Introduction

DR LOVE: Good afternoon, everyone. This is Neil Love from Research To Practice, and welcome to Meet The Professor. And today we talk about the management of Hodgkin and non-Hodgkin lymphoma with Dr Andy Evens from the Rutgers Biomedical and Health Sciences University in New Brunswick, New Jersey. We have a great faculty for this program, and later on we’ll show you the results of a survey we did of the faculty of their usual treatment practices. This is actually the last in our series that we’ve been doing over this past year for our lymphoma Meet The Professor series.

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

We know a lot of people end up listening to replays of webinars and our audio podcast series Oncology Today. Check that out, including a bunch of interview and presentation programs, including one on the recent ASH Meeting in lymphomas with Dr Lunning.

We do webinars all the time now. Tomorrow we’re really excited to meet with Professor Harrison and talk about myelofibrosis, hear what she has to say about the new approval of pacritinib and the recent long-term follow up from the COMFORT trials of ruxolitinib. And then on Thursday, April the 12^th we’ll be doing our Year in Review series on prostate cancer, and of course talking about the big GU symposium at the end of February. We saw the ARASENS trial with darolutamide and the PROpel and MAGNITUDE trials now in first-line therapy using PARP inhibitors.

Our Year in Review program continues April 13^th with hepatobiliary and pancreatic cancer. We’ll talk about the HIMALAYA study, first-line therapy of HCC, tremelimumab and durvalumab. We’ll see if this gets approved and competes with atezo/bev. Also some great data coming out for cholangiocarcinoma. Maybe we’re going to see IOs and chemo as up-front treatment.

We’ll continue our CLL series with Dr Brown from Dana-Farber’s CLL program, here what she has to say about new BTK inhibitor pirtobrutinib and the GLOW study of ibrutinib study of ibrutinib and venetoclax. We’re going to launch our targeted series in lung cancer on April 18th with Dr Camidge. Of course we’re going to talk about ALK-positive disease and hear what he has to say about some cases.

And then our big, spectacular — we go every year for the last 15 years to the ONS Congress. We’re going again this year at the end of this month. We’re starting out on Thursday morning, 6 am in Anaheim on prostate cancer. We’re finishing 2 days later, on Saturday. We have 15 hours of content, 40 nursing and physician investigators. Really looking forward to that. And we’re doing 10 programs in these 3 days. And another interesting thing about that meeting I want to talk about in a second.

But first I want to kind of tell you where we’re heading today. As always, we have a bunch of docs from community-based practice, in this case a bunch of general medical oncologists who are going to present some cases for Dr Evens to react to. Here’s where we’re heading. We’re going to start out talking about a couple areas of particular interest to Dr Evens, Hodgkin lymphoma and Burkitt lymphoma. Then we’ll move into diffuse large B-cell, FL, then we’ll get into the journal club and see some of the work that Dr Evens has been doing.

But first I want to say something about the ONS meeting. I was telling you, Andy, that I have an announcement here, at least it’s important to me, and that is for the first time in 2 years I’m going to a meeting. I’m going to ONS. I’m finally going to get on an airplane and see what it’s all about again, folks, and see if I can get through this. But I want to know, if you know me, why you think I decided to finally go to a meeting. Because I didn’t go to ASH. I didn’t go to San Antonio, GU, GI, but I think it’s time to do it.

I want to know why. Am I going there because I love to go to Anaheim? Am I going to go there, this is our poll question for the audience, because I want to see whether the Marriott there has gotten Diet Coke in yet? I’m going to because I miss being in airports and TSA. I’m going to go because of the music. I’m going to go because I have a personality disorder. Or you have no clue why I want to go.

Well, Andy, you say 4. Let’s see.

So Andy, you know because you’ve done so many of our live meetings that when we started doing live meetings in 2002, and our AV people say we have to have the best speakers, you know we want all the best stuff. I started listening to those speakers, I’m like well let’s play some music, too, and that’s been what’s going on now for the last 20 years, trying to teach some of the millennials about good music. Any thoughts, Andy? I’m looking forward to it.

DR EVENS: I look forward to it. You’ve got a great ear for the tunes, so that’ll be great, Neil.

DR LOVE: I’m looking forward to it. And our audience, most of our audience is physicians, but talk to your nurses, send them over to Anaheim. Get them there on Wednesday, and they can leave on Saturday. 15 hours. We’re going to have a great time there. Send your nurses over there. We want to see them live. This is going to be an event. It’s not just an education. It’s an event in oncology that we’re really excited about. So let’s see if maybe — and then tune in online too and see what we’re doing.

Case: A woman in her late 80s with Stage II classical Hodgkin lymphoma (HL) — Spencer Henick Bachow, MD

DR LOVE: Okay, let’s start out with Hodgkin lymphoma. We’ve got a bunch of cases that we’re going to get into. And actually later on I’m going to present a case from Dr Gupta that she actually presented to me last summer. I’ll get to that in a second. But as you know, I’ve been doing these — we’ve done more than — we’ve recorded more than 1,500 cases so far using this technique. And I met, actually, with Dr Gupta again yesterday, and she told me about another case that she has that she wanted some feedback on, a patient with Hodgkin lymphoma.

I’m going to present that in a second, but first I want to go to a patient that really represents your interest. And you’ve done such a great job taking a leadership role in Hodgkin’s in the elderly. Everybody thinks about young patients with Hodgkin, but you’ve been a leader in pointing out the number of older people who develop the disease, and the approach there, obviously, is very different. So we’ve got case just for that topic. Here’s Dr Bachow from Boca Raton, Florida.

DR BACHOW: I’m in Boca Raton and Delray Beach, Florida so we have a much older population where I am. So this is garden variety for us. 87-year-old woman who was diagnosed with classical Hodgkin lymphoma. She originally found a mass on her right elbow.

She also had some adenopathy below the diaphragm as well. Mixed cellularity, subtype classical Hodgkin lymphoma.

The patient was very, very reluctant, and so was her family, about doing any form of treatments. She’s in charge, of course.

We repeated a PET scan and it showed right axillary lymphadenopathy that increased in size and avidity, some new inguinal lymph nodes. We felt that she had Stage III disease.

She declined any form of chemotherapy whatsoever.

DR LOVE: What was her functional status?

DR BACHOW: Functional status was very good. ECOG performance status was 0. She had a mood disorder and she had some essential hypertension and hyperlipidemia. She really didn’t have any other comorbidities.

DR LOVE: What’ve been her primary concerns about being treated?

