Brexu-Cel Secures Full FDA Approval in R/R MCL: Reflections From ZUMA-2

The treatment landscape for mantle cell lymphoma (MCL) has evolved rapidly over the past decade, yet patients with relapsed/refractory (R/R) disease—particularly after failure of Bruton tyrosine kinase (BTK) inhibitors—have continued to face poor prognoses and limited options. The FDA’s recent decision to grant full traditional approval to the CD19-directed chimeric antigen receptor T-cell (CAR T) therapy brexucabtagene autoleucel (Tecartus; brexu-cel) in this setting thus signals an encouraging advance, reinforcing the role of cellular therapy in this historically difficult-to-treat population.

Initially receiving accelerated approval in 2020,² brexu-cel had demonstrated high response rates and durable remissions in patients with heavily pretreated disease in cohort 1 of the phase 2 ZUMA-2 trial (NCT02601313). Full approval is now supported by longer-term follow-up and additional data from a third cohort (NCT04880434), expanding the evidence base for its use.³

In an interview with Targeted Oncology, Michael Wang, MD, Puddin Clark Endowed Professor in the department of Lymphoma and Myeloma at The University of Texas MD Anderson Cancer Center and ZUMA-2 lead investigator, recounted the evolution of the MCL treatment landscape, key findings from ZUMA-2, and outlined practical considerations for clinicians in the community managing patients treated with this CAR T therapy.

Targeted Oncology: What treatment gap in this setting motivated the ZUMA-2 trial?

Michael Wang, MD: MCL, many years ago, was mainly treated with high-dose intensive therapy with autologous stem cell transplant for young patients, or by a very heavy chemotherapy regimen—hyper-CVAD, rituximab [Rituxan], alternating with methotrexate and cytarabine. Those treatments are not curative; therefore, the patient would relapse, and then we didn’t have other agents. We would give them chemotherapy again, and the patients [would experience significant toxicity]. It was a horrible malignancy…which used to be the most difficult lymphoma to treat, but over the past 25 years, significant progress has been made. …

In 2017, the second-generation BTK inhibitor acalabrutinib [Calquence] was approved by the FDA for relapsed MCL⁴…much less [adverse] effects [AEs], especially less atrial fibrillation. Another second-generation inhibitor, zanubrutinib [Brukinsa], was approved by the FDA in 2019 for relapsed MCL,⁵ and so BTK inhibitors were widely used. After treatment with BTK inhibitors, the patient [can] become resistant to BTK inhibitors; they only have less than 1 year to live. Because of that, we developed the first CD19-directed CAR T-cell therapy [for R/R MCL], brexu-cel.

Can you walk us through the design of ZUMA-2, including the different study cohorts and how they evolved over time?

There are 3 cohorts in this trial. Cohort 1 had 60 [treated] patients with a response rate of 87% and CR [complete remission] of 62%. Remember, the study population has less than 1 year to live with the BTK resistance; with brexu-cel, the median overall survival was 4 years. The first FDA approval [based on cohort 1] was in 2020, but it was provisional; [the FDA required] more data and longer follow-up to make it a full approval. Seventy-four [patients in cohort 1] have safety data. In these patients, the infusion was 2 million CAR T-cells.

Kite Pharma designed a second cohort because they were afraid that 2 million cells could be too toxic. The 14 patients in cohort 2 received 4 counts less of CAR T cells, around 0.5 million cells. But after a while, the 2 million cells were tolerated well, with good efficacy, and reducing the CAR T-cell infusions didn't show any difference in response rate or toxicity. Therefore, there was no need to enroll any more patients beyond 14 patients.

The long-term follow up of cohorts 1 and 2 [did not] convince the FDA to give full approval of brexu-cel for relapsed MCL; that's where the third cohort comes in. The first 2 cohorts had an overall patient population of 82 patients, but in cohort 3, the cohort size was 86 patients. [In] cohorts 1 and 2, the patient has to have received a BTK inhibitor before they enroll in the study, but in cohort 3, no [prior] BTK is allowed.

What key efficacy and safety findings from cohort 3 supported the full approval?

Among the 86 patients who received no prior BTK therapy, with a 23-month follow-up, the overall response rate was 91% and CR rate was 79%. The toxicities are very reasonable. The pooled data showed that 93% of patients had CRS [cytokine release syndrome], but only 12% of patients had grade 3 and higher CRS, so that's much better. The [rate of] ICANS [immune effector cell-associated neurotoxicity syndrome] was safe; 80% of patients had ICANS, but only 33% of patients had grade 3 or higher. Infection was in 63% but only 33% had grade 3 and higher.

