Diffuse Large B-Cell Lymphoma and Hodgkin Lymphoma — Christopher R Flowers, MD, MS

DR FLOWERS: It’s my great pleasure to talk about some of the highlights from the year 2022 in diffuse large B-cell lymphoma and Hodgkin lymphoma. And really, over the last year, there have been a number of interesting insights, particularly in the realm of diffuse large B-cell lymphoma that I’ll highlight.

The first is a randomized control trial in frontline diffuse large B-cell lymphoma, the POLARIX trial. So this was a trial that randomized patients to 6 cycles of polatuzumab/R-CHP with a vincristine placebo versus R-CHOP, the standard of care therapy with a polatuzumab placebo. And then following those 6 cycles of therapy on both arms, patients had 2 additional doses of rituximab for cycles 7 and 8. It enrolled patients with an IPI score of 2 through 5 and stratified patients by IPI score. And you can see the other enrollment characteristics. This was published in The New England Journal of Medicine in the tail end of 2021 and really is the first randomized control trial in the frontline for diffuse large B-cell lymphoma to meet its primary endpoint as being a positive trial.

What you see here in terms of the safety and adverse events of the trial is that the pola/R-CHP arm shown to the left looks very similar to R-CHOP in terms of the major adverse events. When you look at peripheral neuropathy, those were quite similar. And there was actually a specific presentation on that at the ASCO meeting that showed in more detail that there was really no major differences in safety with neuropathy with those resolving after completion of therapy for the vast majority of patients. The one place where there were differences, there were differences in the rates of neutropenia and febrile neutropenia that were higher in the pola/R-CHP arm compared to R-CHOP.

There really were no major differences with the exception of neutropenia and febrile neutropenia with those being higher in the pola/R-CHP arm. But importantly, those did not translate into differences in infection rates between the 2 arms.

When you look at this slide, this shows the updated efficacy results from what was presented this year at the ASH annual meeting. Shown to the left are the primary analysis that was presented in the New England Journal of Medicine with a median follow-up of 28 months. And to the right, you can see the analysis at 39 months. And you can see that the primary endpoint of progression free survival still showed a separation between the pola/R-CHP arm shown in the orange and the R-CHOP arm shown in the blue, where at 2 years, there was a difference in progression free survival of 6.5%, so being 76% in the group that received pola/R-CHP. And that was maintained with much further follow-up.

So that works out to being a hazard ratio of 0.73 at 2 years for progression free survival and 0.76 at 3 years of follow-up.

The other important analysis that came out of this year’s ASH meeting was this analysis that was also presented looking at circulating tumor DNA in the POLARIX trial. Now here, what are shown are both arms of the trial combined looking at progression free survival and looking at overall survival shown to the right. But what you can see is that those patients who had clearing of their circulating tumor DNA by cycle 2 day 1 shown in the blue curve versus those patients who did not clear circulating tumor DNA shown in the red curve show marked distinctions in terms of the progression free survival and in terms of overall survival with a progression free survival hazard ratio of 2.4 and an overall survival hazard ratio of 2.78 where neither one of those hazard ratios cross 1. This suggests that we can now tell with a great degree of certainty that those patients who have clearing of their circulating tumor DNA are likely to be patients that are longer-term survivors, both in terms of PFS and over — OS. What we really want to see in future clinical trials are ways to be able to translate these into therapeutic modalities that use circulating tumor DNA with early responses as met at cycle 2 day 1 as ways to be able to stratify patients and then to provide different therapies for those patients. What also will come out of this trial in a subsequent analysis is now looking at end-of-treatment circulating tumor DNA and that may provide other insights for the ways that ctDNA can be used in the frontline therapy for diffuse large B-cell lymphoma.

DR LOVE: Have you actually been using polatuzumab? Have you been able to access it? Have you tried to access it?

DR FLOWERS: So I was involved both in the polatuzumab clinical trials in the relapsed and refractory setting and was on the US Steering Committee for the frontline POLARIX trial, so I’ve used it in both of those settings. You may be aware that the NCCN just recently added data from the POLARIX trial to their guidelines. And so now, we're really waiting to see what the impact that will have. Polatuzumab is now approved in over 50 countries and we're waiting to see from other results kind of what impact it will have in the United States.

DR LOVE: Have you attempted to access it in the upfront setting? And if you were to access it, or even if it got approved, would you generally use it in most patients or would you maybe subset it out?

DR FLOWERS: Yeah. When you look at the patients where it is relevant, essentially across the patients who are eligible for the trial, it looks to be active in those subsets. I think we need to be a little bit cautious about doing unplanned subset analyses of different subsets within the context of the trial. And there have been forest plots that have looked at that. I think that those are generally less valuable except in areas where the subsets have been planned as parts of the analysis. But, in general, for patient populations that would have been eligible for the trial, and those include the broader IPI population of 2 through 5, those are patients that I think this would be a valuable regimen to use.

DR LOVE: All right. Please continue.

DR FLOWERS: Next, I’m going to turn to data from the RE-MIND study. So this is RE-MIND2. So this is an observational matched cohort study looking at tafasitamab and lenalidomide versus systemic therapies. And as you recall, tafasitamab/lenalidomide is a therapy that is approved as a combination for patients who are not transplant eligible where if they had 2 or more lines of therapy. And what they did was they took several thousand patients that were pooled who had either received bendamustine/rituximab or gemcitabine/oxaliplatin with rituximab and pooled as systemic therapies and then performed a matched analysis to the tafasitamab/lenalidomide trial of 81 patients. What you can see through the matching process, those more than 3,000 patients ultimately whittled down to about 75 patients who were matched to the group that received tafa/len in the pooled analysis and also in the BR and R-GemOx groups. The curves to the right show a comparison of those patients where you can see that the tafa/len group in the light green had improvement in progression free survival compared to that matched cohort. And this was published by Greg Nowakowski in 2022.

The other components of this are the L-MIND subgroup of patients who were treated for more than 2 years. And you can see that those patients who had either 1 line of prior therapy or more than 2 lines of prior therapy shown in the light yellow curve, both had favorable progression free survival if they were treated for more than 2 years on tafa/len. But I will point your attention to the bottom left of the curves to see the numbers of patients who started off, so 16 in the prior lines of therapy and 11 who had 2 or more prior lines of therapy. So just that these are very small subgroups that we're following here, but this was presented at ASH in 2022 to show the durability of response for those patients who received L-MIND.

This just shows a subgroup analysis of patients treated for greater than 2 years in terms of the safety with the major toxicities being seen being those that occurred in cytopenias with neutropenia, thrombocytopenia, leukopenia, and anemia. And that shows the all-grade frequency in those patients who had greater than Grade 3 in person years with neutropenia being the most common event that occurred in more than Grade 3 toxicity. It also shows in year 2 and year 3 the toxicity that occurred when patients went on to tafasitamab alone.

