Introduction

DR LOVE: Good afternoon, everyone. I’m Neil Love from Research To Practice and welcome to Meet The Professor, as today we talk about the management of Hodgkin and non-Hodgkin lymphomas with Dr Mike Williams from the University of Virginia School of Medicine in Charlottesburg, Virginia.

We have a great faculty for this series and later on, we’ll show you the results of a survey we did of the faculty of their usual treatment practices. As always, if you have any questions or cases you’d like to run by Dr Williams, just type them into the chat room and we’ll bring up as many of these as we have time today.

We know a lot of you check out our audio programs, our podcast series, including replays of these webinars. We also have our Oncology Today series and we had a recent program with Dr Lunning from the University of Nebraska on papers in lymphoma from the ASH meeting. We do webinars all the time. Tomorrow, we’re going to do a great one on castration-resistant prostate cancer with Dr Armstrong and talk about the big PARP plus hormone therapy trials that were just presented a couple weeks ago at the ASCO GU meeting. And then on Thursday, we’ll meet with Dr Bill Wierda from MD Anderson and talk about CLL and all that’s going on there. Next week on Monday, we’ll be with Dr Aggarwal talking about immunotherapy in lung cancer. And then on Tuesday, we’ll continue our Year in Review program with Drs Plimack and Powles talking about renal cell and bladder cancer. The next day, on Wednesday, March 9^th, we’ll be working with Dr Olin on AML. And then on March 10^th, we’ll start a new series on myelofibrosis with Dr Verstovsek.

But today, we’re here to talk about lymphomas and particularly a glance back at the ASH meeting and all that was presented there and also over the last 6 months and year. As always, we have some general medical oncologists from community-based practice here to present cases to Dr Williams. I sit down with these docs, they present myeloma, CLL, bladder cancer, lung cancer. They’ve got to stay on top of everything, a tremendous challenge, and they do an amazing job.

Here's where we’re heading. We’re going to start out with some cases and discussion about mantle cell, diffuse large B-cell. What an ASH meeting it was for diffuse large B-cell. And then in the second part of the program, we’ll talk about follicular lymphoma, Hodgkin lymphoma. Then, we’ll go through some of the survey results.

But, Mike, I just want to start out with a topic that’s just of some much interest to everyone and you have been contributing a lot of important work and your colleague, Dr Ayers, presented some work at the ASH meeting on the topic of COVID. And your work was looking at vaccines. I’m just kind of curious, in general, Mike, what you presented, but also what’s going on at your place? How you’re dealing with vaccines. How you’re dealing with the antibodies. How you’re dealing with this, particularly in patients on anti-CD20 agents, Mike?

DR WILLIAMS: Yeah. Neil, thanks again for inviting me to take part today. And good afternoon to everyone on the call. So we’re all absorbed in our practices for the past 2 years with COVID questions. And one of the challenges that comes up, especially in our heme malignancy group, is the recognized poor response to many vaccines, but especially to flu vaccines and, say, the COVID vaccines in patients with, say, B-cell malignancies, CLL, lymphomas who are on treatment. But even in CLL patients not treated, they often don’t respond very well just because of the intrinsic immunosuppression. So what we wanted to know is whether patients with these disorders getting a vaccine, an mRNA vaccine for the most part, could mount an immune response. And what we found is that the majority did not get a detectable antibody response using very sensitive, not just the clinical tests that we have in our diagnostic lab, but in a research setting with our immunology colleagues. So most patients don’t get a good antibody response, if any.

But the question is, can they still mount a T-cell response which may actually provide some protection? And so the data that my colleague, Dr Emily Ayers, presented at ASH, and we’re pulling this together now to publish, is that a subset of patients who have no antibody response, we can detect, in fact, show a T-cell response. T-cell assays are tough to do, but we’re going to be very interested to see whether we can show that there’s some level of protection through vaccination. And we’re now looking at what happens when they get boosted. But, Neil, as you said, it’s — we’re now not just in the vaccine world and are they getting a fourth dose as a booster and who gets the monoclonal antibody therapies, either prophylactically or to treat?

DR LOVE: And, of course, that last question, I don’t know if there’s a definitive answer to. But just kind of curious, at your place, what are you doing?

DR WILLIAMS: Well so I know I’m not supposed to say the generic — the trade name, but I don’t know the dual antibodies that are in Evusheld, so I’m using that.

DR LOVE: That’s okay. Oh yeah. We looked that up once.

DR WILLIAMS: Yeah.

DR LOVE: Right.

DR WILLIAMS: Yeah. There’s 2 antibodies there. And as many of you know, you’re probably getting calls from your patients, they just announced that because of the Omicron variant and some of the subvariants, they’re recommending double the originally recommended dose. So we’re having people come back to get another injection. But what we’re doing is patients with high-risk CLL or lymphoma that are on treatment, especially with an anti-monoclonal, maybe they’re on maintenance therapy that they want to continue, we’re giving them the Evusheld antibody prophylactically because their risk of serious infection is really quite high if they were to develop a COVID infection.

Case: A woman in her mid-50s with Stage IV mantle cell lymphoma — Priya Rudolph, MD, PhD

DR LOVE: All right. Well let’s get into some cases here. We’re going to start out with a case from Dr Priya Rudolph, a patient with mantle cell. I’ve got to tell you, Mike, really amusing, last night we did one of the few times we do multidisciplinary meetings. We had Roy Herbst from lung cancer, Sara Tolaney, breast cancer, and Jeff Weber from melanoma. And so, of course, they were trying to compare notes about what’s going on in their field. And at the end, I was saying, hey we’re doing this thing tomorrow night with Mike Williams. And Roy Herbst from Yale said, hey I just took the boards. And I said, Roy, when you took the boards 2 years ago, did they have 3 BTK inhibitors in mantle cell in CAR T? Which is, I think, kind of an indication of how quickly things are going in oncology nowadays.

DR WILLIAMS: Yeah.

DR LOVE: Incredible. You take the boards and 2 years later, it’s completely outdated. Here’s the case from Dr Rudolph. This 56-year-old lady who had mantle cell picked up on a colonoscopy.

