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Dr. Brad Kahl:
Welcome to The ASCO Post Roundtable Series on Clinical Advances in Mantle Cell Lymphoma. I'm Dr. Brad Kahl from Washington University in St. Louis. Joining me today are two of my colleagues.
Dr. Jonathan Cohen:
Hello, Brad. I'm Jonathan Cohen from the Lymphoma Group at Emory University's Winship Cancer Institute in Atlanta.
Dr. Peter Martin:
Thanks, Brad and Jonathan. I'm Peter Martin from the Lymphoma Program at Weill Cornell Medicine in New York City.
Today we'll be discussing recent updates in mantle cell lymphoma and integrating these new developments into three patient case studies. Our second installment will focus on an older patient in the front-line setting.
Mr. TK is a 74-year-old man who presents to his primary care physician for evaluation of worsening back pain after not having come to the clinic for the past 2 years due to concerns about COVID. His past medical history is notable for hypertension, osteoarthritis, and he is a current smoker. He's on omeprazole and ibuprofen. He is married with three adult children and five grandchildren, all of whom live nearby and can provide support. He is a retired construction manager.
We see here CT scans which show bulky retroperitoneal and mesenteric lymphadenopathy. This led to the performance of a biopsy, which led to the diagnosis of mantle cell lymphoma, cyclin D1 positive with a Ki-67 of 15%. His blood counts and LDH are normal. The PET imaging shows extensive disease with an SUV max of 13. The marrow is involved at a level of about 20%, and his MIPI-C score was determined to be high intermediate.
Let's talk about this patient. Peter, maybe I'll start with you. You have an older gentleman with some comorbidities who smokes, but has a pretty high tumor burden and back pain as a result. What are going to be your initial treatment considerations for this gentleman?
Thanks. In terms of breaking it down, if we think first of the lymphoma-related considerations and then of the patient-related considerations, the lymphoma is likely to be a classical mantle cell lymphoma given the low Ki-67, but we're missing a little bit of information here, including morphology, as I mentioned. Additionally, we don't have information regarding p53 expression or TP53 mutations, or a karyotype that would look at complex cytogenetics. All of those pieces of information, I think, are, we're learning, increasingly relevant to the management of mantle cell lymphoma, although we don't necessarily have all of the answers regarding how this patient would be managed based on those variables.
In terms of the patient-related factors, this is an older person with some clear comorbidities. None of them is especially overwhelming, but my guess is that this is not likely to be the ideal candidate for a very intensive chemotherapy regimen. So I think what we're looking at is either some sort of less intensive chemotherapy regimen, which today would mean something based on bendamustine, or if the pathology points us differently, consideration; I think we're all debating maybe becoming increasingly comfortable with the concept of off-label use of novel agents if the pathology really points us in that direction. But that's still clearly debatable and definitely very far into the off-label category.
Jonathan, are you routinely checking for p53 mutations in all of your mantle cell patients now?
They're certainly trying to, if we have tissue and are able to complete the assessment, we will obtain it. I think, to Peter's point, we don't always know what to do with that information. If somebody is negative, then I think you can be a little bit more reassured that you can expect them to respond well to more traditional chemotherapies. If they do have a TP53 mutation or p53 overexpression, we recognize that those are patients that traditionally haven't done as well with chemotherapy. And again, there's consideration for novel agents, although this is really a group of folks that would be best suited with a clinical trial. I know there's interest in exploring novel combinations in the front-line setting for such a high-risk patient.
Peter, so you had indicated your most typical approach might be something like bendamustine/rituximab for a patient like this. Suppose you had found a p53 mutation, would that change your strategy here?
Yeah, it has recently changed my strategy. For a while, I think, as Jonathan mentioned, we knew that it was associated with poor outcomes with standard chemotherapy. So my approach was to choose basically less intensive chemotherapy, expecting an early recurrence, and then being able to move on to novel agent. Obviously clinical trials, as Jonathan mentioned, would be the go-to, no question, hands down, but outside of a clinical trial, my earlier approach would have been less intensive chemotherapy with the plan to move into something else, hopefully with less preexisting toxicity from a prior regimen. More and more I find myself using off-label novel agents, non-chemo agents, and this is not straightforward for a variety of reasons, particularly including coverage. But also, we just don't know which of these non-chemo regimens is the best one to reach for, and I don't think we will know that for a long time. But I do think that if we look at chronic lymphocytic leukemia as a roadmap here, that pretty clearly took us down a non-chemotherapy path.
Right. Jonathan, let's suppose this patient does not have a p53 mutation and you don't have a clinical trial. Are you likely to offer say, bendamustine/rituximab as standard therapy induction for this patient?
Yeah, I would. That's typically what we've been using at our center and what I've used in my clinic, and fortunately most patients tolerate this quite well. I do think though that this is an area, as Peter's mentioned, where there are opportunities to improve on our current approaches. So bendamustine can be quite myelosuppressive, there can be some associated cytopenias and opportunistic infections and so forth. So I think this is where novel strategies are particularly appealing. As you know, there is an upcoming NCTN trial that's going to be exploring a chemo-free approach for older patients with mantle cell lymphoma to try to determine the most appropriate duration of treatment and so forth. And there are other studies that are also ongoing looking at novel therapies in this older patient population. But today I would typically use BR.
