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Peter Martin, MD: Hello. I'm Dr Peter Martin from the lymphoma program at Weill Cornell Medicine and the Meyer Cancer Center in New York. Welcome to Medscape's InDiscussion series on mantle cell lymphoma. Today we'll be discussing bendamustine in mantle cell lymphoma, which on the surface might seem straightforward, but I think we'll get in to some of the nitty gritty and maybe some of the controversy around it. And I'm glad to have joining me, my guest, Dr Kami Maddocks. Dr Maddocks is a professor of clinical internal medicine practicing at the James Cancer Hospital at the Ohio State University in Columbus, Ohio. She serves as a lymphoma program director and director of lymphoma research in the Division of Hematology Oncology and has a particular interest in aggressive B-cell lymphomas, including mantle cell lymphoma. Dr Maddocks, welcome to InDiscussion.
Kami Maddocks, MD: Thank you for having me, Dr Martin.
Martin: So, Dr Maddocks, you have established your foothold in research in multiple areas in lymphoma. Initially, a lot in chronic lymphocytic leukemias, a lot of work with tafasitamab in DLBCL (diffuse large B-cell lymphoma), targeted therapies across a broad spectrum of lymphoma subtypes, but also a really clear focus on mantle cell lymphoma, including especially in the cooperative group setting in multiple observational studies as well, some of which we've collaborated on together. One important study that we'll get to in more detail shortly, which I think was the first study of bendamustine plus ibrutinib in non-Hodgkin lymphoma. What was it in all of this work that really drew you to mantle cell lymphoma?
Maddocks: When I started, I did a lot of work in CLL (chronic lymphocytic leukemia). But often there are patients who are diagnosed initially, and there's a question of CLL or mantle cell, or they're diagnosed with one but really have the other. And even though I had a large population of CLL patients, I started to have mantle cell lymphoma patients sneak in there and I really enjoyed seeing these patients. I think mantle cell is really a heterogeneous disease. You have patients who have very indolent disease but you have patients who have very aggressive disease. I just really enjoyed the variable populations and approaches to treatment in these patients.
Martin: I agree. It is intellectually a pretty satisfying disease to be able to help with. The goal of this podcast is to dive into the past, present, and future of bendamustine in mantle cell lymphoma. And the start of that, obviously, is the past. I'm going to ask you if you can help set the stage for us with respect to how bendamustine established itself as a treatment for mantle cell lymphoma.
Maddocks: There were two large randomized trials, the StiL trial and the BRIGHT trial, that led to us using bendamustine-rituximab (BR) as frontline treatment in patients with mantle cell lymphoma, particularly in those patients who were older or not considered candidates for more aggressive chemoimmunotherapy and autologous stem cell transplant induction. Both of these two large randomized trials compared bendamustine-rituximab with chemoimmunotherapy with R-CHOP (rituximab in combination with cyclophosphamide, doxorubicin, vincristine, and prednisone) or R-CHOP and R-CVP (rituximab with cyclophosphamide, vincristine, and prednisone), and established that the BR regimen showed less toxicity overall, with superior progression-free survival in mantle cell lymphoma and similar survival rate. If we look at the trials individually, the StiL trial was a trial that enrolled over 500 patients randomized to BR vs R-CHOP, and a little less than 20% of these patients had mantle cell lymphoma. This did show an improvement in median progression-free survival for those patients treated with BR in the entire population of patients and in the patients with mantle cell lymphoma compared to that with R-CHOP, with less toxicity. The BRIGHT trial was the second trial, and this actually looked at BR vs investigator's choice of R-CHOP or R-CVP. This trial enrolled a little under 500 patients with somewhere between 15% and 20% having mantle cell lymphoma and, with longer follow-up, showed that the BR was non-inferior to the R-CHOP or R-CVP. But really when you looked at the patients with mantle cell lymphoma, it showed improvement in complete response, event-free survival, and progression-free survival, with BR over that of the other chemoimmunotherapies.
Martin: Yes, I agree. When you look at the trials, the StiL trial really seemed to be positive across the board. But in the BRIGHT trial, it was the mantle cell lymphoma patients that appeared to gain the most benefit from bendamustine-rituximab. And I think that's particularly relevant in the current era because we're starting to witness maybe a little bit of a backlash against bendamustine, particularly in follicular lymphoma, and it may or may not be appropriate to extrapolate that to mantle cell lymphoma, where there might be more efficacy benefit. Do you think that's a fair assessment?
