Braunschweig Makes the Case for Earlier Use of CAR T-Cell Therapy in DLBCL

CAR T-cell therapy has shown robust responses and curative potential in patients with diffuse large B-cell lymphoma, regardless of cytogenetics or age.

Ira Braunschweig, MD

CAR T-cell therapy has shown robust responses and curative potential in patients with diffuse large B-cell lymphoma (DLBCL), regardless of cytogenetics or age, said Ira Braunschweig, MD, who added that the early use of tocilizumab (Actemra) and steroids has made it all the more likely that the modality could be moved to the up-front setting.

“It’s important to distinguish [between] the options a patient with aggressive lymphoma has, [particularly when it comes to] distinguishing between options that could help them versus options that can cure them, and CAR T-cell therapy stands alone as an option that could cure patients,” said Braunschweig.

In an interview with OncLive® during the 2020 Institutional Perspectives in Cancer webinar on hematologic malignancies, Braunschweig, director of the Stem Cell Transplant Program, clinical program director of Hematologic Malignancies at Montefiore Medical Center, and associate professor in the Department of Medicine (Oncology) at Albert Einstein College of Medicine, discussed the utility of CAR T-cell therapy in lymphoma and the rationale behind moving the modality to the up-front setting.

OncLive®: How do tisagenlecleucel (Kymriah) and axicabtagene ciloleucel (axi-cel; Yescarta) compare with one another in terms of efficacy and tolerability?

Braunschweig It’s difficult to say, as far as efficacy, which [product] is better than the other because they’ve never been compared head-to-head and probably never will be. It does seem that tisagenlecleucel [can be given as an] outpatient [therapy], which is nice.

What is known about how patients with high-risk genetics respond to CAR T-cell therapy?

Based on the data we have so far, we know that [these patients] respond very favorably [compared] with other subgroups. A [patient with] double hit or triple[-hit lymphoma] is not someone who will not respond [to the therapy], which is extremely encouraging.

What has been the experience with axi-cel at Montefiore Medical Center?

We learned that axi-cel is as good as advertised, and [comparable with] what we saw on the clinical trial. Patients do not have to be in perfect condition to be able to tolerate and benefit from [the product], which is extremely important—not every one of our patients is a marathon runner.

How do responses differ between younger versus older patients?

There was no difference between the older and younger populations [in terms of] response, which is also very encouraging, because we treat a lot of older patients. [Knowing] that [the product] is effective in that group [of patients] as well is great.

How are you applying these data to practice?

[CAR T-cell therapy is a fantastic option for] a [patient with] primary refractory or multiply relapsed [disease] or [a patient with] relapsed [disease] posttransplant. For a certain number of patients, [CAR T-cell therapy] will likely be a curative therapy. [CAR T-cell therapy] has been truly a game changer for these patients.

What are some of the factors that help you determine whether to pursue autologous transplant, allogeneic transplant, or CAR T-cell therapy?

For a chemotherapy-sensitive patient, autologous transplant is still the standard of care, largely, in part because we have decades of experience with those patients. When we get to a primary refractory patient, it would seem that CAR T-cell therapy is the clear choice. Only a few years ago, we used to offer a [patient with] relapsed [disease] post-autologous transplant an allogeneic transplant, and there are data that that treatment could be curative for such a patient.

However, we have to recognize that there is a lot of graft-versus-host-disease and ongoing health issues [that accompany] allogeneic transplant. With CAR T-cell therapy, if [patients] get through the first couple of weeks of toxicities, there’s a lot less of a concern about their long-term health. In fact, with CAR T-cell therapies, data are coming out that we can treat these toxicities effectively without worrying about abrogating the antitumor response, which makes it even more attractive.

What approaches are being using to mitigate the toxicities of CAR T-cell therapy?

There are data that early tocilizumab can, at the first fevers, abrogate the CRS toxicity without abrogating the antitumor effect. Even [early use of] steroids, which are lymphocyte killers, is supported by data for neurotoxicity and does not seem to abrogate the antitumor response. If we could [treat patients even] earlier [with these interventions] and not have them become confused, or [enter a certain coma level], that could be even better.

What emerging approaches could be investigated with this modality?

Once we know that it’s extremely effective for [patients with] relapsed/refractory [disease], and we know that it’s effective for [patients with] high-risk genetic genetics, perhaps we could offer those patients up-front CAR T-cell therapy after some cytoreduction with chemotherapy as a consolidation approach.

Are there any concerns with moving CAR T-cell therapy up front?

If we know a patient has a high risk of relapse, it makes perfect sense to offer [CAR T-cell therapy] to them up front. It’s an effective therapy for those patients. If we know that they’re ultimately going to fail [treatment], then why wouldn’t we [offer it to them up front? For those patients that could be cured with R-CHOP, R-CHOP is still probably the way to go. [We’ll have to] figure out who’s not going to do well with R-CHOP [and may be a candidate for CAR T-cell therapy up front].

What efforts are being made to overcome resistance mechanisms to CAR T-cell therapy?

[There’s research evaluating] dual targets. Can we combine novel agents with CAR T-cell therapy to increase its effectiveness? Maybe we’ll offer more than one infusion of CAR T-cell therapy. If so, there might be a tandem CAR T-cell therapy one day. Those things are being looked at.

What is your take-home message to your colleagues?

The most important point is that a [patient with] multiply relapsed [or] even refractory lymphoma [should be considered for CAR T-cell therapy] as a curative option for treatment.

We have a robust CAR T-cell therapy unit. We’ve treated the first [patient] in the nation with the FDA-approved [brexucabtagene autoleucel (Tecartus)] for mantle cell lymphoma with excellent results, and we have ongoing trials with CAR T-cell therapy in multiple myeloma as well.

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