Introduction

DR LaCASCE: I’d like to welcome everybody What Clinicians Want to Know: Addressing Current Questions and Controversies in the Management of Hodgkin and Non-Hodgkin Lymphoma, I Ann LaCasce from Dana-Farber Cancer Institute and I’m doing my best to channel Neil Love. I am no Neil Love, but I hope I can do him proud here.

And I’d like to introduce you all to our panel. Sitting here first, Dr Jeremy Abramson from Mass General Hospital, Dr Loretta Nastoupil form MD Anderson Cancer Center. We have Martin Dreyling form LMU University Hospital in Munich and Gilles Salles from Memorial Sloan Kettering.

I’d also like to bring to your attention 2 additional sessions later today, starting at 3:15 this afternoon will be the content on multiple myeloma. And then following this evening at 7:00 PM, focus on AML and MDS.

So I want to bring to your attention this group of clinicians who have put forth cases that they’ve seen in their practice and really the focus of this session is to discuss how to manage patients in the context of all the new therapies that we have available in lymphoma. So a big shout-out to all of them.

So a few housekeeping items here. If you want to look at the program slides, the link is posted in the chat at the start of the program. There are survey questions we’d love for you to take a look at and answer and will be presenting the results of those questions throughout the meeting.

If you’d like to submit a question or challenging case, please feel free to put that into the chat. And at the end of the program a CME credit link will be in the chat as well.

And I’m sure everyone here knows how to Zoom and the chat below.

This is an enduring program, so the meeting is being video- and audio recorded. You can go back to it later if you’re interested. And it will an enduring web-based video and PowerPoint program. An email will be sent once that’s available to be viewed. And to learn more about the educational programs for Research to Practice, the link is there at the bottom.

Diffuse Large B-Cell Lymphoma

DR LaCASCE: So with that, we will get started on our agenda today. And we’ll be starting off with diffuse large B-cell lymphoma and Dr Salles will be presenting. First we’ll start with some Real-World Cases.

DR LOVE: Good morning, everyone. I’m Neil Love from Research To Practice and our Real-World Virtual Case Library. The first patient is presented by Dr KS Kumar, an 87 year old woman who was treated 12 years ago with R-CHOP for diffuse large B-cell lymphoma. Recently, although asymptomatic, the patient was found to have extensive recurrent disease.

DR KUMAR: She’s very, very nervous. Every time she comes to the office she’s actually shaking. So she’s very frail. Now the nodes are increasing in size. She has a pretty large conglomerate nodes of 5 cm.

So the question is she’s 87 years old right now, should we use R2 regimen? Or should we use tafasitamab and lenalidomide?

DR LOVE: The next case was presented by Dr Khuda Dad Khan.

DR KHAN: 67-year-old gentleman. Very interesting gentleman.

He has these skin lesions on his upper part of his left chest which had been growing for a while.

Now he has multiple, thick nodules. And when I reviewed pathology with our hematopathologist he turned out to have diffuse large cell B-cell lymphoma, which I have not seen that much in the skin only.

Radiation oncologists were of the opinion of giving involved-site radiation therapy, up to 30 Gy, should we stay just with chemotherapy, or should we lean towards combined modality therapy with 3 courses of chemotherapy followed by involved-site radiation treatment.

DR LaCASCE: Loretta, would you mind discussing these cases, please?

DR NASTOUPIL: Yes, so the first case, I think some of the interesting aspects, this is an 87-year-old female he describes as being frail, there’s a 12-year gap from the initial diagnosis of large cell lymphoma to what appears to be a recurrence, and so that’s a long time. Now the Mayo group has described POD24, but for patients who have underlying indolent, they tend to relapse a little bit later. So the first thing I would make sure is that we know this is actually large cell lymphoma and not an indolent lymphoma that’s relapsing after R-CHOP.

If this was a younger patient, we might have discussions in our group about whether or not this is a second primary and have a lengthy discussion about whether to rechallenge with an anthracycline, but given this is an 87-year-old, we’re assuming this is a recurrent large cell lymphoma, I think this is where we can start at least discussing some of the novel agents, particularly tafasitamab/lenalidomide, based off of the L-MIND study. Eighty-seven year olds are often underrepresented in our prospective studies, so it’s going to be hard to know how this patient will tolerate that regimen. But generally older patients have reduced creatinine clearance, and so with the appropriate dose of lenalidomide, I would at least try that, given that the outcomes from the L-MIND study, particularly in second line look very promising.

Outside of that, if she’s too frail or there’s substantial comorbidities, then a palliative approach is probably the best thing to consider for this patient.

The second case is a 67-year-old gentleman with what appears to be a primary cutaneous diffuse large B-cell lymphoma which is often also described as a leg type, they tend to have worse prognosis, so generally we will approach this with a combined modality approach, so an anthracycline-based chemotherapy regimen with the potential for radiation. I think that’s debatable now in the modern era in terms of the role of radiation, the potential for late toxicity in second cancers. But this is a subtype of large cell lymphoma where I do worry about higher rates of relapse. And if this will fit within one radiation field, I would probably approach it with an R-CHOP followed by radiation consolidation.

DR LaCASCE: Great, thank you. We have a couple of minutes. Would, Loretta, in a patient like this, would you consider CNS prophylaxis? This is certainly an area of great controversy.

DR NASTOUPIL: Yes. I think that’s what we’re really struggling with right now. And the problem again is we don’t have probably adequate prospective studies to really answer that. But, yes, this is someone that I would be concerned. We could calculate a CNS IPI risk. The problem though is if they are higher risk, are we going to do high-dose methotrexate? IT-chemotherapy? I think that’s debatable. And I think Gilles had a New England Journal paper that says maybe no CNS prophylaxis is adequate.

DR SALLES: Well, I don’t think I have a New England Paper on that, but let’s put it like that. I think it’s clearly debatable and we will see during this meeting at least 2 presentations regarding the role of high-dose methotrexate, suggesting that there is no benefit. Well, when I sit with many experts, we still like to do something. So I don’t know if we are wrong. I don’t know if the real-world data that we see are really evidence-based or not. I think we need to focus.

I personally believe that was is more important is really the adequate rapid control of the tumor with an adequate treatment. And that may explain sometimes the reasons why patients treated with doses such as EPOCH, which are usually patients with high risk of CNS relapse, don’t seem to relapse that way. That was maybe the same reason for patients treated with more dose intensive regimen in Europe. But I don’t know the answer.

DR LaCASCE: Martin, it looks like you had a comment?

PROF DREYLING: Maybe just another question to Loretta for the first patient. Would you consider pola in any setting in this relapse after R-CHOP?

DR NASTOUPIL: Yeah, absolutely. I think where we’re struggling is would I tack on bendamustine? And I probably would not. I think the data is probably inadequate to say pola alone would be adequate. So I probably would do tafa/len first, dosing the len appropriately, and then consider pola next.

DR LaCASCE: Jeremy, would you do anything differently?

DR ABRAMSON: No. I agree entirely with my esteemed colleagues. And I also agree that I think tafa/len would be a terrific option for the second patient. The other, I think good option is a polatuzumab-based option, although as Loretta points out, the bendamustine is not a heavy-hitter in large cell lymphoma, it does have significant myelotoxicity and lymphodepletion. So I’ll often give polatuzumab with rituximab and omit the bendamustine because of safety concerns, particularly in an octogenarian.

DR LaCASCE: Thank you. And I think we’ll be getting to a lot of these issues in Gilles talk. But next, we’re going to show some questions here. Regulatory and reimbursement issues aside, which first-line therapy do you recommend for an otherwise healthy 65-year-old patient with diffuse large B-cell lymphoma?

R-CHOP? Polatuzumab plus R-CHP? Dose-adjusted EPOCH plus rituximab? Or other?

And here are the voting results from the audience here. So 86% of you voted for R-CHOP. Loretta, what do you think? Do you agree with this?

DR NASTOUPIL: I think that’s the right answer. I think we’re all really interested to see the data from POLARIX, but I absolutely agree.

DR LaCASCE: Gilles, you mentioned R-EPOCH to get systemic disease under control. Is that something you would consider in a patient like this?

DR SALLES: Well, I think we don’t have a lot of characteristics of these patients. So I will more reasonably choose R-CHOP, although maybe we’ll discuss in a few minutes what we still know about POLARIX. And in a couple of days we’ll hear more.

DR LaCASCE: Great. Next question. Which therapy would you generally recommend first for an 80-year-old patient with diffuse large B-cell lymphoma who experiences disease progression on front-line R-CHOP and is not eligible for high-dose therapy?

Polatuzumab vedotin with bendamustine and rituximab? Tafasitamab/lenalidomide. Selinexor? CART T cell therapy? Or loncastuximab tesirine?

And you can see here the majority of the audience voted for polatuzumab with bendamustine plus Rituxan as a package. Any thoughts on that, Martin?

PROF DREYLING: Well, I would absolutely agree with my colleagues that I would skip bendamustine. So there are also some data published on pola in combination with rituximab and you still achieve rather high remissions but it’s not long-term remissions, fair to say.

DR LaCASCE: Jeremy, would you consider tafasitamab/lenalidomide in a patient like this?

DR ABRAMSON: I absolutely would. I think the data look very good in second line from the L-MIND data, with really quite impressively durable remissions in the responding patients. The one concern I always have when thinking about tafasitamab is, am I going to consider this patient for a CAR T cell in the third-line setting? Because we really don’t know if giving a prior CD19-directed agent is going to impact the potential curative intent of a CD19-directed CAR T cell. Those concerns may ultimately be allayed as we get more data, and there’s preliminary suggestion that it may not impact things much. But in the absence of really knowing, I’m cautious about that.

At 80 years old, I would consider this patient a candidate for a CAR T cell, particularly a 41BB co-stimulated CAR T cell which has less toxicity than a CD28 product. And so I think Pola-R would be entirely reasonable in second line if I’m thinking forward to this, if this patient is fit, thinking about a CAR T cell in third line.

If I thought this patient wasn’t going to be a great a great candidate for a CAR T cell even in the third-line setting, I’d probably go with tafasitamab/lenalidomide.

DR LaCASCE: We have one more poll question. Is it reasonable to offer treatment to a patient who has experienced disease progression on or after a CD19-directed CAR with tafasitamab/lenalidomide or loncastuximab tesirine and vice versa? This is a key question.

Loretta, what do you think?

DR NASTOUPIL: Yeah, I think we need more data, but yes, I think as long as they have CD19 expression, yes.

DR LaCASCE: Gilles, anything to add?

DR SALLES: Well, I think we just have a paper that’s coming out regarding the fact that there is a masking of the CD19 antigen by the antibody during a couple of days or weeks. So there is probably an issue regarding some delays. But this is very compatible with the delay you have when you have manufacture CAR T. So I think I will not necessarily hesitate. And I haven’t seen any data suggesting the loss of CD19 in opposite to what we see sometimes after CAR T.

DR LaCASCE: Great. All right, we’ll move on, and Gilles will present on diffuse large B-cell lymphoma.

DR SALLES: Thank you and good morning everybody. And happy to be here in person for one of these meetings.

So my goal this morning is to try to review with you some of the recent data regarding the management of diffuse large B-cell lymphoma, excluding CAR T therapy, which will be discussed by Jeremy later today.

And is start with data that are going to be presented on Tuesday morning in the Late-breaking Abstract session, which are the data from the POLARIX study. This was a randomized study, accruing patients with newly diagnosed diffuse large B-cell lymphoma with an IPI of 2 to 5, 18 to 80 years old. And as you can see, patients received either standard R-CHOP plus polatuzumab/placebo, or RCHP/Pola plus vincristine/placebo. It was double-blinded, so clinicians and patients were not aware whether they’re received vincristine or pola in order to assess safely the rate of neurotoxicity.