DR RUDOLPH: Very healthy, active researcher went in for what should have been a routine 5-year follow-up colonoscopy and it showed patchy moderate inflammation diffusely throughout the colon. Biopsy, interestingly, showed mantle cell lymphoma with a Ki-67 of 10%. There was bone marrow involvement and mild to moderate metabolic activity on a PET scan noted in the neck, abdomen and pelvis. She was Stage IV and was low-risk on MIPI score. I would really like investigators to guide us through how they’re selecting upfront treatment, particularly at her age. Should we be aggressive and give her something like R-CHOP? Or is bendamustine/rituximab, would that suffice with someone with a Ki-67 of 10%? I would love to know if there’s any role for BTK inhibitors in the upfront management of mantle cell lymphoma. I would like to know if there are any significant side effect profile differences between acalabrutinib and zanubrutinib. Has CAR T replaced autologous stem cell transplant in mantle cell lymphoma similar to what appears to be in diffuse large B-cell lymphoma?

DR LOVE: So I told you they could ask a lot of questions in 1 minute, Mike. But maybe we can just start out with your thoughts about this case and how you’d be thinking about management.

DR WILLIAMS: Right. So this is a relatively young individual with Stage IVE disease. She does have low-risk by MIPI, but she’s got the colonic involvement. So she’s going to need systemic therapy. And one of the challenges in mantle cell is that we don’t have a current standard of care for frontline therapy. I think bendamustine/rituximab would be a reasonable choice for this individual. Another option is to use a more traditional high-dose cytarabine-based regimen which has been shown in comparison with R-CHOP to give more complete remissions. And then the other question with this person is going to be, do you do an autotransplant to consolidate that which is a common standard of care for patients under the age of 65 with mantle cell lymphoma in advanced stage? So here’s what I would ideally offer, what we would offer this patient here is the clinical trial that’s being — the ECOG4181. So that’s looking at a standard regimen with BR plus high-dose cytarabine, the R-BAC regimen, versus that same regimen with acalabrutinib or dropping the Ara-C, the third arm is BR plus acala alone. And so that’s the study that we would offer. So it’s asking us, is there benefit to adding a BTK inhibitor in the frontline as you suggested or considered? And the other is, do you really need the high-dose Ara-C if you’re getting a good deep response with BR and the targeted agent?

DR LOVE: So Mike and I were having a little bit of a debate here, so I want to ask the audience a question. We were debating how you were going to answer this. So here’s the question. I want to know, audience, this is a yes, no question. I want to know, in general, do you consider autologous transplant after induction chemo/antibody or chemo/biologic, chemo/R, do you consider that standard of care? Do most of your younger patients like this, not so much this case but, in general, your younger patients under age 60, are you sending them for autologous transplant? Yes or no? So, Mike, we’re going to see what the audience says. Actually, it looks like they’re like about two-thirds saying yes, one-third saying no. What do you say, Mike?

DR WILLIAMS: Well so I would say yes to that. There was a study going back over probably 20 years ago now comparing transplant with no transplant as consolidation and it showed a benefit for transplant. So the study since then in younger patients have typically included an autotransplant consolidation. The LEMA study which did 4 cycles of rituximab plus DHAC, so it’s high-dose cytarabine and a platinum plus dexamethasone, and then everybody got a transplant, these were younger patients, and then they got 3 years of maintenance ritux or no maintenance and their disease free survivals for the people who went on to the transplant were approaching 90% at 5 years. And even the ones who did not get maintenance ritux, still had very good survivals. But there was actually a significant survival advantage for maintenance ritux after an autotransplant. So that’s, I think, a standard of care for younger patients.

Now the other side of that coin is, and Neil and I also talked about this, so now that we have agents and regimens that can give really deep remissions, so negative for measurable residual disease or MRD, the follow-on study that ECOG is doing right now is taking patients who get any induction regimen, so you all can treat patients with BR or R-CHOP and refer them to a transplant center and if they are MRD negative, then they can go into a study where they get randomized to a transplant and maintenance or just maintenance ritux alone. So that’s going to answer, I think, the key question, Neil, that you’re raising is, does everybody need an autotransplant consolidation, especially if they’ve already received a very deep response?

And coming back to Dr Rudolph’s point about bringing a targeted drug like a BTK inhibitor upfront, I think that’s where we’re heading, to get less chemo intensive regimens for these patients and to leverage these really effective targeted drugs like the venetoclax or BTK inhibitors earlier on in treatment.

DR LOVE: So do you consider second line therapy is going to be BTK? If so, which BTK do you prefer? We saw the intriguing data with zanubrutinib in CLL, early data, maybe a treatment benefit compared to another BTK, ibrutinib, maybe not. What about — is that second line therapy? And which agent?

DR WILLIAMS: Right. So I think a BTK inhibitor is second line therapy. And we generally now use a second generation drug, either acala or zanubrutinib. And the reason is that the 3 BTK inhibitors are all equally efficacious. They give good responses in at least 70% of patients. But the second generations have much less in the way of bruising and bleeding risk, they have lower AFib risk and generally better tolerated. So we tend to favor acalabrutinib or zanubrutinib as second line therapy.

DR LOVE: And CAR T third line?

DR WILLIAMS: For younger patients if they’ve not had a transplant, but have relapsed after a second line, then I think CAR T is where I would go next or after an auto for sure.

DR LOVE: Can you kind of provide, rather than going through all the data which we’ve done quite a few times, a more global take on what you expect when you send a patient with mantle cell to CAR T? What a typical outcome is going to be.

DR WILLIAMS: Yeah. So my expectation is that we have several good agents. We can bridge them to that CAR pretty readily with various agents that we have. And the data from the ZUMA trial was that about 90, 93% of patients had a response and about two-thirds of them had a CR. And going out now to 2 years and a little beyond that, somewhere around half of the patients are still in remission. Now whether they’re cured, we don’t know. But for relapsed mantle cell, a lot of these patients would likely have progressed at that point if they were going to. So we’ll see whether we’re seeing late relapses. But I think that’s where I would — that’s my expectation when I refer these patients.

