Treatment of R/R DLBCL: Beyond CAR T Therapy

EP: 1.Standard of Care for Relapsed/Refractory DLBCL

EP: 2.CAR T in Transplant-Eligible and Transplant-Ineligible DLBCL

EP: 3.L-MIND Study in R/R DLBCL

EP: 4.RE-MIND Study in R/R DLBCL

EP: 5.Phase 2B SADAL Trial in R/R DLBCL

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EP: 6.Treatment of R/R DLBCL: Beyond CAR T Therapy

John M. Burke, MD: Julio, you brought up advantages and disadvantages. We have a few more minutes to wrap things up. We now have 3 new targeted drugs approved in relapsed large cell lymphoma for patients who are either not going to get CAR [chimeric antigen receptor] T-cell therapy or they’re post–CAR T. How do you select from these drugs? What are some of the advantages and disadvantages? What’s the algorithm? Julio, why don’t you start, but let’s have everybody weigh in on the future of treatment.

Julio Chavez, MD: That’s a good question. We now have 3 new options other than CAR T: polatuzumab, tafasitamab, and selinexor. Depending on what the patient’s wishes are, 1 of the things I look at in cancer is: Is this an indefinite treatment, or is this a time-limited treatment? Polatuzumab plus bendamustine-rituximab offers a time-limited treatment of 6 cycles. Patients can achieve good PFS [progression-free survival] of almost a year. That’s attractive to patients. Many doctors are familiar with bendamustine-rituximab, so the treatment can be done in a community. That’s something I consider.

Many doctors are also familiar with tafasitamab-lenalidomide and know how to manage the adverse effects. Even though lenalidomide is not approved for DLBCL [diffuse large B-cell lymphoma] as a single agent, we are very familiar with it because we use it for other diseases like multiple myeloma, mantle cell lymphoma, and follicular lymphoma, and we frequently use tafasitamab-lenalidomide for DLBCL.

Tafasitamab is an Fc-engineered antibody. We have a few engineered antibodies approved, such as obinutuzumab. Doctors are familiar with monoclonal antibodies and how to use them. However, 1 of the disadvantages is that it’s an indefinite infusion, so treatment involves continuous infusions until disease progression. As we can see, the data look good, so many patients ended up with long-term treatment. I wish we could predict which patients will respond with limited therapy. Can we use tools like MRD [minimal residual disease] or PET [positron emission tomography] scans to determine for which patients we can stop treatment? That will be an important question.

For selinexor, we know the toxicity is novel. Selinexor is approved for multiple myeloma, so it has been around for some time. Some doctors should be familiar with the management of the adverse events like anorexia, fatigue, or nausea. The advantage is that it’s administered orally, so patients don’t have to have a line and it can be done with a local oncologist. We have to monitor closely, but it’s an indefinite therapy. We don’t know how long patients have to stay with this treatment, especially good responders. Also, we don’t know who the best responder will be—that’s something that we need to understand more from long-term data with more patients.

John M. Burke, MD: Greg, any other thoughts?

Grzegorz S. Nowakowski, MD: In relapsed/refractory DLBCL we are now moving toward what folks in myeloma have been dealing with for a long time. We have a number of agents, which are active. The question will be how to sequence, combine, and apply them to prolong patients’ lives with immunotoxicity.

Some of the unanswered questions we have are: How many patients of this particular therapy are resistant after progression, and how many of them will respond to subsequent treatment? You brought up a very good question: Are folks who are treated with tafasitamab-lenalidomide responding to CAR T therapy? Is the opposite true? We can acquire those answers from real-world data as we are using those combinations. Because, systematically, randomized studies are probably not going to be common in this space.

The other question is: If you use a certain treatment that results in toxicity, will this toxicity prevent patients from entering subsequent therapy? We know that some patients who relapse after CAR T-cell therapy are so beaten up with low counts, that they are unfortunately not candidates for clinical trials or any other therapies, which is a negative aspect of this treatment. The same could happen with some of the regimens using chemotherapy backbone. For example, bendamustine-Rituxan [rituximab] is myelotoxic and some of those patients can develop myelosuppression after the treatment, which may render them ineligible for other therapies.

We have to learn how to better sequence these drugs. A lot of the evidence regarding how to use them will be coming from real-world data. I hope as a community we can work together to generate these real-world data in order to learn the best sequence and get the most out of these therapies for our patients. Overall, this is a very welcome change. We now have more drugs than we had before that have manageable toxicity, and we’ll be able to apply them better and better over time.

John M. Burke, MD: Great. Nathan, your thoughts?

Nathan H. Fowler, MD: I think that’s all well said. As I was pointing out with selinexor and with the tafasitamab-lenalidomide, there appears to be a small tail on these curves of patients that achieve durable remissions. That tells me 2 things. One is that unfortunately, even with these newer therapies, they are not curative. The median remission times for the majority of patients are often a year or less, so patients are still succumbing to this disease. There are some hints that there may be some populations that we can cure or even achieve durable remissions. I hope that as a field, we invest in trying to find out who those patients are, because then we can really change the course of the disease, not just get a 6-month PFS.

John M. Burke, MD: How do you identify those folks or that tail? It’s tough.

Nathan H. Fowler, MD: Yeah.

John M. Burke, MD: Relapsed large cell lymphoma has never been a chronic disease, unlike some of the other blood cancers we treat. It has a terrible prognosis and patients unfortunately can die quickly. There are occasional patients who are slow progressors and live a long time, but they are the minority.

You wonder with all these new targeted options, are we going to be able to string these together, 1 after the other? I don’t know. I mean, they are all now suddenly available at the same time, and there probably are not many people in the world who have been through 1 after the other, probably 0 or very few. If we string these together, will we be able to turn this into a more chronic disease than it’s been so far? It’ll be interesting to see. I would echo the thought that some real-world data might answer that question.

It’s good that we raise these questions. For a change in relapsed large cell lymphoma we have a lot of new options for our patients. It’s a great position to be in. We’re seeing more and more hope in a disease that has been tough to treat. When CAR T-cell therapy first became available, I said suddenly there’s hope where previously there was none. Now we’re seeing more of that with some of these targeted therapies in the relapsed setting.

Thank you all for this excellent discussion. We hope that you found the information to be valuable to your clinical practice. Thank you for watching the OncLive® News Network®.

Transcript Edited for Clarity