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. Jonathon Cohen:
Hello. Thanks, Brad. I'm Dr. Jonathon Cohen from the Lymphoma Program at Emory University's Winship Cancer Institute in Atlanta.
Dr. Peter Martin:
Hi. Hi, Brad. Hi, Jonathon. I'm Peter Martin from the Lymphoma Program at Weill Cornell Medicine in New York City.
Dr. Kahl:
Today we will be discussing recent updates in mantle cell lymphoma and integrating these new developments into three patient case studies. Our first installment will focus on a younger patient in the front-line setting.
So case number one, Mr. RL, is a 54-year-old man with newly diagnosed mantle cell lymphoma. He presented with inguinal lymphadenopathy and increasing fatigue. On examination it was notable for widespread lymphadenopathy in the 3-4 cm range, and the spleen tip is palpable.
He had a normal white blood cell count, but the hemoglobin was 10.5 and the platelet count, 135,000. LDH was normal. He had a lymph node biopsy that showed classic mantle cell lymphoma with a Ki-67 of 35%. He had PET imaging, which showed involvement of most nodal regions with the largest nodes in the iliac chain, 7 cm in long axis, with some compression of the bladder. The maximum SUV was 18. A bone marrow biopsy was done. It showed involvement by mantle cell lymphoma with about 40% involvement, but there was no 17p deletion or P53 mutation detected.
So if you calculate a MIPI-C score for this patient, it turns out to be 5.6, which puts them into the low intermediate category. Not the best prognostic group, but certainly better than some of the more high-risk groups.
I guess I'll pause for my first question. Jonathon, are there any additional studies that you would perform in a case like this? Do you do endoscopies? Do you do lumbar punctures? Are there any other tests that we should have considered in evaluating this patient?
Dr. Cohen:
So in general, I would say that this patient has been appropriately staged and I would be comfortable moving forward with treatment.
I think there are other factors that we could consider evaluating that might assist with prognostication. So, for example, we know that having a complex karyotype is something that's associated with higher risk disease, and so that may be an additional test we would consider for patients that have already had a biopsy where we can assess their karyotype. I don't know, however, if I would necessarily utilize that information to make a clinical decision, but it can sometimes be helpful with counseling patients on what to expect about their disease.
I typically, in the absence of clinical symptoms, have not been performing routine endoscopic evaluation on patients who don't have any evidence of GI involvement on their staging studies and who don't present with bleeding or other symptoms. And similarly, in most cases I haven't been considering an LP as a part of the routine evaluation of patients with mantle cell, unless there are other factors like a blastoid variant or other features that we know are associated with CNS involvement.
Dr. Kahl:
Great. Peter, any other tests that you would like to see done?
Dr. Martin:
No, I agree with Jonathon on this one.
Dr. Kahl:
Okay.
Dr. Martin:
Probably on most things as well.
Dr. Kahl:
So Peter, you've published on the fact that not every mantle cell lymphoma patient needs immediate therapy. How would you approach this patient? Is this patient a candidate for a watch and wait strategy? Or do you think he needs treatment sooner rather than later?
Dr. Martin:
Yeah, Jonathon and I both have taken this up as a particular interest. Obviously, we're not going to cure anybody with mantle cell lymphoma without treating them. On the other hand, I'm not sure that our historical chemoimmunotherapy is likely to cure the majority of patients, or arguably any patient with mental cell lymphoma, either. And there are obvious advantages to deferring therapy, including the avoidance of side effects, toxicities, and the potential for future treatments to come along and get better.
Nonetheless, this patient, I think, does have indications for treatment; the symptoms are relatively mild, but they're there. The lymph node size is pretty big, 7 cm, and it's also causing some organ compression. So I think those indications probably are the reasons, just based on scan. What we don't really talk about are a lot of symptoms, in this case maybe some increasing fatigue, which is a little bit vague and a lot of people have that, but certainly any symptoms are a clear indication.
Ki-67, this is sort of a tricky one. I think that somebody with a clearly elevated Ki-67 probably is going to need treatment sooner rather than later. This one is kind of on the fence.
Dr. Kahl:
Okay. Jonathon, would you treat this patient now? Or would it be a watch and wait candidate in your practice?
