BTK Inhibitor Refractoriness and Platelet Count Are Prognostic for Survival With Brexu-Cel in MCL

Survival With Brexu-Cel in Mantle Cell

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BTK inhibitor refractoriness and lower platelet counts prior to lymphodepletion were significant predictors of overall survival (OS) in patients with mantle cell lymphoma (MCL) who received brexucabtagene autoleucel (brexu‐cel; Tecartus) in a real-world setting, according to data from the observational, prospective CART-SIE study (NCT06339255) published in the British Journal of Haematology.1

Findings demonstrated that patients who received the CAR T-cell therapy and were BTK inhibitor refractory (n = 29) experienced a 1-year OS rate of 56% compared with 92% among those whose disease relapsed following a BTK inhibitor (n = 54; P = .0001). Moreover, the 1-year progression-free survival (PFS) rates were 48% vs 68%, respectively (P = .01).

Patients with lactate dehydrogenase (LDH) levels above the upper limit of normal prior to lymphodepletion (n = 25) experienced a 1-year OS rate of 66% compared with 93% among those with normal LDH levels (n = 75; P = .0003); the 1-year PFS rates were 39% vs 75%, respectively (P = .01). Patients who were thrombocytopenic with a platelet count below 75,000/µL prior to lymphodepletion experienced a 1-year OS rate of 70% vs 86% among those who were non-thrombocytopenic (P = .04); the 1-year PFS rates were 47% vs 67%, respectively (P = .04).

“In addition to the established clinical factors associated with survival of [patients with] MCL receiving CAR T‐cell therapy, such as the presence of the blastoid variant and elevated LDH levels, our study identified refractoriness to BTK inhibitor treatment and [lower] platelet count as significant prognostic factors,” lead study author Federico Stella, MD, of the School of Medicine at the University of Milan in Italy, and colleagues wrote in the publication of the data.

In July 2020, the FDA approved the brexu-cel for the treatment of adult patients with relapsed/refractory MCL.2

Diving Into the CART-SIE Study Design and Baseline Characteristics

CART-SIE was a multicenter study that included patients with relapsed/refractory MCL who received brexu‐cel across 20 centers in Italy.1 The goal of the study was, “to present real‐world data from a prospective, multicenter cohort of patients treated with commercial brexu‐cel and to assess the impact of in‐vivo expansion on outcomes.”

Kaplan-Meier estimates were used to determine PFS, OS, and duration of response (DOR) outcomes. Investigators also performed longitudinal monitoring of CAR T cells in peripheral blood via multiparameter flow cytometry.

At baseline, the median age of the overall population with MCL who received brexu-cel (n = 106) was 63 years (range, 42-79). Most patients were male (79%), had classical MCL (70%), had Ann Arbor stage III or IV disease (92%), had refractory disease (53%), received prior autologous stem cell transplantation (58%), received bridging therapy (79%), and did not respond to bridging therapy (72%). The median number of prior lines of treatment was 3 (range, 2-5). Patients had stage-Modified International Prognostic Index low (35%), intermediate (20%), high (45%), or missing (14%) disease risk status.

Additional Efficacy Measures and Safety Data

Additional findings from CART-SIE demonstrated that at a median follow-up of 12.1 months (interquartile range, 6-18), the 1-year OS and PFS rates in the overall population who received brexu-cel were 82% (95% CI, 74%-90%) and 62% (95% CI, 52%-74%), respectively. The 1-year DOR rate was 70% (95% CI, 59%-84%).

The best overall response rate (ORR) was 88%, including a 75% complete response (CR) rate. The 90-day ORR and CR rates were 77% and 70%, respectively. Findings from a univariate analysis revealed that the presence of bulky disease was the only baseline clinical factor significantly associated with a lower CR rate (odds ratio [OR], 0.17; 95% CI, 0.05-0.53; P = .002). The 1-year OS rate among patients who achieved a CR was 94% compared with 19% in those who experienced progressive disease (P < .0001).

In vivo expansion data were available for 57% (n = 61) of patients treated with brexu-cel. Data from a multivariable logistic model adjusted for bulky disease showed that in vivo expansion had an independent effect of CR rates (OR, 4.7; 95% CI, 1.2-25.0; P = .03). Additional in vivo expansion data demonstrated that the 1-year PFS rate was superior in strong (n = 28) vs poor expanders (n = 33) at 74% vs 54%, respectively (P = .02). CAR T-cell persistence was not associated with improved PFS; the 1-year PFS rates were 80% vs 78% among patients with at least 5 CAR T/μL (n = 18) and less than 5 CAR T/μL (n = 31) at day 30, respectively.

In terms of safety, any-grade cytokine-release syndrome (CRS) was reported in 95% of patients; 21% experienced grade 3 or higher CRS. Any-grade and grade 3 or higher immune effector cell–associated neurotoxicity syndrome (ICANS) occurred at rates of 48% and 18%, respectively. Platelet counts above 75,000/μL at the time of brexu-cel infusion were associated with lower rates of grade 3 or higher CRS (OR, 0.15; 95% CI, 0.05-0.42; P < .001) and ICANS (OR, 0.07; 95% CI, 0.0-0.39; P = .01).

“BTK inhibitor refractoriness [emerged] as a critical issue for patients treated with brexu‐cel; the optimal strategy for bridging in MCL remains unclear; [and] invivo monitoring of CAR T‐cell expansion using multiparametric flow cytometry has proven feasible and, together with other clinical factors, could inform patient risk stratification,” the study authors concluded.

References

1. Stella F, Chiappella A, Magni M, et al. Brexucabtagene autoleucel in-vivo expansion and BTKi refractoriness have a negative influence on progression-free survival in mantle cell lymphoma: results from CART-SIE study. Br J Haematol. 2025;206(2):644-651. doi:10.1111/bjh.19961
2. FDA approves brexucabtagene autoleucel for relapsed or refractory mantle cell lymphoma. FDA. Updated July 27, 2020. Accessed April 7, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-brexucabtagene-autoleucel-relapsed-or-refractory-mantle-cell-lymphoma