The next study that I'll turn to is the LOTIS-2 trial, so this is a single arm, open label, Phase II study of patients with diffuse large B-cell lymphoma in the relapsed and refractory setting where patients received the antibody drug conjugate, loncastuximab tesirine, a CD19-directed antibody drug conjugate. And you can see there, the ways that the drug was dosed both in terms of the first 2 cycles, and then after 2 cycles. And then patients after completion of 1 year of therapy were followed up every 12 weeks for up to 3 years.

And this just shows the response rates for that study with 25%, nearly 25% of patients achieving a complete response with a median progression free survival of 5 months for patients in the LOTIS-2 trial. And this was published at the tail end of 2021 by Paolo Caimi and colleagues.

This shows a follow-up publication from Dr Alderuccio in Blood Advances in 2022 where he looked at the high-grade B-cell lymphoma subgroup of the loncastuximab tesirine trial. And you can see that the response rates in this setting also were quite high for this poor-risk population where you can see a response rate of 33% in that group and the timing that it took to CR shown at the top half of the curve. Again, those light blue curves for individual patients in the swimmer's plot show relatively few patients, but you can see for those patients who were responders on therapy, that those responses could be quite durable, even the high-grade B-cell population.

This just shows the changes in overall health from a follow-up publication that came in 2022 in Clinical Lymphoma, Myeloma and Leukemia looking at the loncastuximab tesirine trial. Again, looking at the responders in the light blue dotted line versus non-responders. You can see that the overall health state for patients tended to improve with subsequent trial — cycles of therapy for those responders who were able to remain on therapy.

Next, I'll turn to another important randomized control trial that was presented in ASH of 2021 as one of the Plenary Abstracts and then published in late 2021 and another publication that I'll turn to next that was published in early 2022. This first trial is the ZUMA-7 trial, so a randomized controlled trial of axi-cel CAR T-cell therapy versus the approach of giving sequential chemotherapy with platinum-based chemoimmunotherapy, and for those patients who are responders, going on to autologous stem cell transplantation. And this just shows in this large, randomized control trial of relapsed refractory large B-cell lymphoma with 359 patients, the key eligibility criteria shown to the left, with 180 patients randomized to the axi-cel arm and 179 to the standard of care arm.

And these important data really showed a benefit in standard of care CAR T-cell therapy for patients who were early relapsers of large B-cell lymphoma. So these were patients who were primary refractory to their first line therapy or who had relapsed within 12 months. And you can see here that axi-cel had improvements over the standard of care arm of giving salvage therapy and going on to autotransplant for responders, meeting the primary endpoint of event free survival where the median event free survival was 8.3 months in the axi-cel arm versus 2 months in the group that received standard of care with a stratified hazard ratio of 0.4. This approach really stands to reason given that we've identified in those patients who relapse early within 12 months or those patients who are primary refractory, patients who are non-responders to traditional chemoimmunotherapy. So it stands to reason that an approach of giving more intensive chemoimmunotherapy of another type and going on to autologous transplant may not be as good as an approach like CAR T-cell therapy that is using a different modality of cellular therapy to address the refractory disease.

There was a second trial that also addressed this, this TRANSFORM trial that confirmed this strategy. And this trial also took patients who were relapsed or refractory within 12 months after first line therapy and randomized them to lisocabtagene ciloleucel as the CAR T-cell therapy versus standard of care with the addition of chemoimmunotherapy followed by autologous stem cell transplant. This trial did allow crossover whereas the prior trial, ZUMA-7 that I showed you, did not allow crossover in that trial.

And these are the primary results for the TRANSFORM trial that was published at the beginning of 2022 in Lancet by Manali Kamdar and colleagues. And what you can see here, again, was a benefit for the approach of using CAR T-cell therapy here with liso-cel with a median event free survival of 10 months in that arm versus 2.3 months in the standard of care group. Again, with a hazard ratio that looks quite similar to what I just showed you of 0.35 in this particular trial, again, showing the benefit of CAR T-cell for these early relapsed and refractory patients with diffuse large B-cell lymphoma.

There was additional follow-up that was presented last year in 2022 in ASH by Jeremy Abramson that showed that that benefit continued with additional follow-up with a stratified hazard ratio of 0.35 that was almost identical to what I just showed you from the publication. Again, with liso-cel having a marked benefit compared to what formally was the standard of care for patients with early relapse. And here with an 18-month event free survival rate of 52.6% for lisocabtagene ciloleucel versus 20% for that group that received salvage chemoimmunotherapy followed by the approach of autologous stem cell transplant for those patients who were responders. So this really has planted that traditional approach for patients with — as we care for patients in 2023 and beyond.

What I'll turn to next is another approach for patients with a relapsed disease, and that is the role of selinexor. This was a large study that had 267 patients who were ultimately eligible for enrollment of the trial. And you can see, the 140 — 134 patients who ultimately were analyzed for the primary endpoint. A follow-up publication came from Dr Schuster in Clinical Lymphoma, Myeloma and Leukemia in 2022 looking at subsets of those patients who received selinexor in terms of the response rates according to their prior treatment and their refractory status.

And what you can see here when you look at the overall response rate for selinexor across different populations, those patients who had 2 lines of therapy previous to receiving selinexor had an overall response rate of 27.8%. But you can also see those who had 3 or more lines of therapy had response rates that were quite similar of 30.9%. Likewise, responses occurred in patients who had a prior transplant, but were lower in those patients who had no prior autologous stem cell transplant, probably owing to the fact that these were patients that were not eligible for autotransplant for some other reason. And you can see that the response to the last line of therapy really was a determining factor in terms of the response to selinexor where those patients who had had a PR or CR to their prior line of therapy, had an overall response rate of nearly 36% versus 16% in those patients that were not responders.

DR LOVE: So, of course, we've been talking about selinexor for a while in our myeloma programs. And the issue of tolerability has been coming up, particularly in the community-based oncologists, the investigators. Joe Mikhael is a good example. They use it a lot. They feel like if they're very aggressive with supportive care, the patients do well. Have you actually used it yourself? And I’m just kind of curious what you've seen or what you've heard about tolerance.

DR FLOWERS: Yeah, I have used it and was part of the selinexor trials when I was at Emory. I think one of the challenges with this agent is the way that patients feel when they're receiving it with kind of the asthenia and malaise that patients experience that really makes it difficult to tolerate the drug, particularly at the higher doses. You'll see from the slide that I showed you previously that really, these results are being described for those patients who received selinexor at the 60 mg dose. The group that got allocated to the 100 mg dose really has not been as well evaluated in part because that dose was not as tolerable. In the myeloma group, they really have found ways to be able to adjust the dosing of selinexor, spread it out over time, and see ways to make it more tolerable to patients. That has been much less well explored in the realm of diffuse large B-cell lymphoma in part because we don't really know whether the efficacy that we see in the settings where we're giving the doses that I just described really would hold with lower doses and with spreading doses out. And the efficacy that we see is quite modest compared to some of the other options that I've already described and some that I would. And so I think in instances when you're using selinexor, you really want those patients to be responders and to have the benefits of the efficacy. So it has been a little bit more of a challenge here to balance the effectiveness of the drug versus the tolerability.

