Real-World Experience With Brexucabtagene Autoleucel for MCL in the United States

In this interview, Amer Beitinjaneh, MD, MPH, MSc, Sylvester Comprehensive Cancer Institute, University of Miami Miller School of Medicine, Florida, discusses results from a study evaluating the safety and efficacy of brexucabtagene autoleucel (brexu-cel) in standard of care practice for patients with relapsed/refractory mantle cell lymphoma (MCL) among centers in the US Lymphoma CAR-T Consortium.

These results were presented at the 2021 ASH Annual Meeting.

Watch the video version of this interview on Oncology Learning Network.

What existing data led you and your coinvestigators to conduct this research?

MCL is an aggressive type of B-cell non‑Hodgkin lymphoma (NHL). Patients that have relapsed/refractory MCL through second line of therapy have a median overall survival (OS) of less than 1 year.

That prompted, in 2016, a national multicenter phase 2 trial called ZUMA‑2, where we looked at a novel chimeric antigen T-cell therapy with CD28 signaling domain, called brexu‑cel, against CD19 relapsed/refractory MCL. This was a big study published in 2020 in the New England Journal of Medicine and led to the approval for brexu‑cel for those subgroups of patients who need that therapy.

Since then, the treatment has become commercially available in specified centers. When clinical studies are designed, you typically have more stringent eligibility criteria. The outcomes of those studies may or may not apply to the general populations in a clinical practice.

This is what prompted us to work with other centers—we're about 14 academic centers with experience in CAR‑T—under 1 group called US Lymphoma Consortium. We looked at our own experience with patients with MCL who received brexu‑cel on commercial basis and assessed whether their outcomes are consistent with what we've seen in clinical studies.

Could you briefly describe the study and its findings? Were any of the outcomes particularly surprising?

By July 2021, we gathered data for 107 patients who had leukapheresis. Cells were collected to produce CAR‑T. Overall, 93 of the 107 patients received CAR‑T. What's interesting in the study is that as we expected, the patient population were different than those seen in the ZUMA‑2 study.

For example, 45% of our patients have the aggressive blastoid or pleomorphic variants vs only 31% in the study population. In addition, 46% of patients in the real-world population had TP53 mutations or alterations and known risk factors compared to only 17% on the ZUMA‑2 trial.

We had 7% of our population with CNS involvement, where that was an exclusion criteria for ZUMA‑2. On the study, we tried to avoid CNS involvement because we were concerned about CNS toxicity. Here on our commercial basis, we have patients with CNS involvement.

In fact, 73% of the 107 patients did not meet the criteria on ZUMA‑2 for reasons including worse performance status, cytopenia, organ dysfunctions, liver or renal dysfunction, and CNS involvement. Many patients would not have been a candidate for the ZUMA‑2 and they still received the commercial treatment.

This study had a follow-up of 3 months. At 3 months, the response rates were as good as those seen in ZUMA‑2. The overall response rate was 86% with complete remission rate of 64%, which is quite remarkable.

We also saw patients who did not receive a prior BTK inhibitor. On the ZUMA‑2, failure of a prior BTK inhibitor was a requirement. In this study, we had 18% of patients who did not receive a BTK inhibitor. These patients actually experienced better response than those patients who failed BTK inhibitors.

The 3-month median OS was 82% and toxicity was comparable to that seen in ZUMA‑2, with 8% of patients experiencing grade ≥3 cytokine release syndrome and 33% with grade ≥3 neurotoxicity. We did not see any associated deaths from those toxicities. Approximately 26% of those patients required ICU care, which is likely less than what we've seen on the study.

Use of steroids in our real‑world experience management early on—driven by more recently published experience with using steroids—did not affect the efficacy of CAR‑T and did reduce the toxicity associated with CAR‑T.

Efficacy and toxicity were equal to what we've seen in the study (even a little bit better). These overall outcomes were very surprising and very encouraging to report at the last ASH Annual meeting. We have more follow‑up to come.

Do you and your co-investigators intend to expand upon this research? If so, what will be your next steps?

We have already included more patients. Including more patients would enable us to be able to answer more questions. We're looking for more clinical data points, like MRD, looking for more clinical special labs, the effect of the tumor burden, pretreatment, and the long‑term outcomes.

We're looking forward to seeing outcomes of patients who progress or did not respond to CAR‑T. We already have studies ongoing that we plan to be present and publish soon.

Is there anything else pertaining to your research and findings that you would like to add?

The cellular therapy field is moving very fast. We're very encouraged by that. Our group here is very interested to learn more about how we improve the response rate for those patients who received CAR‑T with different consolidation therapy right after the CAR‑T.

We're very interested in looking at reasons why some patients have more resistant tumors than others. We have ongoing correlative studies done in our centers with collaboration with other centers to better understand how we optimize this treatment.