Maddocks: I do think that's fair. I think in the StiL trial, having mantle cell lymphoma was a negative prognostic indicator overall. But really in both trials, it did seem to be that mantle cell lymphoma patients benefit even if the PFS (progression-free survival) wasn't as long as the other patients in a group as a whole. The benefit did seem to be better over R-CHOP or R-CHOP and R-CVP than it did in the other populations.
Martin: Then we moved on to some combination studies that were built on bendamustine-rituximab as the backbone. And I will admit that I remember feeling very optimistic about a lot of these studies. I felt like BR was pretty easy to give (and it was) low toxicity, in that it was kind of a no-brainer to combine it with other drugs. So we started an intergroup trial of the E1411 trial, which was built on the bendamustine-rituximab backbone along with bortezomib. During induction, there was also a maintenance arm with lenalidomide and rituximab vs rituximab, and that trial had been initially presented by Mitch Smith. And then the final results presented by Mitch Smith essentially showing that there was no benefit from the addition of bortezomib to induction or lenalidomide to maintenance. That whole maintenance question is kind of a long discussion in and of itself, but this was maybe a little bit surprising and obviously disappointing that it was hard to build on the success of that trial, but it wasn't so depressing, in that while that trial was getting going, we were also seeing the development of the BTK (Bruton tyrosine kinase) inhibitors and ibrutinib. And you were on the beginning end of that in CLL and in mantle cell lymphoma. And even before ibrutinib was approved, you had already started with a phase 1 trial of bendamustine-rituximab and ibrutinib. Can you walk us through that trial, the design, and the results?
Maddocks: Sure. We had a trial here at OSU that was a phase 1 trial of bendamustine-rituximab in combination with ibrutinib. It was a dose-escalation trial with dose expansion. So the escalation occurred in patients with non-Hodgkin's lymphoma. And then there was a 10-patient expansion in follicular lymphoma, mantle cell lymphoma, and diffuse large B-cell lymphoma. The phase 1 portion enrolled patients at two different dose levels of ibrutinib, 280 mg and 560 mg, and there were no dose-limiting toxicities, kind of declaring standard BR in combination with ibrutinib at 560 [mg] as the dose to move forward with. As I mentioned, there were three 10-patient expansion cohorts in follicular large cell and mantle cell lymphoma. About three fourths of patients responded, with about half of those patients receiving a complete response. This was in 48 patients. Looking at the patients, particularly with mantle cell lymphoma, which we're discussing here today, nearly all of the patients responded. There were 17 patients. The majority had received prior treatment, although there were a few patients who had not received prior therapy. Nearly all responded, with three fourths of them achieving a complete response. Looking at toxicity, cytopenias and rash were the most common toxicities. Cytopenias appeared similar to what was reported previously with BR, but we were a little surprised by the grade 3 rash: 25% of patients had grade 3 rash in this study. Interestingly, it all occurred in (patients diagnosed with) follicular and large cell. And whether there's a reason for that or it just was happenstance is hard to say. But this suggested that maybe in mantle cell lymphoma, this combination could improve on either BR alone or ibrutinib alone.
Martin: Did you see any interesting or unusual infections with that combination?
Maddocks: No, not really. We did have one death on this study with an ARDS (acute respiratory distress syndrome)-like presentation. There was no infection identified in that patient.
Martin: I remember reading it and thinking at that time that the rash was interesting, but that it looked like a pretty promising regimen to take forward. And obviously, we were not the only people to think that because that led to the genesis of the SHINE trial, which was presented this past summer. Can you walk us through the design and results of the SHINE trial? In particular, I'm curious about your interpretation based on your experience.
Maddocks: We did see the long-awaited results of the SHINE trial this summer. This was a randomized phase 3 trial that enrolled patients who were 65 and older and considered not candidates for consolidation with autologous stem cell transplant. Patients in this trial were randomized to what is considered standard treatment with six cycles of bendamustine-rituximab, followed by 2 years of rituximab maintenance vs that BR rituximab maintenance regimen with the addition of ibrutinib during both bendamustine-rituximab and then with rituximab maintenance. And then ibrutinib was continued until progression of disease or unacceptable toxicity. Over 500 patients were randomized on this trial, and it was reported with a median follow-up of a little over 7 years. It's interesting to note that the median time that patients were treated with ibrutinib on this trial was a little over 2 years. So this was a positive trial. There was a benefit in progression-free survival with the addition of ibrutinib from 52.9 to 80.6 months, which translated into a 2.3-year benefit in progression-free survival. Cytopenias, diarrhea, nausea, and rash were the most common toxicities. When they looked at toxicities of interest, there was a higher rate of bleeding, including grade 3 or higher bleeding, and a higher rate of atrial fibrillation, including higher-grade atrial fibrillation in patients who were treated with ibrutinib. There was no difference in overall survival. So just looking at how the populations of patients did, there was a higher rate of discontinuation due to toxicity in the ibrutinib arm, but a higher rate of discontinuation due to progressive disease in the standard arm. And the same thing when you looked at deaths: there were a higher number of deaths due to progression of disease in the standard arm, but a higher number of deaths due to treatment-emergent adverse events in the arm with ibrutinib. So taking it all together, I think the addition of ibrutinib clearly provided a progression-free survival benefit. At the current follow-up, we don't see an overall survival benefit. That benefit did seem to come at the risk of higher toxicity in patients, including leading to treatment discontinuation, and even a higher rate of death. I don't think that this is what I would say is a new standard for all patients. But that being said, when you identify a newly diagnosed patient and weigh the risks and benefits, I don't think it's for no-one either. I think that it's reasonable. There are patients who will benefit from prolongation of progression-free survival who maybe don't have the baseline risk for some of the toxicities that we see with ibrutinib and may be right for this combination … should it be approved, of course.