DR LOVE: Yeah, the preliminary data doesn't look as exciting as some of the other things you talked about, but I like the mechanism of action. I just like the idea that it's sort of different.

DR FLOWERS: Yeah, it is nice to have a number of options for patients with relapsed diffuse large B-cell lymphoma. That's really changed dramatically in the last 5 years as compared to when we had chemo, we had autologous transplant, and after autologous transplant, we had allotransplant or various forms of chemotherapy that we might alternate. Now, we have a whole host of options for the patients in that setting.

So moving on to some agents that are still in development in diffuse large B-cell lymphoma, I'll talk next about the bispecific antibodies. So this is a series of different agents that include both a component of the agent that is CD20-directed, so a CD20-directed antibody, as well as a CD3-directed antibody that brings T cells in close proximity to the CD20-positive diffuse large B-cell or also follicular lymphoma or other CD20-positive malignancies.

So the first of these trials that I'll talk about was published by Dr Dickinson in The New England Journal of Medicine in 2022 looking at glofitamab. These are the pivotal results from the Phase II trial in relapsed and refractory diffuse large B-cell lymphoma. I think some of the things that we’ve learned about the bispecific antibodies is that we can potentially mitigate some of the early cycle toxicities that we see in cycle 1 with cytokine release syndrome or CRS by giving pretreatment with obinutuzumab in this place — in this case, and also using step-up dosing. And so you can see here in cycle 1, there was administration of obinutuzumab followed by step-up dosing of the glofitamab until a full dose of 30 mg of glofitamab was given on day 1 of cycle #2. And the primary endpoint for this study was the best response rate or CR rate by independent review.

And so these show the results in relapsed and refractory diffuse large B-cell lymphoma for glofitamab. Shown on the curve to the left are the percentage of patients starting with those patients who were in complete response, so at 100%. So you can see 61 patients in all who were in CR, and then following them over time. And so the median duration of complete response at the time of publication was not reached. When you look at the progression free survival for all patients, that median progression free survival was 4.9 months with 37% of the population being progression free and alive at 12 months within this study.

When you look at the safety profile of glofitamab, what you can see here, and it's quite similar for the other bispecific antibodies, is that major adverse event was cytokine release syndrome being the most common with that being predominantly Grade 1 in severity for most patients, although there was some Grade 2 and Grade 3 CRS. And that predominantly occurred with cycle 1 of therapy. The other major toxicities tended to be cytopenias with neutropenia, anemia, and thrombocytopenia.

Next, I'll turn to the epcoritamab trials. So this is another CD20/CD3 bispecific antibody that is administered subcutaneously. These show the results of the EPCORE Phase II trial that included patients with large B-cell lymphoma as well as patients with follicular lymphoma Grade 3B. And this had a cohort of 157 patients. Again, step-up dosing was used. And you can see the ways that epcoritamab was administered subcutaneously at a dose of 48 mg given weekly for the first 3 weeks and then every 2 weeks for cycles 4 through 9, and then once monthly for cycle 10 and beyond.

And these show the results, again, for those patients who were responders with a CR rate in this trial of 38.9% and overall response rate of 63% and with a median follow-up of 10 months, that duration of response at a median was 12 months. The progression free survival curves shown here show a median progression free survival of 4.4 months in the curve to the right. And this was published by Catherine Thieblemont in the JCO in 2022.

Looking at the safety of the epcoritamab trial, this looks relatively similar to what I just described for you for the other bispecific antibody, glofitamab, where you can see the most common toxicity was CRS again occurring most commonly in the early cycles of therapy with 32% of those being Grade 1 toxicity in the CRS. And the other common toxicities were fever, neutropenia, anemia and fatigue.

Next, moving on to odronextamab in relapsed and refractory diffuse large B-cell lymphoma. In that patient population, this was looked at where the primary response rate — the primary endpoint for the trial was overall response rate by independent review. And it was presented at ASH at the end of 2022. So in terms of the odronextamab trial, the overall response rate was 49% with a complete response rate of 30.8% and a step-up regimen was used in these cases as well. And you can see that the overall response rate across 2 different approaches to the step-up regimen was really quite similar in terms of the overall response and complete response rates observed.

And this shows the duration of response curves and the duration of complete response curves for this trial. You can see here starting with 64 patients who were responders, a duration — a median duration of response of 10.2 months. And then looking at the complete response duration with 40 patients who were complete responders, a median duration of complete response of nearly 18 months in this trial. Again, these responses and durability of response look quite similar across the CD20/CD3 bispecific antibodies.

All right. And finally, I'm going to close out with some data from the Hodgkin lymphoma studies. This first study is looking at the ECHELON-1 data. As you recall, that was a pivotal trial in the frontline for Hodgkin lymphoma looking at the combination of AVD with brentuximab for patients with advance-stage Hodgkin lymphoma in comparison to the former standard of care ABVD in the frontline setting. And you can see that patients had an end-of-treatment PET and then follow-up every 3 months for the first 36 months and then every 6 months until the study closure. And what's new for 2022 in the publication of these results by Steve Ansell in the New England Journal of Medicine is both the data on progression free survival showing the benefit of AAVD versus ABVD with a 32% risk reduction. If you recall, the very first publication of these results described a modified progression free survival that is more commonly considered something like event free survival. Here, is shown the former progression free survival data for this curve with a median follow-up of 73 months meeting a hazard ratio of 0.68.

I think what's more compelling are these data, the overall survival results from this study where you can see that the overall survival favors the use of brentuximab/AVD versus ABVD with a 41% risk reduction and a hazard ratio of 0.59. Really, for the first time showing an improvement in overall survival in a tolerable regimen in the frontline setting for patients with Hodgkin lymphoma. And this has really moved into the standard of care for patients who are eligible for this regimen with long follow-up in this study.

The other thing is that this regimen is now moving into other settings, now looking at the first line treatment of early-stage unfavorable Hodgkin lymphoma. And this is a trial from the EORTC and the LYSA group looking at the criterion for enrollment there. And you can see that this involved a 2:1 randomization to 4 cycles of brentuximab/AVD versus ABVD followed by radiation with a primary endpoint being PET response after 2 cycles of therapy. And this showed a difference in the PET negative rate for the group that received BV-AVD of 82% versus 75% in the group that received ABVD. And you can see the progression free survival curves shown to the right, again, favoring the group that received BV-AVD. And published in the JCO at the tail end of last year.