Dr. Cohen:
Yeah, I completely agree with Peter. This is somebody that I would not generally recommend for sort of indefinite watchful waiting.
I do, at least in my own practice, tend to divide patients into those with indolent behaving disease that can be observed sort of indefinitely. And I'm sure we all have patients that have this diagnosis and 3, 4, 5 years later or even longer have never required any therapy. And then you have the patients with very aggressive-behaving disease, where they're either already in the hospital or they need to get started this week on treatment.
This sounds like a patient that probably doesn't have to drop everything and start therapy, but I would want to likely get started in the 4 to 6 week range. Often I'll ask people if they have a wedding coming up or a big vacation, but once the schedule allows I would plan to get started.
Dr. Kahl:
Okay. So let's think about how we might treat this patient. And I'm going to ask you both if you're opting for treatment, which you both are, what are your overarching treatment considerations? Talk about the kind of induction strategy you might recommend here, talk about any consolidation strategies, stem cell transplant or not, talk about the use of maintenance rituximab.
Let's just take those three first and then we'll circle back and talk about novel agents and chemo-free. But let's just talk about how you might approach it from the option of standard therapies. And Jonathon, I'll start with you.
Dr. Cohen:
So the first thing for me is looking at the patient in front of me and making sure, or identifying what therapies they may or may not be eligible for. So in this particular case, we have a young patient who at least doesn't appear to have any overwhelming comorbidities. And so this is a patient that I would consider to be eligible for any potential therapy that we may recommend.
And so once I know that I have a patient that I can feel comfortable treating, however we feel like they need to be treated, then the next step is trying to identify what we can do to maximize the duration of their initial remission. We know that mantle cell is a disease that generally will relapse if patients live long enough. And again, in a 54-year-old patient who you're looking at 30 to 40 additional years of life, you expect that at some point the disease will come back. So whatever I can do to try to prolong that is going to be at the top of my list of priorities.
And so for me, at least in my practice, that typically means an induction regimen with chemoimmunotherapy. I typically will still strongly consider a cytarabine-based induction for patients that are young and fit, based on a number of studies that have suggested that this is a preferable approach compared to some of our older regimens. And I think that in most cases patients are able to tolerate this and get into remission.
I think where we really are now trying to figure out what's the most appropriate approach is whether or not to incorporate novel agents like the BTK inhibitors into this induction therapy, and whether patients require or should receive a consolidation with an autologous transplant.
In the past, this was part of my standard approach for patients who were eligible based on really some almost now 20-year-old data that suggested that there was an improvement over conventional induction therapies alone.
So the question about rituximab maintenance I think is an interesting one, and this has been an area of interest, I know of yours, Brad, and just in general in the lymphoma community over the last several years.
There have now been several projects that have evaluated the role of rituximab maintenance. And it does appear that in most cases rituximab maintenance is associated with improved progression-free survival and in some instances even with improved overall survival. And so I typically do consider it.
I think it's important to keep in mind that in the current era, with COVID and other viral infections, that it does increase patients’ risk for complication, especially if it's given in combination with a BTK inhibitor. But I do feel that in many cases a combination of rituximab, potentially with ibrutinib, can result in prolonged remission. And I certainly consider it for most of my patients.
Dr. Kahl:
Peter, how would you approach a patient like this?
Dr. Martin:
Yeah, I think Jonathon phrased it really well. There are obviously lymphoma-related considerations in this case, there's really nothing in this lymphoma that tells me that I have to manage the patient in one way or another. Chances are with this kind of profile the lymphoma is going to be well controlled regardless of the treatment we choose. Then there are obviously patient-related issues, and as Jonathon said, this is somebody who could probably tolerate any kind of treatment specifically.
So then my general focus then is on what is our goal? What is our goal of care? And that's where I think there's a lot more variability oftentimes. And so then it becomes a trade-off of what somebody is willing to give up in terms of side effects with the expectation that there may or may not be a longer or shorter remission duration on the other side of it.
I don't personally think that a choice of chemotherapy is likely to impact overall survival. And I'm not even 100% convinced honestly that choice of chemotherapy impacts progression-free survival other than adding cytarabine to the R-CHOP regimen. I think that clearly does benefit things. But my view of bendamustine also is that it's quite powerful, and I think it may have a role in younger patients like this as well, as we're studying in that cooperative group setting. So I think there are a lot of chemotherapy options available.