DR BACHOW: She has a son that had ALL when he was in his teens and obviously went through years of chemotherapy.

She saw all the side effects he had.

But it’s a work in progress.

DR LOVE: So any thoughts?

DR EVENS: Yeah. First of all, thanks for the invitation, number 1. Number 2, I love the Monday Night Football Manning setup you have here, Neil. But most importantly, this case. It’s, as you can imagine, not just elderly or older Hodgkin lymphoma patients, but any older patient in general much less over 80 years. It’s very individualized.

But in this specific case it sounds like a fit 80-year-old, although for what it’s worth, and I think it’s a lot, any older patient over 60, especially 70 and 80, I will at least involve our geriatric oncology colleagues and at least perform an assessment of activities of daily living, number 1, and number 2 comorbidity assessment. We use the SIRs-G score. It sounds like a lot. It takes 5 minutes to do. But just based on age alone in most scoring systems she would be unfit, and so even if she didn’t want — I mean even if she wanted chemotherapy she might not be appropriate for it.

So this would be a patient, and there is published data to this end, where single-agent brentuximab vedotin plus/minus maybe a checkpoint inhibitor would be a consideration.

DR LOVE: Can you talk a little bit about what we know about Hodgkin in the elderly and some of the work that’s been done looking, usually single-arm studies, at various approaches to these patients?

DR EVENS: Yeah. To your earlier point, I think it’s more common than we appreciate. We obviously know there’s a bimodal age-related incidence curve that first peaks in the 20s to 30s. And actually, if you look at most recent SEER, that second peak peaks in your 80s. Some of the older SEER data was closer to 60, so I think it’s frankly an aging society of why that second peak has shifted to the right. But another way to say it is about 20% of patients in the United States and Western world with Hodgkin lymphoma are over age 60, so that’s a significant percentage of patients.

And the good news, I would say, not that there wasn’t good work done in the 1990s and early 2000s, but there’s been, suffice it to say, a renewed interest in not just doing retrospective work but actual prospective clinical trials. So now it’s mostly Phase II data, but it’s really data we didn’t have, and so it’s just a lot more data emerging. Of course we need even more.

DR LOVE: So this lady’s actually now progressing on brentuximab. You heard her thoughts in terms of getting chemo. What would you be thinking about in her? And incidentally, she’s 87 not 80.

DR EVENS: Yeah, yeah. And obviously I would have been super careful even with the brentuximab vedotin with neuropathy. I might have started at 1.2 mg/kg in A priority dose reduction, just obviously extreme caution there. I mean really I think the next go-to, especially in someone who was not interested in chemotherapy, would be a checkpoint inhibitor. And we might not call that, I’ll use the word curative, although she’s 87 years old, but even in some of the single-agent checkpoint, whether for initial or in this case relapsed disease, you do see a several-year plateau to the curve. So I would say checkpoint would make a lot of sense.

DR LOVE: Okay. So I found the data from this case here with Dr Gupta. I’m just going to run through it real fast. This is a rocket case, like you’re going down an elevator and somebody’s telling you about a case, because she was curious about your feedback. 21-year-old man last May got COVID, very sick, was unvaccinated, recovered, then developed night sweats, fever, lost 15 pounds, came in, got worked up, pancytopenic, shotty nodes and pulmonary nodules, FDG avid, splenomegaly, liver lesions, bone lesions, Stage IVB disease, offered a clinical trial. He denied it. Classic Hodgkin’s lymphoma, started on chemo with AVBD — AVD+BV. After 2 cycles he had PET — a CR. After 3 cycles he comes in short of breath, hypoxic, gets admitted, does a CT scan, is found to have bilateral ground glass opacities, and they make a clinical diagnosis of brentuximab pneumonitis, which I’m not sure I’ve heard of before.

DR EVENS: That’s pretty rare.

DR LOVE: He gets steroids — steroids, hypoxia resolves. She gives him 1 cycle of AVD and now is trying to figure out what to do. She’s nervous about stopping. He has extensive disease. Any thoughts about what you’ve heard?

DR EVENS: Yeah, a tough one, and I’d obviously want to work through the nuances of that case. I mean obviously I’d want to make sure — it seems, and maybe we’ll just assume it was correct that it was brentuximab vedotin-associated pulmonary disease. Obviously I’d want to make sure it wasn’t COVID related, but assumingly they ruled out he didn’t have a recurrence of the COVID —

DR LOVE: Right.

DR EVENS: — or some other atypical infection. We’ve seen PCP not uncommonly. So to me it would be making sure it’s not infectious would be a lot more common, even though that’s not common, but more common than BV-related pneumonitis.

Interestingly, the reason we have AVD, in other words the bleo’s not included in the initial Phase I/II study that Anas Younes presented, there was a significant proportion when brentuximab was given with bleomycin —

DR LOVE: Right, right. Yeah.

DR EVENS: — of pulmonary toxicity. So there must be —

DR LOVE: Right.

DR EVENS: — some interaction there. But as a single agent it’s pretty rare. In this case, again, assuming all the infectious is definitively worked — ruled out, et cetera, and they think it’s BV, it sounds pretty severe. I probably would finish out with AVD. I wouldn’t add back the bleomycin if he has lung disease. So try to finish out and keep your fingers and toes crossed that AVD can finish it out.

DR LOVE: So yeah, it was brentuximab.

So I think the audience might have heard, as we were coming on we were still talking as we were getting started about the press release that came out on survival in the ECHELON-1 study. And we’ve been waiting for that for a while. Hopefully, we’re going to see that, maybe I guess ASCO would be the logical place, I would imagine. But I was pretty struck by the hazard rate for survival in the press release as 0.59. All this debate going back and forth, hazard rate survival 0.59. Any thoughts or comments? Were you expecting it?

DR EVENS: Quick answer, no, I wasn’t, as much as an optimist I am and a Hodgkin lymphoma guy. But I think in a word or 2 words, Neil, it’s game changing. I don’t think there’s any other way to say it. And in other words we know in the last 20-plus years a preponderance of good, randomized clinical trials, in whether early stage or advanced stage, many of them have shown a progression-free survival, not all, many of them PFS advantage. But this is the first that has shown an overall survival advantage, number 1. And number 2, it’s with a novel targeted therapeutic agent.