DR LOVE: Any comment on management of very high-risk patients such as blastoid? Any thoughts about going to, you know, in diffuse large B-cell, you’re seeing trials looking at CAR T upfront, is that being done in mantle cell?

DR WILLIAMS: It’s not at this point although I think we’ll be seeing some of that data fairly soon. I’m not aware of active trials that are looking at that subset of patients. But you’re correct that the ones with blastoid or pleomorphic morphology, they often have p53 mutations and those that do have a p53 are really in a subgroup that probably don’t respond or benefit much from an auto. So I think those are places where a CAR may actually be brought in earlier. Historically, we would be taking those young, fit patients to an allo, but I think nowadays, we would be thinking CAR rather than an allo at that point. But we’re sort of out on the fringes of limited number of cases. But that, I think, would be the discussion.

DR LOVE: I was just flashing on some papers we’re going to go through with Dr Wierda on Thursday in CLL about BTK and del(17p). Pretty good outcomes with BTK.

DR WILLIAMS: Oh yeah.

DR LOVE: What do we know about BTK in mantle cell in del(17p)?

DR WILLIAMS: They’re more effective than chemotherapy. So I think if you know you have a 17p deletion or a TP53 mutation, then I think you want a targeted drug, either a BTK or venetoclax, in the mix.

DR LOVE: So speaking of venetoclax, a couple papers of yours I just wanted to ask you about. First, this review article on leukemic variant of mantle cell. Want to give us sort of a snapshot of that?

DR WILLIAMS: Yeah. So this is a reminder that mantle cell lymphoma is a real specter of disease. We just got through talking about the very high-grade blastoid subtypes, but there’s also an indolent subtype of mantle cell that presents like CLL. And so it’s often leukemic phase, splenomegaly, minimal adenopathy. And these patients sometimes can be followed for months or even a few years without treatment. So it’s important to recognize this subset and A, not to confuse it with CLL and B, not to think, oh it’s mantle cell and it’s leukemic so that’s a bad thing and you have to be very aggressive with it. So that’s an important subset to understand.

So we’re also looking at combinations of targeted drugs. And this is one that my colleague, Dr Craig Portell, just published. And there was another study from Constantine Tam and the European group. So ibrutinib has marked synergy with venetoclax as well as proteasome inhibitors and so this combination is a very active regimen for relapsed refractory mantle cell. And I think things like this will find their way into earlier lines of therapy.

DR LOVE: So a question from Tavestan in the chat room. I think what the question is, is whether these patients that you were just talking about, leukemic type of mantle cell, do they tolerate intensive therapy? Do they have the marrow to tolerate it? Is there any difference than, say, the regular mantle cell patients?

DR WILLIAMS: Yeah. Good question. I think they might well have more cytopenic complications in the early going. But these are patients that you may be able to — I’ve treated some elderly patients with just a monoclonal antibody alone, rituximab, for example. Or you can use cycles of just BR as we do in CLL.

DR LOVE: Here’s another good one, it’s great to have you on, you’ve had such a leadership role in mantle cell over the years, from Hassan in the chat room. What about bispecifics? So exciting in other arenas.

DR WILLIAMS: Yeah. So it’s still early days in mantle cell with the bispecifics. So not a lot of information there. So can’t say that I can quote any at least preliminary or promising data about what role they’re going to find. Mantle cell has become kind of a — it’s interesting that when it was first discovered now 25+ years ago, it was really a challenging disease to treat, but now it’s actually been a pathway for approval for lots of targeted, several of the targeted agents. So it’s been a really good clinical model to understand response to these targeted drugs.

DR LOVE: I can remember when we were all excited about having, I think, 3 agents. There was bortezomib, lenalidomide all of a sudden and then 2 years later we forgot about all that.

DR WILLIAMS: Sure.

Case: A woman in her early 50s with nongerminal-center DLBCL with renal, adrenal and cardiac involvement — Neil Morganstein, MD

DR LOVE: Anyhow. Let’s get back to our cases here. We have a young patient, 52-year-old woman who presents with nongerminal cell diffuse large B-cell with extensive involvement. Here’s Dr Morganstein.

DR MORGANSTEIN: Her CT scan showed very advanced disease, renal involvement, adrenal involvement, cardiac involvement. She had infiltration of her myocardium. And she was just started on dose adjusted R-EPOCH which she is currently in the first cycle of right now. Already, the mass on her forearm has shrank by 90+%. So I guess my question is, and we have this all the time, who should be treated with dose adjusted R-EPOCH? Who do we do CNS prophylaxis? And what is the ultimate prophylaxis that we use? More recently, there’s been this wonderful tool, this CNS IPI tool and if we could discuss that. And then how should CNS prophylaxis be given? Are we still doing IT therapy? Or is there any role for high-dose methotrexate in these patients? How often do you see myocardial involvement with diffuse large B-cell lymphoma? How do we give EPOCH? Is it given through a port or through a PICC line? And then in high-risk lymphomas, is there any role for upfront CAR T therapy? Can you move polatuzumab upfront in high-risk situations? Is that paradigm going to shift now that we have polatuzumab coming out?

DR LOVE: So lots of questions. First, any comment about how you would approach this patient outside of clinical trial setting? Let’s say, put aside reimbursement issues.

DR WILLIAMS: Right.

DR LOVE: Assume you could access polatuzumab for this purpose. How would you think about managing this case?

DR WILLIAMS: Yeah. So this is a scary case. This is really about as dramatically advanced disease as you can imagine and exceedingly high-risk with the renal/adrenal in terms of CNS progression. So that’s an appropriate question, of course. And then the cardiac involvement is just a wild card as far as what that’s going to mean in terms of risk and toxicity. So I think typically, I would be treating this patient historically with R-CHOP, but with the cardiac involvement and this very high proliferation rate, it was close to 100% as I recall, I think EPOCH is a good choice for this patient because the pharmacodynamics of that regimen, especially as opposed to giving, say, a bolus of anthracycline, I don’t know what to expect with the cardiac risk for arrythmias and other complications. So I like EPOCH because it’s got that low-dose continuous infusion which is less cardiotoxic. So I think that’s a reasonable choice in this patient. And it’s important if you’re going to use it to actually dose adjust, not just to stick with sort of the first level of dosing. But if they tolerate it appropriately then to dose escalate them.

