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 lymphoma with Dr Sonali Smith from the University of Chicago in Chicago, Illinois.

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 Smith, just type them into the chat room and we’ll bring up as many as we have time today.

If you’re into audio programs, we know lots of people end up listening to these webinars in their car and when they’re raking the leaves, check out our Oncology Today podcast series including a recent program reviewing ASH presentations on lymphoma with Dr Lunning. We do webinars all the time now. On Thursday, we’re doing one on CLL with Dr Hillmen. Should be very interesting. This coming Saturday, 2:30 PM Eastern Time, we’ll be out at the SGO meeting doing a program on ovarian cancer. So check it out. We’ll be doing a simulcast Saturday afternoon. Next week, we’ll be meeting with Dr Goldberg to talk about immunotherapy in lung cancer. And then continuing with our CLL series with Dr Rogers. We’ll be starting an MDS series on April 5th with Dr Komrokji, so check that out. And then on April 27^th, the end of April, we’re heading out to Anaheim for the ONS meeting. For any nurses who might be interested, right now, we’re going to be up to 8 symposia. We may be doing as many as 10. So let your nurses know that we, as always, will be out at the ONS meeting.

But today, we’re here to talk about lymphomas. And as always, we’re going to have a bunch of cases presented. We actually have 8 general medical oncologists in community-based practice who are going to be presenting cases today that we’ll make rounds with Dr Smith on.

Here's where we’re heading. We’re going to go through these cases. We’re going to show you the results of a survey. And then, we’ll go through some of the papers that Dr Smith has done in a journal club.

But I just want to start out, I saw you’re the Elwood Jensen Professor at University of Chicago. There was just a press release about this SERD that actually failed. But it made me remember that really, your professorship is a very famous person, you could say maybe ushered in biomarker-driven therapy, personalized care. I think Dr Jensen is known for discovering the estrogen receptor. So it’s really interesting that that’s your heritage there in your position, Sonali.

DR SMITH: Yeah.

DR LOVE: I think you said Dr Huggins was there too at one point, right?

DR SMITH: That’s right. So Dr Huggins and Dr Jensen worked down the hall from where my office is right now and discovered the biologic basis of prostate cancer, or the hormonal basis of prostate cancer and breast cancer. So very honored to have that title.

DR LOVE: All right. Well we’re going to make rounds with Dr Smith. We’re going to start out with some cases of diffuse large B-cell and mantle cell. But before we do, before we jump into diffuse large B-cell, I just want to kind of give you a little preview of the journal club. And I picked out this paper of a particular interest of Dr Smith and mine too which is older people, particularly those with diffuse large B-cell and this interesting SWOG study, R-miniCHOP plus or minus oral azacitidine, CC-486. We talk about that all the time in our AML series used as maintenance therapy. You presented this at the ASH meeting and you had this great paper that I highly recommend people check out. And so many questions about older people with diffuse large B-cell. Sonali, can you comment a little bit about the issue, in general, of diffuse large B-cell and what this trial is looking at?

DR SMITH: Yeah. I really appreciate you pulling out this paper. I think the main thing is that trials that have been done in this space have ignored the largest percent of people who actually have diffuse large B-cell lymphoma. Like one-third of patients with DLBCL are over the age of 70 and they’re not represented. And we know that there’s both the risk of overtreatment if they’re too frail and undertreatment if based on age they don’t get the standard of care. And so we need to start changing this and that’s what S1918 is trying to do.

Case: A woman in her late 70s with diffuse large B-cell lymphoma (DLBCL) receiving tafasitamab/lenalidomide — Priya Rudolph, MD, PhD

DR LOVE: So we’ll get into that, I think, as we get into these cases because actually the first patient is a 78-year-old woman. This is a patient of Dr Rudolph. A woman who presented with extensive disease as you’re going to hear. And so the first question she has is how would you treat this patient? Here’s Dr Rudolph.

DR RUDOLPH: She’s actually a neighbor living in my neighborhood. She has Child-Pugh A cirrhosis secondary to non-alcoholic steatohepatitis. Her platelet count at baseline hangs around 75,000. Back in August 2016, she presented with a 20-pound weight loss, very sick. She had abdominal pain. CT scan showed multiple liver lesions and large spleen, retroperitoneal lymphadenopathy. Multiple bone lesions. Pulmonary nodules. Really suggestive of possible hepatocellular carcinoma, but we were all surprised when her liver biopsy came back with diffuse large B-cell lymphoma, germinal center B type, with a Ki-67 of 99%. She reported some numbness in her chin. Interestingly, her MRI of the brain showed focal area of dural enhancement suggestive of leptomeningeal disease, although her CFS cytology was negative.

DR LOVE: So, Sonali, we call these the real-world cases because people put up these theoretical cases, it’s never like that in the real-world. So I’m curious what your thoughts are, how you would treat the patient, what you’d do about the CNS and how the cirrhosis and hypersplenism would feed into the whole decision.

DR SMITH: Yeah. That is a really difficult case. And you’re right about real-world. And what I was getting to earlier too with the S1918 trial is that all of these patients have been excluded and there’s no biologically driven way to evaluate them. And to be honest with you, even this trial would not have somebody with cirrhosis and thrombocytopenia. So we’re still going to have a number of people where it’s going to be a data-free zone. My suspicion here with such advanced disease and extranodal involvement in a GC phenotype is that this might actually be a double-hit or a triple-hit lymphoma given how aggressive it appears.

DR LOVE: Although it wasn’t.

DR SMITH: It wasn’t. Okay.

DR LOVE: No. It wasn’t.

DR SMITH: All right.

DR LOVE: I should have mentioned that.

DR SMITH: Yeah. That’s interesting just because germinal center phenotype always should trigger a search for double-hit lymphoma. But the point is that in older patients, it almost doesn’t matter because you can’t really give EPOCH-R or any one of the more intensive regimens. So for this person, even with the liver dysfunction, I probably would go with R-miniCHOP as a start. And the reason I would do R-miniCHOP is that if you try to do a frailty assessment and look at all the comorbidities, there’s a very high risk of morbidity and mortality. And even with R-miniCHOP alone, about 20% of people will die of toxicity. So full-dose R-CHOP, I think, would be too much. So I would start with R-miniCHOP. In terms of the CNS disease, this is not prophylaxis. This is probably treatment. She’s symptomatic and has an abnormality on the MRI. And I think intrathecal methotrexate is an appropriate consideration because she has disease. But another option, and this is really outside of any data here, to be honest with you, is that when she’s all done with treatment if things are stable, both ibrutinib and lenalidomide cross the blood-brain barrier and I would have a conversation about one of those 2 agents.