And yeah, there were preplanned annual analyses. So to your point on the hazard reduction it was 0.59, relatively we would say a 41% reduction in the risk of death. Obviously, we already know the overall know the overall survival is high, so the actual delta is likely not going to be large. But it’s still — we’ve not been able to say, at least I’ve been doing this a little over 20 years, that we can improve overall survival with any front-line therapy. So obviously you’d like to know who are those patients who garner that benefit, but like most randomized studies, even for PFS, we don’t know. Maybe we’ll be able to flush that out somehow, but it’s an absolute gamechanger.

DR LOVE: It’s so interesting to watch how people respond to new data sets and whether they jump onboard. I was talking the other day, remembering when the BR versus R-CHOP data came out. Nobody could believe it, and for a year or 2 nobody was doing anything, at least not people in practice. They couldn’t believe something would be considerably better than R-CHOP.

So it’s been very debatable over the last 6 years since the data first got presented. I know you were involved in making the decision about what the next Phase III study using — and you all made the decision to use ECHELON-1 as your control arm.

DR EVENS: You’re right.

DR LOVE: And I guess I’m not going to say you got a lot of heat, but let’s just say it was discussed a lot. I guess you all feel a lot better nowadays.

DR EVENS: Yeah, yeah. We do. And it’s not a right or wrong, it’s — it was a judgment call. And let me just say there was significant discussion and debate, so that is S-1826. So to the numbers — so we designed it in 2018, meaning that’s just when E-1 initial data reported out with that initial modified progression-free. But we really went through the data in excruciating detail, and it’s a SWOG-led study, Alex Herrera is the overarching PI. The senior PI is Jonathan Friedberg. But it’s — obviously it’s a CTCN study, so all the cooperative groups, including children’s oncology groups, so that study is enrolling ages 12 and above. And since it’s not PET adapted, and there’s no BEACOPP, meaning there’s no upper age limit, so we’ll be able to enroll older patients, which has been a problem with many of the PET studies because once you include BEACOPP you really cannot/should not include older patients.

But to your point, we — what was our standard of care arm, and we debated back and forth. We said we don’t want to second guess, so ECHELON-1 was our standard arm. The “experimental” arm is nivo/AVD (nivolumab). And just a quick update for your audience, Neil, here, believe it or not we’re almost to — I’m sorry, 800 patients of the thousand planned have enrolled. So we’re really excited. It probably will finish enrollment later this calendar year.

And then lastly I’ll just mention just a lot of really neat correlative studies layered in. A lot of scientific, quality of life, et cetera. So should be some really important information.

DR LOVE: Yeah. That translational stuff should be really interesting.

Speaking of IOs, I meant to ask you before when you were talking about older people, do you ever — would you ever consider just an IO and no brentuximab? For example, somebody with neuropathy. And actually, what would you expect in terms of responsiveness of IO versus BV? Because you had that study. It looked like IO was better.

DR EVENS: Yeah. And first of all, I think I would even step back just 1 quick second, because I think some time and maybe our data/my data has contributed to it, it’s like sometimes I just always want to make sure we’re thinking of cure. Just like you would a 68-year-old or an 80-year-old with diffuse large B-cell. We wouldn’t give them rituximab. You’d at least give miniCHOP. And so you always don’t want therapeutic nihilism, so make sure we don’t throw the chemotherapy baby out with the bathwater.

So — but let’s assume, one reason or another, you just cannot give any chemotherapy, including anthracycline. So there is data with single-agent IO. I can tell you it’s a little disappointing. Yes, you get a decent response rate, but there were some — Lisa presented a front-line study using checkpoint inhibitor plus/minus vinblastine for nonresponders, and it actually closed early just due to increasing relapse rate. And so I wouldn’t say it’s palliative treatment, but it certainly isn’t curative, but maybe for the right patient who either absolutely doesn’t want chemotherapy but is unfit or even frail, maybe I would think about it in that situation.

DR LOVE: I mean that’s a good point because you do see, I don’t know if they’re cures, but you see really long responses with brentuximab. So that’s maybe a little closer to that concept.

DR EVENS: You do. So yeah. I mean I would really think about if I was non-chemo or mostly non-chemo novel it would be BV plus an IO front line, but there’s some more data that’s out there that hopefully will get published soon.

Case: A woman in her early 30s with sclerosing HL who achieved a complete response to ABVD — Priya Rudolph, MD, PhD

DR LOVE: So let’s just go through some other kind of management issues that have come up in Hodgkin lymphoma. Obviously, what we’ve been talking about, first-line therapy, is a critical issue. But I want to hear what — I want you to hear what Dr Rudolph has to say about this 30-year-old woman who is responding to ABVD.

DR RUDOLPH She was started on ABVD and after her first cycle presented with new onset headache, neck stiffness, fever. She was neutropenic at that time and got admitted with a diagnosis of bacterial meningitis and was sent home on a 2-week course of antibiotics which subsequently delayed her second cycle by an additional 2 weeks.

Went on to finish a total of 6 cycles of ABVD. Achieved a complete remission after her 3 cycles with a Deauville Score of 3.

My question, people become very neutropenic with ABVD. Because of bleomycin, we’re not giving them growth factors because of the risk of pneumonitis.

In her particular case, she was admitted with neutropenic fever. So knowing that complication, do investigators use growth factors or do they delay, or do they dose modify?

I could have used the ECHELON-1 regimen; I could have also used the RATHL approach technically and changed her after 2 cycles of ABVD to additional cycles of just AVD without the bleo.

DR LOVE: Any thoughts about this case? Any advice?

DR EVENS: Yeah. Yeah.

DR LOVE: Yeah. It’s the real world.

DR EVENS: Yeah. You’re throwing me some heaters today.

DR LOVE: Yeah. The real world, it’s not like when you put up these simple little — and also a question in the chat room about growth factors with A + AVD, so as long as she brought it up with ABVD.

DR EVENS: Yeah.

DR LOVE: So any thoughts.

DR EVENS: Yeah. I’ll touch on both those. Yeah. So to the point about being frequent that we see neutropenia, we actually have published a paper, when I was at Northwestern 15-plus years ago, about ABVD, and that you’re almost always neutropenic. Interestingly, though, on day of treatment your percent monocytes are almost always up, so it’s almost — I think of that as a pre-neutrophil. And so I was taught, my original mentor, Leo Gordon at Northwestern, never used growth factor. Not that it wouldn’t make a number look better, but what we showed in our albeit retrospective analysis is that yes, everyone’s neutropenic, but at least in younger patients the risk of febrile neutropenia is 0.4%.

