Novel Therapeutic Targets for Elderly Patients With Diffuse Large B-Cell Lymphoma

At the 2023 Lymphoma, Leukemia & Myeloma Congress in New York, New York, Jennifer Amengual, MD, Columbia University, New York, New York, discusses novel therapeutic targets and treatment strategies for elderly patients with diffuse large B-cell lymphoma (DLBCL) who are not candidates for chimeric antigen receptor [CAR] T-cell therapy. 

Transcript:

Hi, my name is Jennifer Amengual. I'm from Columbia University, New York, and today at the Lymphoma [Leukemia &] Myeloma Congress, I'll be speaking about novel therapeutic targets and treatment strategies for elderly patients who really are not appropriate for CAR-T therapy. 

As you know, although CAR-T therapy has really made a huge impact in the treatment of relapsed/refractory diffuse large B-cell lymphoma, there are many limitations to this therapy.

First, you need to be close to an academic center and need to be able to get there and stay there over time. [Second], there are toxicities that are limiting, and this could be a challenge, especially for elderly patients or those coming from outside the community. So, having therapeutic options that are not so intensive for more frail patients is something we need in our treatment strategy toolbox.

I'm very excited because I've been working with the cooperative group [Southwest Oncology Group] (SWOG) through the [National Cancer Institute] (NCI) to develop some novel therapeutics in this space. As we heard in some of the earlier talks here at the Lymphoma [Leukemia &] Myeloma Congress by scientists Wendy Béguelin and Michael Green, epigenetics is a very important target for diffuse large B-cell lymphoma. 

Recently, there've been sort of little micro-clusters of diffuse large B-cell lymphoma and some of them really rely on epigenetic drivers for disease, whereas others rely on the [Bruton’s tyrosine kinase] (BTK) pathway and activation of NF kappa B ([NF-κB]). So, with this in mind, we developed a clinical trial that could take advantage of these molecular drivers of diffuse large B-cell lymphoma and build them on top of a backbone that is tried and true in diffuse large B-cell lymphoma and is safe and easy to give to older patients.

We're using the tafasitamab/lenalidomide backbone, which has been studied in the L-MIND trial. This uses the anti-CD19 monoclonal antibody tafasitamab in combination with lenalidomide, an oral immunomodulatory drug. And together, the 5-year updates from this study have held up with robust overall response rates and overall survival over time.

But, this study, really, this combination, [is] not targeting any specific biology driving diffuse large B-cell lymphoma. So, with SWOG, we'll be using that backbone and we'll be randomizing patients to either receive zanubrutinib, which is a BTK inhibitor, to target the BTK pathway and NF kappa B. And, the other arm will be randomized to the addition of tazemetostat which is an [enhancer of zeste homolog 2] (EZH2) inhibitor, and targeting the epigenetic drivers of lymphoma.

We're hopeful with this clinical study that we will be able to improve the quality of life of patients who are elderly or frail, [who] are not candidates for CAR-T therapy or transplant. We're very hopeful that we'll also improve progression-free survival. 

We'll be doing a lot of quality-of-life studies in this clinical trial, and I think that will be really important to see how patients do long-term with this great backbone with the addition of biologically targeting agents.

Source:

Amengual J. Debate (Novel Agents): Older Patients with Aggressive Lymphoma Should Receive CAR-T cells vs Novel Agents. Presented at Lymphoma, Leukemia & Myeloma Congress; October 18-21, 2023. New York, NY