Introduction: Brexu-cel is an autologous anti-CD19 CAR T-cell therapy approved for adults with R/R MCL and R/R B-ALL. BL is a rare, highly aggressive B-cell malignancy characterized by translocation of the MYC oncogene. Pts with R/R BL have limited treatment options and outcomes are poor with a median overall survival (OS) of 2.8 mo after salvage therapy (Short NJ, et al. Am J Hematol. 2017). ZUMA-25 (NCT05537766) is a Phase 2, open-label, multicenter basket study designed to evaluate the safety and efficacy of brexu-cel in adults with rare B-cell malignancies. Here, we report the preliminary efficacy and safety of brexu-cel in pts with R/R BL in ZUMA-25 (Substudy C).

Methods: Eligible pts were aged ≥18 y, had an ECOG performance status 0-1, histologically confirmed mature B-cell NHL Burkitt lymphoma/leukemia, and R/R disease after ≥1 prior line of chemoimmunotherapy. Pts underwent leukapheresis, optional bridging therapy, lymphodepleting chemotherapy, and infusion of brexu-cel (2×106 anti-CD19 CAR T cells/kg; dose was validated in a run-in phase with 3 pts before enrolling additional pts). Primary endpoint was objective response rate (ORR; complete response [CR] + partial response [PR]) by investigator assessment per the Lugano classification (Cheson BD, et al. J Clin Oncol. 2014). Key secondary endpoints were CR rate, duration of response (DOR), OS, progression-free survival (PFS), time to first response, time to best response, safety, and patient-reported outcomes (PROs) per EQ-5D-5L index. Exploratory analyses included CAR T-cell levels. Outcomes were analyzed descriptively without hypothesis testing for the primary endpoint due to early termination of the trial given low pt enrollment.

Results: Twelve pts were enrolled and underwent leukapheresis, of whom 10 (83%) received brexu-cel (2 pts did not receive brexu-cel due to death from progressive disease [PD; n=1] and withdrawal from study [n=1]). There were no manufacturing failures; median vein-to-vein time (range) was 25.5 d (23-28; n=4) and 37.0 (28-51; n=6) for pts in the US and EU, respectively. As of Dec 17, 2024, median follow-up in treated pts (N=10) was 5.6 mo (range, 3.8-24.2). Median age was 50.5 y (range, 36-70), 50% were male, 30% were Hispanic/Latino. At baseline, 8 pts (80%) had an ECOG performance status of 1; 5 pts each (50%) had refractory and early relapse BL (<6 mo from first remission); median number of prior therapies was 1.5 (range, 1-6) and included chemotherapy and/or rituximab; 1 pt received prior autologous stem cell transplantation (SCT). Eight pts had bridging therapy, including radiotherapy (n=3) and/or chemotherapy (n=6).

Among treated pts (N=10), ORR was 100% (95% CI, 69-100; CR rate, 50%; PR rate, 50%). Median time from infusion to first/best response was 29 d (range, 25-284), with 1 pt converting from stable disease to CR at Mo 9; no pt with PR converted to CR. Median (95% CI) DOR, PFS, and OS were 5.0 mo (2.2-not estimable [NE]), 5.8 mo (3.1-NE), and 12.9 mo (3.8-NE), respectively. Among pts with CR, the 6-mo (95% CI) DOR, PFS, and OS rates were 75% (13-96), 75% (13-96), and 100% (100-100), respectively. DOR for each of the 5 pts with CR was 4.83+, 4.96, 10.18+, 11.33+, and 14.88+ mo (+ indicates censoring); at data cutoff, 4 pts were still alive and in ongoing response without subsequent therapy and 1 pt died due to PD after subsequent therapy and SCT. Among the 5 pts with PR as best response, DOR ranged from 0.03-4.24 mo; at data cutoff, 2 pts were still alive with PD, and 3 pts died (2 due to PD [1 with subsequent SCT] and 1 due to an adverse event [AE; pneumonia, deemed unrelated to brexu-cel] with subsequent SCT).

AEs occurred in all pts; 9 (90%) had Grade ≥3 AEs. The most common AEs were pyrexia (100%) and decreased neutrophil count (50%). All pts had any-grade cytokine release syndrome (CRS); 1 (10%) had Grade 3 CRS. Neurologic events occurred in 8 pts (80%); 6 (60%) had Grade 3.

Median peak, area under the curve, and time to peak CAR T-cell levels were 41.9 cells/μL, 450.1 cells/μL × days, and 8 d (range, 8-57), respectively. Most evaluable pts (6/7) had stable or improved quality of life 3 months after screening.

Conclusions: To our knowledge, this is the first prospective study of a commercial CAR T-cell therapy in pts with R/R BL. Preliminary efficacy, safety, and PROs are promising in this difficult-to-treat pt population; this analysis is limited by its small sample size and short follow-up.

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2025
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