DR LOVE: Wow. Ibrutinib, lenalidomide. Interesting. Okay. Well actually, the case continues. The patient got R-CHOP, intrathecal methotrexate and unfortunately, relapsed. And on relapse, went to CAR T, had no problems with the CAR T, but also, no response whatsoever. And was put on tafa/len and is doing well right now. Here’s Dr Rudolph.

DR RUDOLPH: She tolerated the CAR T cell therapy extremely well, but to our surprise, in August 2021, she had severe abdominal pain and very significant lymphadenopathy in her abdomen. Long story short, CAR T cell did not touch this patient. Now she’s on tafa/len. She is responding very well. She was bedridden after her relapse. And now she’s out raking her leaves again. She’s in my neighborhood, doing very well. She’s off her pain medications.

DR LOVE: Any questions about CAR T in general?

DR RUDOLPH: Yes. Through your webinars, I have come to learn that there is no correlation between cytokine release syndrome versus responses. She had zero symptoms, none whatsoever. She was very surprised how tolerable it was. But I would like to know if there is any difference in efficacy between the different CAR Ts?

DR LOVE: And also, difference in tolerability. The message that I think I’ve been getting is not so much there’s no correlation, but you can see patients who have no issues with a CAR T respond. But I don’t — I assume that maybe you see more likely response if they have, for example, CRS. Is that the case?

DR SMITH: I think toxicity, both CRS and neuro toxicity, are related to the tumor burden and not necessarily predictive of outcome. What Dr Rudolph said is correct in that you can have somebody with no toxicity and have a great outcome and others who have significant toxicity and no response at all. So I think that’s very hard as a predictive factor. The challenge with CAR T, and Dr Rudolph asked about the 3 different kinds, so we now have 3 constructs that are FDA approved. And I’ll nickname them axi-cel, liso-cel and tisa-cel. And I think, in general, axi-cel is a little bit different. It has a different internal component of the CAR T construct which is not 4-1BB, it’s CD28. And what that does, at least on a practical level, is that it does have a slightly higher incidence of both cytokine release syndrome and neurotoxicity although it’s well tolerated and reversible in the right setting, meaning an experienced CAR T center. But I guess the thing about the CAR T, and this poor patient is an example of that, which is we’re all excited about CAR T. It has absolutely been a paradigm shift. But 60 to 70% of people who get CAR T are not going to respond in the third line setting. And so there’s still a lot of room to go.

DR LOVE: So, of course, we saw the big CAR T versus autotransplant papers at ASH. 2 of the 3 were positive. Later on, we’ll show you the faculty survey saying that they kind of buy into the data, in general. What about transplant after CAR T?

DR SMITH: Yeah. It’s definitely feasible and I think it’s encouraging that you can do a transplant after CAR T does not work. It’s only a handful of patients where we have the data there, but the fact that it’s safe, it’s feasible and potentially has some long-term outcomes that are good makes that appealing. What you’re referring to, Neil, is a little different than, obviously, what Dr Rudolph was sharing here in that she was talking about CAR T in a relapsed — or actually, I guess I don’t know how quickly that patient relapsed. But what was done at ASH this year were 3 trials looking at CAR T for patients with diffuse large B-cell lymphoma who relapsed within 12 months of their initial therapy, either relapsed or refractory. And as you said, 2 of them were positive with a significant improvement in progression free survival and 1 was negative. And I think the negative trial had a lot to do with the time from collecting the cells and infusing them. And it just reenforces that in diffuse large B-cell lymphoma, time matters, speed matters.

DR LOVE: Interesting. Hassan in the chat room wants to know about bispecifics after CAR T.

DR SMITH: Yeah. So all of the CAR Ts that are FDA approved right now are against CD19. So they are CD19 engineered CAR T-cells. And the bispecifics that are moving forward in the lymphoma space are against CD20 and CD3. So there’s a really exciting potential for bispecific agents to be active after CAR T and there’s a number of studies showing that there is activity for some of the bispecific antibodies. There’s also —

DR LOVE: So I want to go on to —

DR SMITH: I’m sorry.

DR LOVE: Go ahead. Sorry. Go ahead. Please.

DR SMITH: I was just going to say that there’s also a trial in development hopefully open through the NCTN in the next year looking at preemptive bispecifics after CAR T.

DR LOVE: Like consolidation bispecifics sort of?

DR SMITH: Right. Right.

DR LOVE: Wow. Interesting.

DR SMITH: So great question.

Case: A man in his mid 50s with DLBCL transformed from follicular lymphoma — Neil Morganstein, MD

DR LOVE: All right. Let’s go on to another case. This is a patient of Dr Morganstein. A 54-year-old man with diffuse large B-cell after prior follicular lymphoma. I mentioned the fact that you have a paper reviewing that. But here’s the case.

DR MORGANSTEIN: This is kind of a weird case. I met him back in 2009 when he presented with back pain and ultimately had an epidural mass and cord compression. He ultimately needed a laminectomy and decompression, was diagnosed with Grade 2 follicular lymphoma. He was treated with radiation to the lesion and then was observed until 2017. So really, what, 8 years with nothing. 2 or 3 months ago, he started to develop severe leg pain, ultimately diagnosed with a pathologic fracture, and he was diagnosed with diffuse large B-cell lymphoma. He’s currently being treated with R-CHOP and has a nice improvement both in his pain and on his imaging studies. So in this gentleman what is the best treatment for transformed lymphomas? Still R-CHOP? Any role for intensification, possibly, with dose-adjusted R-EPOCH? Any role for up-front transplant?

DR LOVE: So any thoughts?