What I have got from the abstract is that the median age of patients accrued in this study were 65, and almost two thirds of them had an IPI 3 to 5.

These are the results that you can see in the abstract, which is online, with a median follow-up over 2 years, which start to make us comfortable in the field of diffuse large B-cell lymphoma. The primary endpoint was met. It’s a hazard ratio of .73. And you can see the differences that are noted in the abstract in PFS rate at 2 years, 60 — 76.5 for Pola-R-CHP versus 70.5 for R-CHOP. The CR rate is slightly higher but not significantly higher for Pola-R-CHP.

We heard from the abstract that there is a benefit in terms of event-free survival and disease-free survival, but no benefit in terms of overall survival. And we read also that subsequent therapy was more frequent for patients that receive R-CHOP, including more frequent use of autologous stem cell transplant or CAR T therapy.

Regarding toxicity, as you can see from this table, again retrieved from the abstract, same number of Grade 3/4 events, same number of deaths during therapy. Same number of adverse events leading to dose reduction of 1 of these compounds, including either vincristine or polatuzumab vedotin, not knowing which one could be responsible of neuropathy. And you can see an equal number of neuropathy and a very low rate of Grade 3/4, and neuropathy again in the double-blinded study.

So what are my conclusions? This is a study that clearly shows an improvement of progression-free survival with Pola-R-CHP in patients with newly diagnosed DLBCL with an IPI 2 to 5. The abstract says 27% reduction of the risk of progression, relapse or death. And we don’t see an increased risk of toxicity. So the question is, is that going to become a new standard of care?

While usually when we look about diffuse large B-cell lymphoma, we have learned that usually progression-free survival benefit translate into an overall survival benefit. Well, the situation may have changed. Ten, 15 years ago, we know that, except a few patients that benefited from autologous transplant, there were probably no way to salvage patients that failed diffuse large B-cell after R-CHOP and that ultimately they were all going to die.

Maybe things have changed with CAR T cells or new efficient agents that we have discussed already. So that may explain a little bit what we see right now.

The second point is that apparently the disease-free survival is different, so there may be no difference at the beginning, but a little bit later. And maybe we have to look further over the years what are the results.

So let’s look Tuesday morning at the presentation. I hope we’ll able to read a final report in the near future. What will be exactly the safety of this regimen? What will be the efficacy in the more difficult to treat patients? Patients with high-risk IPI? Patients with double-hit, double-expresser and so on? Let’s look at that to see whether this could be a new standard of care.

This puts me to the use of polatuzumab vedotin added to bendamustine/rituximab in the relapse setting. I don’t have to go over these results that were published by Dr Senn and colleagues a couple of years ago, which are actually updated in Blood online in a recent update. As you know, a significant higher number of patients with a CR benefit in terms of PFS and OS in a small, randomized study, 40 patients in each arm. Well, what was interesting is that the study was, in fact, continued as a single-arm study in Pola-BR cohort. So it’s not anymore comparative study, but because of some changes in the manufacturing of polatuzumab vedotin, a couple of other patients received this regimen in the relapsed setting.

The characteristics of these patients were a little bit different from the randomized study, a little higher proportion of severe patients. But the results that you show here are interesting, and these are those that are just recently published in Blood online. As you can see, in second line, the best of all response rate and CR rate is high, but unfortunately it’s a little bit inferior in patients that were refractory to their last primary therapy, or primary refractory which probably comes back to the patient we discussed earlier.

If you look at the outcome of these patients. On the left, you have the curve from the randomized study, on the right you have the extension cohort. And as you can see, the curves are relatively comparable. The median PFS in the extension cohort is of 6.6 months. The median OS is 12 months.

So I think these are encouraging data concerning the role of this drug in the relapsed setting. Obviously, if it moves in the future in the first-line setting, that will be a different story.

Very briefly, regarding tafasitamab. This is a modified anti-CD1 antibody, modified to increase ADCC, and the L-MIND study combined this antibody with lenalidomide with quite a frequent administration of tafasitamab during the first 3 cycles and lenalidomide at the standard dose but could be eventually modified.

We published the results 1 year ago and just recently, the updated result with 3 years of follow-up. And as mentioned by Dr Abramson, what is really interesting with this regimen is what you see here in the duration of response curve, the orange curve, clearly patients that responded to this therapy had a prolonged response, particularly those that had a CR. I will say this is comparable to what we see with CAR T therapy.

The CR rate was 40%. Knowing that this quite elderly patients, the median age was 72, but there were clear underrepresentation of primary refractory patients.

A few other hints from the paper. As you can see benefited to most of the patients according to their risk category, except a very high IPI. I will say that’s not surprising. Based on this data, a couple of things. I don’t think we learned a lot regarding safety.

A couple of things regarding the use of this regimen in the first line. There is an ongoing study, First-MIND, that included tafasitamab, either with R-CHOP or with R-CHOP/lenalidomide.

In terms of safety, the results were presented were during the last EHA meeting. There is a significant number of patients with Grade 3 or 4 cytopenia. And the results will be presented — or efficacy will be presented during this meeting.

As you can see, the overall response rate at the end of treatment is encouraging, whether it’s better than what we have a standard of care remain to be defined. And a randomized study will be planned.

A few words regarding the newcomer in the field, which is loncastuximab tesirine, or Lonca-T, which is another antibody drug conjugate targeting here also CD19, but with a different toxin and a different safety profile.

The data that led to the approval of this drug, at least in the US, are derived from the Lotis-2 study, and are shown here. This was relapsed/refractory patients. And as you can see, the response rate as a single agent of Lonca-T is in the range of 50% with half of the patients having a complete response. While the median PFS is in the range of 5 months, again we were discussing median PFS, which are a little bit more extended with other the drugs, but cross-trial comparison are very difficult. And again, duration of response looks encouraging. What is being done with this antibody these days is shown here.

There are a couple of toxicities which are mild. But what will be presented during this meeting is an interesting combination of Lonca-T plus ibrutinib. And some subanalysis of the trial regarding the using of antibody also after CAR T therapy. We have to some more.

Finally, and to conclude, while this drug was approved.

Finally, and to conclude, a few words regarding bispecific antibodies. Most of them are CD3, CD20. These are the results presented from the different meetings that took place in the Spring. As you can see in the DLCBL field, we have a novel response rate from 40- up to 75%. A CR rate from 20- to almost 50%.

What we’ll hear during this meeting is some extended results of glofitamab. And you can see a complete response rate for aggressive lymphoma of 39%, so 40%. Encouraging result. And the curve on the bottom left is also encouraging to my point of view.

Other agents will be updated. And we’ll hear also some data regarding combination of these bispecific antibodies either with polatuzumab vedotin, with R-CHOP in the first-line setting, or in other settings. And I think these are really exciting agents that are currently in development.

Well, thank you for your attention. I will try to answer any questions if we still have time.

DR LaCASCE: Thank you, Gilles. One question we have from the audience. Do you think an overall survival benefit is required for Pola-R-CHP to replace R-CHOP as standard of care in the front-line setting?

DR SALLES: Well, I think that in DLBCL, clearly what we aim to do is to cure the patient with this first line of therapy. So, again, we have to look at the full data set in more detail. And we have to look also what are the regimens that were used in the relapsed setting for these patients because clearly, with CAR T, we salvage efficiently a couple of patients. But if I can avoid to bring patients to CAR T or transplant or another form of therapy, I would prefer to avoid that.

So I will say the field is changing and moving, but let’s look at the results in more detail. I will hope to see that today, or in the future, maybe some diverging curves regarding overall survival, but I think this is a significant benefit right now.

DR LaCASCE: Great. I think we have time for one more question. Jeremy, I’m going to ask you, what are your thoughts on the — or actually, I was surprised that tafa/len was the second-line recommendation by panelists rather than pola or Lonca in the beginning. Any comments on that? And was it the patient characteristics or other things that made you suggest that?

DR ABRAMSON: I think it’s several things. One is, that’s where it was studied. It was studied in the second line and later setting and that’s where the results looked the best for tafasitamab/lenalidomide, the second-line patients having the highest response, deepest response and durability of response. Polatuzumab was also studied in the second-line setting, though notably its approval in second line is in Europe, but in the United States it’s not approved in the second-line setting. And so that’s part of why I tend towards tafa/len in the, particularly in the older patients.

One can also take other considerations, obviously the patient’s age, comorbidities and performance status as well can inform the decision. I think they’re both reasonable options.

DR LaCASCE: Great. Thank you.

Thank you, Gilles.

Follicular Lymphoma

DR LaCASCE: And we’ll move on to follicular lymphoma and Loretta is going to present. But we’ll start with a couple of real-world cases first.

DR LOVE: The next case is presented by Dr Sunil Gandhi, a 54-year-old man with progressive abdominal pain.

DR GANDHI: This guy is a very, very busy guy. And he’s kind of an executive in one of the company. He had so much abdominal pain he came to emergency room. And emergency room, CAT scan showed lymphadenopathy. It was follicular lymphoma. But he had liver mets. I even biopsied liver mets to make sure it is lymphoma.

So, because of the liver mets, I went with R-CHOP kind of regimen. And then put maintenance rituximab.

This patient has finished 2 years.

So, I had a long discussion last meeting with him. He wants to continue rituximab. The guy is very smart. Looks up everything.

DR LOVE: The next case was presented by Dr Erik Rupard, a 74-year-old woman who in 2002, received R-CHOP for diffuse large B-cell lymphoma with some follicular lymphoma elements. A complete response ensued, and the patient has been followed since that time.

DR RUPARD: In 2021, she called and asked for an appointment sooner than usual, so I knew something was going on.

She reported new symptoms of fatigue as well as some new, kind of modest, non-tender neck and axillary lymphadenopathy. But definitely there and definitely had grown since the last visit with me and indeed the biopsy showed a WHO Grade 1-2 follicular lymphoma.

I treated her with just plain old rituximab. She got 4 weekly treatments.

I met with her last week, and we discussed the option of just observation and retreating with the rituximab as needed versus a maintenance therapy, and she was very much in favor of the maintenance treatment.

So the questions that arise from this case, how often do you use plain old rituximab as a treatment for a low-grade lymphoma? Are you more likely to pull out obinutuzumab or other treatments in that situation?

Would you treat this patient any differently, given her history of diffuse large B-cell lymphoma?

DR LaCASCE: All right, Martin, would you care to comment on these?

PROF DREYLING: Well, that’s just a couple of questions. Let’s first of all have a look at the first patient, a patient with aggressive lymphoma, relapsing with an indolent proportion — sorry — that was the liver patient. And the question is, how would I have treated it first line?

Well, it’s fair to say liver infiltration potentially indicates transformation, so these cases seem, in the majority, are more aggressive. Having said that, I also oversee a couple of patients with pure indolent lymphoma. Anyway, I would have also started with R-CHOP for essentially a couple of reasons. First of all, specifically in this benda — in the COVID era, I am a little bit reluctant for bendamustine, although Germany is the bendamustine country, fair to say. So I would more tend to R-CHOP, similar as in this patient.

Secondly, then the question is, what about the R-maintenance? And we would keep that for 2 years and not extend that. The reason is maintenance, again specifically in the COVID era, I would be a little bit reluctant and I’m aware that in US, maintenance, per se, is less frequently been applied, but in a patient with such an indolent lymphoma, I still would be in favor.

What are the options in a patient who wants to get some additional treatment? I think R-squared may be an option, but I would keep this R-squared potentially right now for third line with the exception of elderly patients with early relapses where we don’t foresee additional treatment options.

Now for the 74-year-old woman, the situation is slightly different. The question is how to go for this patient? And I think it’s — don’t forget the old options. Don’t forget simple things like CVP, almost forgotten, but you might consider to combine CVP in combination with obinutuzumab, for example. So improving the antibody that’s slowing down chemotherapy. I think this is still a valid option.