So it’s not zero, and so obviously this patient would fall into this 0.4% where she was febrile, and really, bacterial meningitis, very bizarre. I’m trying to think if I’ve ever seen that during ABVD in a younger patient like this. But the bottom line is she had it, and so it’s interesting. So yes, there is that, and I’ll even use the word theoretical risk of increased bleomycin lung, but I wouldn’t say it’s a guarantee. In fact, most of the data, there is animal data, actually, on that, but a lot of it is retrospective data. And so this probably is the rare patient who would probably benefit from growth factor support.

By the way, I probably wouldn’t give pegfilgrastim more than you need. So this would be someone, if I’m going to give GCSF, I know it’s harder to do, but I might give it like days 6 to 10 of a cycle. Usually, you only need like 3 or 4 doses at most. Maybe it’s easier to give Onpro or Neulasta.

But to the other good point that the oncologist made, I would definitely adopt, if she was PET CR, a RATHL strategy and drop the bleomycin; still might need growth factor. So that’s ABVD. AVD: different. You have to use growth factor out of the gate, A priority in all patients all cycles. Without it the risk of febrile neutropenia is over 20%, and you reduce that by at least 50% with growth factor. The upside there, there’s no bleomycin given so you’re at least not concerned about that.

DR LOVE: So we were talking about this paper. You have a bunch of really great papers looking at real-world experiences about ABVD, speaking of ABVD in this case, and I was really amazed by what you found there. Can you talk about it?

DR EVENS: Yeah. And this is maybe, and it is what it is, where there’s maybe a little bit of a disconnect between let’s say pathways, NCCN or whatever, and what happens in the real world. Because many pathways, and this is before the overall survival data, I think it should change, frankly, where there’s a recommendation to use RATHL.

So what is RATHL? So the good RATHL is PET2 negative, meaning Deauville 3, 2, or 1. You drop the bleomycin after 2 cycles. And people forget RATHL included Stage II unfavorable, so not just advanced stage. That study also included Stage II. Our 1826 study is strictly Stage III/IV, so it’s not always apples to apples when you’re looking at these studies.

And it’s one that unfortunately, with any of these PET-based studies, now that there was a randomized study to show it, but if you’re PET2 positive the recommendation on RATHL is escalate to BEACOPP and give 6 cycles of escalated BEACOPP. And the reality is — and what that publication you were showing, and that at academic centers. I bet at other forums with community oncologists, even at academic centers, despite those recommendations, less than 25% of us are escalating to BEACOPP. And in a way I don’t blame them because partly PET positive is not PET positive, but it’s tough to give escalated BEACOPP, and we know there’s false positives on PET. So I just think it’s tough in these PET2-positive patients, and I would just chalk that up, frankly, as still a definite unmet need in Hodgkin lymphoma.

DR LOVE: So just thinking a little bit more about this survival thing that we were just talking about for ECHELON-1, and I’m curious. There’s been this thing out there that AVD is good if you have high risk, but maybe not if you’re low risk, and honestly I never really understood that argument. It’s like if it’s better relatively, whatever. We know how to look at these numbers. Do you think that seeing the survival data’s going to affect the way this high risk/low risk — and did you buy into — do you but into that to start with?

DR EVENS: Yeah. I don’t see how I can’t, honestly. Now I’m speaking for myself and just as someone in the Hodgkin for a couple decades and never seeing an overall survival advantage. How can you not give a patient a treatment that is extending life, increasing the cure not just a PFS? But even before that I wouldn’t say I bought in right away, at the 2-year mark, but I think as we started to see 3-year data, 4-year data, 5-year data, because there was a hypothesis, as there should have been, as well okay, you have this — what was modified PFS, all right? Then we had regular PFS. Are the curves going to come together? So I would say they, if anything, if not stayed stable, widened a little bit.

And then the other good news that we started to see is yes we knew there were increased toxicities like neuropathy, et cetera, but over 3 to 4 years that totally evened out to the 3- and 4-year mark, where there was really almost no difference in neuropathy recovery, and you had that PFS advantage. Now like anything, even 20 years later, who are the 20% of patients who benefit, or 15%, whatever the number, from rituximab in diffuse large B-cell. We don’t know 20-plus years later. We give it to a hundred patients, probably only 15 to 20 benefit. We’d love to know who’s high risk, who should get the rituximab or not.

But I think we have to — I think we overinterpret, honestly, forest plots sometimes. To me those should be hypothesis generating not always super actionable, and so I think some folks that dove into the forest plots and kind of just A priority said it should be this group or that group. I think unless you have individualized patient data, thousands of simulations and machine learning, it’s hard to make those conclusions. And to your point, I think until we have better biomarkers, whether clinical, biology imaging, yeah, it’s hard to make those overinterpretations of the data.

DR LOVE: I call it lumping and splitting, and we argue about this all the time. You cannot imagine how much the argument goes on about PD-1 subsets and whether or not to use it where the subset doesn’t show benefit.

Case: A man in his late 20s with Stage IIA HL — Raman Sood, MD

DR LOVE: Anyhow, one more Hodgkin case, another very common question I hear. This is Dr Sood whose got a 28-year-old man.

DR SOOD: Young guy, minimally symptomatic at this point and had palpable nodes. So, biopsy is confirmed. So he has Stage IIa disease. A mediastinal mass which is non-bulky and cervical lymph nodes. So the question is, we know he’s going to do well, is to sort of de-intensify the treatment.

Instead of 6 cycles that we used to back in the days, can you get away with 4 or 2 cycles? So my plan was to give him 2 cycles, do a PET scan, and if that’s negative, just do 2 more. I would stay away from radiation.

The radiation, everybody can agree that we should not be offering radiation unless there’s residual disease after therapy.

And then the other question was, the brentuximab, is there a role for that? I’ve had different thought leaders have different take on that, the data. Some propose it. Not for this particular patient because he would not be high risk, but somebody with high risk, is that pretty much standard of care now to use that for more advanced disease? So I think I’d like to know more about brentuximab use.

DR LOVE: Any comments?

DR EVENS: Yeah. A lot of good points out of that 1 case. So I guess when it comes to early stage, and maybe every Hodgkin’s, I’m a splitter not a lumper. In other words, not one size fits all. You try to individualize, that’s number 1. Number 2, I’ll quickly say, there’s no maintenance therapy for early stage or advanced stage newly diagnosed. Yes, maybe for post-transplant we might give a year of brentuximab vedotin.