DR SMITH: Yeah. What a great case. It’s so unusual to have a limited-stage indolent lymphoma in the CNS, but actually I think we see this a little bit more than I would have expected. I’ve seen several cases like that. And the fact that radiation alone was effective for so long is fantastic. But the question now is if you have a transformed lymphoma to diffuse large B-cell lymphoma, what is the right treatment? And I think there’s 2 pieces of information to keep in mind. One is what is the prior therapy that the patient has had? And two, what is the current histology at transformation? So if a patient has had prior anthracycline, then I typically go to salvage chemo and an autotransplant at the time of transformation. If they are anthracycline naïve or just with rituximab or, in this case, radiation, I would just stick to R-CHOP. For this patient, I don’t think there’s any role for consolidative transplant. There’s actually data that people can do quite well. And if they’ve had prior bendamustine and now have a transformation, that’s where we really don’t know what to do. I err on the side of doing a transplant but, again, there’s very little data there. So the prior treatment affects what you do now. And I would not consolidate this patient with a transplant.

The other piece, which is the histology, is to remember that when people transform, it’s not always to diffuse large B-cell lymphoma. Sometimes, they can transform to double-hit. And if that happens, then I would substitute EPOCH-R instead of R-CHOP, but still have that similar approach and algorithm.

Case: A man in his early 50s with intense abdominal pain is diagnosed with DLBCL — Laurie Matt-Amaral, MD, MPH

DR LOVE: Okay. Well let’s do one more case of diffuse large B-cell. You have a great paper in the journal club concerning limited-stage diffuse large B-cell. I’m curious what you think about this patient of Dr Matt-Amaral.

DR MATT-AMARAL: This is a man that I recently just got referred to from his primary care physician who presented for pretty intensive abdominal pain. So the primary care doctor felt a pretty large mass in the epigastric, towards the left upper quadrant. CT scan showed a pretty significant mass concerning for possible cancer. There was also some splenic lesions noted. Of note, the patient was having pretty intense night sweats, not so much weight loss, but at the same time having decreased appetite as well. Ultimately, they were able to come up with a diagnosis of diffuse large B-cell lymphoma. He’s being treated mostly a Stage IIb for bulky disease, but he does have some lymph nodes, so he’s a questionable clinical Stage III.

This is a picture of his PET scan. Final measurements about 16 cm in size.

DR LOVE: So any thoughts about this case? And maybe take a step back and talk about your approach to limited-stage disease.

DR SMITH: Yeah. So limited-stage diffuse large B-cell lymphoma is about 20 to 25% of the cases that we see. There’s a debate as to whether or not it’s more likely to be extranodal or not extranodal and maybe that’s something we could talk about. But the standard of care, I would argue, started with a SWOG trial that looked at, in the pre-rituximab era that looked at 8 cycles of CHOP versus 3 cycles of CHOP plus radiotherapy and kind of established combined modality therapy as the approach of choice based on improved — or similar progression free survival — I’m sorry, improved progression free survival and decreased toxicity. In the rituximab era, all of the data for combined modality therapy has been more single arm trials, but I think for a long time, that was a very acceptable option.

There’s 3 studies that were published and presented in the last several years that I think challenge combined modality therapy. The first is the FLYER trial which looked at IPI 0 patients, really favorable patients with limited-stage DLBCL, and showed that 4 cycles of R-CHOP with a negative PET is absolutely appropriate and patients do really well. The other is the SWOG trial which was PET adapted showing that if somebody has a negative PET scan after 3 cycles of R-CHOP and then gets a fourth cycle, they also have a progression free survival that is over 90%. The nice thing about this particular situation is that even before the PET data, I think I would have been really worried about giving radiation, for example, to the abdomen and I would have tried to give just 6 cycles of R-CHOP. I think now between the FLYER trial, the SWOG trial and then the third study which was more of a retrospective analysis from British Columbia, I would just stop at 4 cycles of R-CHOP, especially if the PET scan is negative, and not worry about radiation. I think the twist there though is she said even at the end that it might be Stage III. So I don’t know. If it’s Stage III, I would do 6 cycles.

DR LOVE: So before we go on, I want to just take a breath and show you some data from the survey we did related to diffuse large B-cell, but particularly as it relates to the POLARIX study looking at polatuzumab in the upfront setting that we just saw at ASH with a disease free survival benefit, hazard rate of about 0.7, but too early to talk about survival. So right after that, we did a survey of 20 investigators and I’m curious what your thoughts are about how they answered the questions. So the first, we said, and we generally sort of put aside, we know cost is a big issue, in general, but we kind of try to look at the clinical science and the risk/benefit of the decision making here. In any event, so we asked these 20 investigators suppose you don’t see a survival benefit as the trial matures, do you, from the point of view of risk/benefit, do you still think it’s worth doing? Majority say yes. What are your thoughts about that?

DR SMITH: Yeah. The issue about the survival advantage is that now that we have so many improved second and even third line options, it’s going to take a really long time. So I think that the improved progression free survival will prevent more transplants, prevent more CAR T and overall if it’s similarly tolerated, I think it’s going to become a good and appropriate new standard of care.

DR LOVE: And actually, we also said do they buy into the concept that it is similarly tolerated? And, again, the majority say yes. And I think the data supports that, particularly in terms of peripheral neuropathy. Didn’t seem to be a huge difference. This is what I really thought was interesting, it was kind of surprising. As you know, there was a subset analysis done in the POLARIX study. I don’t know if it was planned or not. But it looked like the benefit was much greater with ABC. There are the splitters and the lumpers in this world and some people look at the overall approach, the overall criteria for the trial which is positive and then other people look at the breakdown within it in the forest plot. So you see here, pretty much a consensus for ABC, but when we say germinal, it starts to split out a little bit. So I am curious what you’re thinking right now in terms of how you think through the POLARIX data. We’ll get to CAR T in a second. And, again, I know there are definitely cost issues, but from a clinical point of view, what are you thinking and what do you think about the fact that some of these investigators, at least at this point, are less open to bringing in pola if it’s germinal center?

DR SMITH: Yeah. I have to be honest, I’m really on the fence about some of the subset analyses. Patients who were younger, had a lower-risk IPI and germinal center phenotype didn’t seem to have as much of — the magnitude of benefit was less. And so if we follow those subsets and we’ve got maybe cost in mind, then I would think R-CHOP is great and we wouldn’t necessarily need it. But because the question here says regulatory and reimbursement issues aside, I also think it’s very feasible or it’s very reasonable to use pola/R-CHOP. But I think this is something where we will see more as time goes by. But definitely, it doesn’t benefit all patients equally. And that’s a theme we’ve seen in all of these DLBCL trials.

