Using Lenalidomide and Rituximab, Tazemetostat, or Bispecific Antibodies to Treat Patients With Follicular Lymphoma

At the 2024 Great Debates & Updates (GDU) in Hematological Malignancies meeting in New York, Peter Martin, MD, Weill Cornell Medicine, New York, argued in favor of alternative treatment regimens over CAR T-cell therapy for follicular lymphoma, highlighting 3 managements.  

Transcript:

Hi, I'm Peter Martin from the Lymphoma Program at Weill Cornell Medicine here in New York, at the 2024 Great Debate[s] and Updates Hematolog[ic Malignancies] Meeting. 

Today, I have the pleasure of debating [with] Caron Jacobson from Dana-Farber [Cancer Institute] on the role of CAR T-cells or not CAR T-cells for patients with previously treated follicular lymphoma. In my debate, I am arguing on behalf of all the other therapies. I think we're at a very fortunate time in the history of follicular lymphoma to have a number of excellent options.

There is clearly a role for CAR T-cells in follicular lymphoma, and I think she'll do a great job of explaining what that role is. But I will do my best to explain a little bit [about] what some of the alternatives are. And really, I'll focus on 3 particular classes.

One is the R² regimen, [which is] lenalidomide [and] rituximab, one is tazemetostat, and then lastly, we have the bispecific antibodies. I think all of these have a great role [in] relapse[d]/refractory follicular lymphoma.

Obviously, there's still chemotherapy, but I think we're all moving beyond that. [With] lenalidomide [and] rituximab, I think now has a wealth of data, both from the AUGMENT and MAGNIFY studies, as well as a number of other studies that have come along, clearly showing that many people with relapsed/refractory follicular lymphoma can be managed very easily with a well-tolerated regimen that will work on average for somewhere between 2 and 5 years, depending on how heavily pretreated somebody had been previously and what their response to those therapies [was]. I think it's a great option.

I'll [also] highlight the fact that compared to rituximab alone, the addition of lenalidomide has an overall survival benefit in follicular lymphoma. It's not something that we see very often in clinical trials with follicular lymphoma, so when we see it, it's something to take note of.

Tazemetostat is a first-in-class [enhancer of zeste homolog 2] (EZH2) inhibitor. EZH2 is a histone lysine methyltransferase that essentially is responsible for [the] transcriptional repression of genes that are involved in differentiation. Essentially, [the] activity of EZH2 blocks the expression of certain genes that would be responsible for differentiation or exit of germinal center B cells from the germinal center reaction.

Its activity is therefore critical to many follicular lymphomas. Whether or not it's mutated, about 20% of patients have an activating mutation in EZH2 and [in] those patients, EZH2 probably has an even greater role. Tazemetostat is an inhibitor of EZH2, which thereby allows cells to terminally differentiate and then die. Its biggest claim to fame is how tolerable it is.

It has reasonable activity, probably in the range of 50% to 60% [with] a median [progression-free survival] (PFS) of probably about a year. Its tolerability profile [and] safety profile is quite remarkable with very few grade 3 side effects, mostly a little bit of asthenia fatigue, maybe some [gastrointestinal] upset, [with] almost no significant cytopenias, so it's a great option for patients whether they have an EZH2 mutation simply because it's so well tolerated. Then lastly, maybe most exciting, are the bi-specific antibodies.

We have now seen a handful of clinical trials showing that it's a class effect. These are all clearly effective in people with previously treated follicular lymphoma. I think the best comparator [is] the old [Phosphoinositide 3-kinase] inhibitors. Obviously, these are not available anymore for a variety of reasons, but in patient populations that were very similar to the clinical trials that got the Pi3 kinase inhibitors approved, the bispecific antibodies are now being tested. They show response rates that are at least double what we were seeing with PI3 kinase inhibitors. kinase inhibitors and progression-free survival rates that are also at least double.

The downside is that they are administered parenterally, mostly intravenously or subcutaneously, but they’re pretty easy to do. They have a unique side effect profile, which is cytokine release syndrome. That said, grade 3/4 cytokine release syndrome is rare. 

So, these are clearly moving up and taking the place of a lot of therapies, certainly chemotherapy, [and] potentially other therapies. And maybe [the] most exciting, bi-specific antibodies may be a great platform, as we've seen with rituximab, for [the] development of combinations. There are a number of combination studies ongoing in the relapsed/refractory setting, and in the frontline setting, too. With Sam Yamshon at [Weill] Cornell [Medicine], we have a clinical trial with mosunetuzumab and tazemetostat in the frontline setting, which is, I think, exciting. So, [in] follicular lymphoma [there are] lots of great options, more than ever before. Compared to what we had in the past, even novel agents in the past, some of the new novel agents are working even better. So, there [is] lots of good news.

Source:

Martin P. Debate- CAR-T Cells Should Be Rarely Used in Relapsed Follicular Lymphoma. Presented at the 2024 Great Debates & Updates in Hematological Malignancies: April 5-6, 2024. New York City, NY.