But the only thing I’ll maybe disagree with is I wouldn’t just totally shun radiation for all patients. I think it’s individualized. Now there are some lymphoma experts that say I give radiation to no one. I think it’s individualized, Neil, and I think that’s number 1. Number 2, I try, as hard as it is, you tried to have shared decision-making with the patient. Interestingly, when you look at discrete experiment analyses of patients and providers number 1 most important to patients, not stated this way, is progression-free survival, the highest remission rate, I don’t want a relapse.

And we know, even in the PET-adapted era, even in PET2 negative, if you do not give radiation you will increase your risk of relapse anywhere between 5% and 10%, in some cases higher. And maybe that’s okay if you say well I project in my mind or gut that they’re going to have too many late effects. And I don’t want to minimize late effects, but I think we overestimate certain late effects. Now it depends. This is a man.

And so what I would say in this case, what I heard was mediastinal and cervical. So that would be 2 sites of disease. So he would actually have favorable early-stage Hodgkin’s, so to me a possible treatment I would discuss with the patient would be 2 cycles of ABVD and 20 Gy involved-field radiotherapy. I think that’s common. It’s an option.

If someone, whether a doctor or patient, said no, I want no radiation, then it probably would be 4 cycles. But then you do enter into a little bit of a PET adapted. You know there’s an increased risk of relapse. What are you going to do for PET2 positive? Are you going to escalate to BEACOPP? But the last thing I’ll say is if there is a patient population that probably garners the biggest benefit to involved-field radiotherapy it’s early-stage favorable. We learned that off of H10 EORTC data. So I would at least have the discussion with the patient and not just say no radiation a priority.

DR LOVE: And what about the future of brentuximab in this situation?

DR EVENS: Yeah. The good news is, I guess — how much can I say? Well, it’s public. The good news is there is a protocol approved in North America that’s being actually led by COG, Tara Henderson and Kara Kelly. The protocol’s not finalized, but there is initial letter of intent approval. The protocol’s being written and finalized for a new North American front-line early-stage clinical trial that’s going to involve all the groups led by COG. But it will include all the adult groups, that is going to integrate both brentuximab vedotin and checkpoint inhibitor therapy to front-line treatment as a superiority study over combined-modality therapy, meaning with chemotherapy and radiation, but using kind of like a RATHL or kind of like an H10 like approach. So that probably is a few months away from opening, but everyone should look out for that this summer and fall, for a new North American cooperative group front-line study in early-stage Hodgkin lymphoma.

DR LOVE: So really exciting, and I recommend to the audience, as always we have a bunch of great papers. I really wanted to get to that ASH presentation, but I think we’re just going to move on. But check out the papers in the slide set and all the great work that’s been done by Dr Evens and his team on Hodgkin lymphoma.

Same thing, we put a bunch of — we haven’t talked about Burkitt’s lymphoma in this series, Andy, so I just want to give you like 2 minutes because I know you’re one of the few people who has some expertise in this area. Again, we stocked up the slide set with a bunch of papers that you did. Can you kind of just give us a 2-minute summary of where we are today and what some of the big issues have been the last couple years in the disease?

DR EVENS: Yeah, sure. I mean I think we learned, as everyone knows in the adult Burkitt lymphoma world, a lot from our pediatric colleagues, that initially out of the 1970s and 80s that intensive therapy is important. So whether it was initially hyperCVAD or so-called Magrath regimen, Ian McGrath from the NCI, which was called CODOX-M IVAC. And then we had very exciting data from Wyndham Wilson and Kieron Dunleavy that well maybe kind of medium escalated dose associated — I’m sorry, dose-adjusted EPOCH-R is also a potential curative regimen for patients.

And so that was done. The EPOCH-R data in more single-center studies. And there really hadn’t been a good real-world big data analysis. So thankfully a bunch of colleagues from 30 cancer centers across the United States teamed up, and we were able to put together over 630 untreated adult Burkitt lymphoma patients and put out an initial real-world report in Blood.

And then we wanted to go a further route and say well, we found 4 significant prognostic factors: age 40 years or above, performance status 2 or higher, LDH 3 times normal, or CNS involvement, any CNS involvement, whether parenchymal or lepto, et cetera. And those, whether zero factors, you had a 3-year PFS of 92%, and if you had 2 or more factors it was 53%. And so we went out to external international colleagues, Australia, Europe, and we were able to validate that and were able to come up with a Burkitt lymphoma IPI score.

So that was one thing that came out of it. The other thing that came out of it is there are some patients where I think dose-adjusted EPOCH is just fine. And who are those patients? I would say more lower risk and no CNS involvement. If you start to trend toward intermediate or high risk or — and/or if there’s any CNS involvement probably dose-adjusted EPOCH is not enough. We’re treating someone right now with McGrath CODOX-M IVAC in that same vein. So I think some of that data came out, and we also had a lot of HIV-treated patients with similar themes that came out of it.

DR LOVE: How often do you see it?

DR EVENS: And by the way, Neil, the last thing, I’m sorry, I would say, is I would love, because this is retrospective data, I mean we want to use it as a springboard to a prospective study. And even though it’s rare, we know that, but it’d be great to integrate a novel therapeutic agent and decrease our reliance on chemotherapy even in Burkitt lymphoma. So we’re starting to germinate and discuss that in the cooperative groups.

DR LOVE: I was just going to ask you how often you see a new patient with Burkitt lymphoma. What’s the typical clinical situation and what happens?

DR EVENS: Yeah. I mean we’re treating a patient right now. I saw him in clinic literally 2 hours ago. He’s status post cycle 1 of CODOX-M. So he was at a community hospital and literally, not surprising, had a neck mass doubling in size every 24 hours, got to the point, healthy, young, really otherwise healthy 25-year-old man, just was exploding with disease and also had cross vision, blurred vision, had CNS involvement, transferred here. We actually gave him a prephase because he had almost gotten to where he had a performance status of 2 or 3. I mean really for a healthy guy it is unbelievable.

DR LOVE: Wow.

DR EVENS: Gave him a little prephase, like a CVP or fractionated cyclophosphamide because he had some spontaneous tumor lysis as well, rasburicase, et cetera. And then came in — starting to grow back — I mean significant reduction, started to grow back 2 weeks later, then brought him in for CODOX-M. And he did have some toxicity that’s predictable related to that, but his disease has shrunk back down, so we’ll try to get him through it.

DR LOVE: What a traumatic scenario to be dealing with.