DR LOVE: So a couple other questions we asked that were, I thought, interesting. One, second line therapy. Having just seen those trials, it looks like the majority of people buy into the fact in those patients there’s an advantage. This is something, another thing that’s interesting, all of a sudden, we have all these options for relapsed disease. We were curious what people tend to go for in patients either who’ve already had a CAR T or are not eligible for a CAR T. And tafa/len seems to be ahead. Also, pola/BR. Selinexor and Lonca-T theoretically are also used in the relapsed setting. How are you approaching sequencing these agents? And does it matter if they’ve already had CAR T or going to go to CAR T?

DR SMITH: Yeah. The difficulty that comes in is that both tafasitamab and loncastuximab tesirine both are anti-CD19 agents and so theoretically, there has been a concern that the CAR T may be less effective if that’s where you’re headed or vice versa, if you had the CAR T first, will those agents not be as effective? I think the early data shows that despite those concerns, it’s actually not true, that people can get one of the anti-CD19 agents followed by CAR T and vice versa and there’s still efficacy preserved, especially if CD19 is still expressed and hasn’t been downregulated. When it comes to picking between those 4 regimens that you just mentioned, whether it’s tafa/len, pola/BR, Lonca-T or selinexor, we have zero data on sequencing. And so I think most people will pick it based on toxicity and patient preference which is absolutely appropriate. I personally think tafa/len is going to be very well tolerated. And the problem is not with the pola part of pola/BR, but it’s the bendamustine which is very myelosuppressive and in the day of COVID, it’s immune suppressive as well. So I think tafa/len probably has a slight edge there.

Case: A woman in her early 80s with relapsed MCL — Benjamin Parsons, DO

DR LOVE: All right. Let’s move on and we’ll do a couple cases of mantle cell. We actually had Mike Williams on this series a few weeks ago. We were just reflecting how amazing, Mike’s been a great leader in mantle cell, how incredible things have — it’s all of oncology nowadays, but in mantle cell included. So Dr Ben Parsons has an 84-year-old woman — 83-year-old woman with relapsed mantle cell. Here are his questions.

DR PARSONS: We started her on acalabrutinib 100 mg bid. Within a week she had severe issues with tolerance, lots of gastrointestinal side effects, diarrhea, and she started to develop rash. So we decreased from 100 mg bid to 100 mg daily. We ultimately stopped therapy.

Started her on zanubrutinib. She’s actually tolerating it amazing. She said, doc I feel better. I feel like I’m back to myself again. We did do response assessments on acalabrutinib and she was responding, but just having toxicity. My question to my expert colleagues is, when you’re choosing a BTK inhibitor in mantle cell lymphoma, do you have a preference between ibrutinib, acalabrutinib, and zanubrutinib? And then once you have a patient who has seen BTK inhibitor therapy, what is your next line of therapy for these patients with mantle cell lymphoma?

DR LOVE: What would it be for you?

DR PARSONS: So venetoclax-based strategies or now we have CAR T-cell.

DR LOVE: Yeah. So usually, I hear stories about how much trouble people had on ibrutinib and then they go on acala and they do great. This is, I’ve never heard a case like this. I don’t know if you’ve seen anybody who had this kind of issue with acala. Any thoughts about choosing BTK inhibitors? And what kind of cross tolerability issues do you see?

DR SMITH: Yeah. I’ve moved away from ibrutinib just because there are tolerability issues related to more chronic low-level toxicity rather than anything really major. But I do think ibrutinib is a great drug if that’s what’s available. My preference has been to use zanubrutinib or acalabrutinib. And between those 2, I think insurance really dictates which one I go to. I also have not had somebody with such severe toxicity with acalabrutinib. The one thing that does affect acalabrutinib choice is that there is an interaction with proton pump inhibitors. And so if I have a patient who needs to stay on that, I prefer to go to zanubrutinib although my understanding is that there’s going to be a new formulation of acalabrutinib that will allow PPIs to be used. And so 6 months from now, this may not be as much of an issue. But right now, it’s really driven by insurance in my mind.

DR LOVE: Yeah. That was presented at ASH. That was really interesting. We hear a lot of cases where that’s an issue. A lot of people on PPIs. Any thoughts, you know, we have this trial that was presented last summer at EHA in CLL that showed, it looked like greater efficacy than ibrutinib with zanubrutinib. Now, of course, that’s CLL. There have been questions about maybe it’s too early in that trial. Maybe the way they evaluated response. Any reason to think you’re going to see a difference in efficacy with any of the BTK inhibitors?

DR SMITH: I think if you can stay on treatment longer and not have to stop it or have the dose reduced necessarily, maybe that’ll contribute to the improved efficacy. And compliance too. If somebody has a lot of nausea and diarrhea, they might be tempted to skip a day or skip a dose and I think that may be part of it.

DR LOVE: Yeah. That’s a really good point.

Case: A man in his early 50s with MCL, blastoid variant — Justin Peter Favaro, MD, PhD

DR LOVE: So the other case of mantle cell we have is a young patient, 53-year-old man, a patient of Dr Favaro with blastoid variant mantle cell. I don’t know if we’re going to get to the paper, the transplant consensus paper you were part of, but I noticed that you didn’t exactly have a great solution for that right now. So I’m curious what your thinking is about how to treat these patients. Here’s Dr Favaro.

DR FAVARO: This is 53-year-old man who works as a bus driver for the city, and he presented with slow enlargement of his left lower neck and axillary lymph nodes. Biopsy showed mantle cell lymphoma, blastoid variant, with a Ki-67 of 95%. He’s got bulky lymphadenopathy in the axillae, neck, activity in the spleen. His brain MRI was negative. The questions are, patients that have mantle cell lymphoma, blastoid variant, what are the extra risks for these patients? Do they have a higher incidence of intracerebral or CNS metastasis? Do you routinely use intrathecal prophylaxis for blastoid-variant patients? And the other question is do you use a more aggressive chemotherapy regimen for these patients because of the more aggressive nature. The other question that comes up is Ki-67 95%. How do you prophylax them against tumor lysis syndrome?