The question about how to give the EPOCH, so I usually give the first cycle of EPOCH in hospital, but then after that, I’ll treat them as an outpatient if they’re able to do that, both with logistics of their support and their insurance and things. And I have treated them with a port rather than an external like a Hickman or a PICC line. And you have to be careful about securing those because you don’t want the pump to be infusing these agents subcutaneously. But they’re relatively dilute so I think that you can do it through a port with good caution.

This patient, in terms of the CNS IPI, you’ve sort of created a story here where this person has almost all the high-risk factors. Renal and adrenal involvement alone puts people at about a 15% risk of CNS progression and then high LDH, advanced stage are also risk factors for that. So she’s at a very high risk, probably in at least the 15 to even 20% or higher risk for CNS recurrence. So up until a year or so ago, we would have said this patient needs high-dose therapy and I treat younger patients with good renal function with high-dose methotrexate, 3.5 gm/m2, for at least 2 cycles and I usually try to intercalate that with their other therapy. It’s hard to do with EPOCH because you can’t really dose adjust. But I would be thinking 2 cycles of high-dose methotrexate. The reason for that is that these people often will recur with parenchymal, not just leptomeningeal disease which is why I favor that dose of methotrexate which also covers the spinal fluid compartment as well. The challenge we have now is that there have been a couple of large studies, one of which came from work that my colleague, Dr Portell, did with Dr Orellana-Noia who was a fellow, now he’s on faculty down at Emory. But these retrospective studies have found it very hard to show any benefit for CNS prophylaxis with high-dose methotrexate or intrathecal methotrexate. So then the question is, well what do you do now with a patient like this who is at very high risk? And some centers have stopped doing CNS prophylaxis at all. Others haven’t changed. We’re kind of in the middle ground. And for a patient like this with such high risk with multifocal extranodal disease, renal and adrenal, I would give this patient 2 cycles of high-dose methotrexate and I would put it at the end of the EPOCH induction.

DR LOVE: So I should mention, I forgot to mention, this patient actually presented with a mass on her forearm. That’s how she picked it up and then they found all this other disease.

Case: A man in his mid-60s with bulky DLBCL and gastric outlet obstruction — Anthony Nguyen, MD

DR LOVE: Let’s go on to another case. This is a patient of Dr Nguyen, Anthony Nguyen. A 65-year-old man had progressive gastric outlet obstruction, weight loss and had retroperitoneal adenopathy. Here’s Dr Nguyen.

DR NGUYEN: This 65-year-old gentleman with a long history of COPD, he presented to one of our outside hospitals with abdominal pain, dysphagia in July of 2020 unable to tolerate any oral. CT scan showed a posterior mediastinal mass with extensive thoracic adenopathy. Core needle biopsy was consistent with diffuse large B-cell. His functional status was about ECOG of 2 to 3. He was getting TPN at that time since he had gastric outlet obstruction actually. So I started him on standard R-CHOP and about 3 cycles in, he had a dramatic response. His gastric outlet obstruction actually resolved and he was able to take orals, able to gain weight, his ECOG function basically improved to 0. And I did consult radiation oncology for radiation to initial sites of bulky disease, but they recommended observation.

DR LOVE: Any comments on this case and the issue of radiation therapy?

DR WILLIAMS: Yeah. So this is a patient I would have done exactly what you did. And it shows that you can rescue a poor performance status when they’re poor because of lymphoma symptoms. And so I think R-CHOP was the right choice for that patient. And I agree with the radiation therapists that even though he had this bulk site of disease causing the outlet obstruction, I would not do radiation to the abdomen for that. The — what was it? There was another question, Neil, that —

DR LOVE: I think that was actually the main question that he had on that.

DR WILLIAMS: Yeah. So yeah.

DR LOVE: I wonder — go ahead.

DR WILLIAMS: So R-CHOP without the radiation. Yeah.

DR LOVE: And I just want your thoughts about the POLARIX study and particularly how people are thinking about taking it into practice, assuming it does become available. I think people have seen the data and the key outcome here of progression free survival with a hazard rate of 0.73. At this point, no survival benefit. I just put this trial up because I thought it was super cool. Somebody was asking about bispecifics and it’s so exciting. Glofitamab is really exciting, mosunetuzumab. And here, being combined with R-CHOP, but also POLARIX in a randomized study. Any thoughts about where that might be heading?

DR WILLIAMS: Well I think this is a really important study because we know that with our R-CHOP-based therapies and even with R-CHOP/pola which is showing this incremental benefit, you’re still going to fail in treatment with a lot of these higher risk DLBCLs. So I think bringing a bispecific into the frontline, essentially it’s coming back to your point earlier, Neil, about bringing CAR Ts earlier on. This is sort of an off-the-shelf CAR. It’s a bispecific that’s engaging T-cells with the lymphoma cells. And so this may be a gamechanger for these high-risk patients. I’ll be interested to see where they go.

As far as the pola/R-CHOP, there’s certainly an incremental benefit there. And we’re maybe a conservative group here in Virginia, so we’ve not adopted it across the board yet, but I think when you read through the data, there was more benefit in older patients above the age of 60 who had nongerminal center B-cell type. So we are, in fact, we have adopted it for that group of patients and we may adopt it more widely as we see a little longer follow-up from that study.