Case: A woman in her late 60s with transformed diffuse large B-cell lymphoma (DLBCL) after R-CHOP with a complete response ­— Justin Peter Favaro, MD, PhD

DR LOVE: All right. Let’s go back to some cases of more common situations. We’re going to start out with a patient of Dr Justin Favaro who has a 69-year-old woman, previous history of localized marginal zone that was radiated, many years later was diagnosed with transformed disease, diffuse large B-cell. Here’s Dr Favaro.

DR FAVARO: My questions are, what do to after completion of 6 cycles of chemotherapy?

She’s got such a high risk of recurrence, would you consolidate her with CAR T therapy? Would she be considered a consolidation for autologous bone marrow transplant?

Any other options to prevent relapse?

Is there any role for maintenance rituximab considering that she did transform from a lower-grade lymphoma?

And I’m also curious about how investigators may try to prevent tumor lysis syndrome in patients that have high-grade disease. She had Ki-67 of 95%. Her uric acid was normal, but her LDH was elevated.

I actually gave her rasburicase prophylactically at the time, right before I gave her the first dose of rituximab. And then the second day I actually gave her the CHOP; she did great. No evidence of tumor lysis syndrome. But I am curious how others will prophylax patients like this.

In patients who have relapsed diffuse large B-cell lymphoma what is the role of autologous transplant versus CAR T therapy? There’s also the substitution of vincristine — POLARIX for vincristine, a recent trial out of ASH. Do you envision us incorporating that data for up-front treatment for our patients?

DR LOVE: So you can imagine we’ve talked a little bit about POLARIX and the CAR T versus transplant trial since ASH, but before we get to your thoughts on it what about this specific case, and also his questions about tumor lysis?

DR EVENS: Yeah. I think you have to be cautious. It’s not super common in diffuse large B-cell lymphoma, but you certainly can see it. I mean I’ll give most patients allopurinol. Now arguably I’m probably overtreating many of them. Usually they just need it for the first cycle. But someone like this with fairly aggressive escalating disease, and obviously especially if uric acid is north of 10 or especially if there’s any early renal dysfunction, in other words true tumor lysis syndrome, then a dose of rasburicase is sometimes all you need. And by the way, sometimes you only need 3, at most 6 mg, and you’ll see it go from 17 to 1 usually off of 1 dose. I don’t follow the package insert for that, just a 1-time low dose like that, and then allopurinol, hydration, et cetera.

To the point of maintenance therapy in someone with transformed lymphoma, that’s a little tricky. Obviously you’re giving the R-CHOP or similar therapy to try to, I’ll use the word cure, the more aggressive transformed diffuse large B-cell lymphoma. But more often than not — the hope is you cure that with R-CHOP or whatever you’re going to give, but more often than not the indolent follicular or marginal zone, whichever the indolent, will relapse down the road. Hopefully it’s 5, 10 years down the road. So I’ll at least think about maintenance rituximab, but really the data there is for follicular lymphoma. So I think it’s at least a consideration, obviously looking at other factors, COVID, patient wishes, et cetera.

DR LOVE: What about his thought, his uneasiness? He wants to do something else. He thinks this patient’s — no way this patient’s going to do well. Thinking about CAR T. I don’t if you could do that. But any thoughts about that?

DR EVENS: Yeah. The quick answer is I wouldn’t do it right now, Neil, just in the absence of I think maybe good data to drive us, at least from an evidence-based standpoint. Certainly are good thoughts, and there are studies — there are studies looking at consolidation in this case with CAR T-cell therapy in high-risk patients. So we should see more data.

Now that’s Phase II data that’s coming out, not randomized data. Though in the past there have been plenty of maintenance studies or strategies looked at in let’s say de novo diffuse large B-cell, not so much transformed like this case, and so far everyone’s been negative. I think part of that is it’s like Burkitt’s less so, where you’ve got to get it early. Not to say maintenance won’t add anything, but I think it’s something that if we’re going to change the natural history of diffuse large B-cell or Burkitt for that matter it’s got to be done, something during those 6 cycles.

Now maybe we just haven’t had effective enough therapy to make a difference, and maybe CAR T afterwards, or some other targeted therapy like polatuzumab vedotin. I would just say the jury’s still out, and as long as the patient enters a complete remission, the most I would do in a case like this would be maintenance rituximab, for the indolent part, not for the diffuse large B-cell.

DR LOVE: So speaking of TLS, how do you deal with that with Burkitt’s? This guy with the thing growing so fast, what do you do there? Do you use rasburicase there?

DR EVENS: We do, yeah. And not at A priority prophylactically, but most patients will have an elevated uric acid, north of 10, and start to have some early renal dysfunction, true tumor lysis syndrome. For sure, yes, in that case. And rasburicase doesn’t improve survival, but it definitely decreases the risk or need for hemodialysis, et cetera. So fluids, rasburicase, starting allopurinol, aggressive electrolyte replacement, and you really have to stay on top of it early and aggressively.

DR LOVE: So speaking of lumping and splitting, and again I refer the audience to the survey that we have in the slide set that goes through a lot of these things, but I really just want to chat here today. So one of the things I was very surprised at in one of the surveys that we have in the slide deck, speaking of lumping and splitting, is that about half of the investigators differentiate based on subtype, A, B, C versus germinal, whether or not they do POLARIX. That really surprised me. I’m curious what your thoughts are about that.

DR EVENS: Yeah. And we’ve had cell of origin for almost 20 years now, and where I feel cell of origin is right now is, I would call it prognostic, in a way. In other words prognostic maybe for just general outcome, and then as we start to integrate treatments into it the question is it truly predictive. And listen, I’m one who’s probably over-published on prognostic markers. But when I say prognostic, Neil, of course that’s meaning some clinical or other factor affects outcome. But is it really predictive and affect benefit or non-benefit from a treatment? And to really cross that chasm from prognostic/predictive you need randomized controlled trials.

Now the question is can you use a forest plot in the absence of a randomized study, like with POLARIX or something, and I just don’t know. And I think we all want to glom onto prognostic/predictive markers, and I think we just have to be cautious. And I think yes, does a study like POLARIX front line, does it look like there’s bigger bang for the buck, figuratively and literally, to patients who are nongerminal center A, B, C and/or patients who have high IPI, yes. But I think, again, unless you have thousands if not tens of thousands of cases and individual patient data and run simulations, I think we have to be a little cautious sometimes in interpreting forest plots.

DR LOVE: So I guess one other thing I’m curious about, again, so much discussion about the papers presented of CAR T versus transplant, 2 out of 3 positive. What are your thoughts?

DR EVENS: I’m sorry, Neil. What was that?