And finally, I'll close out with a novel antibody drug conjugant that is used in the relapsed setting for follicular lymphoma in trials and data that were presented by Alex Herrera at the SOHO meeting in 2022. This is camidanlumab tesirine, so an anti-CD25-directed monoclonal antibody conjugated to the same antibody drug conjugate tesirine that I described earlier in the presentation in diffuse large B-cell lymphoma. So this is an ongoing Phase II clinical trial. And you can see the ways that dosing was given here with the primary endpoint being overall response rate.

And in looking at the response rates that were observed in this trial, you can see that the total overall response rate of 70% for patients enrolled in the relapsed setting for Hodgkin lymphoma here with a CR rate of 33% for those patients and a progression free survival curve shown to the right with a median of 9 months with about 10 months of follow-up. I think it's important to note that there are adverse events that are unique to this agent, changes in hepatobiliary function tests, in skin and nail reaction as well as autoimmune-related abnormalities that we see with other — that we see with PD-1 inhibitors, and Guillain-Barre syndrome that has been seen in selected patients. And so it's important as this moves forward to really — to understand the specific toxicities that we see with this agent.

And there was an additional exploratory analysis that was also presented by Alex Herrera at the ASH meeting in December looking at different subgroups of patients and looking at the response rates, both in terms of overall responses and complete responses to that. In particular, I'll point your attention to those patients who had prior stem cell transplant or not where you can see that the response rates and complete response rates were slightly higher in the group that had received prior stem cell transplant. And then looking at the bottom in terms of patients who had had a response to their PD-1 inhibitor in the past and both patients who were refractory or relapsed after a PD-1 inhibitor had high response rates and high CR rates suggesting that this is an agent that holds some promise across various subgroups in relapsed Hodgkin lymphoma. And we'll wait to see where this pans out in the future for the role of this agent in relapsed patients.

Thank you all for your attention. Really, an exciting year in 2022 for both Hodgkin lymphoma and diffuse large B-cell lymphoma. And we look to see how each of these trials and some of the new trials progress in the year ahead in 2023.

Follicular Lymphoma and Mantle Cell Lymphoma — Laurie H Sehn, MD, MPH

DR SEHN: Hi, I’m Laurie Sehn from BC Cancer in Vancouver, Canada, and today I’m going to be talking about some recent updates in follicular lymphoma and mantle cell lymphoma.

So for follicular lymphoma, we know that front-line therapy still relies on chemoimmunotherapy. The GALLIUM study was a seminal trial that compared obinutuzumab to rituximab as the initial CD20 monoclonal antibody, combined with an investigator choice of chemotherapy backbone. And what we’ve seen recently is the long-term GALLIUM study follow-up that was reported by Dr Townsend at EHA this year. This included follow-up of up to 8 years of really a prolonged look at the result of this trial.

This trial’s primary endpoint was progression-free survival. And at the time of reporting, we found that there was an improvement with the use of obinutuzumab over rituximab in terms of progression-free survival, and that that absolute value was approximately 7%.

Well, now with 8 years of follow-up, it’s reassuring for this indolent lymphoma, that that difference has been sustained. But it’s pretty much parallel to where it was.

So I’d say that the conclusion is actually quite similar, that we see this modest improvement in progression-free survival with the obinutuzumab rather than the rituximab upfront. But still, with the longer follow-up, no difference in overall survival.

What was intriguing was that they also looked at the safety over time with the 2 monoclonal antibodies. So this slide divides the safety follow-up for the induction phase, followed by the maintenance, and now, during the post-maintenance observation phase.

Although, at the time of initial reporting, the progression-free survival was significant, and that led to the approval of obinutuzumab, I have to say that the uptake has probably been partial across the community of people that treat lymphoma. So I myself continue to use rituximab. And part of my reluctance was perhaps the modest benefit, but also a slight increment in toxicity with the use of obinutuzumab. And early on, you can see that that really related to the infusion-related reactions, which was higher, but also a higher level of neutropenia and infection. And particularly in the patients receiving bendamustine with the obinutuzumab, there was actually concern for fatal infections.

Over time, with the maintenance phase, that seemed to also persist with a higher risk of infection in the patients who were receiving the obinutuzumab.

Now in the observation phase, with all patients off treatment, I think it’s still intriguing to see that there’s a slight signal of increased sustained neutropenia in the obinutuzumab arm, as well as a slightly higher rate of infection in the patients in observation.

So I think it’s interesting to see this long-term follow-up. The efficacy endpoint hasn’t been altered, but I think it’s noteworthy that this slight excess in toxicity has been sustained over time. And would definitely need to be considered by clinicals using obinutuzumab preferentially.

DR LOVE: So the hazard rate for PFS is comparable, 0.77. I mean I’ve seen action taken on those kind of hazard rates in other situations. But maybe it’s just more for historic interest. But one of the issues has always been the amount of drug and whether that’s the issue as opposed to the drug itself. I don’t know if there’s any way to resolve that. Any thoughts about that?

DR SEHN: So the schedule of administration is very similar. The dose of obinutuzumab though, is optimized for its unique pharmacokinetic profile. So, although it is probably milligram for milligram, a higher dose than rituximab, the optimal dose was based on really its own unique pharmacokinetic profile. So I’m not so sure it’s a dose effect. I think it is an agent effect. I mean it is a different monoclonal antibody and clearly, has more efficacy in follicular lymphoma. And this is one indication where — one of the indications where it really has shown to be more effective.

I think the issue is here, is that this is a non-curable lymphoma at this point in time. And patients will go on to get successive therapies most of the time. And although, progression-free survival is the primary endpoint that we look at, because overall survival is so prolonged that it’s impossible to run trials that really use that as an endpoint. Everything gets balanced in terms of progression-free survival against toxicity. And here, I think there is definitely a signal of excess toxicity with obinutuzumab — or increased toxicity, I should say, so it becomes a risk-benefit balance. And while many clinicians have universally switched over to it, I think that rituximab is still fair game in this setting.

It’s also, of course, slightly more expensive than rituximab in some environments, particularly now with rituximab being available with biosimilars. So there’s also a cost issue in some settings to consider access issue.

But for myself, I would probably individualize it on a patient-by-patient basis. We know that patients with higher-risk disease or higher FLIPI scores, maybe we want to be a little bit more aggressive in those patients and use of obinutuzumab is probably more justifiable.

But if I had kind of a lower-risk patient, I’d say I would be more comfortable using the rituximab because of the lower toxicity profile.

DR LOVE: All right, great. Please continue.

DR SEHN: So although chemoimmunotherapy is still embedded as the front-line setting for follicular lymphoma, I think we’re all enthusiastic about moving away from chemotherapy. Everybody remembers the RELEVANCE trial, which was the large, up-front trial that was aimed at bringing in a non-chemotherapy approach into the front-line setting, namely rituximab and lenalidomide, what we refer to as R-squared.