DR LOVE: So yeah. I want to let you compare notes with what you just said to what some of your colleagues just said. But just to remind people that also we had these incredible CAR T versus transplant trials also presented at ASH. ZUMA-7 has been published in the New England Journal along with this second line study of tisagenlecleucel, the BELINDA study, which didn’t show a benefit. And then finally, the lisocabtagene trial, the TRANSFORM study, that also was positive, similar incredible hazard rate of 0.4. We’re going to talk a little bit about some of the follow-up treatments to diffuse large B-cell. But, Mike, I want to kind of take you through some of the trial data. I’m just going to kind of skip through these. I want to take you through the survey of your investigators and you tell me whether you agree or disagree. I think we already see that there’s a little bit of controversy at this point about POLARIX. First question we asked the audience — or asked the 20 investigators in the survey we did a few weeks ago was, if it turns out that you don’t see a survival benefit in the polatuzumab study, do you still think it’s beneficial to do this? And the vast majority of the investigators say yeah. But I think you were one of the people that said no. What were you thinking?

DR WILLIAMS: Well I was thinking that I would probably slice it a little thinner and look at what the cell of origin was. And so, as I mentioned, I would adopt it for the subset that I said —

DR LOVE: Right. Yeah.

DR WILLIAMS: But for other upfront patients, I’d use R-CHOP.

DR LOVE: Yeah. We didn’t think to change the survey because I didn’t think people were going to do it. But what you said is exactly what we saw. We’re going to show it in one second. So we also said, what were people’s take, you know, we saw the data, it looked like about similar toxicity, what was their global take? And, again, most people thought that there wasn’t an increase in toxicity by adding or substituting the pola. This is what really surprised me. I just did not expect that people were going to be splitting stuff up like this, but here it is. We say you have ABC subtype, almost everybody says POLARIX. We say germinal cell and now you see a 50/50 or, you know, a split. And that’s what you were talking about. We’ll see whether or not what the FDA says, we’ll see what people do in practice, et cetera. Let me skip here to double-hit. This is interesting too. I guess the issue of dose adjusted R-EPOCH plus pola is not going to be on the table, Mike, or would it be?

DR WILLIAMS: I think for double and triple-hit lymphomas, those patients don’t do well in the majority of cases and so I think, as you saw there, most of us would use dose adjusted EPOCH for that patient.

DR LOVE: So we also wanted to know what they thought about these CAR T trials and most people are pretty excited about it and I think maybe even were almost expecting it. I don’t know if they expected that kind of hazard rate. Mike, are you in that group? Are you ready to go to substitute CAR T if you can at first relapse?

DR WILLIAMS: Yeah. So if you have a transplant eligible patient or a CAR T eligible patient, which is a little broader, and if they had progressed within 12 months or so of their primary therapy, they have a poor-risk and generally a poor outcome with standard high-dose chemo and an auto. And so that group of patients, I think, should be going to CAR T-cell now.

DR LOVE: So one final thing that was interesting, we said what about in a patient who is either not eligible for CAR T or has already had CAR T? And, of course, we have tafa/len as an option, pola/BR which was before POLARIX, and the antibody drug conjugate, lonca teserine, which is also an anti-CD19. So tafa and lonca both target CD19 which is the same target of CAR T. So we don’t see anybody saying lonca or selinexor, at least in this particular situation. Mike, what’s your experience with tafa/len? I hear people say it works and not very toxic. Is that your experience?

DR WILLIAMS: Yeah. It works well. I think our group and probably many of the people on the call today have used lenalidomide/rituximab. So they’re pretty comfortable with using an IMiD-based therapy in the relapsed setting and it can work well. And tafa/len is reasonably well tolerated. You can see a fair amount of cytopenias in these patients with that regimen, but that’s — so you have to do some dose titration for it.

DR LOVE: This comes up in myeloma with BCMA targeted therapy where they have belantamab that’s also BMCA targeted. You have lonca as well as tafasitamab targeting CD19. Are you okay using that before or after CAR T, Mike?

DR WILLIAMS: Yeah. So that’s an unknown right now and most of the time we try to avoid a CD19 if we think that a CAR is in that patient’s future. And so that’s where for those patients if we need to bridge them, we will try to do that with a pola-based therapy. And what we’ll do is actually try pola with just pola/ritux without the benda to see whether you can get a response there. And that way, if you give benda, then it can be harder to collect their T-cells and you can always add it in to the next cycle if they’re not responding sufficiently. So keep in mind things like pola/ritux as a bridge.

DR LOVE: So I got kind of carried away with mantle cell so we’re going to have to skip a couple cases. We’ll throw them at the next person.

Case: An otherwise healthy man in his late 80s with Grade III FL — Laurie Matt-Amaral, MD, MPH

DR LOVE: But let’s move on to follicular lymphoma because we’ve got some great cases here. This is a patient of Dr Matt-Amaral. I love the fact that this 89-year-old man is not on any meds and is out all day long in his yard. I love to hear those kind of stories. But he also has Grade 3 follicular lymphoma that’s a problem. Here’s Dr Matt-Amaral.

DR MATT-AMARAL: The plan is to treat him semi-aggressively as he’s a relatively healthy man. He works outside, he’s very physically fit. I’m sort of wondering how the experts would treat this patient. I’m sort of leaning right now, given some of his side effects and some weight loss that he’s most recently experienced, of doing an R-CHOP type regimen for him, but I don’t know if they think a mini regimen would be more appropriate or just treating him as a follicular lymphoma with bendamustine or rituximab.

DR LOVE: Any comorbidities?

DR MATT-AMARAL: No. Surprisingly, not really. He’s a pretty tall, thin, lanky guy, but no. He doesn’t have any cardiac dysfunction. He doesn’t really take any medications. He’s outside mowing his lawn. I was actually surprised. He is a very healthy 89-year-old guy and very physically fit. I do worry about some toxicity for him only because he doesn’t have much weight to lose.

DR LOVE: So they say age is just a number. But what would you be thinking about in this situation, Mike?

DR WILLIAMS: Yeah. So for somebody, for his particular situation, I do think he’s probably going to need an immunochemo regimen and I would favor starting with bendamustine/rituximab, but I would, given his age and I’m assuming that he’s got good renal function because that’s an issue with benda, you need to make sure that creatinine clearance is above 30. But I’ll often start a patient like this with 60 or 70 mg/m2 instead of 90 and give them the ritux and then see how they do with that. Mini-R-CHOP is also a consideration for higher grade follicular and can work quite well. But in somebody who is 89, I find that if you start using regimens sometimes like that, they suddenly look every bit of 89 years old. And so I think I would go cautiously with that approach.

