John P. Leonard, MD: One of the most challenging consults in my practice, and I’m sure yours as well, is the patient with newly diagnosed mantle cell lymphoma. You’re assessing them, you’re deciding what treatment—do they even need treatment? What’s the prognosis? Tycel, take us through how you look at a new patient, and once you have some of the data we’ve talked about, what’s your thought process as far as approaching their treatment?
Tycel Jovelle Phillips, MD: I think you adequately touched on some of the issues we have. Part of the problem is there’s no standard care for mantle cell lymphoma, and you will see some degree of regionality as far as treatment choices. But generally, when I see a newly diagnosed patient, some of the things I’ll take into account obviously are symptoms. I think from the paper that originally came out of your institution, we’ve shifted a bit from treating every patients with mantle cell lymphoma who walks in the door and take into account whether these patients are symptomatic.
At the University of Michigan, what we will do now is, for all patients who don’t have a blastoid variant, we will basically observe those patients unless there’s an indication to treat, with the understanding that most of those patients will need some sort of treatment within a short time from diagnosis. But explaining to the patients that we don’t have any evidence that that will impact overall outcome, it does provide some reassurance for those patients.
Once they do need treatment, some of the factors that have already been touched on, especially TP53 mutation, blastoid variant, Ki-67, do come into play.
For those with known TP53 mutations, I don’t think anybody knows the right way to treat those patients. Most of the literature suggests that those patients probably don’t benefit from high-dose chemotherapy and transplant. So standardly, if possible those patients have been directed into clinical trials, hopefully utilizing some sort of novel agents. Outside of novel treatments, I’ve been trying to use some of the approved agents in a relapsed/refractory setting up front, such as ibrutinib, zanubrutinib, acalabrutinib, or even R-squared [lenalidomide and rituximab] in this patient population, given the short PFS [progression-free survival] that has been noted with transplant that’s come out of the Nordic Lymphoma Group trials.
Standardly outside of that, I mean it’s usually the idea of age and fitness. If it’s a young, fit patient, again outside of a clinical trial setting, we will still treat with a Nordic regimen with a plan of trying to get those patients to transplant.
With the current ECOG study now, I’m encouraging most of the patients who do get high-dose chemotherapy to enroll in that study, which will randomize patients to transplant plus maintenance versus maintenance if they are MRD [minimum residual disease]-negative after induction therapy.
For those patients who are not fit or eligible for transplant, we generally use bendamustine. In the era of COVID-19 [coronavirus disease 2019], that has taken a bit of a twist out of concern for the immunodeficiency that we know that comes with bendamustine-based regimens. So in that time, we’ll probably lean into more R-squared [lenalidomide and rituximab] in patients who are unfit for aggressive therapy, knowing that the data at least presented now appear to suggest that regimen is very effective up front in patients with mantle cell lymphoma.
John P. Leonard, MD: Andy, I want to go to you. Tycel referenced the watch and wait. Are you watching and waiting with most patients? How do you decide that? And then, what are your 2 big buckets of younger, fitter patients? How do you generally approach them? And then the older, more frail patients, how do you generally approach them?
Andrew D. Zelenetz, MD, PhD: I completely agree with Tycel that there’s a lot of regionalization. We look for certain biomarkers. Non-nodal leukemic phase and GI [gastrointestinal] tract only, we typically are monitoring those with active surveillance.
The other patients, even if they’re nodal—though they are frequently not nodal—are patients with IgHV mutation. Like CLL [chronic lymphocytic leukemia], mantle cell lymphoma falls into IgHV-mutated and unmutated, and like CLL, unmutated has a more aggressive course, mutated has a less aggressive course. The unmutated cases, we tend to commit to treatment, particularly if they’re younger, have proliferation fractions of greater than 30%, clearly if there’s pleomorphic or blastic mantle cell.
But we’re also viewing this through the lens of whether there is a TP53 aberration. Right now, as I mentioned before, there’s some controversy about the importance of TP53 deletion, but there’s no controversy whatsoever about the role of TP53 mutation. That has a big impact because the Nordic Group trials show that you shouldn’t transplant these patients up front, and the reason to transplant someone with mantle cell lymphoma up front is not to cure them, it’s to give them a long durable remission. And they’re not going to have a long durable remission if they’re TP53 mutated. We have to take all of this stuff into account. I probably observe fewer patients than Tycel, but we observe plenty of patients—probably one-third of the patients get observed.
John P. Leonard, MD: Right. Krish, anything to add there?
Krish Patel, MD: No, very similar. I will say that those buckets of fit versus not-fit, sometimes you find that slim bucket in the middle, somebody who’s in their late 60s, and that’s a space where we’ve been kind of combining the approaches of bendamustine-based therapy with lower-dose cytarabine, the R-BAC500 [rituximab, bendamustine, cytarabine] regimen. That’s been a regimen that I think allows us to treat that unique subgroup of patients. And then, of course, their transplant eligibility is going to be maybe a little different, but we’ve had relatively good outcomes using that regimen as well.
Transcript Edited for Clarity