The alternative now for these relapses are monotherapy, I pick for patients with low tumor burden, low risk of disease. And normally, to be honest, nowadays in third line, or I used to use it in third line. I think we have plenty of options in the first, second line, so, therefore, I would be probably more in favor of combinations.

DR LaCASCE: Thank you. Gilles, I’d like to ask you, the issue of maintenance rituximab in patients who achieve a complete remission after initial chemoimmunotherapy, how do you approach that, maybe in the pre-COVID and now in the COVID era?

DR SALLES: Well, thank you. That’s clearly a question. In the pre-COVID era, I tended to recommend to most of my patients to start with rituximab maintenance, or obinutuzumab — have them receive obinutuzumab as an anti-CD20, and to stop it if they start to encounter infections or any significant adverse events. So that was my usual recommendation.

Since the pandemic, I don’t recommend that to the patient, except maybe a few patients with really high-risk disease. Things are changing. We see now our patients that are fully vaccinated when the disease develop. We see also the approval recent of the antibody given as a prophylaxis. Maybe things may change in a few months. But my recommendations right now is to avoid rituximab maintenance in these patients usually, in order to let them potentially be immunized in the near future. Because the window, if you start maintenance, is clearly going to be much longer in terms of possibility of vaccines against COVID, which, I think, is really important, a patient with hematological malignancies.

DR LaCASCE: Thank you. Loretta, what would you use a second-line therapy in a patient needing treatment?

DR NASTOUPIL: My favorite regimen for second line is lenalidomide/rituximab. And I think it’s just based off of the AUGMENT data, the PFS looks quite good. And I recognize that was probably studied in a favorable patient population because rituximab monotherapy was the control arm, but it looks good to me. And I think, similar to what we saw in large cell lymphoma, if you use these CELMoDs in earlier lines of therapy you might get better outcomes because those patients aren’t as heavily pretreated.

DR LaCASCE: Great. Thank you.

So I think we’ll move on now to another poll question. What is your usual third-line treatment for a patient with follicular lymphoma, EZH2 wild type, who receives first-line bendamustine plus rituximab, second-line lenalidomide/rituximab and then develops disease progression?

And you can see here 23% of patients would choose idelalisib. The second most common would be R-CHOP. There’s a smattering of many options here.

Jeremy, how would you approach this patient?

DR ABRAMSON: I am a little bit loathe to use PI3 kinase inhibitors, just because of the toxicity issues, and even umbralisib does have the incidence of hepato-toxicity that we see with the other, though at a lower incidence of severity. Usually, I’d honestly, probably, try R-CHOP in a patient who has never received an anthracycline. And so in this case, I would probably select that. I don’t think idelalisib or another PI3 kinase inhibitor would be wrong.

Axi-cel is, of course, approved in the third-line or later setting, that’s not usually where I’m using it. Potentially, I’ll use axi-cel in a patient with early POD who’s then failing second-line therapy, meaning a high-risk patient. Otherwise, in this patient, I’m probably thinking R-CHOP in third line and reserving axi-cel for the fourth line of therapy.

DR LaCASCE: Thank you. Martin, would you do something different in Germany?

PROF DREYLING: Well, I think it’s fair to say the voters, this is really a mixed bag. So there are a lot of different opinions and that tells you that there is no golden solution for this situation.

Having said that though, it seems to be more European vote because in Europe we only have idela being registered, and that would be definitely not my favorite because of toxicity, as discussed by my colleague. So I think it’s really pending. I would not go for tazemetostat because this is wild type. And I would probably also consider either a chemotherapy-based, and if it’s aggressive presentation, in favor of CHOP, or would go for the better tolerated PI3 kinase inhibitors.

DR LaCASCE: Great. Thank you.

Our next question. If you were going to administer a PI3 kinase inhibitor to a patient with relapsed or refractory follicular lymphoma, which would you generally prefer? Loretta, which would you prefer?

DR NASTOUPIL: I think sometimes patient insurance will inform me if I have patient where an oral regimen is just not going to be financially feasible. I might choose copanlisib in that setting. But generally I’m using umbralisib, just based off of the toxicity profile as my first choice.

DR LaCASCE: Gilles, do you agree that umbralisib is less toxic than idela or duvelisib?

DR SALLES: Well, the data suggests so, and I think we have always to be a little bit careful from data from not direct comparisons. I mean we have been learning how to use these drugs and what are the patients that may side effects. We have been learning about the prophylaxing. Having said that, I still believe it’s probably less toxic. My worries, whether it’s as efficient. So I’m little staying with the old guy and staying with the idela if I have the choice. But maybe it’s because I use more of the first one, which is here for many years, not umbralisib, which was not available when I was in Europe a couple of months ago.

DR LaCASCE: Jeremy, any last comments?

DR ABRAMSON: No. I agree completely.

DR LaCASCE: Great! All right, we’ll move on to Loretta’s presentation, please.

DR NASTOUPIL: Thank you. So I’m going to cover follicular lymphoma quickly. And I think what you just learned from those slides is that there is no single approach to this disease. And the more we study practice patterns, the more we realize these patients are grossly heterogeneous, particularly as we enter in that third-line or later setting and there’s a paucity of randomized data. So I’m going to walk you through some of the studies and share some of my sort of editorializing.

So the GALLIUM was the study that led to the approval of obinutuzumab in combination with chemotherapy in high tumor burden, previously untreated advanced stage follicular lymphoma based off of this study design.

It met its primary endpoint, actually relatively early in terms of a front-line follicular lymphoma study with less than 4 years of median follow-up. Now you could look at these curves and say well, it’s not a dramatic improvement. It did have a significant improvement in progression-free survival among those patients who received obinutuzumab in combination with chemotherapy. And it’s projected that over time these curves might extend out, similar to what we’ve seen with longer follow-up with the PRIMA study. I think the challenge with obinutuzumab and why the uptake has probably been low is based off of the toxicity profile.

So this is in the supplemental of The New England Journal of Medicine paper. And maybe if you look, based off of age, there’s potentially a benefit in younger patients and younger those 60 and younger, or 65 and younger, may be speaking to the fact that they’re better able to tolerate some of the toxicity associated with obinutuzumab, which is generally higher rates of Grade 3 infusion reaction, higher rates of Grade 3 neutropenia. That being said, it’s probably logistically challenging as well, and that patients received more intense dosing during the first cycle with the dose on day 1, 8 and 15. These are my opinions as to why maybe the uptake has been lower, despite having a positive randomized Phase III study.

At ASCO this past year we saw a Phase IV trial looking at obinutuzumab in combination with the same chemo options as studied in the GALLIUM trial. The real question in this Phase IV study is can you safely administer obinutuzumab in 90 minutes in that second cycle and beyond for those patients who did not have a Grade 3 or higher infusion reaction with the first cycle? And you can see here that appears to be true, that it can be safely done in 90 minutes, which I think is important for patients. And I think also important is that you can see pretty high response rates in this Phase IV study, essentially reproducing what was seen in the GALLIUM study. So maybe a little bit ease of use with that second cycle and beyond with faster infusions might be a reason to consider obinutuzumab.

Can we move away from chemotherapy in front-line follicular lymphoma? Well, the RELEVANCE study attempted to do that. So it was a randomized Phase III study of lenalidomide in combination with rituximab versus R-chemo. A little bit different in terms of how the study was conducted, investigator choice as to chemotherapy backbone. And there is lots of debate we could have about the proper dosing and duration of treatment of lenalidomide and rituximab, but this is the study schema.

It was not a positive study. We did not move the needle forward at all, but I’ve heard pp look at the results and say, well, it’s pretty good in terms of a non-chemo option. We see very similar response rates. Very similar PFS. You’ll see an update at this meeting, now longer follow-up. Still looks identical in terms of efficacy. The toxicity, in my opinion, is different, but may be a little bit more favorable with the non-chemo arm. So in the US that’s an option. In my practice I don’t regularly do it.

I think the more practice-changing study was the AUGMENT trial, which I just alluded to, which was lenalidomide/rituximab in relapsed follicular lymphoma, marginal zone lymphoma. I like the study schema in that 12 cycles and discontinuation of treatment was pursued in this trial. Now, again rituximab monotherapy was the control arm, so I’m sure this selected out for favorable patients, but you can see a pretty significant improvement in median PFS for the patients who had lenalidomide/rituximab. And the toxicities that we worry about with lenalidomide-based therapy was not more prevalent in the R-squared arm, which is why I find this a favorable regimen for my relapsed patients.

And there was an overall survival advantage among the patients who had R-squared versus rituximab monotherapy. Which now leads me to question who would I give rituximab monotherapy to in the relapsed setting?

GADOLIN looked at obinutuzumab in rituximab-refractory patients, so these are patients that failed to respond to rituximab-containing therapy or progressed within 6 months. I don’t like the study design and that this is obinutuzumab/bendamustine versus bendamustine alone, dosed at 120 mg/m², with 90 in the experimental arm, which is more common practice. But it did meet its primary endpoint of a significant improvement in PFS and actually, also, in an overall survival advantage for those patients who had obinutuzumab. So I do think that for patients that are failing rituximab in the relapsed setting, obinutuzumab is a very good option.

So this is my brief summary of who do I give obinutuzumab to? Well, in the front-line if I have a young, fit patient who I’m really trying to get any advantage I can to give them a long treatment-free interval, I might consider obinutuzumab combinations in the relapsed setting, anyone who’s refractory to rituximab. And we’re all eagerly awaiting the SWOG 1608 study which looked specifically at those POD24 patients with obinutuzumab in all of those arms. But I do think that rituximab is a very effective therapy that’s pretty easy to use.

You just heard there are 4 FDA-approved PI3 kinase inhibitors for the treatment of relapsed follicular lymphoma. They’re pretty similar in efficacy, though you did also hear that maybe umbralisib a little bit less impressive in terms of overall response rate. But the toxicity profiles are probably what distinguish these agents for me.

We did see Phase III data of copanlisib plus rituximab versus rituximab monotherapy in relapsed follicular, marginal zone, or other indolent lymphoma subtypes. The downside to this is that copanlisib is dosed until progression or intolerance. And not surprising, there was a pretty significant portion of patients who stopped therapy early, but they also probably stopped because there were higher CR rates than we’ve seen with some of the single agents, now leading me to question, well, if I’m going to give a PI3 kinase inhibitor, should I partner it with rituximab? And what is my preferred PI3 kinase inhibitor?

At this meeting, you’ll see an update to the CITADEL-203 study, which is parsaclisib. So the list of PI3 kinase inhibitors just continues to grow. But what we’ve learned is, you’ve also heard is we’re getting better understanding the safety profile of these agents and what parsaclisib has done is they have sort of a dose intensity for the first 8 weeks and then they do either a treatment break with 20 mg once a week, or lower dose, down to 2.5. And the overall response rate that you’ll hear this weekend is 75%, about 18% of patients had a CR, and it does appear to be better tolerated.

So I don’t think we’re done with understanding how to dose the PI3 kinase inhibitors, but I echo some of the comments that the safety profile does lead, in my opinion, to third line or later space.

Tazemetostat is an EZH2 inhibitor. And in about 10 to maybe 30% of patients with follicular lymphoma will have a EZH2 mutation and it does appear to be stable. So testing at diagnosis or at relapse can probably give you the same information.

It’s probably important in a number of different aspects. To be brief, it’s important in terms of B-cell maturation arrest. It’s also important in the microenvironment in terms of skewing that phenotype of the microenvironment to a pro-tumor environment. And that’s probably why we see similar duration of response among the EZH2 wild type or mutant population, the single arm, Phase II study that was enriched for mutant patients.

Now, I fully acknowledge that the response rate was dramatically different, about 70% for the EZH2 mutant population versus about 30% for the wild type, but the median duration of response was the same and the median PFS was not that much different, 11 versus about 14 months. And the safety profile of tazemetostat is one of the best we’ve seen, with no Grade 4 toxicity. Very few Grade 3. Very few patients that actually discontinued treatment as a result of toxicity.