So in the RELEVANCE trial, R-squared was pitted head-to-head against rituximab and chemotherapy, again investigator choice chemotherapy, in the front-line setting for follicular lymphoma.

This trial was designed as a superiority trial. It was aimed to show that R-squared was actually better. And unfortunately, because it didn’t meet that endpoint — so it was essentially declared a negative trial, meaning that there was no benefit to R-squared over R-chemotherapy — R-squared didn’t get an indication in this setting but was quite noteworthy with the initial publication of this, which had a median follow-up of about 3 years, it was noteworthy that the curves were pretty much superimposable. And had it been designed and statistically powered for non-inferiority, we would have said that the approaches were non-inferior. But ultimately, the outcomes looked identical.

So this year we saw publication of the longer-term follow-up of RELEVANCE, so now we’ve got 6-year data. and I think it’s really quite compelling, as you can see on the right side of this slide that the progression-free survival and overall survival with longer follow-up has really shown to be identical.

I think this also provided reassurance that despite the use of lenalidomide and rituximab upfront, there was no hint of excess toxicity in that group, no hint of an increase in secondary malignancies of relevance. And, also, when patients went on to need second-line treatment, and many of them went on to get chemoimmunotherapy, there seemed to be no compromise in the outcome following second-line therapy.

So I think this has been a reassuring long-term follow-up in my mind. So if I had a patient where I wanted to avoid chemoimmunotherapy, I would feel comfortable with R-squared upfront, being a quite comparable alternative to R-chemotherapy. And also knowing with this longer-term follow-up, that I’m hopefully not causing the patient any untoward harm in the long-term and they still have the same doors open to them and outcomes, hopefully, when they go on to get secondary therapy.

So along the lines of moving away from chemotherapy for follicular lymphoma, I think the really game-changer is that we are now seeing the evolution to bispecific antibodies. So, we’ve been talking about bispecific antibodies for a long time in lymphoma and follicular lymphoma, and now we just had the recent FDA approval of mosunetuzumab for patients with relapsed/refractory follicular lymphoma. So we can stop talking about the bispecific antibodies coming and say that they’re actually here now and should be available for clinical use very shortly, if not already.

So what we saw presented at ASH was the longer-term follow-up of the pivotal data of mosunetuzumab in patients with relapsed/refractory follicular lymphoma. This had been presented last year at ASH, and was initially published by Dr Budde in JCO, but now we saw even longer-term follow-up presented by Dr Bartlett at ASH.

So, this is a trial that looked at mosunetuzumab as monotherapy for follicular lymphoma in patients who had received at least 2 prior lines of therapy. This is a finite therapy. Mosunetuzumab, in this trial, was given intravenously. For all of the bispecific antibodies in cycle 1 of therapy, there’s a requirement for step-up dosing. So it gets given in baby doses prior to the full dose being administered, as a way of trying to reduce the risk of cytokine release syndrome.

So here we have it administered 3 times in the first cycle. And then subsequently, it gets given once every-3-weeks. It’s intended to be given for 8 cycles total, and then patients get restaged. Patients in a complete remission would stop after 8 cycles only. And those who are not in complete remission would go onto receive up to 17 cycles of treatment. So again, finite-intended treatment.

In this pivotal experience where 90 patients were treated, what was so remarkable is that despite the fact that this was a high-risk cohort of multiply treated patients, median number of prior therapies was actually 3 prior therapies, the overall response rate was 78% and the complete response rate was 60%. So, here was a group of patients that was largely refractory to CD20 monoclonal antibodies, largely refractory to their last therapy, and we saw remarkable response rates noted.

But of course, we’re more interested in, what is the durability of benefit? So with this analysis that had up to approximately 18 months to 2 years of follow-up, what we can see here is that for the patients who responded and actually achieved complete response, the median duration of that complete response has not yet been achieved.

So you can see on the left side of this curve we see the duration of complete response. And on the blue curve, you can see that the patients receiving mosunetuzumab, up to the 2-year mark and beyond, the majority of those patients are still sustaining a response. The red curve is how they did with their last prior therapy.

So one of the paradigms that we’ve seen with follicular lymphoma is that patients, they go on to get successive lines of therapy tend to do worse with their next line of therapy. So response rates are lower. Progression-free survival, duration of response is lower. This is a shift of that expectation, where you see the blue curve of the mosunetuzumab doing much better than what patients achieved with their last prior line of therapy. And on the right side you can see the progression-free survival, where we now have the median progression-free survival reported as 24 months, which, again, is quite impressive for this multiply-treated patient population. And you can see here again how there’s that shift in our expectations, where the red curve on the right is how the patients did with their last line of therapy and progression-free survival, and the blue curve is how they’re currently doing with mosunetuzumab.

But what about the toxicity? So this is an agent that I would say is very well tolerated. The main toxicities are seen in the first cycle, where cytokine release syndrome is a potential side effect. But for the most part, it was low grade in nature, and mainly treated with supportive management. So, relatively few patients in this trial needed tocilizumab administered. And in all cases, the cytokine release syndrome was largely reversable and transient.

Aside from cytokine release syndrome, we see some element of neutropenia. But the infection rate was quite low. And in terms of other side effects, most of them were quite low grade.

So I think it’s quite exciting that we’re really seeing now the emergence in the clinical setting of these agents for the first time, that our expectation is that this will become a highly utilized treatment for patients with follicular lymphoma. And I think that, ultimately, we’re going to see really improved outcomes in this patient population as a consequence to this new therapy becoming available.

But mosunetuzumab is not the only agent being tested. Of course, there are several anti-CD20, CD3, bispecifics in development. We saw another one, just recently presented at ASH. This was the pivotal data in the follicular lymphoma cohort for odronextamab, which is also an agent that’s fairly long in development in numerous non-Hodgkin lymphomas.

This agent is given a little bit differently. So, again, what they presented was data in the pivotal follicular lymphoma cohort. This drug is given intravenously every 21 days as well, but is given more frequently in the initial cycle. So beyond the step-up dosing in cycle 1, it gets given weekly for the first 4 cycles and then gets given every second week up to progression. So it’s not finite, but given, technically, indefinitely, as long as patients are tolerating it. But again here what we saw in this highly pretreated patient population, very high overall response rates, in the range of over 80, and a high complete response rate here of 75%.

And here you can see again the median duration of response in this experience was just over 20 months, and the median duration of complete response was approximately 26 months. So very durable benefit for many of these patients.

I think now, now that we’re seeing emergence of monotherapy and bispecific antibodies, what is also a very active area of investigation is probably going to combine these with other treatments to make other treatments better or to find more effective combinations and how might we move them forward into earlier lines of development.