DR LOVE: So I was going to ask you before with the other case, but I think it relates here too. Also, the issue of BTK upfront. I know there are trials combining it with chemoimmunotherapy. Are there any situations where you’d do that outside of trial? First of all, blastoid variant. How do you treat those patients outside of trial? And any trial concepts you’re excited about?

DR SMITH: Yeah. So the consensus paper you were referring to was a joint international EBMT, CIBMTR analysis of treatment patterns and an analysis of the data. And one of the biggest sort of findings is that we really don’t know how to treat blastoid variant mantle cell lymphoma and it’s an area of need. So there is no specific path forward there.

For our group, what we do, especially for a 53-year-old, is that we would use a cytarabine containing induction regimen with a plan to go to an autotransplant in first remission. And so that addresses the CNS prophylaxis piece because cytarabine does cross the blood-brain barrier. And we also use high-dose methotrexate often in some of those regimens. So the Nordic regimen and others include some of the methotrexate and cytarabine in them. So I would use intensive induction and try to get them into remission as a first step.

The tumor lysis syndrome piece is really important, not just because of the high Ki-67, but also because of the tumor bulk that’s there. And often with mantle cell, you have GI involvement and so you have a risk for bowel perforation. So we typically use prephase with cyclophosphamide and prednisone. And there’s a number of different types of prephase around the world that people have used. We have used the CALGB Burkitt lead-in which is 5 days of cyclophosphamide at 200 mg per m2 per day along with prednisone. And this has allowed us to go ahead and get the rest of the chemotherapy in.

But this is a patient who is unlikely to stay stable for too long. And you asked about whether or not BTK inhibitors should be used. This is actually one time where ibrutinib does cross the blood-brain barrier and we don’t have that data for zanubrutinib or acalabrutinib. I’ve asked the companies, I’ve asked investigators and there’s just not a lot of information about that. So if a BTK inhibitor is going to be used and there’s a concern about CNS disease, I think ibrutinib would be the right one. Frontline, it’s not approved. And there is a trial though, an intergroup study, that’s ongoing. If anybody is interested, it’s open to you right now which is BR with or without cytarabine and with or without acalabrutinib in the frontline setting. There’s also the SHINE trial which is BR with or without BTK inhibitor that’s going to be presented at, or may be presented at, a meeting coming up some time this year. So today, we have no data for BTK upfront, but I think that that will change sometime soon.

DR LOVE: This is the paper that we were just talking about, really comprehensive paper. I thought it was really interesting. I just pulled the numbers on how many lymphoma patients the people who wrote the paper see. I was just amazed. On average, more than 20 CAR T patients, more than 75 new lymphoma patients a year. Really interesting. Question in the chat room, I haven’t heard this before, from Dillop, says there’s been concern that the recommended BTK doses are unnecessarily high. I haven’t heard that before. Also, curious about your thoughts about venetoclax in mantle cell.

DR SMITH: Yeah. So Dillop is right. With ibrutinib, when that was first approved, it was looking at BTK receptor occupancy. And the dose that was approved far exceeds the dose necessary to desaturate the receptor. And MD Anderson, Varsha Gandhi and others have shown similar, using a different assay, similar findings. And I think this is why with ibrutinib so many patients need either a dose reduction or a dose delay or holiday at the 1, 2 or even 3-year mark. So that is true for ibrutinib. For acalabrutinib and zanubrutinib, I don’t know that that is necessarily true. I think they are closer to the dose needed to saturate the target. And then, of course, there’s a new generation of BTK inhibitors that are different, LOXO-305 which is being developed in CLL that may overcome some of these receptor issues as well.

DR LOVE: And, of course, that drug, pirtobrutinib, is super exciting in terms of not only lack of toxicity, benefit after previous BTK. I think, didn’t they have mantle cell patients though in pirtobrutinib that responded?

DR SMITH: They did. They did. And it’s a very small number. And just, again, we forget how rare mantle cell lymphoma is. Only 3,000 to 5,000 new cases per year. And then the venetoclax question that he asked as well and I think so did the other doctor who presented the case. I use venetoclax after progression on a BTK inhibitor, but what’s changed for me in the last 2 years is that I don’t think venetoclax holds people for too long. And especially for somebody with blastoid variant, I would try to get them over to a CAR T sooner rather than later. And I will admit, the trial that was done and published in New England Journal shows that it didn’t have very many patients with blastoid variant. That being said, I still think it’s a really interesting and appropriate option for a young patient.

DR LOVE: Any comments on your experience with CAR T in mantle cell? The numbers look great. What’s your experience?

DR SMITH: It’s actually been really good. Maybe it’s because we are very careful about who we select to go to CAR T, but we’ve actually had really great outcomes with that, consistent with what was published in the New England Journal. So I’m excited because outside of that, we only have allo and allo is hard.

DR LOVE: Yep. All right.

Case: A man in his mid 70s with newly diagnosed follicular lymphoma (FL) — Khuda Dad Khan, MD, PhD

DR LOVE: Let’s go on to follicular lymphoma. I was talking with Dr Williams about the RESORT study he and Dr Kahl did that they presented updated data at ASH that I thought was pretty interesting. But let’s start out with this situation which is the question about first line therapy in an older patient, 75-year-old man. Here’s Dr Kahn.

DR KHAN: In this particular case the question was clear to me that this patient needs treatment. Then the question is what is the best possible regimen to get a maximum response? In my practice bendamustine/rituximab is the standard regimen for follicular, but I don’t know whether there is a better way. R-squared, I have used in the second-line setting after failure of chemoimmunotherapy. The question is can you use, in a symptomatic patient, R-squared in the first-line setting?

DR LOVE: So we were talking about the POLARIX study. And it’s always fascinating to me how people respond to data and kind of what it takes to change people’s practice. When I saw the R-square study, I thought people were going to jump all over it and that did not happen whatsoever. But just curious for your update. How do you approach first line therapy outside of trial setting? And any trials right now that you’re excited about putting patients in?

