The Role of CD19 in the Targeted Treatment of Relapsed/Refractory DLBCL - Episode 8

The Future of DLBCL Treatment

Mazyar Shadman, MD, MPH, and Brian T. Hill, MD, PhD, consider potential treatment options for relapsed/refractory diffuse large B-cell lymphoma in the future.

Mazyar Shadman, MD, MPH: Well, talking about future directions, for both TAFA [tafasitamab] as a CD19 antibody and also Lonca [loncastuximab tesirine] as a CD19 ADC [antibody-drug conjugate], we should expect a lot of combination studies that may happen, right? We can, in theory, combine it with any chemotherapy backbone and a lot of novel agents.

Brian T. Hill, MD, PhD: Yes, I agree, there are still other medications and pathways that have shown some activity. We all are familiar with the BTK [Bruton tyrosine kinase] inhibitors that are tremendously successful for CLL [chronic lymphocytic leukemia] and mantle cell lymphoma. So far they haven’t panned out in the large phase 3 PHOENIX trial. We had R-CHOP [rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone] plus or minus ibrutinib, and maybe because of some of the cardiovascular toxicities in older patients, it wound up being on balance a negative trial. But there are other better tolerated BTK inhibitors that are being explored in this setting, in diffuse large B-cell lymphoma. Clearly it works better in the ABC [activated B-cell] subtype, and even within the ABC subtype, there are more distinct molecular subtypes that have been recently identified through more advanced molecular profiling, and these are the subtypes that may preferentially benefit from B-cell receptor pathway inhibition.

Another one out there that’s been studied is venetoclax. We know that BCL2 overexpression is a major part of B-cell pathogenesis of lymphomas, particularly follicular lymphoma and germinal center-derived diffuse large B-cell lymphoma. I’m sure you’re aware, and maybe the audience is aware, that the big randomized phase 3 trial done through the cooperative groups was targeting double-expresser lymphomas and comparing R-CHOP with or without venetoclax. It will be interesting to see how that turns out, because venetoclax may be a partner for some of these novel agents as well.

Mazyar Shadman, MD, MPH: To wrap up the future directions and related to CD19, there are, of course, in earlier phases natural killer [NK] cell therapies, like NK therapies targeting CD19-positive lymphomas in general, and large cell lymphomas are one of the diseases that most needs a CAR [chimeric antigen receptor] NK product or also targeting. We’ll just need to wait for those studies to become more mature and see where the treatment landscape is going. Of course, there are allogeneic CAR products as well. Any comment on those?

Brian T. Hill, MD, PhD: I agree. I share the enthusiasm for the potential for off-the-shelf CAR T-cell therapies, which may obviate this whole requirement for self-collection, apheresis, manufacturing, which has to be done in each individual patient. It’s going to take time to show that an off-the-shelf approach is as good as an autologous CAR T cell. But there may be a group of patients, particularly those who had CAR T-cell treatment and didn’t achieve durable remission, where off-the-shelf is the best approach, particularly because of the impact on the immune system of all the prior therapy up to that point, which often renders autologous CAR T cells difficult to administer.

Mazyar Shadman, MD, MPH: I think this was a great discussion. I definitely learned a lot. I wonder, let’s say in September 2021, in the patient with relapsed lymphoma, maybe we can both talk about our standard of care approach and see where these new agents fit in that treatment landscape.

Brian T. Hill, MD, PhD: I think for the rest of 2021, we’re still going to be approaching fit, relapsed patients with diffuse large B-cell lymphoma as potential candidates for curative therapy with autologous stem cell transplant, usually after demonstrating chemotherapy sensitivity from second-line therapy. For the rest of the year, for patients who are sensitive to chemotherapy, R-ICE [rituximab, ifosfamide, carboplatin, etoposide] or platinum-based therapy, transplant I think still should be considered standard of care. Once we see the data of the randomized trials, I think the community will probably vote with our feet and vote with our actions in terms of how compelling we think it is to move CAR T in front of auto transplant for all patients. I would keep in mind that the studies were really targeting high-risk patients, who relapse within a year of diagnosis or treatment failure. And many times we see patients who are coming in with later relapses—maybe they had prior follicular lymphoma. In those settings, if you have good chemotherapy sensitivity and you’re in complete remission after some second-line therapy, autologous stem cell transplant has a proven track record of being curative therapy. So I’m not sure it’s going to be completely supplanted by CAR T.

In terms of the novel agents and the CD19-targeted drugs we discussed, a lot of it will depend on whether polatuzumab really is adapted as part of frontline therapy as we anticipate it may, but we’re eagerly awaiting more details on the POLARIX study. But certainly, for patients who are not candidates for CD19-targeted CAR, I think the CD19-targeted monoclonal antibody tafasitamab with lenalidomide or loncastuximab tesirine as a single agent are both very attractive options.

Mazyar Shadman, MD, MPH: That was a great summary. I would 100% agree. When I look at auto transplant and CAR T, they’re 2 potentially curative treatments. So for me to give one up, I have to have very strong data suggesting that, OK, auto is out. I think it’s not a matter of which one is better or the winner, it’s a matter of what sequence provides the best outcome for the patient. So yes, in relapsed patients, I agree, if somebody is eligible for a transplant, at least until we get the data from the randomized trials, auto transplant would be my recommendation. For those who are not transplant eligible, we will of course try to get them to CAR T therapy or the TAFA/LEN [tafasitamab and lenalidomide] combination is also a very viable approach either as a therapy they would continue until progression. Or sometimes patients, after being on treatment for a while, their comorbidity changes or their disease burden changes and maybe they become eligible for other treatments.

CD19 Lonca or CD19 ADC is also an important drug. I expect to use it more and more as polatuzumab moves to the first line, and if it does, I think we’ll be using more Lonca before CAR to make patients stable and to use it as a bridge therapy or even after CAR. CD19 loss is not the most common reason for CAR T failure, so the CD19-targeted therapy would be an option even after CAR T. And polatuzumab is there, we’ll see where it sits, somewhere between first and third line in the next 2 years. We didn’t talk about selinexor, that’s something that’s also approved, and there may be a patient who benefits from that. But the safety profile is something to think about.

I think that will be my summary for treatment. Again, thank you very much, Dr Hill. This was a great discussion. Thanks to our audience for watching this Targeted Oncology™ presentation on “The Role of CD19 in the Targeted Treatment of Relapsed/Refractory Diffuse Large B-Cell Lymphoma.” We hope that you found this discussion useful and informative.

Brian T. Hill, MD, PhD: Thank you.

This transcript has been edited for clarity.