Acalabrutinib, Rituximab, and Brexu-cel Yields High Response Rates High-Risk MCL

Data from the phase 1 Window-3 trial (NCT05495464) indicate that treating patients with previously untreated, high-risk mantle cell lymphoma (MCL) using a specific combination regimen yielded promising results.¹

The treatment sequence—starting with the combination of acalabrutinib (Calquence) and rituximab (Rituxan), followed by brexucabtagene autoleucel (brexu-cel; Tecartus)—led to high rates of response and the presence of undetectable minimal residual disease (MRD) in these patients.

Findings presented during the 2025 ASH Annual Meeting and Exposition demonstrated that evaluable patients (n = 20) treated with this regimen achieved an overall response rate (ORR) of 95%, comprised exclusively of partial responses (PR). The lone non-responder had stable disease (SD), and the population received a median of 1 cycle of acalabrutinib plus rituximab (range, 1-2). Following treatment with brexu-cel and maintenance acalabrutinib, the ORR at day 30 improved to 100%, with 95% of patients achieving a complete response (CR). In evaluable patients, responses were ongoing beyond 12 months.

Regarding safety, 1 patient experienced a grade 3 adverse effect (AE) during treatment with acalabrutinib plus rituximab (skin rash); no grade 4 or higher AEs were reported. Following treatment with brexu-cel, all patients experienced cytokine release syndrome (CRS), including 5% of patients with grade 3 CRS and 10% of patients with grade 4 CRS. The median time to CRS onset was 3 days (range, 0-7). Any-grade immune effector cell–associated neurotoxicity syndrome (ICANS) was reported in 75% of patients, including grade 3 ICANS in 30% of patients and grade 4 ICANS in 15% of patients. The median time to ICANS onset was 6 days (range, 2-15); all ICANS resolved at a median time of 3 days (range, 1-37). Forty percent of patients required intensive care due to CRS or ICANS, lasting for a median duration of 3 days (range, 2-25).

Additionally, grade 3/4 neutropenia occurred in 60% of patients, grade 3/4 thrombocytopenia was reported in 20% of patients, and grade 3/4 infections were experienced by 20% of patients. No grade 5 AEs were reported during the study.

“The study’s limited sample size and absence of a control arm constrain definitive attribution of acalabrutinib’s effects on CAR [T-cell] fitness and toxicity,” lead study author Preetesh Jain, MBBS, MD, DM, PhD, said during the presentation. “However, extended follow-up…[with] comprehensive translational analyses are currently underway to assess response durability and the impact of acalabrutinib maintenance on [long-term] safety and efficacy.”

Jain is an assistant professor in the Department of Lymphoma/Myeloma of the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center in Houston.

What was the rationale for exploring a frontline treatment approach with acalabrutinib, rituximab, and brexu-cel in high-risk MCL?

Jain highlighted that preclinical studies have shown synergy between BTK inhibition and anti-CD19 CAR T-cell therapy, allowing for improved CAR T-cell expansion, effector functions, and engraftment. This approach has also shown reductions in immunosuppressive cell populations such as myeloid-derived suppressor cells, regulatory B cells, and regulatory T cells.

Window-3 was a single-center study conducted at MD Anderson Cancer Center that enrolled patients at least 18 years of age with high-risk MCL.² Patients needed to be eligible to receive acalabrutinib, rituximab, and CAR T-cell therapy; have an ECOG performance status of 0 or 1; and be cleared by cardiology to receive acalabrutinib and CAR T-cell therapy. No prior treatment for MCL was permitted, and patients who were primary refractory to acalabrutinib/rituximab were not allowed to participate.

Enrolled patients began treatment with acalabrutinib at 100 mg twice per day plus rituximab at 375 mg/m² once per month for the first cycle, and treatment with the combination continued until patients achieved a PR or stable disease, or for up to 9 cycles.¹ Any patients with a CR or progressive disease after acalabrutinib/rituximab would not receive CAR T-cell therapy.

Within 1 week of achieving PR or SD, patients underwent leukapheresis for brexu-cel manufacturing. Patients then underwent lymphodepleting chemotherapy with fludarabine and cyclophosphamide on days –5 to –3 prior to infusion of brexu-cel on day 0. Thirty days following brexu-cel infusion, patients could receive acalabrutinib maintenance for 24 months, and the study also included a cohort with no maintenance.

Safety served as the trial’s primary end point. Secondary end points included ORR, CR rate, progression-free survival (PFS), and overall survival (OS). MRD assessments were an exploratory end point.

The 20 enrolled patients had a median age of 62 years (range, 44-73), and 85% of patients were male. Most patients had bone marrow involvement (95%), gastrointestinal involvement (95%), a serum lactate dehydrogenase above the upper limit of normal (55%), TP53 aberrations (50%), and SOX-11 –positive disease (90%). Per MCL International Prognostic Index classification, 5% of patients had low-risk MCL, 30% had intermediate-risk disease, and 65% had high-risk MCL. Additionally, 25% of patients had a Ki-67 expression below 30%, and 60% of patients had an expression below 50%.

What additional efficacy data were reported in Window-3?

Findings also demonstrated that both the median PFS and OS were not reached at the data cutoff. At 2 years, with a median follow-up of 17 months, the PFS rate was 89% and the OS rate was 100%. Two patients experienced progressive disease at 6 and 12 months, respectively.

At a 10^-6 sensitivity, undetectable MRD rates were 25% at day 0, 84% at day 15, 89% at day 30, 95% at 3 months and 6 months, 94% at 9 months, and 100% at 12 months, 15 months, 18 months, 21 months, and 24 months.

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 December 8, 2025. https://www.clinicaltrials.gov/study/NCT05495464