So there are many clinical trials right now looking at combining bispecific antibodies with standard therapy. A favorite to combine it with is R-squared, so rituximab and lenalidomide, to make, I’d say like a triplet immunotherapy. Since we would think that, hopefully, the bispecifics and the use of lenalidomide with the bispecifics might actually augment the effectiveness of both. So it’s sort of a logical combination to include together. And at ASH we saw 2 presentations of epcoritamab, another bispecific antibody in development, combined with lenalidomide and rituximab.

In this presentation, they looked at a group of patients in the relapsed/refractory setting for follicular lymphoma. Here we’ve got, of course the R-squared given in a finite way with up to 12 cycles. So 1 year of therapy of the lenalidomide. And then the epcoritamab was dosed up to 2 years of treatment.

This is still fairly early data, but very encouraging to see that there are very high, overall response rates here, 96%, and an 83.5% complete response rate. And the median duration very impressive here, but still early data, with a median follow-up only 6 months. But demonstrating feasibility of combining this as an approach and also early suggestion of high benefit.

These same authors actually explored these, so the same bispecifics, so epcoritamab with lenalidomide or rituximab, here in untreated follicular lymphoma. So, similar to RELEVANCE, which demonstrated R-square as effective front-line, here adding in the bispecific front-line. And, again, very intriguing overall response rate of 94%, complete response rate of 86% and very impressive duration of response, although still too early to say.

So we’re starting to see now combination approaches with bispecifics emerging, again, demonstrating safety and strong signals of benefit.

What about other novel therapies in follicular lymphoma? So tazemetostat, which is an EZH2 inhibitor, has already been approved and is available for treatment of follicular lymphoma in the relapsed/refractory setting.

What we know about tazemetostat is that it works best, or at least was shown in the pivotal data, to have better efficacy in patients that had what we call mutant patients, patients that had mutations in EZH2, and that’s only about 15% of the follicular lymphoma population. So the majority of our follicular lymphoma patients will have wild-type EZH2.

The pivotal trial showed benefit in both subgroups, but higher response rates and maybe slightly progression-free survival in the mutant subtype.

This analysis was a re-look at that trial and that data, but performing this time on matched analysis. Because we look back at that pivotal trial, what we saw is that the patients that were included in the mutant arm of the trial actually had more prior treatment, sort of had higher-risk disease, so they weren’t really comparable cohorts in terms of clinical characteristics. But this was an intriguing attempt to match the patients according to clinical characteristics to try and pick out apples and apples, so the same kind of patient. And you can see here that on this propensity score matched analysis of that initial data, the progression-free survival is actually quite comparable whether or not you had mutant or wild-type follicular lymphoma.

So I think this tells us that this agent has potential efficacy in both, and maybe better efficacy in wild-type than we were led to believe from that initial trial when we matched patients sort of with similar characteristics.

So this agent is also moving forward in development in the combination setting. So it’s being combined in several trials with lenalidomide and rituximab, for example.

At ASH, we saw the safety data emerging from a planned, an ongoing trial, that had a built in safety Phase Ib study, with plan to push this forward to a Phase III study. So the intention is to compare R-squared versus tazemetostat in R-squared, but the initial Phase Ib run-in was performed to look at safety and also an initial signal of efficacy.

So what we saw here in the patients included in the safety analysis, which is 40 patients, the majority of them had wild-type as we might expect by the distribution of the patient population. But what we saw was that it was actually very safe. There were no concerning signals of augmented toxicity associated with the R-squared. You can see here that the overall response rate was very high, 97% in the wild-type and 100% in the mutant subgroup population. Again we can see maybe a little bit of difference here in the complete response rate which was 70% in the mutant type patients and 45% in the wild-type. But again, numbers are small in a safety cohort. But looking at the right side of this, you can see that the progression-free survival was similar in both cohorts.

So I think this provided the signal of benefit that they needed to move this forward in the signal of safety. So I look forward to the initial and future results of the Phase III trial that will be ongoing for some time.

The other novel therapy that’s become available for follicular lymphoma, of course is CAR T-cell therapy. So based on ZUMA-5 data, axicabtagene ciloleucel was approved for follicular lymphoma after 2 prior lines of therapy. Now this was recently published and this trial looked at a group of patients with follicular lymphoma as well as marginal zone lymphoma.

We can see here that the response rates were high in both cohorts, but there was a signal of maybe more activity in the follicular lymphoma cohort where the overall response rate was very high as you can see there, at 94%, with the majority of those patients achieving a complete response slightly lower response rate of 83% in the marginal zone cohort of patients.

But with the progression-free survival, we can see here quite intriguing benefit in the follicular lymphoma patients. The blue line shows sustained benefit for a high proportion of patients, now out with a median follow-up of about 18 months. But you can see there are patients out now beyond the 2-year mark with sustained progression-free benefit.

Interestingly, that red curve with the marginal zone lymphoma does come down a bit more; still the smaller cohort of patients so I think it’s hard to make too much out of a small cohort. But, again, I think we’re seeing a signal that this may be more effective for follicular lymphoma than marginal zone lymphoma.

But we also saw data published and updated at ASH, looking at tisagen, essentially, or tisa-cel, in follicular lymphoma. So this was a comparable study, here using tisa-cel and we’re seeing very similar results with high level of efficacy seen in patients with follicular lymphoma. You can see that patients, particularly those achieving a complete response, are having quite durable benefits with follow-up in this trial being over 2 years. So the median follow-up was 29 months and many patients having sustained benefit.

I think the intriguing thing is in terms of a chronic disease that we don’t think we have a curative approach for at this point in time, I’d say that data on CAR T-cell therapy is still too early to say whether or not this is going to be a game-changer in terms of something that may offer curative potential. So we still need much longer follow-up than we have right now. But this is the longest follow-up analysis we have of CAR T-cell therapy in follicular lymphoma. And you can see here with a median follow-up of 29 months of those patients who achieved a response, so the CR and the PR patients, I don’t know, you can argue that we might be starting to see a bit of a plateau, or at least certainly those patients achieving a CR. Those that are progressing are doing so within the first 2 years and beyond that we’re not seeing further progression.

So certainly I’m excited to see the longer-term data of this, which I think is going to be what we require to really know whether or not we’re going to be seeing any cures with CAR T-cell therapy in follicular lymphoma. Nonetheless, it is showing itself to be a very effective treatment.

So I’m going to switch gears here and talk a little bit about mantle cell lymphoma. Mantle cell lymphoma, of course, is an aggressive B-cell lymphoma that is still a very big challenge to treat because at this point in time, we don’t really have a curative treatment option. On the positive side, this is a very active area of clinical research and we’re seeing novel therapies coming to fruition, but we’re still challenged with how to best optimize the treatments that we do have to offer patients the best control of disease possible.