I agree with Jonathon's take on rituximab maintenance. I also agree with Jonathon's take on autologous stem cell transplant. We have used it, probably there will still be patients that we continue to use it in, but I guess my bias, and I think the bias of our institution at Cornell, has probably been to not use stem cell transplant maybe as much as some other institutions. And I think I'm also more prepared to move more fully into the novel agents setting and leave even chemotherapy behind. I'm eager for that, which I think is going to be a topic of future discussion.
Dr. Kahl:
Are there any chemo-free regimens that are ready for front-line adoption?
Dr. Martin:
I think there are a lot of very active chemo-free front-line regimens. Jia Ruan from Cornell showed that R2 was very active. We've added to that acalabrutinib, and she presented that at ASH as well. It's clearly very active.
All of the BTK inhibitor plus BCL2 inhibitor data all look very promising. Are they better than chemotherapy? Equivalent to chemotherapy? I don't know yet.
But especially in somebody who is in their 50s, who's supposed to be living out their best years, I think we really do have to ask that question of whether chemotherapy is going to be in this person's best interest in the long-term, and whether even the non-chemotherapy options might have some benefits beyond just the here and now, but also decades down the road.
Dr. Kahl:
I'm going to show our viewers the schema for the TRIANGLE trial. This was presented at the 2022 ASH meeting just a few months ago. This is not yet published, but this was one of the plenary presentations at the meeting.
It was a big trial done in the European MCL Network aimed at younger patients with untreated mantle cell lymphoma. The trial had three arms. One of the arms was their standard control arm, which is three cycles of R-CHOP with alternating R-DHAP, and then autologous stem cell transplant consolidation. And then when the trial was initiated the plan was observation, but then maintenance data came out during the conduct of the trial, and so patients could receive maintenance rituximab depending upon that country's practice.
Then there were two experimental arms. The arm called A+I, ibrutinib is added to the induction therapy and for 2 years post-transplant. And then the third arm, which is just called I, the stem cell transplant is actually subtracted while the ibrutinib is added during maintenance and then again for 2 years. So it's asking an ibrutinib addition question as well as an ibrutinib substitution question.
And these were kind of the bottom line results presented at that meeting. And the failure-free survival curve that's performing the worst here is the arm that does not contain ibrutinib, so the two ibrutinib-containing arms were superior for failure-free survival.
And then when they looked at toxicity, the arm that subtracted the transplant definitely had less toxicity. So the author's conclusion was that arm C, or the third arm where ibrutinib is added and the transplant was subtracted, is looking like the most favorable treatment arm. And that gets back to what Jonathon had said a minute ago, about having this conversation about adding in novel agents and potentially then sparing the patient the stem cell transplant procedure.
Now we have the slightly awkward situation now of ibrutinib having just been withdrawn from the US market in the past month or two. And so even though this data is very encouraging, it may not be a strategy that we can pursue at this time because of availability of drug and regulatory issues.
So I'm going to get to the key clinical takeaways now. And my first one is the optimum management of mantle cell lymphoma in younger patients right now is currently in flux, truly in flux. Because we have this really exciting data that I think most of us would like to adopt, we'd love to be able to spare our patients the stem cell transplant and substitute it with a novel agent, but that novel agent isn't approved in this indication. In fact, it's not even available for mantle cell lymphoma anymore.
But I think a big emphasis in the field is going to be more of these studies where we try to deintensify the treatment. That first year treatment can be very difficult for these patients, so we would love to take away some of the intensity and difficulty of the treatment by adding in novel agents and maybe subtracting some of the high dose chemotherapy.
And this emerging data does suggest that the intensity can be reduced and we can still generate excellent outcomes. So perhaps reducing chemotherapy intensity with incorporation of novel agents. And as we mentioned, we may even get to the point where we adopt chemotherapy-free strategies, although those aren't quite ready for prime time right now.
So this brings us to the end of this case. Please see the other segments for further discussion about the latest data in mantle cell lymphoma or visit ASCOPost.com. Thank you.