DR LOVE: That was the CAR T versus transplant trials presented at ASH —

DR EVENS: Oh, yeah.

DR LOVE: — in diffuse large B-cell.

DR EVENS: Yeah. And now published in prominent journals.

DR LOVE: Right.

DR EVENS: I think that’s also very important data and probably game changing, as well, because as we know, autologous stem cell transplant has been the standard for multiple decades. Now I would give, like anything, a caveat to that, and it’s obviously they have to fit the study criteria. In other words, these were patients who relapsed within 12 months, and in the case of ZUMA-7 it was they — and understandably, they did not want to muddy the waters, so patients were not allowed with axi-cel to receive any chemotherapy pre-CAR T. And I understand that. And they didn’t, again, want to — wanted a really kind pure study of CAR T versus salvage therapy and autologous transplant.

So I think there’s maybe been some debate in the transplant circles of well, was it — is it EFS (event-free survival), PFS? Overall survival’s too early. But I think that data’s pretty positive and hard to ignore. And we now have at least 2 of the 3 randomized studies with CD19 CAR T were indeed positive. So I think if I had a patient who was fit for CAR T, and they fit the study criteria, then that probably would be a lead option over salvage therapy and stem cell transplant.

DR LOVE: If you could, putting aside reimbursement costs, et cetera, would you enlarge it?

DR EVENS: I think I’m not sure I would. I don’t know. I tend to be, maybe wrongly, a data purist, and I think you try to look outside the bounds. Now clinical trials are clinical trials. We know we’re trying to do a better job of enrolling real-world patients who might not otherwise qualify. But I think I would really probably in this case, even regulatory aside, be strictly in the confines of the clinical trial — of the clinical trial parameters. But listen, to your point, what if someone relapses 14 months after or 13 months, and they have very high-risk disease? I think you tend to individualize those situations.

Case: A woman in her late 70s with relapsed DLBCL — Ranju Gupta, MD

DR LOVE: So let’s go through another case and another development in diffuse large B-cell that’s been so interesting is a series of therapies now that have been approved in the relapsed setting either after CAR T or in people who aren’t eligible for CAR T and transplant. Here’s a case that’s kind of interesting in that regard of a patient who got something a little bit different but still did really well. Here again is Dr Gupta but now on video.

DR GUPTA: She is right now 77 years old and so she had diffuse large B-cell lymphoma. We gave her R-CHOP, complete response, and then within 2 years had relapsed disease. We gave her RICE. She went for transplant. She was about 75 at that time.

Did very well and then within 2 years had relapsed diffuse large B-cell lymphoma. At that time, I wanted her to go for CAR T but she had social issues.

She could not travel.

So, I then put her on rituximab and lenalidomide. She is 3 years out and doing well. Complete response. Complete response.

She was germinal type. She was not even the ABC type.

My question was that should I stop lenalidomide? Because she is doing so well, even after 3 years.

DR LOVE: So before we get to all the other things what do you think about this case?

DR EVENS: A lot of good nuggets there. And so to the point of germinal center/nongerminal center, again, if we were a purist and looking at cell of origin a lot of the early data said the benefit to lenalidomide in diffuse large B-cell lymphoma was nongerminal center. And I think this is a perfect example of why we have to sometimes not overinterpret some of that data. Amazing. I mean it is a little uncommon to R2 to have such a deep and durable response like this, and I don’t blame the oncologists for not wanting to stop. And I think a lot of the studies — obviously we look at CLL and its indefinite treatment for at least like BTK inhibitors and others.

The question — I would say if the patient is tolerating it incredibly well there could be a consideration to continue it. I think I would have, with that said, a low bar to probably stop it, especially if there’s any tolerability or other issues. I mean now 3 years out the vast majority of — whether de novo or relapsed large cell relapses, the vast majority are in the first 2 years from diagnosis or time of relapse. So I wouldn’t be surprised if this patient is “cured” from this.

DR LOVE: So any pearls, clinical pearls or comments about the various alternatives that have are now evolving in this space instead of R2? We have tafa/len, of course we think about that, lonca-T, selinexor, and of course pola/BR. How do you sequence them and any comments?

DR EVENS: Yeah. It’s just an amazing world, and all these you just mentioned — rattled off multiple really new therapeutic tools in our toolkit that we didn’t have 5 years ago. So yes, post CAR T. And yeah, it becomes individualized, and so to me kind of in a case like this — not to say R2 wasn’t right, in fact it worked great in this case. I would have thought — been choosing between polatuzumab vedotin and BR versus tafa/len in this case, and I would have kind of gone pros/cons. I think it’s almost 6 and 1/2 dozen. They have different risk/benefit ratios. I mean the benefit’s probably more similar between them and different tolerability profiles on that.

So I’ve been, just because it was approved earlier, maybe a little more polatuzumab, but I think tafa/len is good. And selinexor is out there, a little maybe down — lower down on the totem pole that’s FDA approved.

DR LOVE: So coming back to the CAR T versus transplant, Dr Friemel in the chat wants to know in terms of eligibility in terms of age, performance status, are there patients who are not candidates for transplant who are candidates for CAR T.

DR EVENS: There are some, but as you can imagine that arguably is a subjective decision for the provider. Now are there obviously objective measures of geriatric assessments, et cetera? I think the one thing that has been really fascinating, and some of it’s come from retrospective real-world CAR T data, has been it looks like age, and obviously there’s other factors that go into it besides a number, does not look to be a prognostic factor, at least for the relapsed/refractory CAR T population with its initial approval. In other words whether below 60/over 60 looks to be quite similar outcomes. Now there might be a little bit of tolerability differences. Now when you start to get north of 70, 80, obviously 80 you have to be a little more cautious.

But I think there are definitely, Neil, a handful of patients who we would argue and submit that probably aren’t candidates for a stem cell transplant, but not that it’s a shoo-in, but probably are candidates for CD19 CAR T-cell therapy.

DR LOVE: Someone in the chat room wants to know is BR always necessary? Can you give pola alone? I’ve heard people ask about just pulling out the B also.

DR EVENS: Yeah. Laurie Sehn led a lot of that data, and she did a fantastic job on that. And so there is single-agent activity to pola/BR. Now we actually haven’t had a randomized study to that point. There was a pola/BR vs BR, and we know at least in a randomized Phase II it looked to be pretty significant PFS with even possible overall survival difference in that, so adding pola.

