Five-Year Outcomes of Axicabtagene Ciloleucel in Relapsed or Refractory Large B-Cell Lymphoma: The ZUMA-1 Long-Term Follow-Up

Background

Axicabtagene ciloleucel (axi-cel), a CD19-directed chimeric antigen receptor T-cell (CAR-T) therapy, received approval for relapsed or refractory large B-cell lymphoma based on the pivotal ZUMA-1 trial. While initial response rates were impressive (83% overall response rate, 58% complete response), the durability of these responses beyond 2 years required extended follow-up. We report the prespecified 5-year outcomes of the ZUMA-1 cohort.

Methods

ZUMA-1 was a single-arm, multicenter, phase 1/2 trial in which 101 patients with relapsed or refractory large B-cell lymphoma after at least two prior lines of therapy received a single infusion of axi-cel following lymphodepleting chemotherapy (fludarabine and cyclophosphamide). The primary endpoint of this long-term analysis was 5-year overall survival. Secondary endpoints included duration of response, progression-free survival, and late toxicity assessment. Minimal residual disease (MRD) was evaluated by next-generation sequencing.

Results

At a median follow-up of 63.1 months, the 5-year overall survival rate was 42.6% (95% CI, 33.2-51.8). Among patients who achieved complete response, 31.8% remained in ongoing complete response at 5 years without additional therapy. The median overall survival was 25.8 months (95% CI, 12.8-not estimable). Median progression-free survival was 5.9 months, but the PFS curve plateaued at approximately 24 months, with no relapses observed beyond 24 months in patients maintaining complete response. All patients in ongoing response at 2 years remained in response at 5 years. Late adverse events included prolonged B-cell aplasia (requiring immunoglobulin replacement in 28% of long-term survivors), grade 3-4 cytopenias persisting beyond 12 months (8%), and no cases of late-onset neurotoxicity or secondary malignancy attributable to CAR-T therapy. MRD negativity at 3 months was strongly predictive of durable response (positive predictive value, 89%).

Conclusions

Five-year follow-up of ZUMA-1 confirms that axi-cel can produce durable, potentially curative remissions in approximately one-third of patients with relapsed or refractory large B-cell lymphoma, with a manageable long-term safety profile.