So, right now, most of us use chemoimmunotherapy up front. And for patients who are not transplant candidates, bendamustine and rituximab, I would say, is probably the preferred chemotherapy in many settings because it’s so well tolerated and it’s highly effective.

We saw a publication of the SHINE data. So this was long anticipated Phase III trial that was comparing, head-to-head, a standard approach of bendamustine and rituximab for 6 cycles followed by rituximab maintenance with the same treatment plus the addition of ibrutinib in a 1:1 fashion in patients with previously untreated mantle cell lymphoma who were not planned for stem cell transplant.

The primary endpoint of this trial was progression-free survival. And we can see here that the trial met its primary endpoint with a significant improvement in progression-free survival. So the median progression-free survival was actually improved by 2.3 years with the addition of the ibrutinib, with a hazard ratio showing a 25% improvement.

Unfortunately, there was no improvement at a point of follow-up in overall survival. And I think what was concerning, is that despite the improvement in progression-free survival, we were seeing some excess toxicity in the ibrutinib plus BR arm. So we know that BTK inhibitors are associated with a unique set of toxicities, including the risk of cardiac toxicity, atrial fibrillation, hypertension, arthralgias, bleeding problems, neutropenia. And what we saw, is that in patients receiving the ibrutinib on top of BR, these toxicities did occur and there wasn’t an augmentation in toxicity overall.

So, ultimately, the improvement in progression-free survival that we saw with the BTK inhibitor here was offset in overall survival by more patients unfortunately, dying from unrelated events in the ibrutinib arm. So fewer death due to progressive disease in those getting ibrutinib, but a higher number of deaths due to treatment emergent adverse events.

So I’d say I think the verdict is still out. This is open for discussion I’d say with patients as to whether or not they should receive ibrutinib in the front-line setting. But there clearly is a tradeoff in toxicity associated with this drug.

So I think that it hasn’t fully permeated clinical practice. But it is, I would say, a clinically significant improvement in progression-free survival and clinically meaningful improvement in progression-free survival, but given the increase in toxicity, I think it’s still open for question as to whether or not you might get to the same place if you use this sequentially and come in with your BTK inhibitor as necessary in the second-line setting.

Having said that, we know that BTK inhibitors are firmly grounded in the second-line setting for mantle cell lymphoma and have been a real game-changer in that setting. So the ability to try and move these forward obviously is a high area of research and expectation.

At ASH we saw a very high profile presentation that was actually the number one abstract of the entire meeting and presented in a Plenary session at ASH. And this was the TRIANGLE study, which was performed by the German Mantle Cell Lymphoma — or European Mantle Cell Lymphoma Consortium. And this was a 3-arm study. It is a little bit complicated, but is a 3-arm design, that was initially intended to assess the efficacy and safety of moving ibrutinib into the upfront setting for transplant-eligible patients with mantle cell lymphoma.

So the standard of care arm here is the arm where patients receive R-CHOP, alternating with R-DHAP as part of induction, which is a standard accepted front-line induction, followed by autologous stem cell transplant, followed by observation. We know that many patients are now getting rituximab maintenance post-stem cell transplant, which is more recently demonstrated to improve overall survival.

In terms of the course of this study, it was not built in, but was up to investigator discretion. And I’d say that the data probably evolved over the course of this study, so probably toward the end of the study more patients had the rituximab added in. According to the presentation, about half of the patients received rituximab maintenance. But again, it wasn’t built into this trial; it was investigator choice.

So the standard arm included the alternating induction regimen followed by transplant. And the 2 experimental arms included 1 arm where ibrutinib was added into induction and maintenance and the transplant was left in and 1 arm where the ibrutinib was added into induction and maintenance and the transplant was left out. So, asking several questions in the context of this study.

And the reason why it was the number one abstract is because you can see here that the primary endpoint, which was failure-free survival, demonstrated a significant improvement for the ibrutinib-included arms. So the arm that did the worse, that blue arm, which is the arm that did not have the ibrutinib added in. And the failure-free survival in the 2 ibrutinib arms, including the one that didn’t include the transplant, was actually superior.

I won’t go through all the details. Just to let you know, it was a complicated statistical analysis. So they did 2 by 2 comparisons. But importantly, what they showed was, particularly for that group of patients that had the ibrutinib and the transplant, they were able to demonstrate a significant improvement in failure-free survival.

And these are the overall survival curves. At this point in time, they are not significantly different. But I think what’s most intriguing here is the gray arm of this is that group of patients that had the transplant left out. So the patients who had ibrutinib added into induction and maintenance with not transplant, what we’re seeing is they had a very high failure-free survival and no suggestion that their overall survival is being impacted by the omission of transplant.

So I think, this is a complicated trial design. As I said, the statistical analysis was quite complex, only half of the patients, as we were told in the presentation, had received rituximab maintenance. I personally would like to see more data come out and see the full publication probably for knowing how this should change my own practice. But some people are going to argue that this trial gives us some latitude to consider maybe dropping the transplant from the upfront setting for transplant-eligible patients without inducing sort of unnecessary harm.

So I think this will be debated. We’ve only seen kind of the tip of the iceberg in terms of this data, but I think it’s very intriguing that we may be seeing a shift in standard of care here. And certainly for my own patients, those patients who’d I say were kind of marginal transplant-eligible patients, I certainly would have no qualms about omitting the transplant from their care and considering, if I had access to it, moving ibrutinib forward.

So again, BTK inhibitors, very effective agents for mantle cell lymphoma, typically used second-line and beyond currently, but many trials exploring their use up front.

Here is a trial that was also presented at ASH looking at the combination of acalabrutinib is the BTK inhibitor, combined with R-squared.

So we’ve data of R-squared published in mantle cell lymphoma, largely for patients who were not eligible for transplantation. And in the upfront setting, R-squared actually is quite effective for mantle cell lymphoma and we saw data that showed sustained benefit in a population of patients. So this was an attempt to make a chemo-free, upfront regimen of BTK inhibitor plus R-squared for mantle cell lymphoma.

I like this trial also because it was an MRD-adapted trial. So they measured MRD in real-time, and for patients who achieved MRD-negativity after the 1-year treatment of R-squared, they basically stopped all treatment and were observed, except for some continuation of maintenance rituximab. And the other arm was able to continue with the ongoing treatment.

So this is not a large cohort of patients. It’s only 24 patients. It is proof-of-concept at this point. But what we saw here was a very high overall response rate of 100% in this small cohort, complete response rate of 83%. And you can see on the right that many of these patients, the ones with the light blue arrows, did achieve MRD-negativity, and many of them actually stopped treatment at the 12-month mark and were simply observed with what we can see here, quite sustained benefit.