Martin: Can you comment on the control arm with the rituximab maintenance and how well they did?
Maddocks: When you look at the control arm, their median PFS was approaching 5 years. I think if you look at what we've seen from trials that we've done since the original StiL and BRIGHT trials, like the E1411 that you were referencing, it looks like the median progression-free survival with BR plus rituximab maintenance is somewhere in the 5-years–plus range.
Martin: In an older population, so that's pretty good. It's at a high bar and I think is maybe one of the reasons why it took us so long to see the results of the SHINE trial finally published.
Maddocks: I think if you look at all the things we talked about and some of the things we'll probably talk about, BR plus rituximab maintenance is a good regimen, right? In mantle cell lymphoma, it's a good regimen.
Martin: Okay. Let's walk backwards in time a little bit and look at BR in younger patients with mantle cell lymphoma. Until now, we've mostly focused on older patients. I think the first trial that I can think of that looked at BR in younger patients was the SWOG trial S1106. The 1106 trial, which was presented by our friend Rob Chen, compared BR to hyper-CVAD in younger patients. And I think that was probably a controversial design at that time to give BR to younger patients. But there was transplant planned in that trial and essentially that trial was shut down early due to issues with stem cell collection in the hyper-CVAD arm, so it really limited the interpretation of that trial. But interestingly, in the small number of patients, there was a suggestion that hyper-CVAD and BR were pretty similar. And I think that essentially set the stage for the EA4181 trial that you're involved in. So can you describe that trial to us?
Maddocks: EA4181 is a randomized phase 2 trial that has three arms. The arms consist of bendamustine-rituximab in combination with high-dose cytarabine, each given for three cycles. So that's what was chosen as the standard arm. And that was based on a trial and then some data looking at patients treated in practice with this regimen showing that BR-HiDAC, each given for three cycles, produces very high overall response rates, complete response rates, minimal residual disease (MRD)-negative remissions and had promising 2- and 5-year progression-free survival. So that was what was chosen as the standard arm in this randomized phase 2 trial. And then the addition of the BTK inhibitor acalabrutinib to BR-HiDAC in the third arm is BR-acalabrutinib with no cytarabine. The primary endpoint of this trial is a composite of PET complete metabolic response (CMR) and MRD-negative disease. So PET-CMR, MRD negative. Really looking at if the combination of cytarabine vs BTK vs both with bendamustine produced a higher composite PET-CMR, MRD-negative rate than that with a BR HiDAC combination. This trial was set to enroll close to 400 patients. The primary endpoint is just the response at the end of treatment. And then patients could go on to either not receive any consolidation, get rituximab maintenance, or go on the other 4151, which is a transplant MRD-based transplant study. This trial is still accruing, although a few months ago after the interim analysis, it was closed to accrual. It has now been reopened, but that interim analysis showing that the BR-acalabrutinib arm was unlikely to meet the primary endpoint (which was a 15% improvement in that composite PET-CMR, MRD-negative rate), and the information that was released with that did say that there was less toxicity seen in that arm, but it was not, at the current interim analysis, likely to be superior to the other arm.
Martin: So we may still see some benefit of BR-cytarabine-acalabrutinib vs BR cytarabine, but we won't see a benefit of BR-acalabrutinib vs BR plus cytarabine. Did I say that correctly?
Maddocks: Yeah, I would say we would not see a benefit in terms of superiority in that primary endpoint over the BR-HiDAC. I think the challenge is interpreting that. Of course, every time you design a study, you think, We should have done it this way or Maybe we could have done it this way. But could they be equivalent in terms of that primary endpoint? I think that's what we won't know.