So in my opinion, it is something I think about in third line. It’s probably going to move into earlier lines in combination, particularly if we can harness the mechanism of action in terms of the microenvironment and the tumor biology.

CAR T does have a role in follicular lymphoma. I think it’s most pertinent for those POD24 patients, or those patients who we’re worried about transformation, but maybe we haven’t proved it in terms of histologic biopsy.

The ZUMA-5, you’ll see updates this year at ASH. The median PFS is about 39 months, which is really quite impressive in my opinion for that third- or fourth-line or later patient population. The challenge is the toxicity profile, and I do think it will probably be limited to young, fit patients with high-risk disease.

The ELARA looks at tisa-cel, a single arm, Phase II study. It also met its primary endpoint. Maybe a safer CAR T might be more attractive for patients with follicular lymphoma. My opinion, maybe tisa-cel has a larger role in follicular than large cel lymphoma, based off of the results of this meeting. But it’s a positive trial.

And I’ll end talking about the bispecific antibodies. There are a number under exploration targeting CD20, CD3. It’s hard to pick my favorite right now, but there probably are some differences in terms of administration. Probably differences in terms of Grade 2 or higher CRS. I participated in the Mosun study, but this is a pretty impressive overall response rate. You’ll see updates on this data in the expansion Phase II of mosunetuzumab in relapsed follicular lymphoma.

So now the question is should you use a bispecific alone, or should you use it combination and replace the other CD20, such as rituximab or obinutuzumab? And I don’t know the answer to that, but that’s where all the trials are now headed.

So to conclude, I think there are a lot of different roads you could pursue in the management of relapsed or front-line follicular lymphoma, and they’re probably all right. And there should be some personalization.

We as investigators need to do a better job identifying biomarkers or patient characteristics that will help inform that treatment selection so you don’t have to spend 45 minutes talking through the various options.

And I think it’s just a good time for patients because as we get more and more effective therapies, outcomes continue to improve.

DR LaCASCE: Great. Thank you so much, Loretta.

We have time for a couple of questions. Gilles, I’ll ask you, do you ever use single-agent rituximab in the upfront setting? And if so, how do you give it? Do you give maintenance? And if so, on what schedule or extended induction?

DR SALLES: Well, yes, I think there are some patients who are not candidates for chemotherapy for whom rituximab single agent could be an option. While basically we’ve inherited from the differentiation between patient with low tumor burden and a high tumor burden, not all patients filled very well into these categories. Some patients that we feel are low tumor burden and 6 months, 1 year later, they don’t necessarily have high tumor burden criteria, we want to initiate treatment. There are the patient with low tumor burden that are very uncomfortable with being on watch and wait, which remains my recommendation for these patients. So I use from time to time rituximab single agent in the first-line setting or in the relapsed setting.

My way of using this drug when I use it a single agent is to use the Swiss scheme, as I said, SAKK trial, which basically is 4 weekly infusions and 1 additional — I mean 4 additional infusions administered every 2 months for a total of 4. So, I think it’s reasonable in terms of maintenance. It prolongs PFS from their data. And I think it’s not exposing patients to heavy load of treatment or immunosuppression — I mean B-cell depletion.

DR LaCASCE: Great. Thank you very much.

Mantle Cell Lymphoma

DR LaCASCE: We’re going to move on to our mantle cell module and Martin will be taking the podium.

First we’ll start with a couple of cases.

DR LOVE: The next case is from Dr Justin Favaro, a 67 year old man with extensive mantle cell lymphoma.

DR FAVARO: He did not want intense therapy, but he wanted to be treated. I started him on lenalidomide and rituximab.

He’s done great. Tolerated the treatment. He does have fatigue, but he had a dramatic response after 2 months on treatment. He looks normal. He feels pretty good.

So this has been going on now for about 2 1/2 years on this regimen, and the question is when do you continue it, or do you stop?

DR LOVE: The next case is presented by Dr Amanda Blackmon, an 80 year old man with extensive mantle cell.

DR BLACKMON: He developed a forearm lesion that was biopsied with pleomorphic mantle cell with a Ki-67 of 80 to 90%. He was treated with ibrutinib and then 6 months later he developed a penile skin lesion. Venetoclax was added at this time, and he had refractory disease.

He received liso-cel CAR T on clinical trial, and he relapsed at 3 months. He is now on a Phase I clinical trial.

This is a case of indolent mantle cell lymphoma that transformed into an aggressive pleomorphic variant.

DR LOVE: The next case is presented by Dr Zanetta Lamar, a 73-year-old man with mantle cell lymphoma with marrow and GI involvement.

DR LAMAR: I put him on a clinical trial that evaluated bendamustine and rituximab, plus or minus acalabrutinib. We found out after the fact that he was randomized to rituximab and bendamustine. We found that out when he progressed. So he crossed over to the acalabrutinib arm. He was on acalabrutinib for a few months, but then progressed, and actually progressed pretty rapidly. He had about a 10-cm right inguinal mass that developed over the span of a couple of weeks.

My first question is, in mantle cell lymphoma, now we have 3 different BTK inhibitors. How are you determining which one to use, especially with the new BTK inhibitor zanubrutinib, what would make you prefer one of the other?

This patient met with the transplant team and decided to move forward with CAR T. So, he’s undergoing that process right now.

DR LaCASCE: So our first patient is a 67-year-old male who has newly diagnosed extensive mantle cell lymphoma and when would you use a regimen like lenalidomide plus rituximab. I think the first question is always, does the patient absolutely need therapy? We know that patients who have — who present with circulating disease and splenomegaly, often SOX11-negative, may be observed, or there are patients who have very low Ki-67 fraction who may do well for some time? So I think that’s something to consider.

In patients who were treated in the Phase II study of lenalidomide plus rituximab was a small cohort of, I think it was about 40 patients, the majority had low MIPI score. So I think it is a very good option for an older patient or someone who really doesn’t want intensive chemotherapy. That regimen went on for — the patients could stop at 3 years or continue on with lenalidomide, which, honestly, makes me a little anxious. I know our multiple myeloma colleagues use years of lenalidomide and don’t see problems with bone marrow or clonal hematopoeises. But I do think about it particularly if you’re eventually going to think about a CAR T cell approach.

So I don’t use it a lot, but now that we do not — most insurance companies, at least in the US, will not allow us to give BTK inhibitor upfront. I think it is, in the right patient, a very reasonable option. I think for younger patients, we’re sort of in a quandary right now because our prior standard of care would be intensive induction, follow-up with autologous stem cell transplant, followed by maintenance rituximab for 3 years. And now we have a big study going on in the US to ask the question if patients are MRD-negative at the end of initial induction, do they benefit from transplant in addition to maintenance rituximab? So we’ve been putting a lot of patients on that study. And I think that is a very appealing study at this time because we have CAR T cells as a backup. A few years ago I think I would have felt more uncomfortable about not taking a patient with aggressive mantle cell to an auto because the long-term Phase II studies show a very good PFS without overall survival benefit. So I really look forward to the results of that study.

I think for our older patients this is a really tough situation when patients start with indolent mantle cell lymphoma and then become pleomorphic. I have a guy who’s 92 just like this. Sometimes you can use localized radiation if there is — this is an incredibly radiosensitive disease, so that can be palliative in some circumstances. But I do agree the BTK inhibitors are very appealing in this setting. And I personally very much favor zanubrutinib. You don’t have to worry about proton pump inhibitors. Hopefully less AFib. The data looks look. And patients tolerate it really, really well. So that would be my choice.

When patients start to progress on a BTK inhibitor and are not a clinical trial candidate or someone I wouldn’t take to CAR, I generally would add venetoclax. If they have very aggressive disease, I tend not to stop the BTK inhibitor. You can, but you want to — I always overlap for at least a month because you can get this very rapid progression of disease that can be quite scary if you stop the BTK inhibitor.

Hopefully they’ll be more trials for this patient, the LOXO-305 study, or others. But it is a challenging situation, given that a lot of these patients are elderly.

So in the last one, I think it’s great to hear about so many of these — several of these patients being on clinical trials, and this patient was on a very important clinical trial with BR plus — or minus acalabrutinib and did well. Again, I think acalabrutinib is a great drug. And I think, now that the patient is progressing, I definitely agree with trying to get him to CAR T cell therapy. I think bridging can be an issue in this setting. And again, you could add venetoclax, that would be 1 option. The other option, particularly in a patient who has a localized groin mass that’s progressing, to maybe collect the cells and then radiate, even low-dose radiation may be something that could be considered.

I’ll throw it out. Loretta, any thoughts on, say on the last patient? Would you…?

DR NASTOUPIL: So in mantle cell lymphoma, we don’t sequence probably as much as in follicular lymphoma, in terms of looking for mutations or reasons for patients to fail. So if I have a patient who’s failing a BTK inhibitor, I have to assume that they’re probably going to — they’re going to fail to respond to something other than maybe LOXO. And so I’m pretty quick to try and move on to CAR T if I have that option. If I don’t have that, or the patient’s not a good candidate, then I agree, a BCL2. I think what I’m struggling right now is do we need to do BCL2 inhibitors with BTK inhibitors or do we sequence therapy?

DR LaCASCE: Great. Thank you.

So we have a couple of poll questions next. Regulatory and reimbursement issues aside, what would your most likely treatment recommendation for a 70-year-old patient with mantle cell lymphoma who responds to BR and then ibrutinib on relapse but subsequently develops tumor progression? There’s a lot of options here. And you can see about 40% of people chose CAR T cell with brexucabtagene. Also, we see some venetoclax.

Martin, what would you do with a patient like this?

PROF DREYLING: Well, my 2 favorite options would be in fact also venetoclax. But as has been discussed by Loretta, this is only a bridging in these aggressive cases. And finally, the question is, is this a patient appropriate for CAR T cells or not? I would discourage a little bit the options of R-squared, because based on data we have, response rate is probably between 10%, probably more — closer to 10% than 30% in this patient population. So, the other 2 would be my favorites.

DR LaCASCE: Jeremy, any comment?

DR ABRAMSON: Yeah, I agree entirely that the target for this patient failing a BTK inhibitor really should be brexucabtagene autoleucel in the current context. And I think we’ll have additional CAR T cells in that space. So it really comes down to a question of bridging. To emphasize the point, just stopping a BTK inhibitor cold turkey can lead to this very aggressive, terrifying flare of disease. It’s really remarkable. You can watch the spleen growing before your eyes sometimes. So I would typically add in venetoclax in that context to try and serve as a bridge until — while CAR T cells are collected and manufactured.

DR LaCASCE: Great. Thank you. Our next question, based on available clinical research findings and your own personal experience, would you like to be able to use pirtobrutinib currently for patients with relapsed/refractory mantle cell? Gilles?

DR SALLES: Well, the answer is clearly yes. I mean this is a different BTK inhibitor, non-covalent, which has been developed. It has high response rate in CLL and in mantle cell. It looks like patients that had failed prior BTK inhibitors are responding. So right now we are just able to offer this drug in the setting of clinical trials. But I hope that it will be available in the near future. I think in terms of tolerability profile, it looks not inferior from the previous one, maybe a little bit safer, although we probably need to consolidate these data. So clearly, yes, I would like to be able to use it in the current setting.

DR LaCASCE: Loretta, have you ever used pirtobrutinib?

DR NASTOUPIL: Just on protocol.

DR LaCASCE: On protocol. And your experience with it in terms of toxicity?

DR NASTOUPIL: I think all of the BTK inhibitors have probably gotten better. But as we heard about with the PI3 kinase inhibitors, I think we’re also more tuned into what to watch for and how to manage it.

DR LaCASCE: Great. Jeremy, any comments?