DR SMITH: Yeah. I think frontline for a high tumor burden follicular lymphoma patient, the 2 options really are chemoimmunotherapy or R-squared. And out of the chemoimmunotherapy, BR is absolutely my first choice and I think what most experts, even in your survey, chose as well. The RELEVANCE trial compared R-squared against BR and showed equivalency. So it was a really nice nonchemotherapy way to treat patients with follicular lymphoma. And the patients were matched for tumor burden, response was very, very brisk and it was very well tolerated. Why R-squared hasn’t become the standard of care, I think, is probably a matter of, again, patient preference, insurance. It is a longer treatment. In that study, it was 18 months of treatment as opposed to 6 months where you can just be done. And, again, I hate to keep bringing up the pandemic, but when I’m sitting there in clinic and talking to my patients about 18 months of taking something, the 6 months sounds a whole lot more appealing. So I think that BR is still absolutely appropriate although R-squared is a great option too.

Case: A man in his mid 30s with newly diagnosed Grade I FL with a high proliferative index — Pavel A Levin, MD, PhD

DR LOVE: So another issue that comes up in this next case of Dr Levin is when you, instead of BR, when you use R-CHOP. I remember the STEEL study, it was hard to believe and it took, I think, a while for people to actually change their practice that BR would be better than R-CHOP. You would think R-CHOP, more intense. I don’t know. But the curves were definitely separate. And the question is when do you kind of go the other way? This is a young patient, a patient with Grade 1 disease, but had a high Ki-67. Here’s Dr Levin.

DR LEVIN: The patient was actually a very young man, 36 years old, presented with abdominal pain and was found to have bulky lymph nodes. The biopsy confirmed that it was follicular lymphoma. It was Grade 1 actually, but proliferative index was 70 to 80%. So he got three cycles of R-CHOP and got radiation to the lymph nodes. The question that I was facing at the time, whether R-CHOP would be the right option for him or whether we would go with something more applicable to follicular lymphoma like bendamustine rituximab, or whether we would just do radiation alone because it’s Stage I to II maybe, disease. So what options people would prefer in this kind of situation, what experience they have?

DR LOVE: What’s the patient’s current situation?

DR LEVIN: So it’s been 3 years and he is with no evidence of disease.

DR LOVE: Any thoughts about this case?

DR SMITH: Yeah. So the one thing we didn’t get a chance to hear about is the size of the biopsy. And the reason that could be important is that with follicular lymphoma, in general, it’s very heterogeneous depending on where you get your biopsy specimen from. And so if you’re within, for example, a proliferation center, sometimes you can get a falsely elevated Ki-67. So if it’s a large enough specimen, I think that helps balance it out, but if it’s a smaller specimen, there could be some sampling bias that’s there. And we didn’t hear about the PET scan which may or may not corroborate that this is a very highly PET avid and proliferative disease. All of that aside, R-CHOP is not wrong for follicular lymphoma. And I think this just speaks to the point that grade is not the best correlate necessarily. Grade in follicular lymphoma is somewhat controversial. So R-CHOP is not wrong. I think for me personally, I would have definitely considered R-CHOP, but probably not the radiation. And the main thing is that I just don’t like radiating the abdomen because these are long-term survivors, in general, and so 20 years later, 15 years later, it would be — I just wouldn’t want to be dealing with some of those long-term complications. But R-CHOP is not wrong. I think that was a reasonable thing to do based on what we just heard.

DR LOVE: Certainly seemed to do well by this particular patient. A couple questions from the chat room. A couple cases, actually. One from Anita, Stage IV nodal marginal zone lymphoma presenting with severe anemia and lymphadenopathy. The patient had R-CVP 4 years ago. Any thoughts?

DR SMITH: Yeah. So what’s changed in the last couple years is that we now have BTK inhibitors that are approved for marginal zone lymphoma. I think at this point, if the patient really has that much disease, you could do BR. I think that that would be okay. It would probably give a good deep remission although with some of the cytopenias, you’re going to aggravate that before it gets better. Or you could go to something like zanubrutinib. And zanubrutinib with or without rituximab is very effective for marginal zone lymphoma.

DR LOVE: So another case, this is from Dr Kumar. The patient is 75, slightly frail, but fully active, Hodgkin disease in 1978 treated with radiation therapy, 2005, HER2-positive breast cancer treated with chemo, trastuzumab. Now has a gastric diffuse large B-cell, ABC subtype. Any thoughts?

DR SMITH: This poor person.

DR LOVE: Yeah.

DR SMITH: So they’ve already had — oh my goodness. So now they’re older, they’re frail, they’ve had prior therapy. There are some pretty interesting data coming out about nonchemotherapy options in Hodgkin’s such as BV/nivo for elderly frail. There is some toxicity there. Actually, you have to be kind of careful, both about neuropathy as well as infectious complications and adverse events from the immunotherapy in this population. But I think either a nonchemotherapy regimen such as BV/nivo, although I’m sure the purist there will tell me that BV is chemo because it has vinca alkaloid in it, or to consider something like just a dacarbazine-based regimen like Adria/dacarbazine. There are some other regimens that are in development. But I’d probably favor BV/nivo for this person.

DR LOVE: So this was actually diffuse large B-cell in the stomach.

DR SMITH: Oh.

DR LOVE: This patient had a prior —

DR SMITH: I’m so sorry.

DR LOVE: That’s okay. Started out with Hodgkin’s. You got that. The patient actually, I should have mentioned, had anthracycline adjuvant therapy for breast cancer. I’m not sure how much. But now, gastric diffuse large B-cell, prior anthracycline.

DR SMITH: Yeah. I’m sorry. I was stuck on the Hodgkin’s. Sorry.

DR LOVE: Yeah. Hodgkin’s. Right. No problem.

DR SMITH: But all right. Well, with diffuse large B-cell lymphoma in an older, frail person with prior anthracycline, this is tough. I often, for somebody who has had prior anthracycline or they have cardiomyopathy, will do R-COP. And so you could think about R-miniCOP. In fact, I’m doing that for somebody right now. So that would be a good option. The other, for a non-GC diffuse large B-cell lymphoma, if the R-COP doesn’t work or is not tolerated, R-squared, there is data for lenalidomide in non-germinal center diffuse large B-cell lymphoma. Or tafa/len would be another appropriate option.

DR LOVE: So I want to ask you about one of your cases actually that you wrote up. There actually were 2 cases of people who were Jehovah’s witnesses and got CAR T. I’m just kind of curious what happened. This is the paper where you wrote it up.