Martin: Right? I suppose if they're similar in efficacy but one is less toxic, it would still be attractive.
Maddocks: Yes, it could still be a good option.
Martin: Okay. It's interesting to look at all of these data and figure out where BR fits in right now. We know from observational series that BR is being used increasingly commonly in mantle cell lymphoma. Do you think there's a population where it definitely belongs? Is it in older patients? Should it be considered in younger patients? Should it be combined with something? Or do we really need to wait for more granular data from some of these trials to see where it goes?
Maddocks: What I feel we know is that BR plus rituximab maintenance in more recent trials has shown progression-free survival 5-plus years. And it is a good regimen. We know from your paper in JCO that it is the regimen that's probably — at least in community practices — most used across populations and again showing promising outcomes. I think the challenge is when we look at the combination studies, is it that we are not combining it with the right things? When you look at the combination with bortezomib and then lenalidomide maintenance, is it that that just wasn't the right combo? Because certainly the combo with BTK showed improvement in progression-free survival, but it showed that it did come with toxicity concerns. I'm not sure if we just haven't found the right partner in combination or if we're just going to have a challenge when you consider toxicity and outcomes improving upon what is really a good regimen.
Martin: Right. So, corollary to that question, is there a place where BR clearly does not fit?
Maddocks: I think some of the challenging populations we've seen with the newer therapies we have might really need to be taken into consideration. I think when you look at patients with high-risk disease by, say, TP53 mutations and blastoid disease, we know that they have inferior outcomes to standard therapies. And I think there's been a tendency to say in these patients who are younger since they do inferiorly, we don't want to give them high-dose intensive regimens like hyperCVAD or consolidate them with transplant, because that's a lot of toxicity if it's not going to improve outcomes. But then we think, well, let's give them a less-intense regimen like BR, and then they can be followed with BTK. But I think what we've seen — with the ability now to be able to have a chimeric antigen receptor (CAR) T-cell product in later-line settings, and the response in these high-risk populations — is that it is something that should be used in second line or moved up in those high-risk populations. And we have seen that, because of the effect of bendamustine on T cells, long-term follow-up or 3-year follow-up from the KTE-X19 study showed that patients who had had bendamustine within 6 months did have lower peak levels of CAR T-cell populations. And so, when you think about these high-risk patients who might progress early, you really wonder if they should be treated with novel therapies, targeted therapies, and of course, clinical trials because they may need to move to CAR T in a quicker fashion, and bendamustine might affect their outcomes with CAR T.
Martin: Quickly, do you have any predictions on where we're going to see BR in the next 5 years? Will it still be around? Will it be a backbone of a regimen? Will it be entirely replaced by targeted drugs?
Maddocks: I think probably in the next 2 to 5 years, we'll see it in one role. And then beyond that or beyond 3 to 5 years, we'll see it in another role. I think when you look at the SHINE study, when you look at the other studies with BR and rituximab maintenance, and I think when you look at the recent TRIANGLE studies showing a benefit to BTK in the front line, that probably what we're going to see is people using BR with rituximab maintenance. And then in combination with BTK, either through the whole regimen or maybe BR and then maintenance rituximab and BTK inhibitor in probably all populations of patients. Again, just taking outcomes of all those trials and combining what we're seeing. But I think probably in 3 to 5 … or beyond 5 years where the field really is going is looking at these novel doublet and triplet targeted therapies and even immunotherapies like the bispecifics and CAR T being moved up into earlier lines.
Martin: Thank you very much for leading this discussion and joining us, Dr Maddocks. So today we talked with Dr Maddocks about bendamustine. An interesting topic, bendamustine plus rituximab, particularly followed by rituximab maintenance appears to be very effective in older patients; it's somewhat challenging to combine treatments or other medications with that backbone for a variety of reasons, but obviously still some potential there, including the SHINE trial showing a potential benefit with BTK inhibitors. In younger patients, we're likely to see increasing use of bendamustine-rituximab, but I think we all share some optimism that in the not-too-distant future we'll see more targeted drugs moving in and potentially replacing chemotherapy altogether.
Thank you everyone, for tuning in. If you haven't done so already, take a moment to download the Medscape app and listen and subscribe to the podcast series on mantle cell lymphoma. This is Dr Peter Martin for InDiscussion.
Resources
Ibrutinib Plus Bendamustine and Rituximab in Untreated Mantle-Cell Lymphoma
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Cite this: The Past, Present, and Future of Bendamustine in Mantle Cell Lymphoma - Medscape - Feb 28, 2023.
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