The Role of CD19 in the Targeted Treatment of Relapsed/Refractory DLBCL - Episode 3

CD19 As a Targeted Agent in CAR T Cell Therapy for R/R DLBCL

Drs Shadman and Hill discuss using CD19 as a targeted therapy option in CAR T cell therapy for relapsed/refractory diffuse large B-cell lymphoma.

Brian T. Hill, MD, PhD: Do you want to talk about some of the randomized trials that have recently been reported, that we have seen some press releases from.

Mazyar Shadman, MD, MPH: Of course, there are 3 CAR T [chimeric antigen receptor] products approved for diffuse large B-cell lymphoma after 2 prior lines of therapy. All 3, by the way, target CD19, and that takes us to our discussion that CD19 has always been an important target, but now we have agents that we can go for it. With the CD19-targeted CARs, we have axicabtagene ciloleucel, or axi-cel; lisocabtagene maraleucel, or liso-cel; and tisagenlecleucel, or tisa-cel. Basically, the 3 are available for patients who have had 2 lines of prior therapy.

The question is, can we bring these CARs in the second line, especially for patients who need it most? For the patients who don’t respond to the first-line treatment that we mentioned, R-CHOP [rituximab, cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone] or dose-adjusted R-EPOCH [rituximab, etoposide, prednisone, vincristine, cyclophosphamide, hydroxydaunorubicin hydrochloride], those who relapse within the first 12 months have an extremely poor outcome. The idea of these randomized studies was to directly send these patients to CAR-T therapy as the investigational arm, or just continue the standard treatment: chemotherapy followed by autologous stem cell transplant rescue.

We don’t have the results. We heard from the axi-cel [axicabtagene ciloleucel] study, the ZUMA-7, and the liso-cel [lisocabtagene maraleucel] study, the TRANSFORM study, that they met the primary end point of essentially survival. We need to look at the data when they’re presented or published, hopefully in the near future. But that tells us that a CD19-targeted therapy is coming potentially to the second line for CAR T. That will change the treatment landscape when we have a cohort of patients who receive immunotherapy after only 1 line of chemotherapy.

Talking about CD19, I mentioned that for the second line, this study is anticipated to lead to FDA approval.

Brian T. Hill, MD, PhD: It’s important to recognize that CAR T treatment does have some significant logistical barriers: you have to go to an authorized treatment center that’s experienced with CAR T. You must go through leukapheresis for collection of cells. You have to wait several weeks for manufacturing, during which time sometimes the disease can progress and even preclude further treatment. There are significant toxicities with the –cel therapies you mentioned. Axi-cel [axicabtagene ciloleucel] has high rates of cytokine release syndrome and neurotoxicity, which requires inpatient management most often. Liso-cel [lisocabtagene maraleucel] and tisa-cel [tisagenlecleucel] also can have cytokine release syndrome, they may have less neurotoxicity, but these are toxicities that in some ways limit the number of potential patients who can receive the therapy based on age and comorbidity, as well as geographic location. That’s important to consider.

One final thing before we jump into the CD19-targeted therapies, is that we do have several approvals of novel agents for treatment of diffuse large B-cell lymphoma in relapse, and polatuzumab-vedotin recently was approved in combination with bendamustine rituximab for relapsed or refractory diffuse large B-cell lymphoma. Our clinical experience with this agent is that it can often have activity with relatively mild adverse effects. It targets CD79b, which is another B-cell receptor distinct from the targets of Rituxan and distinct from CD19. There’s some appeal to use polatuzumab in this setting, and I’ve found it to be a generally well-tolerated agent. I’m curious if you’ve had similar experience.

Mazyar Shadman, MD, MPH: I agree. It has been an important part of treatment, especially for patients we’re trying to get to the CAR T treatment. As you mentioned, a lot of these patients do need active treatment either as bridging or while we’re waiting for their arrival to the service or while we’re waiting. We have been using polatuzumab combination with good responses.

Brian T. Hill, MD, PhD: Because we’re talking about press releases, and I suspect you saw that press release as well—it’s hard to practice medicine by press release—of a large randomized phase 3 trial called the POLARIS study, in which R-CHOP [rituximab, cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone] was compared head to head with polatuzumab-vedotin in combination with R-CHP [rituximab, cyclophosphamide, hydroxydaunorubicin hydrochloride, prednisone]. The word on the street is that it’s a positive study in meeting its primary end point of progression-free survival. I don’t have any more insight into that. But I suspect that this very well could be changing the frontline treatment for potentially all patients with diffuse large B-cell lymphoma. I’m curious to see how you think that may be rolled out.

Mazyar Shadman, MD, MPH: I have no additional information other than reading the press release. Progression-free survival is a meaningful end point for frontline large cell lymphoma. We need to look at the toxicity profile. As long as there’s nothing concerning, it’s expected that we’ll have significant change in our first- and second-line treatment of large cell lymphoma in the next few months, depending on—we keep repeating this—when we see the data and if these treatments are approved. It’s an exciting time for patients and for those of us who work in this area.

Going back to that polatuzumab and BR [bendamustine, rituximab] question, 1 practical point for patients who are being referred for CAR T therapy is that we try to avoid bendamustine close to leukapheresis. Even if we use polatuzumab-based therapies, we tend to time it appropriately or wait until after collection to do that, just in parentheses.

Brian T. Hill, MD, PhD: I agree. There’s a lot of concern about the impact of bendamustine on the T-cell fitness. When you’re trying to manufacture a cellular product from a patient and they’ve had bendamustine, there are emerging data to suggest that this is probably not the best thing for T-cell fitness.

Mazyar Shadman, MD, MPH: To wrap up the CAR T part, we have another potentially curative therapy, looking at different studies and products. There’s probably 30% to 40% long-term remission from these, and toxicity profiles are different depending on which product we look at. But there are still patients who either have relapse after these treatments or don’t respond. In addition, as you said, there are a lot of logistical hurdles that patients need to overcome.

This transcript has been edited for clarity.