DR ABRAMSON: Yeah. In terms of the BTK inhibitors, I think the real appeal of this non-covalent agent may overcome mechanisms of resistance with the other available BTK inhibitors, so it could really be the most novel advance in the BTK inhibitor field. But I agree, there are certain class effects that we shouldn’t dismiss with the newer agents. I think the big one to always keep in mind is bleeding and bruising. Even some severe bleeding has clearly gone down with the newer agents, but it is not rare, even with the newer BTK inhibitors. So I have caution about combining any of the BTK inhibitors in patients who are therapeutically anticoagulated.

DR LaCASCE: Great. Thank you. All right, Martin.

PROF DREYLING: Well, thank you very much. I think these 3 cases nicely illustrate the spectrum of mantle cell lymphoma. So we’re talking really about different kinds of diseases, though they had all one thing in common, these were all elderly male and that’s typical for mantle cell lymphoma.

So, I would like now to have a look at the current standards of care and look a little bit into the future, and also the challenges we have to address.

So first of all, when we’re trying to split this general term of mantle cell lymphoma and the different clinical features, here you are. I would say we have the classical mantle cell lymphoma, by the way independent whether it’s leukemic, CLL type, or the classical nodal mantle cell lymphoma, and in these patients I more and more tend to watch and wait, at least if they have low tumor burden.

On your right side you see we have these, what I would call transformed, aggressive mantle cell lymphoma, and it always comes up with 3 biological markers: it’s blastoid variant, histological-wise. It’s high Ki-67, as in the 1 case with pleomorphic mantle cell lymphoma, or it’s P53 mutated. And these 3 markers are strongly correlated and these aggressive diseases, we really have to improve out outcome. And that’s illustrated here. If you just take the classical mantle cell lymphoma without risk factor, overall survival, a median is beyond 10 years. Whereas in the aggressive part, we’re talking about a median overall, not PFS, overall survival of only 4 years. So this is where we have to improve.

What is the current standard of care? It has been already mentioned. In younger patients, it’s still cytarabine-based induction followed by autologous transplant or dose intensification rituximab maintenance. And just to give you a glimpse, here we are — this is the advantage of high-dose AraC in comparison to R-CHOP. And you see this is really a major benefit, PFS in the range of 25-, 30%, and these data are updated now for overall survival at this meeting on Sunday morning I think, and they look quite compelling.

Secondly, this is the majority. I told you mantle cell lymphoma usually is a disease of elderly male. So what are our current standards of care? well, most of you would probably discuss BR, R-CHOP or R-BAC, but the formal advantage, or the formal standard, in fact, is VR-CAP. And that’s based not only on a benefit of PFS improvement, but also overall survival improvement in a large study. So simply by substituting vincristine by bortezomib, you really achieve more beneficial, long-term outcome.

Having said that, at this meeting I have the honor to present data on relapsed mantle cell lymphoma, also on Sunday morning. And that is bringing these 2 parts together, high-dose AraC, plus/minus bortezomib. And again, that data looks promising. But this is the future. The future very clearly been said is targeted approaches, and one example when we’re talking about relapsed disease, early relapses which are within 2 years there’s a clear or seems to be a clear benefit. This is a non-randomized observation by our Italian colleagues in favor of ibrutinib over different chemotherapy regimens — by the way including R-BAC.

So, therefore, I think most colleagues definitely would agree that once you have an early relapse, that means within 2 years, you should move on to targeted approaches.

Now, if such approach is to efficient of course you tend to introduce it to first line. And these are the studies which are, first of all, investigating combinations with our current standards, so essentially R-chemo plus/minus targeted approaches, and just have a short look at this. This is the Triangle, purely academic trial, with 870 patients being recruited, where similar as the US trial, we tried to cut out autologous transplant — yes, it’s efficient, but it’s also toxic — and therefore, we tried to substitute with ibrutinib. So we expect the final data of this study next year or a year thereafter.

At this meeting, again on Sunday morning, do Sunday is really mantle cell day, you will see the results of this study, this study for elderly patients, median age is 71 years. We investigated the intensification of maintenance. So you heard already about R-squared, and you had the comments of our chairwoman saying that it’s totally appropriate for the classical mantle cell lymphoma, more indolent kind, and we thought there’s something in it. And so tested this in the maintenance setting and based on the data in the abstract, you will see there is a significant result of the study in favor of R-squared. So this might become the new standard of care, at least for some patients.

But this is already the second next step, and this is really substituting chemotherapy by purely targeted approaches. So if want, this is really opening a new era. And there are couple of these trials, let’s have a glimpse of that. First of all, the data we have so far, there are essentially 2 serious one from MD Anderson in elderly patients being presented by Gine, at previous ASH meetings. And this is the Barcelona series. And what is nice about this series, on purpose they picked the more indolent mantle cell lymphoma, so they skipped the cases with high tumor burden, with high Ki-67 and blastoid variance. But similar to CLL, they also established that you can stop at a certain point. Now in this study, they stop at 24 months if molecular remission was achieved. And what you can see at this cut point of this study, about 19 stopped treatment at month 24. And out of these, only 3 became MRD-positive again, but none of them relapsed clinically so far. So this is really opening the door to a new concept. And I should also add that was not only ibrutinib; that was ibrutinib in combination with rituximab.

Now how can we improve on that? well you can move onto the triple combination, and that has been explored by Steven Le Gouill, and has been published this year in Blood. And what he went for, he went for the combination everyone was talking around about which is BTK inhibitors plus venetoclax plus anti-CD20. And why anti-CD20? Because we have solid data that maintenance — antibody maintenance in mantle cell lymphoma does improve overall survival, so we really believe in this principle. And in first-line treatment, very small number of patients, 15 patients, but at least the short-term outcome is brilliant.

Now at this meeting, we will also see some similar data being presented by Michael Wang, and that is focusing on the triple combination with acalabrutinib. And my personal bias is that I think, specifically in these combinations, the more preferable toxicity profile or tolerability profile of acala might be of significant advantage.

Now when we are moving to first-line BTK inhibition, the challenge is what are we going to do when these patients relapse? And this compound has been already mentioned, the non-covalent BTK inhibitor, pirtobrutinib, the LOXO compound, and that’s in a pretreated, BTK pretreated patient population still achieved response rates of 50%, some of them quite ongoing. And this compound also seems to be very well tolerated. The logical question is then, well can, if you start up right away with the LOXO compound, can you avoid the development of these resistance mechanism and, therefore, a head-to-head comparison is now running between classical BTK and the LOXO compound.

Also at this meeting, there will be data on PI3K inhibitors. Just to remind you, the PI3K inhibitors have also very high response rate in mantle cell lymphoma, but it’s mostly short-term. Last year we had the presentation on the patients being pretreated with ibrutinib. And in this patient cohort, overall response was modest. Well, you could say 30% is great because I told you with R-squared, for example, you’re in a similar ballpark, but again, might be that this compound will find a role in non-BTK pretreated patients.

Finally, CAR T cells. This is, I think, the standard of care. We have to compare to in BTK inhibitors, and again, these data will be updated or complemented by real life experience by Dr Wang, not Michael Wang, but another Dr Wang.

And finally, to finish up, the question is where are the bispecifics? Also, these data will be updated for GLOFI in mantle cell lymphoma. The data, so far, I can say look promising.

So this is it. I think we have to move on to a more individualized treatment, and this is far speculation. This is just getting a best guess for the future therapeutic algorithm. I think everyone will agree that BTK inhibitors will be part of that for the next 5 years. And I thank you for your attention.

DR LaCASCE: Thank you, Martin. Question, how would you manage a patient with TP53 mutated mantle cell in the upfront setting?

PROF DREYLING: Well, unfortunately, in Europe we are rather stuck with the registration label and so far, BTK inhibitors are not registered for first line. So we start with some chemotherapy-based regimens, though having said that, it’s important to understand in these patients, yes you achieve reasonable response rate, but they’re shorter. So my advice would be as far as — as long as this disease is highly chemo-sensitive go on with that, might be even moving to autologous transplant if you have an excellent response after induction. But be aware that early relapses might occur.

DR LaCASCE: So we have a question from the audience about a patient who progressed, 65-year-old male, classic mantle cell, progressed within 1 month of BR. Had bleeding in the retroperitoneum and then was found to have CNS disease with leptomeningeal involvement. So what would, Loretta, what would you do with a patient like that? And how do you think about CAR T in patients who have CNS disease?

DR NASTOUPIL: This is clearly a high-risk patient. I’d try to, this is a little bit controversial, but I’d try to get him on a BTK inhibitor. We don’t know how well it penetrates the CNS, but I would try that in preparation to get to CAR T. We don’t have good data in terms of how effective CAR T is in that setting, outside of the real world experience. Our general practice at our institution is not to take them unless the CNS disease is stable. But this is someone I think that’s probably going to give you your best shot at a reasonable outcome.

DR LaCASCE: Jeremy, any comments? Would you use cytarabine? Or would you…

DR ABRAMSON: I’d probably reserve cytarabine and go to ibrutinib. I think we have the most data for ibrutinib as far as CNS penetration, and we’ve certainly seen that in DLBCL, and then get to CAR T. We do have data for the other CAR T cell products, including prospective data using liso-cel and retrospective data with axi-cel and tisa-cel penetrating the CNS and treating secondary CNS DLBCL. I think it’s a fair extrapolation to suggest that brexu-cel, which is virtually identical to axi-cel, would also penetrate the CNS. And so I would do ibrutinib on route to CAR.

Current and Potential Role of CAR (Chimeric Antigen Receptor) T-Cell Therapy for Patients with Non-Hodgkin Lymphoma

DR LaCASCE: Great. So, thank you, Martin. And along those lines, Jeremy, you’re up next for our CAR T cell discussion. But first we’ll go 2 cases.

DR LOVE: The next case is presented Dr Raji McKenna, an 81-year-old man with extensive recurrence of diffuse large B-cell lymphoma.

DR McKENNA: He’s extremely afraid of CAR T. They looked up all the data when I initially suggested on relapse to go for CAR T, and based on the recent discussions it seems like if he relapses tisa-cel would be an appropriate thing in an older gentleman, or the bispecific antibodies? I’m not sure which one would be better. And if he refuses both, would it be tafasitamab and lenalidomide? Or loncastuximab?

He has had, last year, severe coronary artery disease with 5 stents. But he’s fully functional. He’s still working.

DR KUMAR: CAR T cell, they always say the performance status, even though very poor, they still are accepting patients and doing well. How do I choose in that situation which patient to select to send for referral to CAR T cell?

DR LOVE: Your patient who did so well, did that patient have any acute toxicities?

DR KUMAR: Yes. He did have acute toxicity. He was in the ICU. I actually went to see him at Moffitt, see how he was doing. And he did not have CNS toxicity, but he did have the febrile issues, the cytokine release syndrome, but he recovered very well. And he is doing exceptionally well now.

DR LaCASCE: Gilles, would you like to comment on these cases?

DR SALLES: Yes, I think these are 2 interesting questions which are basically well sequenced. The first one regards the eligibility criteria for CAR T and the comparison in particular with autotransplant and probably those days will come again on the table, given what will be presented. I think when CAR T were developed because of the very specific side effects that were encountered, the cytokine release syndrome, the neurotoxicity, there were a lot of worries regarding these side effects, a lot of consequences regarding the habilitation of the different centers, and the transplant colleagues taking over this kind of treatment in some centers. And while we felt maybe it’s the same, well, I think many of us have appreciated that, in fact, it is different and that we clearly have patients that we will not consider eligible for standard autotransplant, not even talking about an allotransplant, that will be good candidates for a CAR T treatment. And whatever the comorbidities are, these have to be discussed with a team which is experienced in this field. And I will say that in many institutions, even in Europe, also in the States, patients over 80 are discussed for CAR T therapy. So, that’s the first thing.