DR LOVE: So I was really interested in the fact that at the ASH meeting, there was long-term follow-up of the RESORT trial that you and Brad Kahl reported, I forgot how many years ago, of 4 doses of rituximab therapy. You can remind us about that. And boom, all of a sudden, you guys pop up with a follow-up. And these are the conclusions that you reiterated from the first dataset presentation in 2014 basically comparing 4 doses versus indefinite, recommending 4 doses only. In the follow-up data, the one graphic that caught my attention was this one, Freedom from First Cytotoxic Therapy, where you see pretty significant difference although there was no survival benefit. And, in fact, you all kind of stuck with your same recommendation, in general, 4 doses and that’s it. Any thoughts? I know a lot of people in practice go a little beyond 4 doses.

DR WILLIAMS: Right. So we did stick with our initial recommendation that you — this is for low tumor burden and that’s by GELF criteria. So these are patients that traditionally would be watch and wait because they’ve got low burden asymptomatic disease. And in this case, these are patients who wanted to get treated with rituximab. And so there’s a couple points. It did delay the time to first cytotoxic therapy if they were on maintenance, but this maintenance went on indefinitely, so we had patients on it beyond 5, 6 years. And there is risk with that of infections, et cetera. Especially in the current era, we have to be cautious about giving maintenance monoclonal antibody therapy to our lymphoma patients. But one of the other take homes is that there were about one-third of the patients in this study, and this was shown in a European study as well, about one-third of the patients with low tumor burden who got 4 doses of rituximab, at 10 years had not yet progressed. So you can get very durable response in people with a low burden of disease. And so when I’m seeing these patients, I’ll present to them we can watch and wait and treat when the disease shows more activity or people who are not comfortable with an observation status, we’ll give 4 doses and then stop. Now when I treat them again, this is where I’m sort of making it up, if they relapse within a couple of years and are still low burden, I’ll give them 4 doses again, but then sort of have the option of going to maybe 2 years of maintenance as we would do maybe after, say, an R-chemo. So that one’s not so data-driven, but that’s the approach. So I’m generally not, we’re not doing indefinite maintenance for these folks.

DR LOVE: So I’m kind of flashing back on your initial comments about COVID, anti-CD20. And wow, I’ve heard so many things over the last couple years about that. There have been times that people were really, really holding back on anti-CD20. How do you see it right now just, in general, as a threat to the patients? I’m not even clear exactly how much at increased risk they are if they get COVID, you know, for mortality.

DR WILLIAMS: Right.

DR LOVE: Your whole view of the risk to your patients who are, you know, these patients, in general, do you see it differently now with Omicron?

DR WILLIAMS: Yeah. Well so it’s evolved through this pandemic and that is that early on many of us were stopping maintenance therapy or not recommending it after, say, induction for follicular lymphoma. Whereas for mantle cell lymphoma, where there’s a survival benefit for maintenance, we’re still doing it there, but with recognition that they’re not going to respond well to the vaccines, if at all, most people on an antibody won’t, and that they’re at risk for severe disease. Now that we have sotrovimab, I think I said that right, for treating patients who develop COVID and we have the prophylactic Evusheld antibody cocktail that we talked about at the beginning, that’s kind of helping us. So I’ve got patients now with higher risk follicular as well as my mantle cell patients who are going on maintenance rituximab who I’m prophylaxing them with the anti-COVID antibody cocktail so that they can then go on and get the benefit of the maintenance.

DR LOVE: Any information or theories about whether obinutuzumab would be more of a problem than rituximab or less of a problem as it relates to COVID and antibodies?

DR WILLIAMS: I think it’s probably going to be pretty similar. I think they both are very good at blunting response to various infections and also to vaccines.

DR LOVE: So a quick case from the chat room, Dr Kumar. Stage IV diffuse large B-cell, R-CHOP times 6, CR, but 3 months later, relapse in a node, one node, one 4 cm node. CAR T or transplant or something else?

DR WILLIAMS: Wow. So if they’re a transplant/CAR candidate, I would get a CAR opinion. I’d refer the patient for a CAR T opinion. You might sort of temporize things, but have the disease — if they were PET negative at the end of their 6 cycles of R-CHOP and now have documented disease, that’s a bad actor in terms of disease. So I would — the good news is you’re going to have time to do a CAR because they’re likely not going to have hopefully a real rapid progression, you can control it. But I would be referring them for a CAR rather than an auto with that early relapse. That fits perfectly into the ZUMA-7 trial.

DR LOVE: So another quick case from the chat room from Azoma. A 70-year-old noted to have a 14.5 cm pelvis mass that’s excised. I guess that wasn’t what they were expecting.

DR WILLIAMS: Wow.

DR LOVE: Performance status is 0, no symptoms, normal blood work, PET, minimal residual pelvic disease. So what do you think about this?

DR WILLIAMS: And this is a large cell?

DR LOVE: Yeah. It looks like it, I think.

DR WILLIAMS: Did they — yeah.

DR LOVE: Diffuse large B-cell. Yeah.

DR WILLIAMS: Right. So they’re almost NED after that. So I would do, it’s kind of like we occasionally have these situations where you’ve got a large B-cell that’s resected and they’re NED at that point. So typically, we’ll do at least 4 cycles of R-CHOP for those patients. And if they’re young and we want to be really aggressive, we’ll try to get them to 6. If there’s still some residual disease, it’s probably hard to tell by PET after all of that surgery, but I would be considering at least 4 cycles, 4 to 6 cycles of R-CHOP.

Case: A woman in her mid-70s with nonbulky Grade I FL (FLIPI 4) — Dr Rudolph

DR LOVE: All right. Let’s take another case. This is from Dr Rudolph. A 77-year-old woman with Grade 1 FL. Here’s Dr Rudolph.