Based on the longer follow-up and pooled study of all 3 cohorts, the FDA granted full approval for brexu-cel in R/R MCL. I feel so happy because we have the full approval for patients. CAR T therapy with brexu-cel has been a life-saving therapy for many years; with the full approval, I hope that more patients will benefit from this life-saving therapy.

Given brexu-cel’s toxicity profile, what practical guidance can you offer community oncologists for managing AEs—particularly infections—once patients transition back to local care?

The majority of the toxicities are managed by academic oncologists/hematologists, but that doesn't mean the community doctors do not manage [either]. Because of the geographic [distance of infusion sites], the patient sometimes prefers to go home. [Community oncologists] may also participate in the management… The majority of the CRS events happened by day 6 with brexu-cel. It lasts only 7 days, so those times our patients are still in the hospital nearby the center. The ICANS happens about 6 days [in], and it takes 19 days. …

The main lethal toxicity is the infection after CAR T therapy. That is where the community doctor would step in, because the patient cannot stay near the academic center forever. At a certain point after 30 days, they're released into the community without CRS or without ICANS, but they will have a lot of…very rare infections like fungal pneumonia, aspergillosis, fungal infection, histoplasmosis, JC [John Cunningham] virus. Infections we had only studied in textbooks began to appear after CAR T therapy because of profound immuno[deficiency].

First of all, with brexu-cel, the median prior therapy [lines] is usually about 2 to 3. The patients already received other B-cell lymphoma therapies, chemotherapy, or targeted therapy... So because CAR T patients received the CD19 CAR, malignant CD19 cells are killed and normal CD19 cells are depleted, leading to B-cell aplasia. When B-cell numbers decrease, antibody production is compromised, [leading to an] immunocompromised [state]… The infections not only occur [more often], but will often be more lethal. The fungal infections do not only occur in the peripheral sites; it also sometimes occurs in the brain.

As a community doctor, I recommend everybody check immunoglobulin G [IgG]. If IgG is low, the patient should regularly receive IVIG [intravenous immunoglobulin]. This is very important and has proven to be effective to prevent infections. Vigilant screening for any infections is important, because if the patient in CAR T therapy has sinusitis, more than one-third will become pneumonia. That will be life threatening, so it is important to treat any infections very early, not only the sinusitis; UTIs [urinary tract infections] or any infection should be effectively controlled. The sinusitis could be due to the deviated septum, so not only do you need to treat it with IVIG… you need to use other devices to clean the sinus. Also, you need to refer every patient of a CAR T therapy to an ENT [ear, nose, and throat] physician to make sure that all the structures are not obstructed. If the septum is deviated, you will never be able to clear the sinus. So, work with the infectious disease doctor, work with the ENT. If the patient has a recurrent UTI, you need to work with the infectious disease doctor to counter what's going on.

Also… if the patient has diarrhea and other infections, treat it with not only antibodies, but also think about a microbiome therapy to balance that microbiome in the gut. If the patient has any fever, refer them to an emergency department immediately. There's a [higher] chance for patients to catch COVID-19 and other infections; you need to have vigilant screening for COVID-19 and deal with the COVID-19 infection should that occur. The infections are really what fall on the shoulders of all community oncologists/hematologists; we must collaborate together to reduce patient morbidity and mortality.

REFERENCES

1. U.S. FDA grants full approval of Kite’s Tecartus® for adult patients with relapsed or refractory mantle cell lymphoma. News release. Gilead Sciences. April 2, 2026. Accessed April 9, 2026. https://tinyurl.com/3dbjt2m9

2. FDA approves brexucabtagene autoleucel for relapsed or refractory mantle cell lymphoma. News release. United States Food and Drug Administration. July 27, 2020. Accessed April 9, 2026. https://tinyurl.com/5xfp8eaf

3. van Meerten T, Kersten MJ, Iacoboni G, et al. Brexucabtagene autoleucel for BTKi-naive relapsed/refractory mantle cell lymphoma: primary analysis of ZUMA-2 cohort 3. Blood. 2026;147(12):1302-1314. doi:10.1182/blood.2025029734

4. FDA grants accelerated approval to acalabrutinib for mantle cell lymphoma. News release. United States Food and Drug Administration. October 31, 2017. Accessed April 9, 2026. https://tinyurl.com/yt5pn2hx

5. FDA grants accelerated approval to zanubrutinib for mantle cell lymphoma. News release. United States Food and Drug Administration. November 15, 2019. Accessed April 9, 2026. https://tinyurl.com/y39d2dvd