Frontline Acalabrutinib/Rituximab Followed By Brexu-Cel Shows Synergy and Safety in High-Risk MCL

Clinical outcomes with acalabrutinib (Calquence) plus rituximab (Rituxan) followed by brexucabtagene autoleucel (brexu-cel; Tecartus) match preclinical data that suggested synergy between BTK inhibitors and CAR T-cell therapy in previously untreated, high-risk mantle cell lymphoma (MCL), according to Preetesh Jain, MD, MBBS, DM, PhD, who stressed the need for larger, randomized studies to further support bringing CAR T-cell therapies into the front line.

In the phase 1 Window-3 trial (NCT05495464), data from which were presented at the 2025 ASH Annual Meeting and Exposition, 95% (n = 19) of patients achieved a partial response (PR) and 1 patient achieved stable disease (SD) after receiving acalabrutinib plus rituximab.^1,2 At day 30, following treatment with brexu-cel and maintenance acalabrutinib, patients had an overall response rate (ORR) of 100% and a complete response (CR) rate of 95%. Of note, no patients who received the acalabrutinib/rituximab regimen experienced any grade 4 adverse effects (AEs), and only 1 patient experienced a grade 3 AE (skin rash).

“This is a pilot study,” Jain, an assistant professor in the Department of Lymphoma/Myeloma at The University of Texas MD Anderson Cancer Center in Houston, noted in an interview with OncLive®.“We need better types of CAR T-cell therapy and mitigation strategies. For [this regimen] to be ready in frontline settings, there must be a larger study with a control arm where there is no CAR T-cell therapy and a similar degree of high-risk patients.”

In the interview, Jain discussed the potential advantages of BTK inhibitor and CAR T-cell combinations as frontline treatment for high-risk MCL, commenting on their role in the paradigm prior to Window-3 and what the road ahead looks for this approach based on these phase 1 results.

What was the rationale and design of the WINDOW-3 trial?

Jain: [The Window-3 trial] was designed to [assess the] outcome of bringing in CAR T-cell therapies into the frontline setting. There are a lot of preclinical data with BTK inhibitors, particularly acalabrutinib, [showing their] safety and efficacy in MCL. [These preclinical data] are why we wanted to look at the combination of acalabrutinib [and rituximab] prior to administering CAR T-cell therapy. [In this case, our CAR T-cell therapy of choice was] brexu-cel, [which was] approved by the FDA in July 2020, for patients with [relapsed/refractory] MCL.³ We wanted to see whether [acalabrutinib and rituximab followed by brexu-cel] would improve outcomes for high-risk patients with MCL in the first-line setting.

First, we had to identify which patients were high-risk. MCL is a complex but rare disease, so we see [many] different [unique] subsets of MCL.¹ First, we identified [high-risk] subsets of MCL based on their extensive genomic profiling and clinical characteristics. Then, [eligible] patients were screened, [and proceed to] treatment [with] acalabrutinib and rituximab. Patients [who achieved] a PR or SD proceeded to cell collection, then [finally] to CAR T-cell therapy. At each of these steps, their blood levels were monitored to make sure it was safe enough for patients to move on to CAR T-cell therapy. Thirty days post-CAR T-cell therapy, a group of 10 patients were given acalabrutinib maintenance therapy for 24 months whereas the rest of patients were still observed but given no maintenance therapy.

What were the key efficacy data from Window-3?

Even in patients who are high-risk, there was a good chance of response with [acalabrutinib plus rituximab] compared with rituximab alone. The primary end point [of Window-3] was not to evaluate the efficacy of acalabrutinib or rituximab, but we did see that all patients achieved some degree of response with acalabrutinib plus rituximab. When these patients moved on to [receive] CAR T-cell therapy, we saw dramatic responses. At 30 days, 100% of patients had responded and only 1 patient had a PR. Remissions from this trial were very deep and achieved early. Of course, it comes with a price; CAR T-cell therapy toxicities like cytokine release syndrome and immune effector cell–associated neurotoxicity syndrome [ICANS] were observed in these patients

What were the notable safety data from Window-3?

[Safety] was a very critical aspect [of the trial]. Throughout the study we identified that 75% of patients had developed ICANS. Grade 3 and 4 toxicities were also noted in approximately 45% of patients. [Although these data] are similar to what have been reported before in high-risk MCL cohorts but, [the rate of] toxicities is still high. [However], almost all of these toxicities reversed and patients were admitted into the ICU for monitoring.

What CAR T-cell expansion data came from the trial?

Based on the data we have with brexu-cel, [its] expansion is robust compared with other CAR T-cell therapies. [This] is probably related to the biology of MCL, as CD19 expression is higher in MCL compared with other lymphoid malignancies. [Higher CD19 expression] is responsible for CAR T expansion within day 7 or 9; said expansion reached 19,000 cells in one of the patients [on our study]. Moreover, [peak CAR T-cell expansion correlated with] the [development] of ICANS. [CAR T-cell expansion was identified in] 15 patients.

What are the clinical implications of these findings and the next steps for high-risk MCL research?

It should be noted that patients with high-risk MCL have [distinct clinical and genetic features]. [The risk of] relapse [in high-risk] patients with distinct strategies for mitigating CAR T-cell therapy toxicity, as well as a humanized CAR T-cell therapy with less propensity for expansion, needs to be explored further.

[The next steps for this research] include a large, randomized study that is currently ongoing in Germany. [The study] is comparing ibrutinib (Imbruvica) plus brexu-cel with the current standard of care in the first-line setting. This study will be interesting to see, considering it is a multicenter trial with a large cohort of patients and a control arm.

References

1. Jain P, Ahmed S, Ok CY, et al. Acalabrutinib plus rituximab followed by brexucabtagene autoleucel for frontline treatment of high-risk Mantle Cell Lymphoma: the window-3 clinical trial. Blood. 2025;146(suppl 1):666. doi:10.1182/blood-2025-666
2. A pilot "Window-3" study of acalabrutinib plus rituximab followed by brexucabtagene autoleucel therapy in patients with previously untreated high-risk mantle cell lymphoma. ClinicalTrials.gov. Updated August 15, 2025. Accessed January 5, 2026. https://www.clinicaltrials.gov/study/NCT05495464
3. U.S. FDA approves kite’s Tecartus, the first and only CAR T treatment for relapsed or refractory mantle cell lymphoma. News Release. Gilead. Published July 24, 2020. Accessed January 5, 2026. https://www.gilead.com/news/news-details/2020/us-fda-approves-kites-tecartus-the-first-and-only-car-t-treatment-for-relapsed-or-refractory-mantle-cell-lymphoma