DR SMITH: Yeah. They did really well. There’s a lot of ethical discussions about should you put somebody who is a Jehovah’s witness through something where they could have life-threatening anemia and thrombocytopenia? And we were able to work as a team and try to prevent them from needing, you know, they weren’t going to accept a transfusion. And you can tolerate pretty low hemoglobin levels. The platelets are a little bit more scary, but we were able to support the person through really supportive care. So never say no.

DR LOVE: Fascinating. Yep. So I want to ask you about this paper. I think the audience knows whenever I see really cool artwork, it always draws me in. I’m trying to always understand pathways and stuff. So you want to take a crack at just giving me a broad view of what you’re trying to get into with this paper that gets into the biology of FL?

DR SMITH: Yeah. So I think most people know that the hallmark abnormality in follicular lymphoma is the rearrangement of chromosomes 14 and 18 leading to BCL2 overexpression. But what’s kind of interesting is that BCL2 seems necessary, but not necessarily sufficient for many of these follicular lymphomas to progress. And so there’s a really strong body of work showing that the secondary early abnormalities that occur all have to do with epigenetic deregulation. And you can see the main genes that are affected, KMT2D, CREBBP and EZH2 which can be mutated with either loss of function or gain of function as sort of a secondary hit. And then as the follicular lymphoma continues to clonally evolve, there’s a number of later mutations that can occur that include some of the bad acters associated with transformation like TP53, MYC and loss of beta-2 microglobulin. So this cartoon was really just to sort of show what’s fundamental, what’s sort of secondary and then what happens at the end. And then —

DR LOVE: I always love these kind of graphics too, mechanism of action of all these new agents coming in here.

DR SMITH: Yeah. It’s kind of amazing, right? This is all for follicular lymphoma. Our toolbox is bursting, even if we don’t know the sequence of how to use them or the right tool for the right job. But this includes both approved and not approved agents. I will say that there’s one thing on here that after this article was published, a reader came up to me. There’s a new radioimmunoconjugate, Betalutin®, that should be included. There’s an addendum going in under radioimmunotherapy. We always forget about radioimmunotherapy. On the right side of the page there. Yttrium-90-ibritumumab is still around, not that it’s used as much. But there’s a new radioimmunoconjugate in development. So I should, in all fairness, add that. But we have bispecifics here, we have CAR T-cell therapy, antibody drug conjugates. This is very exciting.

DR LOVE: We know a substantial part of our audience are millennials. I don’t even know if they what is radioimmune therapy. I was all excited about it when I first heard about it and then it sort of went away. But anyhow. You were mentioning bispecifics and I’m particularly curious about mosunetuzumab in follicular lymphoma which we were just talking about. If that drug were to become available, and I’m curious if you think it’s going to happen in the near future, the data looks pretty interesting, would you use it and in what situation?

DR SMITH: Yeah. I hope it gets approved. I think that the bispecific antibodies are extremely exciting in both follicular and diffuse large B-cell lymphoma. And mosunetuzumab is the furthest along out of all of these. I don’t know that we can say which one is the best. But it is the furthest along in development and I would use it. Depending on which datasets get approved, it may be very useful, not just in follicular, but in diffuse large B-cell lymphoma as an alternative to CAR T, maybe third line therapy. Or not as an alternative to CAR T, but to add to the non-CAR T options that we have. Yeah.

DR LOVE: I’m curious about the bispecifics. We had Laurie Sehn on a program recently and she’s used, I know, mosunetuzumab on trial. She was, you know, because I was curious about the CRS and other issues that you see and she said it’s really not much of a problem, that you mainly see it in the first cycle. I don’t know if you’ve had any experience with these agents. What do you see tolerability-wise? How much CRS do they get? And can they get neuro toxicity?

DR SMITH: Yeah. So neuro toxicity has been very, very low to nonexistent. And in fact, this table would show you that it’s really not there. The CRS can occur, but there are ways to mitigate that including stepped up dosing or the use of steroids. And this is meant to be given in an outpatient setting. And, again, I think that these are very tolerable treatments.

DR LOVE: So another issue I wanted to ask you about is rituximab maintenance, either after chemoimmunotherapy or as part of rituximab monotherapy. This was a quote from an editorial you did on a paper that looked at 2 versus 1 year of therapy after chemoimmunotherapy. But, of course, we saw the RESORT data also, as I was mentioning, which was R-monotherapy, 4 doses versus indefinite which continues not to show a survival benefit, but does show a delay to go to chemotherapy. I love this quote because you talk about, you know, initially, we were trying to figure out how long we can give it and I think your question is how short can we give it? And now, of course, much more relevant, as you bring out in the editorial, because of COVID. So I am curious, in general, the way you’re approaching anti-CD20, in general, in the era of COVID today and what your thoughts are about maintenance R.

DR SMITH: So when I wrote this, we didn’t have Evusheld yet. And I think that Evusheld has slightly adjusted my approach. But I think, in general, maintenance rituximab offers a progression free and not an overall survival advantage and so for a long time, I was not using it in indolent lymphomas. When I saw the 10-year PRIMA data, I started to change my mind and say, wow, at 10 years, more than 50% of people who got 2 years of maintenance didn’t need any second line treatment and maybe I should reconsider it. And then the pandemic came. And we know that if you get rituximab, it takes at least 12 months to mount a response to the vaccines. And I had a lot of patients get very sick, especially early in the pandemic and even with the Omicron surge. So I think that until there’s really a cure or a survival advantage, I will probably not be using as much maintenance rituximab. And really, we should see, what is the minimum dose? Maybe just — and the Swiss have looked at this, you know, just a few doses rather than 2 years or 5 years. That MabCute article that I was writing the editorial about randomized patients after 2 years to 2 additional years or observation and there was no advantage. So I think if you’re going to do maintenance, 2 years is the max, but I think we need to figure out the minimum.

DR LOVE: So you mentioned Evusheld which I can’t pronounce the generic. So whatever.

DR SMITH: Yeah.

DR LOVE: But I’m curious, we get so many questions from docs about when to use it. So what’s your approach?

DR SMITH: So I’m using it for anybody who is on active treatment right now, especially if there’s an anti-CD20 that’s involved. So any rituximab, obinutuzumab, I’m using Evusheld.

Case: A woman in her late 30s with Stage II lymphocyte-predominant Hodgkin lymphoma (HL) — Dr Morganstein

DR LOVE: So I want to move on now and do a couple cases of Hodgkin lymphoma. We’re going to start out with a patient, a young woman, 38 years old, with Stage II lymphocyte-predominant HL. Here’s Dr Morganstein.