The second question is are there differences between CAR T product in terms of efficacy and in terms of safety? I think in terms of safety, we don’t have comparative data, but we start to have data suggesting that the rate of Grade 3-4 CRS may not be very different, maybe a little bit higher with CD28-based products. But overall, we are in a range of 5- to 10%, maybe a little bit lower with some 41bb product. But again there have been a little bit more experience.

What I think is probably more significant in difference of toxicity is the CNS toxicity which clearly is based on the real world data probably by Loretta and by others, and based on the trial, is higher with the CD28 product. So that led many people to — yes, use a CD28 product in younger patients, in patients without a history that may eventually favor any CNS event.

In terms of efficacy, again, we don’t have head-to-head comparisons, so it’s very difficult to judge. The data from the trials are different. Again, there was a learning curve, but there may have been different patients included in different trials at some time. Besides that, I think that for patients with very rapidly aggressive disease, very rapidly growing, younger patients, many people will prefer CD28 cells because they are rapidly effective and that’s the kinetic of the cells. Where in patients like this one, the 81-year-old, a 41bb product would be probably preferable.

There is an abstract which is presented during the CAR T session based on real world data with propensity score from the French registry showing that, well, in terms of PFS, there may be a difference favoring the CD28 product. But this is only axi-cel and tisa-cel, there were no access at that time to liso-cel.

So that’s the discussion regarding this question of elderly patients and tolerability. And I will recommend for this patient to still continue, if possible, with a CAR T therapy of other options.

Management of CRS I think has — pretty standardized. I mean symptomatic care for patients with Grade 1 disease: monitoring, fluid intake. As soon as we have with Grade 2 or persistent Grade 1, tocilizumab, and continuing with different kind of supportive care and low-dose oxygen. And if the patient — low flow oxygen if the patient requires more, and ICU monitoring.

For CNS-based toxicity, the steroids are really central in the management of this toxicity with different dosage. Tocilizumab is probably only for those who have associated CRS symptomatic. Anda gain, monitoring, anti-seizure and close monitoring.

So I think this is feasible. And I heard clearly what Dr Kumar said, yes, I mean some patients do pretty well. They may have CRS for a couple of days, but they went off. And I think we’ll probably hear during this meeting what are the side effects and the outcomes of patients when they are randomized to autotransplant versus CAR T. And I think the quality of life will be important to look at and see how patient recover from these 2 procedures.

DR LaCASCE: Great. Thank you. We’ll have a couple of poll questions next.

At what point in the treatment course are you referring patients with multiregimen-relapsed follicular lymphoma for consultation regarding CAR T cell therapy?

And you can see here it’s relatively well-balanced between at second and third relapse. We talked about this a little bit. Martin, what are your thoughts?

PROF DREYLING: I would fully agree. I think we have heard that in third-line treatment. There’s a variety of treatment options, but none of these other options really achieves long-term remissions. And one has to keep in mind that specifically in the patients being included both in the CAR T cell trials and the bispecifics antibodies, this is not our standard indolent follicular lymphoma, this is more aggressive disease. So these patients, yes, I would go for discussion of CAR T cells in second relapse.

DR LaCASCE: Jeremy, question for you. Any patient in which you would consider an autologous stem cell transplant in follicular lymphoma? And how do you think about those 2 options?

DR ABRAMSON: That’s a rapidly evolving and controversial question. I think right now the patients that I’m thinking about, really the only patients I’m thinking about are the early POD patients in the second-line setting. I think the more data and longer follow-up we have on the CAR T cells may change that. We really don’t have long enough durability on the CAR T cells in follicular lymphoma to really assess long-term durability. We do have that data with autotransplant. So early POD patients I’m considering.

DR LaCASCE: All right, we have another question here. Regulatory and reimbursement issues aside, which second-line therapy would you recommend for a younger, transplant-eligible patient with DLBCL who experiences relapse 12 months after R-CHOP?

So here 50, about half, auto stem cell transplant.

Thoughts? Loretta?

DR NASTOUPIL: I’m a big CAR T fan, so I’m excited about this weekend. I’m going to go to CAR T in second line.

DR LaCASCE: Great. Gilles, any thoughts?

DR SALLES: Well, I’m along with Loretta, I think I will recommend CAR T based on what we’ll hear in a couple of days.

DR LaCASCE: Martin, what about the European…?

PROF DREYLING: Exactly. I think this opinion, or this scale might change within a couple of days. So, let’s see the data. and I guess it will tend more and more into CAR T cells.

DR LaCASCE: And what’s that cutoff that you think about in terms of who is someone that you would consider potentially chemotherapy-sensitive to take to autotransplant? Is it a year? Is there anything that helps you think about that? Martin, do you want to…?

PROF DREYLING: Well data-based, probably we’ll have to say it’s between 1 and 2 years. There we have solid data. and there we do know that autologous transplants overall survival in comparison to conventional chemotherapy. And we’re missing the data on CAR T cells in these later relapses. So that would be the window for autologous transplant for me right now.

DR LaCASCE: Gilles, any thoughts?

DR SALLES: Well, I think there is still — I mean I will favor clearly CAR T for this patient, but there’s still an area that is a little bit gray, which is how to manage patients towards CAR T. and basically, and I didn’t address that in the previous discussion regarding the toxicity, we do know that some patients with very high bulk, with high LDH, are likely to benefit for CAR T, are more likely to have additional toxicities. So I think what is influence of bridging, does bridging influence the efficacy? There are controversial data regarding this area. So I think for patients in which there haven’t been trials like patients that will relapse at 2, 3 years, I think the debate is still on. And I would say the presentation of the patient, the clinical presentation, there we can bring this patient to CAR T will have to be considered in the choice of these treatments.

DR LaCASCE: Great. Thank you. Jeremy.

DR ABRAMSON: Well that’s a perfect lead-in to thinking into a deep dive in what we know about the CAR T cells products across lymphoma subtypes right now.

You’ve already heard us allude to 4 major, FDA-approved CAR T cell products for lymphoma in the United States. We’ve got axicabtagene ciloleucel, or axi-cel. Tisagenlecleucel or tisa-cel. Lisocabtagene maraleucel, or liso-cel. And brexucabtagene autoleucel, or brexu-cel.

The first 3 of those products are fully approved in relapsed/refractory large B-cell lymphomas, while brexu-cel is approved in relapsed mantle cell and relapsed B-cell ALL. Brexu-cel is effectively identical to axi-cel, they’re both CD28 co-stimulated CAR T cell products, but brexu-cel undergoes an additional purification step to remove potential tumor contamination in the product which is what makes it different.

All 4 of these products target the CD19 antigen of course. The other major difference is the co-stimulation domain, whereas axi-cel and brexu-cel use CD28. And tisa-cel and liso-cel use 41bb. The co-stimulation domain impacts the expansion kinetics of the CAR T cell product and that results in differences in the toxicity profiles, as we’ll talk about.

There are some modest differences in manufacturing and design, use for bridging therapy and dosing. All of these require lymphodepleting chemotherapy, which is usually with fludarabine and cyclophosphamide.

There are also differences in the FDA labeled indications, based on the pivotal trials. So axi-cel is approved in relapsed/refractory diffuse large B-cell lymphoma, high-grade B-cell lymphoma, transformed follicular lymphoma and primary mediastinal large cell lymphoma.

Tisa-cel was also approved in DLBCL, transformed follicular lymphoma and high-grade B-cell lymphoma, but was not studied in primary mediastinal B-cell lymphoma. That does not have that in its label.

Liso-cel was studied the most broadly. So that’s also approved for DLBCL, high-grade B-cell lymphoma, primary mediastinal B-cell lymphoma and transformed follicular lymphoma. But unlike the others, it also has an indication in transformed lymphoma from other indolent histologies, transformed marginal zone, SLL, etc, as well as Grade 3B follicular lymphoma.

So let’s think about the pivotal trials. I’m going to talk for consistency, the phase — about the 2-year data in all 3 of these products. This is the ZUMA-1 trial of axi-cel. This was the first to be approved in large cell lymphoma based on 108-person ZUMA-1 trial. By protocol design, all of these patients were considered chemotherapy refractory, which is defined as either primary refractor or relapsing within 1 year from autotransplant, so refractory to their prior regimen or relapsing within 1 year of auto. Three quarters of these patients who were refractory were second or later line of setting. So this is indeed a high-risk patient population.

I’m also for consistency, going to talk about the response rates based on Independent Review Committee. So, based on independent review, the overall response rate was 74%, with a CR rate of 54%. And at 2 years you can see that 42% of these patients remain progression-free, with a plateau on that curve which in diffuse large B-cell lymphoma, suggests that we’re curing a significant proportion, not quite enough. We still need to do better. But 42%, many of these patients, of course, previously had no curative intent options available, making this really a dramatic advance.

Tisagenlecleucel was studied in the JULIET trial. These are 2-year follow-up from JULIET, which studied 111 patients. These patients, as with the prior trial, had a median of 3 prior lines of therapy. They were slightly less refractory with only 55% of these patients considered chemotherapy refractory. The overall response rate was 52% by independent review, with CRs in 40%. You can see from the progression-free survival curve there, with a median of 3 months’ PFS and the 2-year progression-free survival is about 30%.

Lisocabtagene maraleucel was the most recently approved in large B-cell lymphoma based on the TRANSCEND study. This was the largest study reported in CAR T cell to date with 269 treated patients, with the median age of 63. The oldest patients treated on this trial were 86 years old. These patients also had a median of 3 prior lines of therapy and two thirds of these patients were considered chemotherapy refractory. I mention that this study did include broader eligible histologies and was also the only study to include patients with secondary CNS lymphoma, as well as to not require a minimum absolute lymphocyte count in order to enroll patients. The overall response rate was 73%; 53% of patients had a complete response.

You can see the initial data, as reported in the Lancet shown on your right, but I’ve put at the bottom the update that we’re reporting at this years’ ASH meeting with 2-year follow-up data. you can see the duration of response at 2 years on the TRANSCEND study was 50%, 2-year progression-free survival is 41%, and overall survival if 51%. So you can look for more details on the longer-term follow-up data at this ASH meeting.

Now we’ve heard a lot about toxicity. And so these are the toxicity summaries. Again, these are not comparative trials. These are based on Phase II studies, and so different populations, different timelines of study which can impact it. What you will notice is that axi-cel, the CD28 co-stimulated product, does have the highest rate of cytokine release syndrome at 93%, compared to 58% with tisa-cel, and 42% with liso-cel, and also had the highest rate of severe CRS. I will emphasize that I can only really compare axi-cel to liso-cel because the severity scale of CRS was different in the tisa-cel study. So if we look between axi-cel and tisa-cel, the severe CRS rate was 11% compared to only 2% with liso-cel.

You heard from Gilles moments ago that that also reflected differences in neurotoxicity. You can see two thirds of patients treated with axi-cel had any grade neurotoxicity and it was severe in a third of patients, which is really quite significant. It was lower rates of any grade CRS with either — excuse me — neurotoxicity with either tisa-cel or liso-cel. And severe neurotoxicity only occurred in about 10% of patients receiving tisa-cel or liso-cel.

I’ll also note that this has prompted investigation of potential prophylactic strategies to reduce the incidence of toxicities in patients treated with axi-cel. There is data updated at this meeting using prophylactic corticosteroids, which does reduce the incidence of severe CRS in patients treated with axi-cel, though interestingly, doesn’t appear to substantially impact the incidence of neurotoxicity with axi-cel. There is an interesting abstract being presented of using prophylactic anakinra to try and mitigate that. And so I’ll refer you to those interesting data coming up at this meeting.

Obviously, we’ve also learned how to manage these toxicities and we know that we can use tocilizumab for CRS, corticosteroids for most CRS and neurotoxicity, and rapidly reverse these side effects in the majority of patients.