I don’t know about dropping the B. I mean I’ve honestly not had significant issues, and not to say there can’t be issues. Now with that said, Neil, I tend to be one that tends to be individualized. So if I have a heavily pretreated patient who maybe has had 3 or 4 prior therapies I’ll A priority dose reduce the bendamustine just out of tolerability or if there’s cytopenias that a patient is presenting with, so maybe start 60 or 70 mg/m3, so tend to be a little more cautious with that, whether right or wrong; hopefully right. And so I wouldn’t just throw out the bendamustine because most of our published data is in that combination together.

DR LOVE: So a couple of chat room questions, one from Raji, Dr McKenna, does aging lead to T-cell functional decline. And I guess also in terms of CAR T in terms of collection, et cetera. And Pritpal wants to know what your experience has been using BTK in multiply-relapsed diffuse large B-cell.

DR EVENS: Yeah. So the first question is — what was the first question?

DR LOVE: Do you lose T-cell function with age?

DR EVENS: Oh, T-cell function. Sorry. Yeah. I think of course there’s some loss of T-cell function. Or at least the data I’ve seen as it relates to CAR T is at least anecdotally in the clinic. I’ve not noticed a difference in CAR T collection, but I think that’s a fascinating scientific and biologic question, in fact why there’s a number of ongoing clinical trials using IOs or other therapies before, during, or after checkpoint. Can we augment T-cell function not maybe because of the age discrepancy, but at least because of the can we enhance even better the outcomes of T-cell fidelity?

The second question with BTK inhibitors are yeah, it’s still now — we used it a lot more before we had the agents that you just recently rattled off, but it tends to be further down after the FDA-approved agents. And of course we have bispecific antibodies that are really right on the precipice of being approved, 4 different agents. I hope 1 of them in the near future at least, if not more than 1, will be FDA approved for follicular and diffuse large B-cell lymphoma, and those are incredibly active; some toxicity, infectious, et cetera, to manage. So probably a BTK would be further down the line for all of those, but at least going back to cell of origin it also looks nongerminal center, not that a germinal center can’t respond to BTK. But I think if I was going to give it, it would be multiply relapsed.

The one subset that I think maybe has a little more proclivity of activity, Neil, would be primary CNS lymphoma. And many of them are nongerminal center and BTK addicted. There are some combo front-line studies, but I’ve even had single-agent BTK in some bad relapsed CNS lymphoma respond quite nicely. You have to use a little higher dose, at least we think you have to use a little higher dose, in those CNS lymphoma patients.

DR LOVE: What about pirtobrutinib? I was mentioning that before. Such an interesting agent. What do we know about that in lymphomas compared to the typical — the other BTKs?

DR EVENS: Yeah. Very exciting data. Anthony Mato and others have led those efforts in CLL. I think early days in non-Hodgkin’s lymphoma. Again, part of it is that they just haven’t translated over the current, but maybe that’ll have more of a role. And there are, I know, ongoing studies to look at that.

DR LOVE: I’m trying to remember the waterfall plot, but I think that — didn’t they see responses in mantle cell after prior BTK? Do you know that?

DR EVENS: They did.

DR LOVE: I mean obviously in CLL you do.

DR EVENS: Yeah.

DR LOVE: But in mantle cell too, I think, right?

DR EVENS: Yup. Yup. And it wouldn’t be surprising, at least if we look at the mechanism of action there. So I think that’s one that absolutely — that will — if patients indeed are BTK resistant potentially by a different mechanism.

Case: A woman in her early 60s with Stage IIA, Grade IIIB follicular lymphoma — Neil Morganstein, MD

DR LOVE: So let’s do another case here from Dr Morganstein. Let’s call this “common questions in clinical oncology.” Here’s Dr Morganstein.

How about this 63-year-old?

DR MORGANSTEIN: Oh, so this 63-year-old, she came to me as a second opinion. So she’s a lady who presented with a fairly rapidly growing left cervical lymph node. Ultimately, it was causing her pain. She went to see an ENT, who did a resection of it, removed the whole lymph node, and she was diagnosed with a Grade 3 follicular lymphoma.

Based upon her PET scan she had some cervical lymphadenopathy and some mild axillary lymphadenopathy. And interestingly enough her primary oncologist recommended observation, not to do anything. Say, come back in 6 months, we re-evaluated her.

We looked at her pathology again and based upon that recommended a more intensive course with rituximab-CHOP chemotherapy.

So I guess what my question is in Grade 3B follicular lymphoma what is the standard of care? And even more challenging, which we often face, is how do you treat Grade 3A follicular lymphomas? Grade 1/2 are pretty straightforward, but 3A and 3B often get a little bit more complicated.

DR LOVE: Any thoughts?

DR EVENS: Great questions. Neal is awesome. He’s one of our great New Jersey community oncologists.

DR LOVE: Right. That’s right. Yeah. He’s in New Jersey.

DR EVENS: He refers patients. I know Neal. He’s fantastic.

DR LOVE: Yeah. He’s the best. He’s awesome.

DR EVENS: And his entire group. So he actually said it perfectly, and I don’t have a lot to add. And now with that said, a lot of it’s based off retrospective data, Neil, but the 3Bs track and should probably get lumped more with diffuse large B-cell lymphoma. And at least when we look back at follicular-like treatments they don’t garner as much of a benefit, and I would agree, with a true bona fide 3B.

And now you do need careful pathologic description of that because what to me, in a simplistic way, what follicular grade 3B is, you still have follicles in the lymph node, but there are sheets of diffuse large cells within those follicles. And so — and I’ve even seen some lymph nodes where it’s follicular Grade 1/2 over here, 3A over here, 3B over here, and diffuse large B-cell. Once you have any percent of 3B or especially of course diffuse large B-cell, I would treat accordingly to that paradigm.

3As get lumped, and I think appropriately, with Grade 1/2. Now could there be a little bit of a difference when I think if it’s just otherwise same Ki-67, same other imaging, same other everything else? And most of our front-line follicular lymphoma clinical trials are separated as such. In other words, 1, 2, and 3As and 3Bs are often not included for the reasons just elucidated.

DR LOVE: So Andy, thank you so much for joining us today. We all learned so much from you and really appreciate your coming here today. Audience, thank you for attending. Come on back tomorrow night, we’ll see how Professor Harrison can tease out the various aspects of myelofibrosis. Please talk to your nurses about coming to Anaheim, have them there. 6 am April 27^th, on Thursday, we’re going to go for 15 straight hours. I would love to see a bunch of people show up online and there. Be safe, stay well, and have a great night. Thanks, everyone. Thanks, Andy.