DR RUDOLPH: This is a 77-year-old white female in excellent health. PET scan showed hypermetabolic lymph nodes in the chest, abdomen and pelvis. There were small hypermetabolic skeletal lesions. Her FLIPI score was 4 which is a high score. My question really was, can we just watch her given she does not have bulky lymphadenopathy, she’s not that symptomatic? However, given the level of PET avidity as well as her high FLIPI score, would that be grounds to do treatment? I would like to know if the investigators would have any preference for R-squared as opposed to BR for frontline treatment.

DR LOVE: Any other questions about follicular lymphoma?

DR RUDOLPH: I definitely have a question about tazemetostat. I have taken the stance of I’m going to go ahead and use the drug whether or not there is EZH2 mutation and I’m really curious to see what the investigators do.

DR LOVE: So, Mike, what are your thoughts about this case? And what’s your experience with tazemetostat?

DR WILLIAMS: Yeah. So for this case, I would say that if she’s truly asymptomatic and it’s a low burden of disease, although there are higher risk features that were mentioned, so this is the kind of patient I might even consider the 4 doses of rituximab alone.

DR LOVE: Right.

DR WILLIAMS: And sort of make her prove to you that that’s not going to give her great control of her disease. And it will in a number of those patients. So I would start with that. But then if that’s not adequate to control, I think this is a good candidate for R-squared. The studies comparing that, R-squared, with R-chemo looked quite good. And so I would consider that as an option. Now for relapsed disease, I think it’s reasonable and appropriate to test these patients for EZH2 mutations. And Dr Rudolph is quite correct that EZH2 is actually a critical part of normal B-cell and lymphoid development. It’s essential to make follicles in the lymph node. And so the response rates in people with an EZH2 mutation, it’s a gain of function mutation in these patients, they have about a 70% response rate. But it’s about half that, so not bad, it’s half that in people that are EZH2 wild type. So I think it’s a good option to consider for this patient in the relapsed setting.

DR LOVE: I was interested by the fact that you brought up R-squared. I don’t hear too many people — usually, people bring that up second line other than like Nathan Fowler, for example. What is it about this case that got you to think about it? Most people say, oh I don’t think it’s any less toxic than BR even though it’s not chemo. What’s your thinking?

DR WILLIAMS: Yeah. So I sort of like — they’ve each got their own side effect profile. But I find that in especially elderly patients like this, BR in a subset of patients, you’ll give them a couple of cycles of treatment and then all of a sudden, they’re very cytopenic and they’re very slow to recover. So if I do use BR, I usually start with a reduced dose, as I mentioned on the earlier case, and if they have a great response after 3 or 4 cycles, I’ll stop with that. I don’t feel compelled to push to 6 cycles. So I think they’re both reasonable options. I often will prefer a noncytotoxic approach, however, in these patients that are in the 80-year-old range.

DR LOVE: So we’re going to finish out with a couple cases of Hodgkin, but another case from the chat room. 48-year-old man, primary mediastinal diffuse large B-cell, 8 cm, post-R-CHOP, complete PET negative, but there’s still 3 cm residual mass there. Any thoughts? Would you add XRT?

DR WILLIAMS: Yeah. So if they’re clearly PET negative, I would not use the radiation therapy. So that’s been reasonably shown, probably a little better data after dose adjusted R-EPOCH for PMBCL. But if it’s down to 3 cm and there’s no PET avidity at all, I would defer the radiation.

Case: A woman in her mid-30s with nodular sclerosing Hodgkin lymphoma — Dr Morganstein

DR LOVE: So let’s move on now and talk about Hodgkin lymphoma and a patient of Dr Morganstein, a 34-year-old woman with nodular sclerosing disease.

DR MORGANSTEIN: A 34-year-old woman who during her pregnancy, started to develop cervical lymphadenopathy as well as severe itching. Right after delivery, she started to develop night sweats, nodular sclerosing Hodgkin’s. PET scan showed bulky lymphadenopathy in the chest, axilla and cervical area, bilateral pleural effusion, small pericardial effusion, diffuse activity through the osseous structures and diffuse bone marrow activity. I treated her with AAVD. Her main side effect was neuropathies which did require dose reduction in later cycles. I did do an interval PET scan on her which showed complete resolution of her disease. The question is, what is the optimal treatment of advanced Hodgkin’s lymphoma? Who should we be adding brentuximab to? And then how do we manage what, in my opinion, has always been the most difficult side effect of this with neuropathies? Just thinking forward in this woman, if she does relapse, what would be the optimal therapy for her? What would her best pre-transplant therapy be? Could we incorporate in her immunotherapy? And then post-transplant, now that she already had 6 months of brentuximab, would she still be a candidate for brentuximab maintenance?

DR LOVE: And I’ll add the question of —

DR WILLIAMS: Yeah. Those are great —

DR LOVE: Just to add onto that because he was telling me how frustrated he was when he got this patient that it hadn’t been picked up while she was pregnant. I’m curious also, just to add on to his list of questions, how you manage patients who are diagnosed during pregnancy, particularly earlier on.

DR WILLIAMS: Yeah. Well managing these patients in pregnancy is a real challenge as you know. And so we will generally try to temporize with corticosteroids or various things to bridge them until they can deliver the child, but if it’s very early in pregnancy, then we have to proceed with treatment and avoid the drugs that might put them at greater risk. But we’ll tend to go ahead and proceed with their anthracycline-based treatment. So in this person, she’s got high-risk disease, she’s got advanced stage disease, so I think AAVD is the regimen of choice over ABVD. And it’s good to see that she had a CR after with her interim PET scan. Dose modifying the brentuximab due to neuropathy is common, unfortunately. And so that may truncate the dose intensity of that drug as you get into the later cycles. If they got that upfront and then relapsed, I think maybe the timing of the relapse matters a bit as far as whether you would ever use it as a maintenance therapy after a transplant because she clearly would be high-risk. But I think the bridge to her transplant is going to be a checkpoint inhibitor therapy. You could use a high-dose chemotherapy regimen like ICE instead, but I would probably favor a checkpoint inhibitor for her. And then if she relapsed very early and was clearly progressing on or just after within a few months of her AAVD, then I think the benefit for brentux in the maintenance setting is going to be pretty limited.