Now this has led to our current algorithm which is where we still think about chemotherapy in the second-line setting, either high-dose chemotherapy in fit patients or personalized therapy, as we’ve talked about for patients not fit for high-dose chemotherapy. And in the third-line setting consider patients for CAR T cells. But of course, CAR T cells in the third line assumes high-dose therapy for eligible patients in second line, and we know that high-dose therapy in the second line in the modern era really produces discouraging results. In the pre-rituximab era, we quoted about a 60% progression-free — excuse me — overall survival and about a 50% progression-free survival for high-dose chemotherapy. But that isn’t what we’ve seen in the rituximab era.

Data from the ORCHARD trial shows here that in patients relapsing after R-CHOP and giving chemoimmunotherapy in the second-line setting, we only see CR rates in the 20% range and only about a third of patients proceed to transplant mostly due to having chemotherapy in sensitive disease. And that leads to a durable progression-free survival in less than 30% of patients in the modern era.

We also know that those patients who are primary refractory or relapsing in less than 1 year have particularly poor outcomes. That has led to 3 randomized trials which are being reported at this meeting. These trials are all comparing a CAR T cell versus standard second-line salvage chemotherapy and autotransplant for patients with primary refractory or relapsed disease within 1 year.

ZUMA-7 and TRANSFORM evaluate axi-cel and liso-cel, respectively, and BELINDA looks at tisa-cel.

ZUMA-7 will be reported in the Plenary session with 359 patients. Virtually all the patients received the CAR T cell product, and you can see the median event-free survival was significantly superior for CAR T cells with 8 months versus 2 months, with a significantly significant hazard ratio of .398. That also reflected a higher CR rate for CAR T cells of 65- versus 32%. You can see severe CRS and neurotoxicity occurred in 6% and 21% of CAR T cell patients, respectively.

The TRANSFORM trial is also presented in an oral session at this meeting. Again, 98% of patients got their CAR T cells, again a significant improvement in median event-free survival of 10 months compared to 2 months for standard of care with an improved hazard ratio, which also reflected a higher CR rate of 66% compared to 39%. Notably, lower rates of severe CRS compared to the axi-cel study of 1% and 4%, respectively.

The BELINDA trial interestingly also looking at the same question was really stone-cold negative. Three-month progression-free survival for both the CAR T cell arm and the standard of care arm. And identical CR rates of 28%.

So I think these are practice-changing data for either axi-cel or liso-cel in the second-line setting.

I’ll mention very briefly that you’ll see data at this meeting looking at potentially moving CAR T cells even earlier for interim PET-positive patients with either double-hit or high IPI patients, where positive interim PET patients are taken to early axi-cel. With data at this meeting showing an 89% overall response rate, 78% CR rate, and progression-free survival of 75%.

The value of interim PET in large cell lymphoma is really more controversial than in something like Hodgkin lymphoma. So this really requires a randomized trial to evaluate, but I think these are early interesting data of potentially moving CAR earlier in high-risk patients. Maybe we need a better biomarker than PET such as circulating tumor DNA to guide early intensification to CAR T cells.

Now we additionally have data in follicular lymphoma which you’ve heard about. The only thing I’ll show you in follicular lymphoma is the update of the ZUMA-5 study, which is presented at this meeting, showing, with further follow-up, a CR rate of 79% for axi-cel, with a PFS of 40 months. And in marginal zone lymphoma, a CR rate of 63% with a median of 17 months. So I think these data are showing us that we are seeing encouraging responses in follicular lymphoma with both axi-cel and tisa-cel, which you heard summarized earlier, as well as in mantle cell lymphoma where we already heard that refractory disease to BTK inhibitors denotes a poor overall outcome. And in that context, we’re seeing very encouraging data for brexucabtagene autoleucel, which is my preferred therapy, for patients relapsing after ibrutinib currently the second-line setting, with some early emerging data that liso-cel also appears highly effective in that context.

So with that, I’ll summarize by saying that CAR T cells have really proven transformative in multiple lymphoma histologies and are poised to move even earlier in our standards of care.

DR LaCASCE: Thanks.

Hodgkin Lymphoma

DR LaCASCE: We’ll be moving on to your next module which is Hodgkin lymphoma. And we’ll start with a couple of cases.

DR LOVE: The next case is a patient of Dr Saachi Gupta, a 23-year-old, non-compliant man in a difficult social situation, with extensive stage Hodgkin lymphoma.

DR GUPTA: 23-year-old male, who wanted to be a Navy Seal, diagnosed with Hodgkin’s lymphoma. He was treated with ABVD. He had a great response, but he just decided to walk away from there after 4.5 or 5 cycles.

And he did well for several months until his disease resurfaced, and he was admitted to the hospital. And now, obviously he had recurrent Hodgkin’s disease. Unfortunately, not able to go for transplant due to compliance issues.

DR LOVE: The next case is presented by Dr Chris Prakash, a 30-year-old woman with extensive stage Hodgkin lymphoma who was considered average risk.

DR PRAKASH: I treated her with ABVD two cycles and then took the bleomycin away for the rest. And that’s been my approach. But again, the question comes up, is brentuximab better than bleomycin and how much does it add?

What has your experience been with long-term toxicity with brentuximab, especially long-term peripheral neuropathy and neurologic toxicity in general in young patients who receive brentuximab?

DR LOVE: The final case is presented by Dr Khan.

DR KHAN: 31-year-old gentleman, progressive respiratory symptoms, cough, some anorexia and weight loss.

He was found to have a large hypermetabolic mediastinal mass, but no other extrathoracic disease. Now, he’s a male. He had elevated ESR, he had anemia, lymphopenia, and hypoalbuminemia. And he had bulky disease. So we considered him unfavorable Stage IB bulky Hodgkin lymphoma.

So the first question is, is this still the best way to deal with unfavorable bulky disease, standard ABVD with interim PET scan followed by radiation therapy.

DR LaCASCE: Jeremy, would you like to comment on these cases?

DR ABRAMSON: Three cases sort of running gamut of Hodgkin lymphoma. So I think the first case, a young man who’s relapsing after ABVD who was non-adherent with treatment. Certainly, our goal in second-line therapy for a young patient is to get them to autologous stem cell transplant. And I would work with a social worker and potentially Psycho-Oncology, to think about this patient’s adherence and still try and get this patient to the best curative intent therapy which would be autotransplant.

How do we get that young patient to autotransplant? I’ve historically used ICE in the context. There is some more recent data using novel agents. I think the most intriguing is a study out of Memorial looking at 39 patients treated with pembrolizumab and GVD, gemcitabine/vinorelbine and liposomal doxorubicin. That study showed a 95% complete response rate with only 1 relapse at last follow-up. It’s a small study, but the data are hard to ignore, and it does allow incorporation of pembrolizumab. It also still allows the use of brentuximab vedotin consolidation, which I would use for a patient with high-risk disease, based on the AETHERA trial. A patient with primary refractory disease, or disease relapsing in less than 1 year, or with extranodal disease, had about a 20% improvement in their progression-free survival when given brentuximab consolidation following autotransplant.

So my goal would be to get a young patient back into remission with either ICE or more recently I’d think about pembrolizumab/GVD. And then consider the role of brentuximab consolidation.

For a patient who wasn’t transplant eligible, we can think about a purely novel agent strategy such as either combination of BV-nivo with a high CR rate, about 77%, with an encouraging progression-free survival. Or for a patient, particularly — if they had a lower-risk relapsing patient, relapsing later, for example, or more older, comorbidities, would consider a checkpoint inhibitor alone. We do have data comparing pembrolizumab to brentuximab vedotin as monotherapy in relapsed Hodgkin’s in post-transplant, or transplant-ineligible patients, and find that pembrolizumab is better than BV in that setting. So I’d either use BV-nivo in combination or pembrolizumab alone.

For the second patient, the 30-year-old patient with advanced stage Hodgkin’s, Dr Prakash used the RATHL data, which is my most common approach in advanced stage Hodgkin’s, ABVD for 2 cycles. For those patients who are interim PET-negative, which is the majority, drop the bleomycin, 4 more cycles of AVD alone. That produces a 5-year, updated, progression-free survival of 84%.

The other option, of course, is BV-AVD. This regimen does cause additional toxicity, more peripheral neuropathy, more neutropenia and FN, requiring routine growth factor support, but does produce a progression-free survival without overall survival benefit. The PFS difference at last follow-up, now at 5 years’ follow-up is 7%. So I’d say a modest improvement. But the toxicity in my view is significant. And if we ask about the durable neurotoxicity at 5 years, 19% of patients have persistent peripheral neuropathy. And for a young patient particularly, that’s a troublesome quality-of-life finding long-term.

So where do I use BV-AVD? I look at the subset analyses of the ECHELON-1 trial, the older patients really did not garner benefit. It’s the younger patients who did, younger than 60, and particularly those with IPS scores of 4 to 7. So I’m using BV-AVD in my young, high-risk patients, and otherwise using the RATHL approach.

And then finally for a bulky, limited stage Hodgkin’s, we now have 2 prospective data sets, the most important is presented by our distinguished moderator, Dr LaCasce, has presented the Alliance data of bulky, limited stage Hodgkin’s. This has got 100 patients treated with ABVD. Those patients who have an interim PET complete response get 4 additional cycles of ABVD alone and then no radiation. Their 3-year progression-free survival is an outstanding 93%. So for patients who have bulky disease, I give an interim PET scan. If they’re PET-negative, as the majority are, three quarters in the Alliance trial, they get — finish out chemotherapy alone.

Can you drop the bleomycin, à la RATHL? Well, it turns out that the RATHL trial included 119 patients with bulky, Stage II disease. And it turns out that those patients who were treated with 2 cycles and the PET-negative, dropping the bleo, did great with a 3-year progression-free survival of 92%, identical to what Dr LaCasce has reported in Alliance. So that’s really my standard of care, bulky, limited stage disease, 2 cycles of ABVD, PET-negative, AVD for 4 cycles, no more treatment. If they’re interim PET-positive, it’s a more challenging question. And I always look at the scan. If they’re mildly FDG-avid, Deauville 4, but clearly responding beautifully, I’ll continue their therapy and consider consolidation radiation. If they really have persistent, brightly FDG-avid disease that isn’t a terrific response, I’ll consider escalation to escalated BEACOPP followed by radiation.

DR LaCASCE: Great. Thank you.

We’ll move on. We have a couple of poll questions. Which initial therapy would you recommend for a 26-year-old patient with classic Hodgkin lymphoma with anemia, diffuse adenopathy, hepatosplenomegaly and diffuse bone marrow involvement?

So 43% picked BV-AVD, as Jeremy just discussed. Loretta, how you would approach a patient like this?

DR NASTOUPIL: I agree. I thin for those high-risk patients that are young, I’m going to try and give them the best shot at this. I echo the comments, I think we tend to focus on Grade 3 or higher peripheral neuropathy, but Grade 2 can really be impactful. But I’m going to aim to try and give this patient the best shot at a long life.

DR LaCASCE: Great. Thank you. Gilles, about you? What would you do in a patient like this?

DR SALLES: Well, I think the BV-AVD is a most reasonable option with what we use. As people know, in Europe escalated BEACOPP has been quite developed in this setting of patients with quite good results. I think we should not refer any more to the 6 or 8 cycles. There is abbreviated BEACOPP treatment, de-escalation also by some trial. So I think this remains reasonable options. But in the current setting, in the US, I would say that BV-AVD is probably the most reasonable option.

DR LaCASCE: Great. Thank you. We’ll go on to the next question. Regulatory and reimbursement issues aside, in general what is your preferred second-lien therapy for a patient with Hodgkin lymphoma who is experiencing relapse after ABVD, is not considered to be a candidate for transplant?

