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Peter Martin, MD: Hello. I'm Dr Peter Martin from the lymphoma program at Weill Cornell Medicine in the Meyer Cancer Center in New York. Welcome to Medscape's InDiscussion series on mantle cell lymphoma.
Today we'll be discussing bone marrow transplantation in mantle cell lymphoma. Bone marrow transplant has been an interesting topic over the past couple of decades. We have with us our guest, Dr Brad Kahl, professor of medicine from Washington University, who is going to help us to dive into this topic. Welcome to InDiscussion.
So, Brad, I think a lot of people may know you from the RESORT trial in follicular lymphoma, but I've been following your career for the past 20 years. You were chair of the Mantle Cell Lymphoma Committee at the Lymphoma Research Foundation. You had a paper that probably was one of the most underrecognized papers on VcR-CVAD. You had an interest in mantle cell lymphoma for a long time. Where did that come from?
Brad S. Kahl, MD: Hi, Peter. Thanks for having me. Mantle cell lymphoma has always been a particular interest of mine. I remember seeing some cases of mantle cell lymphoma as a fellow. This was about 25 years ago, and it was a fairly recently recognized entity at that point. We had just gained the ability to recognize mantle cell lymphoma, whereas in previous eras, it wasn't recognized so clearly as a distinct entity. A lot of papers were coming out about this disease, its biology, and in particular the natural history of the disease. It became clear pretty quickly that our usual therapies that worked very well in diffuse large B-cell lymphoma or follicular lymphoma didn't work so well in mantle cell lymphoma. So we found ourselves really struggling with how to best manage these patients. And it just struck me that here's an opportunity for a young investigator who wants to do research in the field and hopefully improve outcomes for patients. Mantle cell lymphoma would be a great opportunity to do that.
Martin: I think one of the ways that we as oncologists used to tend to approach these diseases that were difficult to manage was to use the tools that we had, but to use them in a bigger dose or a more intense fashion. Eventually that led to the concept of autologous stem cell transplant in mantle cell lymphoma. I wonder if you can just walk us through that process.
Kahl: It became apparent early on that a standard approach that we might use for diffuse large B-cell lymphoma, which was initially CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) when I was finishing my fellowship but soon became R-CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone plus the monoclonal antibody rituximab), still only produced average remission durations of about a year and a half in mantle cell lymphoma — pretty disappointing results. Different groups then began looking at autologous stem cell transplant consolidation after CHOP or R-CHOP, and the European Mantle Cell Consortium actually did a randomized clinical trial where patients either received CHOP or R-CHOP, depending on where they were treated and in what time frame they were treated. But then patients were randomized to autologous stem cell transplant consolidation or a strategy of, I believe it was interferon. And the trial suggested a pretty big progression-free survival benefit with transplant and maybe even an overall survival benefit with transplant. For our younger patients, this was the first really encouraging data that suggested that outcomes were being improved. This was around the same time that MD Anderson was producing results from their hyper-CVAD studies, again showing very good outcomes, at least in younger patients. It led to this idea that maybe the intensification of the treatment with either a transplant consolidation or a really intensive treatment like hyper-CVAD could result in better outcomes for younger patients. That's how it all started.
Martin: I guess over the subsequent decades, we saw that maintenance rituximab could improve outcomes further initially after R-CHOP, but then more recently even improvements in overall survival after autologous stem cell transplant. Given this sort of sequential approach of an intense induction followed by autologous stem cell transplant, followed by maintenance rituximab, we're seeing remission durations in the 7- to 8-year range or as an average, which means that 50% of people were having longer progression-free survival than that — which is pretty remarkable given the historically quoted overall survival of just a couple of years. Yet when we looked at statistics in the United States of the proportion of people that were receiving these treatments, it was not necessarily what you'd expect. Why do you think that was?