Case: A woman in her early 40s with Stage IIIB Hodgkin lymphoma in remission who develops triple-negative breast cancer with a BRCA2 germline mutation — Dr Morganstein

DR LOVE: So we have another case I want to run by you. It’s kind of an interesting case. This is a 42-year-old woman who presents with Stage IIB disease, was treated with therapy and is in remission, then develops triple-negative breast cancer and at that point is found to have a BRCA2 germline mutation. We were just talking about this last night on a webinar with Dr Tolaney of the use of adjuvant PARP inhibitors. Here’s Dr Morganstein’s question about this woman.

DR MORGANSTEIN: This lady is still giving me anxiety. So she’s a very, very popular nurse in our hospital. My question, #1, what’s the ultimate and best treatment for Stage II high-risk Hodgkin’s lymphoma? Is there any role for bringing brentuximab into the upfront setting or is the standard the RATHL protocol or any other treatment options? And then, any connection between Hodgkin’s lymphoma and BRCA mutations?

DR LOVE: Wow. I’ve got to hear a little more about this breast cancer.

DR MORGANSTEIN: The question we just had literally yesterday was, is there any risk of myelodysplasia with her PARP inhibitor in a woman who has now had chemotherapy for Hodgkin’s lymphoma and then chemotherapy for breast cancer? If we gave her 2 years of PARP inhibition, is that risk of MDS or underlying hematologic disorders going to be greater? I think pembro if it’s reasonable would be great for Hodgkin’s as well. So I was kind of leaning towards that. And this is all happening as we speak.

DR LOVE: So he was talking about the fact that the breast cancer was triple-negative. Last night, we were saying in this situation, triple-negative BRCA, you could give an IO like pembro, you could give olaparib, you could give both. And that was kind of behind what he was thinking. So any thoughts about his questions and about this case?

DR WILLIAMS: Yeah. So for Stage II Hodgkin’s, I think I would treat this patient as he did with ABVD and use the RATHL algorithm where you get an interim PET scan after 2 cycles. If they’re Deauville 3 or better, then you drop the bleomycin out and you finish out with the AVD for that individual. And I’m unaware of a link between BRCA mutation and Hodgkin lymphoma. So that would be a literature search for me.

DR LOVE: Really interesting though that he brings up this issue of the potential for PARP inhibitors to cause AML and MDS. We actually had a patient who got niraparib for ovarian cancer on our AML series last week. So certainly something to think about, particularly this lady who has had chemo both for Hodgkin’s as well as breast cancer.

DR WILLIAMS: Yeah. But the good news is that ABVD is not particularly leukemogenic like some of the more alkylator heavy lymphoma regimens are. So it’s still a risk. I think he’s completely on point for considering that. But it should be maybe a little bit less risk than some of the other things that we do.

DR LOVE: Any comments? We were talking about bridge to transplant in this patient or the previous patient and I was curious. I was thinking everybody was using what you’re doing which is BV and nivolumab, but I see a bunch of other people using chemo. Any thoughts about this?

DR WILLIAMS: I guess my colleagues are not convinced yet to shift to immunotherapy which, like I said, I would favor. This person has never seen brentuximab since she got ABVD with the frontline. And there’s data actually bridging people to a transplant with just brentux alone. And so I would, again, downshift on the chemo regimen.

DR LOVE: Would you use, you mentioned that you would consider it, would you use B/vedotin again in the post-transplant setting if the patient had a significant interval? It seems a little, I guess, there are not much other options. Nothing has been studied in consolidation.

DR WILLIAMS: Yeah. If they’re expressing CD30 and it’s been a period of time, I think I would give them the benefit of the doubt and do the maintenance for high-risk with a later relapse.

DR LOVE: So one final question. You readily agreed to the idea of the ECHELON-1 approach in the first patient who was high-risk. And I hear a lot of people talking about that and then I look at the data and incidentally, I think now they have a survival benefit.

DR WILLIAMS: Right.

DR LOVE: There was a press release saying that ECHELON-1, I think, now it’s 6 years, actually has a survival benefit. So I guess we’re going to see that data soon. But, again, just sort of thinking back to it, what’s the rationale for why you don’t use it in patients who are not high-risk, shall we say? Or do you?

DR WILLIAMS: Right. So I think the rationale is, and there’s been a lot of debate about this among lymphoma docs, and that is that the majority of people can still be cured with an ABVD regimen and there are mechanisms to decrease the use of bleomycin as was discussed. And so if you can spare the bleomycin except for maybe the first couple of cycles, then the cost of the regimen and some of the toxicity like the neuropathy is less. So I think that’s why some people are still sticking with the more traditional treatment approaches.

DR LOVE: But am I correct in saying the control arm of the upcoming intergroup Phase III trial is going to be ECHELON-1?

DR WILLIAMS: It is. And that was a source a couple of years ago when that study was coming together that there was a lot of debate among the cooperative group lymphoma committees about whether the data at that point was strong enough. I think it’s gotten stronger for the reasons you just mentioned with the new survival advantage. And when the — ECHELON-1 was an international study and when they looked at the data for North American participants in that trial where there was more use of growth factors and things like that, it also showed a bigger benefit than sort of the 7% that was seen in the overall study up front.

DR LOVE: So, Mike, thank you so much for joining us today. Audience, thank you for attending. It seems like every day, we’re kind of going on a new adventure with new data. Tomorrow, we’ll be talking with Dr Armstrong about the landmark PROpel and MAGNITUDE studies just presented a couple weeks ago. Firstline use of PARP inhibitors in metastatic prostate cancer and, of course, what we think is going to be the upcoming approval of lutetium, PSMA label lutetium. So exciting. So exciting to be in oncology in general. Be safe, stay well and have a great night. Thanks a lot, Mike.

DR WILLIAMS: Thank you.