Choosing Treatment Options for Patients With R/R DLBCL Ineligible for CAR T-Cell Therapy

At the 2023 Great Debates & Updates in Hematologic Malignancies in New York, New York, Jennifer Amengual, MD, Columbia University, New York, discussed the process of choosing among non-CAR-T-cell treatment options for patients with recurrent aggressive lymphoma, particularly diffuse large B-cell lymphoma (DLBCL). 

Transcript: 

Hi. My name is Jennifer Amengual. I'm a lymphoma specialist at Columbia University in New York, and I'm here at the Great Debates meeting. 

Today, I'll be talking about choosing treatment options for relapsed/refractory diffuse large B-cell lymphoma for patients who are not eligible for CAR-T, or [for whom] you're not thinking about CAR-T in that particular setting. When I think about treating patients who've relapsed from diffuse large B-cell lymphoma, the first thing I start thinking about is our goals and where they are in their disease stage. So, not really the stage of their disease, but where they are in their treatment course, and what our goal will be with that next treatment.

There's many different types of goals. There's some goals where we're trying to get to transplant. There's some goals where we're just trying to keep the disease at bay and keep the quality of life high. There are some goals where we're trying to consolidate or improve the effects of the last treatment. Those are some of the things that I think about in terms of where [the patients] are in their disease course.
I also think about the patient themselves. What are their goals? How fit or frail [are they] as a patient? And that also leads to what will be the next step after the treatment that I'm giving.

I also try to take into consideration the disease biology. Although we always like to think about disease biology when treating cancers for lymphomas, especially diffuse large B-cell lymphomas, we have very few treatment options that are directed at biological drivers of disease. So that's something that we're also trying to incorporate. And when we can, we try to utilize biologically targeted therapies.

So, for the first step, let's say a patient just relapsed after chemotherapy and we're thinking about bridging them to a transplant. In that setting, there's a very nice study that's recently been presented at ASH called the PolaR-ICE study. This study incorporates polatuzumab plus the salvage therapy rituximab plus ICE chemotherapy. They found that this was very well-tolerated and that a very high percentage of patients, especially those who had relapsed rather than those who were refractory, were able to go onto autologous stem-cell transplants and obtain complete remissions. 

So, this is something we're starting to think about as a way to incorporate a targeted treatment that's been proven to work in the refractory settings such as polatuzumab in with salvage chemotherapy, to give us a better opportunity of complete remission heading into transplant. That's for patients who are very robust, who haven't had a transplant yet that we're thinking about going to that stage. 

Now how about patients perhaps who've already had a transplant, [who are] maybe not so robust, a little bit frail? We have many different treatment options now. We're lucky with that for diffuse large B-cell lymphoma. We have available to us tafasitamab plus lenalidomide. We have polatuzumab plus bendamustine, we have selinexor, to name a few. And so, lonca-T [loncastuximab tesirine] is another one. So, about 4 approved therapies in this setting.

Some of the things that we try to think about are: How aggressive do we want to be? Do we want to incorporate chemotherapy or do we want to remain completely chemotherapy-free? 

We think about what they received in the first line. So, if someone had received polatuzumab in the first line, you might not treat them again in the second or third line with that right away. And so, these are some of the things that we think about. 

We also think about, well, we somehow want to go to CAR-T in the future. And in that scenario, there's sort of conflicting or not clear data at this point, whether targeting CD19 would interfere with going to CAR-T. These are some things that we are considering at this stage. 

If you want to get a rapid response, and the patient has a great performance status, we might think about using polatuzumab plus bendamustine. This incorporates chemotherapy. It does have a very high rate of complete remissions and is very well-tolerated. That combination, however, can lead to cytopenias or low blood counts, so we have to be a little bit cautious.

If we want to be a little bit more gentle, perhaps, go a little bit slower, lenalidomide plus tafasitamab works great. And this is a chemo-free option where tafasitamab targets CD19 and lenalidomide is an immunomodulatory drug that's been very active in lymphomas, especially diffuse large B-cell lymphoma.

I think these are usually the 2 that I reach for first, and [then] gauge where we want to go and what might be the next steps. Now what if a patient had already received CAR-T therapy and maybe they've just relapsed on the heels of CAR-T? 

In that setting, we've learned that chemotherapy really is not useful, and using targeted therapies can really augment sometimes CAR-T by specific antibodies have really been shown to perhaps augment the activity of CAR-T therapy. And there's a very nice study that's recently been activated that enrolls patients with either stable disease or partial responses after CAR-T to mosunetuzumab, polatuzumab, or mosunetuzumab plus polatuzumab, or just observation.

And if someone then progresses, they can cross over to one of those other treatment arms. 

I think this is a really great strategy. Polatuzumab has been shown to be very effective in the post-CAR-T setting, and this can really help guide us in how to maybe capitalize on CAR-T that might still have some activity but is not really getting the job done.

Now when thinking about biology, we know in diffuse large B-cell lymphoma, it's broadly broken down between the germinal center subtype and post-germinal center subtype, or activated B-cell subtype. And now, these disease types are getting broken down to smaller and smaller little clusters. And we're working to try to find biologically targeted agents. 

Lenalidomide we know is effective in the non-germinal center subtype. So, if we're really trying to target that biology, tafasitamab plus lenalidomide might be one strategy. We used to use BTK inhibitors a lot in this setting, and zanubrutinib has recently been studied in this setting as well and has shown some nice activity and is very safe and well tolerated. So, that could be a strategy. And perhaps zanubrutinib using combinations in the future might be a great opportunity to capitalize on the non-germinal center biology.

For the germinal center biology, we know there are recurrent mutations in epigenetic modulators. There aren't drugs approved for diffuse large B-cell lymphoma in that space, but there are other approved agents, epigenetic agents, and we're running a very nice clinical study that combines tazemetostat, which is an EZH2 inhibitor, where there's EZH2 mutation is very common in diffuse large B-cell lymphoma. And belinostat, which is an HDAC [histone deacetylase] inhibitor, where there's many mutations in the histone acetyl-transferases, p300, and CREBBP [cyclic adenosine monophosphate response element binding protein.] And we're looking at this combination in relapsed/refractory diffuse large B-cell lymphoma as a way to target the germinal center biology.

I think we're fortunate that we have a lot of treatment strategies. I think it's really important to think about clinical trials in this setting. There are many clinical trials that are active and many of these are using targeted therapies and in novel combinations. I think we have to think very carefully about enrolling our patients in trials as this is how we learn how to best incorporate these therapies. 

No one really knows the best sequence. So, these are things we're trying to work out. But [overall,] trying to keep in mind the goals of the patient is the main way I think about treatment for these patients with refractory diffuse large B-cell lymphoma.

Source: 

Amengual, J. How Do We Choose among non-CAR-T Options for Patients with Recurrent Aggressive Lymphoma? Presented at Great Debates & Updates in Hematologic Malignancies Conference; April 13-15, 2023; New York, NY.