Kahl: It's a good question. I don't think I have a perfect explanation for it. I know you and I both work at academic medical centers, and most of the younger patients at academic centers are being referred for a stem cell transplant. Over the past 10 or 15 years, sometimes you just have patients will decline. Some will just say, I don't want to do that — which is their right, of course. It's possible that some patients are perhaps being treated in the community who aren't being referred in for the transplant consultation, or maybe patients are self-selecting and saying to their local oncologist, I don't want to go there and I don't want to do that intensive treatment, so just figure out what we can do here locally to maintain my disease. I don't have a perfect explanation for why the utilization of stem cell transplant has been lower in the United States compared with Europe or other developed countries. But that's definitely what the data suggests.
Martin: So then the other really big development over the past decade in mantle cell lymphoma really has to be the approval of the BTK (Bruton tyrosine kinase) inhibitors, starting with ibrutinib in 2013, and then acalabrutinib and, most recently, zanubrutinib. The data there showed, first of all, that those agents were very clearly active in people with previously treated mantle cell lymphoma and appear to demonstrate that the earlier we use those drugs, the better. So people receiving it in the second-line setting vs subsequent treatments appeared to benefit even more or have longer progression-free survival periods. I think naturally that led to this idea that they could be used in the frontline setting. There were a couple of trials that evaluated that, one of them being the SHINE trial, which was presented this summer looking at bendamustine rituximab with or without ibrutinib in older patients. And then just this past weekend at the ASH (American Society of Hematology) meeting, we saw the TRIANGLE trial presented, which is maybe one of the more exciting trials I've seen in maybe my career in mantle cell lymphoma. I wonder if you could walk us through that trial design and what it showed.
Kahl: Just a few days ago, you and I were sitting in the audience seeing the presentation for the TRIANGLE trial. This is a trial that was done in Europe through the European Mantle Cell Consortium, and it was specifically for younger patients with mantle cell lymphoma — so, 65 and under.
The trial had three arms. The control arm would be their standard approach. That's R-CHOP with alternating R-DHAP (rituximab, dexamethasone, cytarabine, and cisplatin) as an induction strategy, which is their most commonly used strategy in Europe. It's followed by autologous stem cell transplant consolidation, then followed by maintenance rituximab, according to the local country's approval and practice patterns. So about half the patients in the trial received maintenance rituximab for 3 years and about half did not because the different countries in Europe have different approvals around the maintenance rituximab issue. So that's the control arm.
The second arm is an experimental arm that added the BTK inhibitor ibrutinib. The ibrutinib was given during the R-CHOP cycles. Then the ibrutinib was given post-transplant for 2 years.
There's two experimental arms. The third arm gives the ibrutinib in the same way during induction, just during the R-CHOP, not given during the cytarabine cycles because they're worried about thrombocytopenia after high-dose cytarabine and bleeding. So no ibrutinib during those cycles. But then the investigators actually subtracted the stem cell transplant. Once patients completed their induction, they just received ibrutinib as a maintenance strategy for 2 years along with their maintenance rituximab if they were in a country that gave maintenance rituximab.
So, there was a control arm, and then an experimental arm that added ibrutinib to the transplant and an experimental arm that subtracted the transplant but added the ibrutinib. Those are the three arms.
Martin: Why was the ibrutinib only given during the R-CHOP cycles and not during the R-DHAP cycles?
Kahl: Out of concern for toxicity, particularly increased bleeding risk. Usually when patients receive high-dose-cytarabine containing therapy, they usually have a pretty significant platelet nadir. It's very common to have grade three or four thrombocytopenia. I think they were worried about having people on BTK inhibition because it has an antiplatelet effect in patients who are about to develop severe thrombocytopenia.
Martin: So what did the trial ultimately show?
Kahl: The two ibrutinib containing arms were significantly better for progression-free survival compared with the control arm — about 15% better at 2 years, if I remember the curves correctly. It did appear that ibrutinib improved the disease control. There was no difference in overall survival, but the follow-up was relatively short. If there is a difference there, that may not emerge for years, but there was definitely improvement in progression-free survival if ibrutinib was included.
Then if you look at the two arms that included the ibrutinib, they really were equivalent for outcomes. But as one would expect, the arm that still contained the autologous stem cell transplant had quite a bit more toxicity compared with the arm which did not include the autologous stem cell transplant. So when you look at the data in total, combining both the best efficacy with the least toxicity, to most of us in the audience, it appeared that the winning arm is the arm that adds the ibrutinib but subtracts the stem cell transplant. That would be practice-changing in the United States and in most of the world, where we have been routinely recommending autologous stem cell transplantation to these patients.
