, is cytokine release syndrome. But what I hear about these bispecifics is it’s not as severe as what you see with CAR T, and I hear investigators saying we think this can be done as an outpatient, even in a general medical oncology setting. Any thoughts about handling these kind of molecules in a general oncology clinic, Robin?

MS KLEBIG: We actually have some studies with some of these agents, and it definitely depends on the patient. We start out with really low doses, and the majority of them do very well, but you have 1 patient that just really gives you a bad taste in your mouth. But the fact that they are eventually able to get it, as long as you figure out what the premedications are and giving them small doses at a time. And maybe if you have to have them in a situation where if you need to transfer them to an inpatient or a more long-term observation you can do that.

But the other thing to keep in mind with these, in addition to the infusions, is the infection risk. They’ll need to have prophylaxis.

DR LOVE: That’s a really good point. But again, the optimist in me looks at this waterfall plot for mosunetuzumab in relapsed follicular lymphoma is like hey, I think I might want to use that drug.

MS KLEBIG: Yeah.

DR LOVE: And here’s glofitamab, also in lymphoma, so super exciting. And speaking of excitement, so I showed you the wild slides that Dr Lunning showed, just to be funny, the wrestling thing, but we did see some much-anticipated data. Again, another of Dr Flowers’ colleague who presented the data on the so-called SHINE study, bringing in BTK inhibitors, which of course we talk about all the time, with CLL for example, into the up-front setting.

Managing Mantle Cell Lymphoma

DR LOVE: This, I guess, is not an untypical mantle cell case that you had, Robin. Older patient presents and gets the typical therapy nowadays, BR with R maintenance, who I guess responds and then progresses. Interesting progression in the mouth. Did he actually feel this?

MS KLEBIG: He did.

DR LOVE: Was he having trouble swallowing?

MS KLEBIG: No. So this is on his palate. He had gotten a new upper partial maybe a few months earlier, and he just felt like this is really rubbing on this. And so he went to see his dentist, and there’s a mass there. It was kind of a symmetrical mass. But he had a biopsy, and there it was, mantle cell, so…

DR LOVE: Of course we know mantle cell, often you see it in the GI tract, but this is interesting, actually in the mouth. And like most patients nowadays, second-line therapy BTK inhibitor. There are actually 3 approved: ibrutinib, acalabrutinib, zanubrutinib. This patient went on acalabrutinib, which a lot of people would use. Of course it’s used all the time in CLL. And he’s still on that therapy today.

How did he do on the acalabrutinib? We hear all the time — just a couple days ago we were presenting a case of a patient — was it last night, I think, actually, of a patient who got a headache on acalabrutinib, which you don’t really see with the other BTK inhibitors. How did he describe the headache, and what did you do about it? I hear caffeine works.

MS KLEBIG: Yes, it does. We pretty much tell our patients to expect it, but we reassure them that it is typically mild. Sometimes people can use acetaminophen. We make sure they’re well hydrated. You’re absolutely right, caffeine can sometimes help. And we reassure them that this is short lived. This is not something that they’re going to have daily for the rest of the duration that they’re on the therapy. It typically resolves definitely within a month, really just a few weeks, and that’s exactly what happened with him. And he’s tolerating it exceedingly well now.

DR LOVE: And of course this is the study that was just presented by Dr Wang from MD Anderson combining BTK plus chemotherapy/R, bendamustine/R the most common approach. And like a lot of these studies we were just talking about you often see progression-free survival first. That’s what we’re seeing here. So far no effect on survival. Usually what comes after these 2 strategies is going to be CAR T, which is going to have an impact. Of course you do see adverse effects associated with BTK inhibitors. In mantle cell it’s an important option.

But just getting back to the SHINE data, I’m just kind of curious where you see things heading in first-line therapy, Chris. Do you think this is going to be the strategy, chemo/R and BTK? What about BTK alone? Where do you see things heading?

DR FLOWERS: Yeah. So I think this creates a new option for patients for those who are going to get BR in the front-line setting, that adding ibrutinib produces a progression-free survival benefit. I think some of the things that we hope to see move forward are chemotherapy-free regimens in the front-line setting the same way that regimens like ibrutinib and venetoclax are moving forward in CLL. And so we hope to see that in the near future in mantle cell as well.

DR LOVE: And of course we were just talking about in CLL the GLOW study that used ibrutinib and venetoclax is published now, and people are really mulling that one over. We’ll see where that heads.

So we’re going to talk about nontargeted therapy of non-small cell lung cancer on Thursday with Dr Johnson. I’m going to actually have — there’s a doc there in general practice who has 2 patients with NRG fusions, which I’ve never even heard of, but he wants to know how to treat them. So come on in — come on back, same time, same place on Thursday. We’ll hear Dr Johnson says about NRG fusions, ALK fusions, RET, BRAF, you name it. This is oncology nowadays.

Chris and Robin, thank you so much for joining us today. Audience, thank you for attending. Be safe, stay well, and have a great night. Thanks, Chris. Thanks, Robin.

MS KLEBIG: Thank you.

DR LOVE: Take care.