DR MORGANSTEIN: 38-year-old asymptomatic woman, presented after evaluation. She had an MRI done for breast surveillance, okay, no breast nodes, and they noticed some small, 2 cm lymph nodes in the axillae. This was biopsied, and she was diagnosed with lymphocyte-predominant Hodgkin’s lymphoma. PET imaging showed bilateral axillary lymph nodes, some very vague inguinal lymph nodes, which were not palpable, with slightly elevated SUVs. She also had something in the rectal area which was negative on colonoscopy. So my question, and we see rarely lymphocyte-predominant Hodgkin’s lymphoma, what is the best treatment and the optimal treatment? Can these patients be observed? Can we treat them with single-agent rituximab, or do they need more intensive chemotherapies with rituximab-CHOP-based chemotherapy? And in these people we don’t see very often, how do we approach them and how do we counsel them as far as their prognosis?

DR LOVE: Any thoughts?

DR SMITH: Yeah. So I think the biggest problem with lymphocyte-predominant Hodgkin’s is that the word Hodgkin’s is attached to it because even though it has the Reed-Sternberg cell, it’s a completely different disease and it’s really a low-grade lymphoma. And I think the most important thing to remember is that the number 1 cause of death is overtreatment. So for this patient with advanced-stage disease, it’s bilateral axillary, perhaps something in the abdomen, asymptomatic, I would recommend observation. At the time of progression, if the patient is symptomatic, if it’s symptomatic progression, similar to a follicular lymphoma, I would probably do rituximab alone. But the biggest risk is whether or not these patients transform and when they do, it’s to T-cell rich diffuse large B-cell lymphoma and so R-CHOP is what I would use if I’m going to use chemotherapy. I think there’s a lot of controversy over how many cycles and I think it will depend on the disease burden at the time of progression and/or transformation.

DR LOVE: So thanks to Dr Kumar in the chat room for telling me it’s tixagevimab and cilgavimab. Maybe tixa/cil. Maybe we can make a short one.

Case: A woman in her early 60s with recurrent HL — Raman Sood, MD

DR LOVE: One more case of Hodgkin lymphoma. And there was a press release actually that came out recently saying the ECHELON-1 study looking at BV that we’ve been talking about for the last 5 or 6 years now has a survival, finally, has a survival benefit. We haven’t seen the data. I don’t know if it’s going — I would guess maybe this summer. Who knows when — it’s AACR. I don’t know when it’s going to be presented. But I’m curious about your thoughts about how that might affect your approach and the approach, in general. But first, let’s go through this case of a 60-year-old woman of Dr Sood.

DR SOOD: I treated her originally in 2013. She had high-risk disease, extra nodal, large lung lesions, everything, leukocytosis, high ESR. So that’s why we went to the escalated BEACOPP regimen. And she did have a CR, which was pretty durable. So after 8 years, when she recurred, one thing I wanted to confirm this is Hodgkin, nothing else, although it was same location. So we did send her back for biopsy and it has confirmed that it’s Hodgkin’s. So I’m actually referring her to a local Hodgkin’s expert to get his input because I am not quite sure. I don’t think she can get more intensive BEACOPP again, just because the limitation of anthracycline use that’s already had 8 cycles. So we are limited in how much more of that she can get. So this may be somebody, transplant is definitely in play. What induction regimen you use for transplant? And the other option is brentuximab-based regimen before transplant in her case. So that’s a lot of open questions there that I’m not quite sure. So that’s why I’m getting a second opinion.

DR LOVE: I’m curious how often you see relapse 8 years later also. Any thoughts about this case?

DR SMITH: Yeah. Seeing a late relapse after escalated BEACOPP is definitely quite rare. But if we just frame it in the sense of she got chemo anthracycline-based therapy and then a late relapse, salvage chemo and an auto is still the standard of care for her situation. In terms of salvage regimens, I would still do ICE at this point as my first choice, but if this was something where the patient either couldn’t get chemotherapy or didn’t want ICE, BV/benda. There’s some really nice data from Ann LaCasce and others showing the tolerability and efficacy there. And then most recently, we have some data of PD-1 inhibitors combined with chemo like pembro-GVD and nivo-GVD that’s coming out. I wouldn’t say that they’re standard of care just yet, but I think either ICE, GEMOX or GVD or BV/benda, any one of those, it’s a little bit up to the patient, and an autotransplant for a late relapse.

DR LOVE: Interesting. And any thoughts, I’m curious how you’ve been dealing with first line therapy? The control arm of the next intergroup study for Hodgkin’s has, the control arm is going to be ECHELON-1 so that kind of tells you something. I’m curious what your thoughts have been over the last 5 years and what you’re thinking if, we want to see the data, but with the survival benefit.

DR SMITH: Yeah. When ECHELON-1 came out, I did convert over to BV/AVD, especially if somebody was young and had high-risk disease. That seemed to be the group that benefited the most. And I was part of the study that was written, S1826, which is the BV/AVD versus nivo/AVD. I helped write that through SWOG. And one with Alex Herrera and Jonathan Friedberg who are the PIs. I’m really excited. I think BV/AVD showing a survival advantage over ABVD is tremendously exciting. I do think that should be the standard of care outside of a trial.

DR LOVE: Do you think it’s going to push people to use it in lower? I hear people talking about the risks and all, but I’m not sure there’s evidence that it doesn’t work with low-risk. Do you think the survival benefit is going to make it more blanket approach?

DR SMITH: Yeah. I think that people will naturally extrapolate. There are trials going on to look at BV/AVD for patients with lower-stage disease and lower-risk disease. But I could understand that people might extrapolate that, especially because right now, if you have limited-stage disease, you’re getting 3 cycles of ABVD and if you could avoid bleo altogether, it’s kind of exciting.

DR LOVE: Yep. I’m sure that would make a lot of people happy in practice for sure. So, Sonali, thank you so much for joining us today and sharing your experience and wisdom with us. Audience, thank you for attending. Come on back on Thursday. We’ll see what Dr Hillmen has to say about new things including what happened at ASH in CLL. Be safe, stay well and have a great night. Thanks, Sonali.

DR SMITH: Thank you. That was really nice. Thank you.