I think this is a great advance for patients. Going through the induction and consolidation for mantle cell lymphoma is very difficult for patients. It's about 6 months of fairly intense chemotherapy, with hospitalizations for the high-dose cytarabine–containing part. Patients often need blood and platelet transfusions during their nadirs, and there is risk for neutropenic infection. Then as soon as they finish that, you say, hey, great job — you're in remission, and now we're going to give you even more chemotherapy. That's when they come in the hospital for their autologous stem cell transplant, which is a really difficult procedure for patients. It's about a month in the hospital, and they usually don't feel wonderful for months after. The whole treatment program really takes about a year out of a patient's life. I would love to be able to not have to do that to a patient. And if we get to the point where we can add the BTK inhibitor and not put them through the stem cell transplant, I think that's a win for patients.
Martin: Do you think the results would have been similar if the BTK inhibitor were used only in the maintenance setting and not in addition to the R-CHOP chemotherapy at the beginning, which could be confusing having to start and stop it the way it was used?
Kahl: That's a great question. Of course, we'll never know the answer to that, but I'll give you my best guess. If you look at the data around response rates and complete response rates, it doesn't appear as though the BTK inhibitor added much to the induction piece. If I had to guess, I would bet the heavy lifting from the BTK inhibitor is occurring as the maintenance strategy rather than as part of the induction strategy. And if I had to choose to give it in one place or the other, I would choose for the maintenance strategy over the induction part.
Martin: It's also interesting that it was only 2 years of ibrutinib maintenance, which is contrary to the SHINE trial, which ended up having a median of 2 years of ibrutinib use. But the goal was treatment until progression or intolerability. This really was a time-limited therapy, which I think is really attractive for our younger patients and surprising. We'll see as time goes on, but it's interesting that only a time-limited treatment with ibrutinib could significantly improve outcomes beyond those 2 years. So that was kind of interesting for me to see.
The other interesting thing that I saw was the subgroup analysis showing specifically that those patients who were most likely to benefit were those patients who are higher risk — so those with high Ki-67 and P53 overexpression. Is that something that should have been more intuitive, or was that surprising?
Kahl: It surprised me a little, just from the standpoint that BTK inhibitors as single agents don't perform as well in these highly proliferative cases. I wasn't sure how much it would add in this setting. We do know, however, that BTK inhibitors, at least in CLL (chronic lymphocytic leukemia) and presumably in mantle cell lymphoma are far superior to chemotherapy for P53-mutated cases. So to see the big benefit for the addition of BTK inhibition in P53-mutated cases, that was not a surprise to see the benefit in the highly proliferative cases. That was a mild surprise to me.
Martin: So now we've got these data. Ibrutinib is not yet approved in the maintenance-type setting.
Brad, I'd like to get your advice on something. I have a patient coming in later this week, and I'm sure we'll be seeing other patients over the next couple of months. My question specifically is what to do with these young patients who may have recently received an autologous stem cell transplant or who are candidates for autologous stem cell transplant? Should we still be considering autologous stem cell transplant in the setting of the TRIANGLE data showing the improved outcomes with ibrutinib?
Kahl: This happens to us from time to time when we see practice-changing data at a meeting. It is not widely disseminated knowledge yet. It has not been published in a peer-reviewed journal yet, and it hasn't achieved any regulatory approval yet. It's not even in any guidelines yet. My thinking on it is we're just going to have to be a little patient. We go through this from time to time, and we're going to have to wait for things to formalize. The publication needs to come out. The recommendation to add ibrutinib needs to come out in the form of guidelines, like NCCN guidelines, or by regulatory approval from the FDA. Without those things, I predict we'll have a hard time providing it to patients because I don't think the third-party payers are going to be willing to pay for it. So I think we're going to be in a position for a while — maybe 6 months, maybe longer — where we might like to give ibrutinib, but we won't be able to. But eventually this will sort itself out and we will be able to recommend and prescribe it to patients.