What's that study going to look like that you mentioned?
This is going to be a trial for older patients over the age of 65, as well as patients that have underlying comorbidities that preclude their more traditional chemotherapy. So patients will receive rituximab and the covalent BTK inhibitor, zanubrutinib, and all patients will receive an induction course. Those patients who achieve a complete remission will then be randomized to either continue on single agent zanubrutinib indefinitely until progression, or to discontinue therapy and be re-treated at the time of progression in the future.
So the goal is really to try to identify whether one strategy is appropriate. I think it would be great if we ultimately are able to treat patients with a BTK inhibitor and rituximab, achieve a remission, discontinue therapy, and then know that we can treat those patients in the future and allow them to have a treatment-free interval. But this is a study that will be helping to answer that question.
Okay. So with this patient, suppose you did end up giving him a BR induction. Would you be offering the patient maintenance rituximab after the completion of the induction therapy? I'll start with you, Peter.
Yeah. This is an area that Jonathan and I both have an interest in, maybe honestly spurred a little bit by your initial work with rituximab maintenance, Brad. We recently published a paper which is based on observational data, admittedly, so lower level of evidence than would be ideal, that I think did pretty convincingly demonstrate, in both a discovery and a validation set, a benefit for rituximab maintenance after bendamustine/rituximab. That observational data has to be balanced by experimental data, which come from a single, smaller randomized phase II trial, the MAINTAIN trial that has not shown a benefit, but really only I think had 40, 45 patients per arm. So my impression of the weight of the data overall favor rituximab maintenance with the caveats that Jonathan mentioned being that bendamustine does have some immunosuppressive qualities and that maintenance after bendamustine can be challenging.
Right. What I liked about this real world analysis that you're mentioning that you published in the JCO last year, it had 1,600 patients in the analysis. What I found convincing was that when you look at the impact of maintenance in patients who received R-CHOP in the real world, it really recapitulated what the clinical trial data had told us previously. So that made me really trust this data set. And then with that trust, then you look at the outcomes for maintenance rituximab after BR, and you saw, similarly, a big benefit in progression-free survival and also a benefit in overall survival. So I came away from that analysis feeling pretty confident that maintenance rituximab is beneficial after BR. I will admit in my older patients, I like to stop it at 2 years because of the prolonged B-cell depletion and these risks that we're talking about, because there is certainly some safety considerations.
I want to talk about the SHINE trial for a minute if you're willing. Jonathan, maybe you could walk us through what the SHINE trial... how it was designed and what it was trying to answer and what the results told us.
Sure. So the SHINE study, which was published last year in the New England Journal of Medicine, was one of the first and largest studies to evaluate the incorporation of novel therapies into the management of patients with mantle cell lymphoma in the front line. This was a study that was open to patients who were over the age of 65 and who otherwise had previously untreated disease and who were not going to be moving forward with an autologous stem cell transplant. Patients were randomized to receive either the BR for six cycles, followed by rituximab maintenance with ibrutinib administered at the standard dose until progression of disease, or BR followed by rituximab maintenance plus placebo.
The primary endpoint was a progression-free survival, although there were additional secondary endpoints that were investigated. This was a trial that accrued, and for which there was a fairly extensive period of follow up before it was reported, which I think speaks to, in general, the improved outcomes for patients with mantle cell lymphoma, in that there were not a lot of early progressions.
What we did see from the study is that although there was an improvement in progression-free survival for patients who received ibrutinib as opposed to those who received placebo, that this did not translate into any difference in overall survival. In fact, if you look at the overall survival curve presented on the slide, you'll see that they almost entirely overlap. So I think these data have been interpreted in a couple of different ways. Certainly it suggests that a patient with mantle cell lymphoma who receives the triplet of bendamustine, rituximab, and ibrutinib can expect to have a prolonged remission compared to a patient who receives BR plus maintenance rituximab alone without the ibrutinib. But again, it doesn't appear to improve overall survival, and it raises the question about whether these patients may also be well served by receiving BR plus R maintenance and then potentially receiving a BTK inhibitor in the future at the time of relapse, without having to commit to such a prolonged course of therapy upfront.
Right. I'm going to move to our clinical takeaways from this segment. For older mantle cell lymphoma in need of first-line treatment, bendamustine/rituximab is probably the most commonly used strategy. We now have pretty strong real world evidence from the Flatiron database that suggests significant clinical benefit for maintenance rituximab given after BR induction. As Jonathan just mentioned, the SHINE trial does show improved disease control when ibrutinib was added to standard therapy, but this improved disease control was offset by some toxicity issues and so there was no overall survival benefit. And then as Jonathan mentioned, there are chemotherapy-free options that are under investigation and he mentioned a soon-to-open NCTN trial, which will look at two chemo-free strategies for these older mantle cell patients.
So this brings us to the end of this case. Please see the other segments for further discussions about the latest data in mantle cell lymphoma, or visit ascopost.com. Thank you.