The Evolving Landscape in Mantle Cell Lymphoma - Episode 4

Lenalidomide and Bortezomib for Mantle Cell Lymphoma

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John P. Leonard, MD: We’ll move into the second part of our discussion, and we’ve talked in the past about the standard therapies, but I think the tremendous excitement in mantle cell lymphoma is the targeted treatments we have. Every meeting I go to, there’s a new agent in just about every class that’s really coming along.

I want to start with Krish, and before we get to BTK [Bruton’s tyrosine kinase] inhibitors, which I think are the most commonly used drugs now, at least in the relapsed setting, there have been a number of different targeted drugs in particular. The first nonchemotherapy, nonantibody drug was bortezomib going back several years, and then lenalidomide also came along. Tell us about your use, Krish, in your patients of either lenalidomide or bortezomib, or both. And anything that’s guiding your therapy in that regard.

Krish Patel, MD: Sure. I can’t say that I use much bortezomib in the relapsed/refractory setting, probably due to the availability of other therapies that we’ll talk about, but just to recognize that VR-CAP [bortezomib, rituximab, cyclophosphamide, epirubicin, prednisone] is perhaps used in Europe and can be a frontline regimen for mantle cell lymphoma.

But lenalidomide is a drug that I use. Occasionally we do have patients for whom there are challenges of giving some kind of chemotherapy, even bendamustine-based chemotherapy, for which we have used R-squared [lenalidomide and rituximab] based on the data that have been developed by your group, Dr Leonard, and others. That’s a regimen that I’ve used. And then R-squared [lenalidomide and rituximab] perhaps in the relapsed setting and certain settings where we’re trying to maybe bridge patients from one type of a therapy, to say a cellular therapy or a transplant perhaps, is where we primarily use lenalidomide.

To remind folks, the data regarding lenalidomide include both as a single agent and R-squared [lenalidomide and rituximab], and commonly I would use it in combination with rituximab if I was going to use it, rather than as a single agent.

John P. Leonard, MD: I’ll occasionally use VR-CAP [bortezomib, rituximab, cyclophosphamide, epirubicin, prednisone] on a patient for a variety of reasons. It tends to be reasonable, not my upfront go-to regimen, but on occasion I’ve used it with good response. It’s one of the few areas where there’s an overall survival benefit in mantle cell lymphoma. Tycel, Andy, do you ever use that regimen or some bortezomib combination?

Tycel Jovelle Phillips, MD: I personally don’t.

Andrew D. Zelenetz, MD, PhD: I occasionally use VR-CAP [bortezomib, rituximab, cyclophosphamide, epirubicin, prednisone], not very often. Occasionally there’s a patient who’s not good for this or not good for that. And then VR-CAP [bortezomib, rituximab, cyclophosphamide, epirubicin, prednisone].

I have to say, recently I had to start a patient, and I was really reluctant to give them bendamustine in the middle of COVID-19 [coronavirus disease 2019]. I started them on VR-CAP [bortezomib, rituximab, cyclophosphamide, epirubicin, prednisone]. There’s less T-cell suppression. You get tremendous long-lasting T-cell suppression with bendamustine-based regimens, but not with VR-CAP [bortezomib, rituximab, cyclophosphamide, epirubicin, prednisone]. It’s a little more like giving CHOP [cyclophosphamide, doxorubicin, vincristine, prednisone] in terms of the T cells. That’s one situation where I found that it had a role.

John P. Leonard, MD: Tycel, how about you and lenalidomide, your use of that agent?

Tycel Jovelle Phillips, MD: I have used quite a bit of R-squared [lenalidomide and rituximab], mostly up front. Originally, in most of my post-BTK failures earlier on, I did use a lot of R-squared [lenalidomide and rituximab], but I wasn’t having a lot of good responses with that. I will use it if it fits, based on toxicities, in BTK-naїve patients, but I tend to defer using it quite often in most patients who’ve already been exposed to a BTK inhibitor, because the responses I had previously were not so good.

John P. Leonard, MD: Our group recently updated a small study at ASH [the American Society of Hematology annual meeting] with about 7 years of follow-up, of lenalidomide, rituximab up front. Patients tended to taper their therapy one way or another for the long-term nature of things, but most of them were still in remission with a 7-year median follow-up. That being said, obviously that needs to be compared to other approaches. Lenalidomide, rituximab is being looked at in the ongoing ECOG-led study as a maintenance regimen after a bendamustine-based treatment. We don’t have those results yet, but we’ll see the impact there. Andy, you all had a study presented at ASH also that included lenalidomide as upfront therapy, if I’m not mistaken.

Andrew D. Zelenetz, MD, PhD: Yes.

John P. Leonard, MD: Tell us about that and your experience with lenalidomide in general in mantle cell.

Andrew D. Zelenetz, MD, PhD: Our frontline study was RL-CHOP [rituximab, lenalidomide with cyclophosphamide, doxorubicin, vincristine, prednisone] induction for 4 cycles, followed by rituximab, HIDAC [high-dose cytarabine], and then 6 months of rituximab, lenalidomide. Patients did not receive consolidation with high-dose therapy and stem-cell rescue. Technically, we didn’t meet our 60% 3-year disease-free survival, which was the primary end point. However, if you eliminate patients with TP53 aberration, we did. It is a very highly effectively, very good regimen if you don’t have a TP53 mutation.

We had progression of all our TP53 patients except for 1, who is one of my patients, luckily for him. But otherwise, it seems to be a pretty good regimen. The other place I use it, and I agree with Krish, I do not use it as a single agent, I always combine it. I’m always tempted to try to combine it with obinutuzumab, but I stick with rituximab. I’ll use it in patients without TP53 mutations if they fail a BTK inhibitor or venetoclax. The thing about the regimen, as you know, if they’re responding early, it does not take months to know if they’re responding. If they’re not responding by the second month and you’re not seeing evidence of shrinkage, you can move on pretty quickly.

John P. Leonard, MD: The point you make about your clinical trial, and we’ve touched on others, when you think about it, interpreting data in mantle cell lymphoma is going to get harder and harder for some trials because we’re going to be either preferentially enrolling TP53-mutated patients in certain types of trials, and preferentially not enrolling certain types of patients in other types of trials. So, the outcomes compared to trials that didn’t even know about that and incorporate that a few years ago, just based on who ends up, based on our biases of, “Well, you wouldn’t put a TP53-mutated patient on a chemotherapy trial any more would you?” That’s going to be interesting, our interpretation of data.

On the other hand, we’re putting a lot of the more challenging patients with these mutations in BTK, venetoclax upfront trials, as an example. I think it’s going to be very interesting to see how we figure out all of that. Hopefully that will lead to better therapy all around, but it may be a lot more complicated to try to figure out beyond what we’ve already talked about.

Transcript Edited for Clarity