Martin: So changing the topic a little bit, there are a couple of trials through ECOG where you're the lymphoma committee chair that are looking at frontline treatment of mantle cell lymphoma. In this last minute or so, could you outline where those trials stand?
Kahl: We have an induction trial, which is kind of similar to the TRIANGLE in that it had three arms and it uses bendamustine plus rituximab combined with cytarabine plus rituximab given in sequential fashion. And then the BTK inhibitor acalabrutinib is combined with standard chemotherapy. So our trial should hopefully answer the question in a pretty clean way about whether the BTK inhibitor improves the overall response rate or the complete response rate, because those are the endpoints for our trial. That trial should be fully enrolled in just a couple of months, and we should have that read out by this time next year. So that'll be great.
The second trial that we're conducting is a transplant vs no transplant trial for younger patients who are in complete remission and also minimal residual disease–negative by next-generation sequencing. That trial is really asking the question, if you've gone through your induction and you're in a very deep, high-quality remission, do you really need the stem cell transplant, or could the stem cell transplant be eliminated in that setting? That trial is essentially fully enrolled at this point, too. We do think both of those trials, when the data are mature, will be very informative for the field.
Martin: I agree. I like the design of both of those trials. Obviously the TRIANGLE trial changes things a little bit, but I think there's still so much to learn about the role of transplant in the maintenance rituximab setting.
First of all, Brad, I'd like to thank you for leading us through the discussion of the TRIANGLE trial and the history of transplant in mantle cell lymphoma. I think there's a lot to look forward to in the near future with mantle cell lymphoma.
Today we talked with Dr Brad Kahl about autologous stem cell transplant and mantle cell lymphoma. Specifically, I think we learned that in the current ibrutinib era, we're likely to see a transition away from autologous stem cell transplant toward the use of BTK inhibitors. But we do want to wait and see all of those data in a peer-reviewed publication and incorporated into guidelines, and hopefully very quickly after that approved by Medicare and the other payers.
Thank you all for tuning in. If you haven't done so already, take a moment to download the Medscape Mobile App and listen and subscribe to the podcast series on mantle cell lymphoma. This is Dr Peter Martin for InDiscussion.
Long Term Follow up of the Resort Study (E4402): A Randomized Phase III Study Comparing Two Different Rituximab Dosing Strategies for Low Tumor Burden Follicular Lymphoma
Phase 2 Study of VcR-CVAD With Maintenance Rituximab for Untreated Mantle Cell Lymphoma: An Eastern Cooperative Oncology Group Study (E1405)
High-Dose Cytarabine and Autologous Stem-Cell Transplantation in Mantle Cell Lymphoma: Long-Term Follow-Up of the Randomized Mantle Cell Lymphoma Younger Trial of the European Mantle Cell Lymphoma Network
Ten-Year Follow-up After Intense Chemoimmunotherapy With Rituximab-HyperCVAD Alternating With Rituximab-High Dose Methotrexate/Cytarabine (R-MA) and Without Stem Cell Transplantation in Patients With Untreated Aggressive Mantle Cell Lymphoma
Primary Results From the Double-Blind, Placebo-Controlled, Phase III SHINE Study of Ibrutinib in Combination With Bendamustine-Rituximab (BR) and R Maintenance as a First-Line Treatment for Older Patients With Mantle Cell Lymphoma (MCL).
Efficacy and Safety of Ibrutinib Combined With Standard First-Line Treatment or as Substitute for Autologous Stem Cell Transplantation in Younger Patients With Mantle Cell Lymphoma: Results From the Randomized Triangle Trial by the European MCL Network
Bendamustine and Rituximab Alternating With Cytarabine and Rituximab for Untreated Mantle Cell Lymphoma
Rituximab With or Without Stem Cell Transplant in Treating Patients With Minimal Residual Disease-Negative Mantle Cell Lymphoma in First Complete Remission
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Cite this: Autologous Stem Cell Transplant for Mantle Cell Lymphoma and the Transition Toward the Use of BTK Inhibitors - Medscape - Jan 31, 2023.