So, again, very early data. Small patient numbers. But what we see here is that the 2-year progression-free survival was over 85%. So an intriguing combination with high response rates and demonstration of potential durable benefit, but particularly in this MRD-adapted approach some patients are receiving more finite therapy.

The other novel agent that many of us are interested in mantle cell lymphoma, not yet officially approved or indicated in this setting, is venetoclax. Venetoclax has single-agent, but by itself has, unfortunately, not very durable benefit for mantle cell lymphoma. So ongoing clinical trials are exploring combinations with venetoclax to see how we might add this effective drug into other combinations and have an effective multiagent combination.

This data that we saw presented at ASH was a combination of venetoclax and rituximab with the BTK inhibitor acalabrutinib, in a group of patients with untreated mantle cell lymphoma. Again, here an attempt to develop a chemo-free combination in the untreated setting.

This also is very early data, and a small cohort, but what we did see is that it was a highly-effective regimen with a high overall response rate demonstrated. One concerning thing with the data that was presented, again a small cohort, is that in this small group of patients, they did have an unusually high rate of patients who died from COVID-related deaths. So, actually 5 patients in this small cohort actually died related to COVID infection.

Now, is this somehow a consequence of the combination? Well, we know that patients with lymphoma are at a higher risk of COVID-related complications and death. We know that patients on active treatment with B-cell depleting agents have a higher risk of COVID-related complications. Is there something concerning about this triple combination? Is it just an unfortunate circumstance in a small patient cohort? I think it’s probably the latter. But it does sort of probably make it difficult for us to fully appreciate the efficacy of this combination. And probably what we’re going to need is more data to understand the safety and benefit of this combination moving forward.

One novel treatment that has become available for mantle cell lymphoma that I think has been an improvement clinical advance is the availability of CAR T-cell therapy. So we saw data presented of KTE-X19 for patients with relapsed/refractory mantle cell lymphoma based on the ZUMA-2 trial. So this was a group of patients who had received at least 2 prior lines of therapy.

And we saw the updated data, looking at 3-year follow-up of outcomes of this cohort. Again, the overall response rate in this multiply-treated patient population was very high here, in the range of over 90%. But with 3-year data now, what we’re seeing also is very intriguing demonstration that the patients, as with all CAR T-cell trials, the ones that seem to have the most durable benefit are those patients who achieve a complete response. You can see the highest curve are those patients achieving complete remission. But we’ve got data out now with the 3-year follow-up and beyond, where there are patients now sustaining benefit without progression even at the 4-year mark.

So I think we’re all eager to see even longer-term data. But in a group of patients where I would say that we’ve had very little to offer sustained benefit, it’s clear that CAR T-cell therapy can offer more than what I would expect with the standard agents we have available.

So I mentioned that BTK inhibitors have been a seminal therapy for mantle cell lymphoma. We’ve got several BTK agents approved in this setting. The most recent one approved has been zanubrutinib, which is now becoming a very popular BTK inhibitor for use across a variety of B-cell malignancies, including CLL, based on its favorable safety profile and efficacy.

What we saw published was the longer-term follow-up of the relapsed/refractory cohort of mantle cell lymphoma receiving zanubrutinib monotherapy. And again, reassurance that this is a very effective BTK inhibitor, with overall response rates that were notably high, including a best response where most patients were achieving a complete response with this agent but now with longer-term follow-up with a median follow-up being 3 years. We can see that the 3-month progression-free survival is roughly at that 50% mark. So, again, with BTK monotherapy, 3 years of follow-up, we’re seeing that about half of the patients are still sitting in remission at that time.

DR LOVE: So that was really great. It was really interesting about the TRIANGLE study. We’ll definitely talk about that. Incidentally, do you think that’s going to change practice?

DR SEHN: I think it will most certainly change practice. Having had some discussion post-ASH with many of my colleagues, I’m surprised at how many people are telling me they’re not yet ready to let go of stem cell transplant despite that data.

I think it was selected as number one abstract because it was anticipated by the Selection Committee that this would definitely change practice. It’s the death of stem cell transplant upfront for mantle cell lymphoma. But I think it’s surprising. I think most people still want to see more details of this trial presented because, as I said, it was complicated design. And it was almost like just glazing the surface of the information that I think most people wanted to see. But I’m kind of surprised in the discussions that some people are reluctant at this point to really let go.

So I’m not so sure in the short-term how much will change. But I think it is telling us that transplant may not be necessary upfront for all patients, and that using these novel agents like BTK inhibitors, maybe we can get to the same place without the same level of toxicity.

So I think in my own practice, as I said, I am compelled enough to say that if I had a patient who I didn’t think, or was borderline for transplant, would definitely make me more convinced that to let the transplant go. But here at my own institution, we haven’t yet been willing to say for all-comers, let’s shift over. I think we’re just going to wait to see more data come out from this trial.

DR LOVE: I guess this is kind of basic question, but how strong is the data on transplant prior to this time?

DR SEHN: Mm-hmm. There’s never been a large randomized, controlled trial assessing the utility of transplant. So we’ve got a lot of suggestive data, cross-trial comparisons, retrospective, era-on-era comparisons to suggest that transplant did improve progression-free survival for these patients, maybe even overall survival. But again, no large, randomized trials, all sort of compilation of the best data that we have. And what we certainly don’t have, and this is really the first trial that’s investigated the utility of transplant in the era of novel therapy. So I think the differences here, now that we’ve got very effective agents like the BTK inhibitors, do you really need to hammer people with chemotherapy when you have these novel agents?

I think that’s a really relevant question for a variety of reasons, not only to try and eliminate toxicity from the front-line setting, but, when you look at what we have in development in the relapsed/refractory setting, we’re really seeing the same thing we’re seeing in other lymphomas, a movement toward immunotherapy.

So what we didn’t talk about today was, there was a trial looking at glofitamab presented at ASH. So, bispecific antibody glofitamab in relapsed/refractory mantle cell lymphoma. And that is showing very high response rates and very strong activity, similar to what we have seen in large B-cell lymphoma and maybe even better activity.

So I think with the availability of CAR T-cell therapy down the road, with the availability likely of bispecifics coming from mantle cell lymphoma down the road, is it really a good idea to be hitting the patients with very strong, high dose, intensive chemotherapy in the form of a stem cell transplant upfront when we’re going to want their immune system to be strong down the road to have the best efficacy out of these next-line immunotherapies.

So I think the discussion around transplant will really pick up speed when we start saying are we doing patients any favors by sort of knocking down their immune system with high-dose chemotherapy when we’re really going to need to go on — because transplant is not curative for mantle cell lymphoma. And these patients will need to go on and get second-line and third-line therapy. And if those therapies are going to be based on immune-related therapies, maybe we don’t want to hit them so hard with transplant upfront if there’s good data to suggest that we could do just as well with novel therapies that isn’t going to have the same, hopefully, prolonged immunosuppressive effect.