So here, the most common choice was bortezomib plus nivolumab, with a smattering of others. Martin, what would you do with a patient like this?

PROF DREYLING: Well, I think this was excellently discussed by Jeremy. I think you could, depending on the general performance status of the patient, either go for combination if you’re health system allows. If you have to pick between the 2 compounds, I definitely would go for PD-1 antibody because it’s better tolerated and seems to, therefore, achieve higher and longer ongoing remissions.

DR LaCASCE: So, let me ask Loretta a question. Now that we have some data, both on BV-nivo in the second-line setting, as well as pembrolizumab plus GVD, how do you think about when yo might use either of those regimens?

DR NASTOUPIL: I’m actually quite impressed with pembro/GVD. So that’s been my preferred. I recognize it’s a small sample size, but then that still allows me the opportunity to use BV at a later point if I need it.

DR LaCASCE: Thanks. Jeremy, any thoughts on that?

DR ABRAMSON: Yes, I think the appeal is that you can still use the BV consolidation for the AETHERA trial. And the Memorial trial, a subset of those patients did receive the BV consolidation, and so that was actually prospectively studied. It’d be great to get more data. The data were actually so impressive they have a cohort ongoing now that’s looking at pembro maintenance as opposed to taking them to transplant at all, which I think will be exciting data to see in the future.

DR LaCASCE: Great. Thank you. And with that, I’m going to talk about Hodgkin lymphoma. I think I’ve been very well set up by Jeremy, who touched on a lot of these issues, but I can show you some of the data just to reinforce a lot of the points he’s already made. And I’m going to be focusing on issues regarding brentuximab and checkpoint inhibitors in sort of all settings, upfront and relapsed.

So again, as Jeremy mentioned, the 5-year follow-up of the ECHELON-1 study was recently published. Again, this is ABVD versus BV-AVD in patients with Stage III and IV Hodgkin lymphoma. And you can see there was a 7% benefit in progression-free survival, which has been ongoing. This appears to be most important in younger patients under the age of 60 where it was statistically significant. There were fewer patients who were elderly, and there was a 5% difference, but this did not meet statistical significance.

When you look at the PET status, the majority of patients were PET2-negativem, with nearly 90% of BV-AVD treated patients, and about 85% with ABVD. The patients who were PET2-negative had a significant benefit as you can see here. In the PET2-postiive patients, the numbers were small and that’s probably why it is not statistically significant, though there did appear to be a significant benefit at 60- versus 46%.

And as brought up by Jeremy, the major issues and others on the Committee or the panel here, is the issue of the peripheral neuropathy.

So what about in the upfront setting? WE have very effective treatment with ABVD and there’s been a real move in the US, in particular away from radiation, can we enhance the number of patients who don’t need radiation by incorporating these novel drugs upfront? And here’s a very interesting study by Jeremy, where patients with non-bulky, Stage I and II, got a run-in with 2 doses of brentuximab and then got BV-AVD, PET adapted, for 4 to 6 cycles. Here we’re focusing on the unfavorable and there are about 40% of the patients who fit into this category.

And when you look at the outcome in terms of CR rate after the 2 doses of monotherapy, it’s more than 50%. And those numbers rise dramatically when you add in chemotherapy. And you can see, although this is a small study of 34 patients, the progression-free survival looks very favorable. As was mentioned, when you combine brentuximab and vinblastine concurrently, the Grade 3 peripheral sensory neuropathy was about 24%, which is significant. Febrile neutropenia, a as we know, is common when giving BV-AVD and needs growth factor support. So I think a question here is, how will this compare to standard approaches?

There was another study here, published last year, looking at a different strategy of combining brentuximab plus chemotherapy in early-stage patients, and this gave 2 cycles of ABVD, and then patients were risk stratified according to whether they had favorable or unfavorable disease and their PET response. So those who were favorable and PET-negative went directly to consolidation with brentuximab. Patients who had a positive-PET and were favorable or unfavorable and PET-negative got 2 cycles of ABVD and those who were unfavorable with the positive PET got 4 cycles followed by brentuximab consolidation, so, therefore, not giving the brentuximab and vinblastine together. Patients who were PET-positive and got radiation, about 45% of these patients were unfavorable. And you can see for the PET-negative patients, all of these patients remained in remission with good follow-up. The patients overall, about 92%. And again, by separating out the BV and the vinblastine. There was only 1 case of peripheral neuropathy that was Grade 3 and 1 infectious death.

So this is the most recent study looking at combining these 2 regimens and came from Memorial, Anita Kumar. She gave 4 cycles of brentuximab plus AVD. This was not — they got an interim PET but was not PET adapted there. Patients who were PET-negative then were treated in 4 cohorts with varying doses of radiation starting with 30 Gy of involved site, then 20, then 30 Gy of consolidative volume radiotherapy to limit the field, and then no radiotherapy. There are about 30 patients in each of these cohorts. About 30% met the standard definition of bulk at 10 cm or more than one third of the maximal thoracic diameter. If you look at a cutoff of 7 cm, which have been validated int eh study done at Memorial, really nearly all the patients, 86%, met this metric.

And when you look at the progression-free survival with this approach, again these are PET-negative after 4 cycles of BV-AVD. It looks excellent. And there was no difference between any of the cohorts, most importantly cohort 4, who did not receive radiotherapy.

So what about our elderly patients who tolerate. Bleomycin is not a good drug to give in patients who are elderly, with poor renal function, in terms of bleo lung toxicity. And giving BV-AVD as we know from the ECHELON study, is difficult in patients who are over 60. So this was a Phase II study, multicenter, from Andy Evans, where patients started with 2 doses of brentuximab and then got up to 6 cycles of AVD with brentuximab out back. This included 48 patients, and 28 patients received all therapy. And you can see here, these were mostly Stage III and IV patients who were high risk.

If you look, here is the progression-free survival curve which really looks very favorable for this patient population. The peripheral sensory neuropathy again was mitigated by this strategy of separating the drugs. Febrile neutropenia was common. And again, we know we need to support these patients aggressively.

So I will say this is our standard approach to older patients. It is very well tolerated and effective.

Another strategy for older patients was to eliminate chemotherapy completely, looking at BV-nivo as frontline therapy in a smallish cohort of 46 patients. Most of the patients had advanced stage disease. The overall response rate was over 90%. Complete remission rate was about 65%. Median progression-free survival, about 18 months. And you can see, I think these results look a little bit less favorable, maybe for those who get a complete metabolic response, they may do better.

There’s a second study looking at this regimen that hasn’t yet been published, so it looks a little more favorable. But I think I would probably reserve this combination for someone who really was not a candidate for anthracyclines.

So moving on, Jeremy mentioned this study as well. This was the confirmatory study of brentuximab in patients with relapsed Hodgkin’s, about 50 — 150 patients in each arm, randomized to pembrolizumab versus BV. These were about 40% of the patients that had prior stem cell transplant and were high risk with primary refractory in 40%. Only a few patients had had prior brentuximab.

The overall response rate was higher in pembro at 66%, compared to 54% with BV. CR rates were similar at about 25%. When you look at the progression-free survival however, pembrolizumab was better at 13.2 months versus 8.3 months.

Toxicity was completely as predicted. We have a lot of experience with these agents now. The serious adverse events were a little bit higher with pembrolizumab, but overall, both of these drugs were relatively well tolerated.

So what about the second-line setting salvage? We talked about this a bit in the cases. We know that if you incorporate brentuximab into salvage with, compared to standard chemotherapy, the complete remission rates are probably better. These were not head-to-head obviously. About 75% complete remission rates, with 2-year PFS of 70- to 80%. Of note, none of these patients had received brentuximab up front.

So this is the BV-nivo study that was mentioned. This was in second-line patients. Almost 100 patients, 40% were primary refractory and another 30% were early relapsers. The overall response rate was 85%. The CR rate was a little bit lower than some of the other BV plus chemo at 67%. But when you look at the progression-free survival curves, they look very favorable, with all patients at 78%. And those who went directly to autologous stem cell transplant is 91%. Again bringing up the issue of perhaps giving checkpoint inhibitors before stem cell transplant may enhance chemo sensitivity.

Not surprisingly, if you look at the bottom curves, those patients who were primary refractory did a little worse.

Pembro plus GVD, again was discussed by several of our panel members, and really looks very encouraging, 40 patients. Again, a very high-risk population. Patients got 2 cycles. If they were in CR, the could then go directly to autologous transplant, which was 31 patients. Seven got another 2 cycles. Everybody but 1 patient went onto autologous stem cell transplant. Some got brentuximab. Overall response rate 100%, CR 95%. And these patients are doing very well. There is mucositis that we see when we use this in our patients but does look extremely appealing as a second-line regimen, particularly for an early relapser, or someone who’s had prior brentuximab.

So what about upfront? There have been 2 studies, 1 of nivo plus AVD, and initially there was a run-in of nivo, then the chemo was added. At 9 months, this looked very favorable, at 21 months it looked more similar to the ECHELON-1 data, 83%. The Deauville score interim did not predict outcome, but end of treatment did.

And then the most recent study we have in the upfront setting is pembrolizumab plus AVD. This did include some early unfavorable patients as well as advanced stage. They got 3 cycles of pembro and then 4 to 6 of AVD. About 40% of patients — or 50% of patients have Stage II disease.

You can see with pembro alone the CR rate was 37%, but all patients achieved a complete remission with the addition of chemotherapy. And with short follow-up, this looks really good.

So I think major issues to look forward to in terms of data coming out is the ongoing US Intergroup study comparing BV-AVD to nivo-AVD. We tend to use BV-AVD in our Stage III and IV younger patients to give them a chance — a best chance at being cured with initial therapy but with that do need to watch toxicity.

I think in the upfront setting, there’s going to be a large US Intergroup study, including COG, comparing chemotherapy to novel agents in a PET stratified manner, hopefully to answer the question do we — is the benefit of novel agents in early-stage patients, what does that look like?

So we have just a couple of minutes. Any thoughts, Loretta, on where we’re headed in early-stage Hodgkin lymphoma?

DR NASTOUPIL: So my question to you is how do you decide? It used to be easy for me to know what to do. So what’s your favorite frontline regimen?

DR LaCASCE: So for, in the early-stage setting, my goal is to use as little radiotherapy as possible. We’re trying to get patients — there are a number of clinical trials, both company and other investigator-initiated studies — I usually start with ABVD. I tend not to escalate to BEACOPP unless maybe if a patient had a Deauville 5. But I’ll get a PET2. If patients are PET2-negative, you can give 4 or 6 cycles. Honestly, I look for a reason to give 6 cycles and do RATHL because I think when you have those patients who get 4 cycles, only they tend to recur later, and we don’t have a lot of long-term follow-up from David Strauss’ Alliance study where at 3 years, the progression-free survival was over 90%. But I worry a bit about those patients. They have low burden disease and have a Deauville 2, 1 or 2, then I may do 4 only. But it is, it’s a very confusing landscape for early-stage disease.

Martin, please. Tell us about …

PROF DREYLING: Yeah, I have no clue what the next step will be, but I absolutely agree, it depends on your first-line standard for low risk or localized Hodgkin’s patients. And what we did, we ask our patients. And we ask them, would you like to get rid of radiation, which was our idea, or would you like to get rid of chemotherapy? And surprisingly, and that has something to do with quality of life, the vast majority of patients wanted to get rid of the 2 cycles ABVD.

So our next trial for the early patients will be really skipping chemotherapy all over, but still keeping radiation for the patients not fully responding. But that’s the vote of the patients.

DR LaCASCE: Oh, that’s fascinating. And I think your data from Germany has really moved this field so far into the future. So that’s a really exciting study.

Well, with that, I think we’re out of time. I’d like to thank our phenomenal panel. That was really fantastic presentations and comments. And thank the audience for your attention. And please consider coming back at 3:15 for myeloma.