Background
Phase II, single-arm, multicenter study. 127 patients with R/R FL (grade 1–3a) or MZL after ≥2 prior lines including anti-CD20 and alkylating agent. Axicabtagene ciloleucel (axi-cel) is a CD19-targeted CAR-T with CD28 costimulatory domain. ZUMA-5 extended the CAR-T approach from aggressive lymphomas to indolent FL.
Interventions and follow up
Regimen: Axicabtagene ciloleucel (axi-cel) 2 × 10⁶ CAR-T cells/kg IV single infusion after fludarabine/cyclophosphamide lymphodepletion in R/R indolent NHL (follicular and marginal zone lymphoma)
Primary endpoint: Overall response rate (independent review committee, FL cohort)
mFollow up: ~60 months (5-year update)
Primary endpoint: Overall response rate (independent review committee, FL cohort)
mFollow up: ~60 months (5-year update)
Results
ORR (primary): 94% (95% CI 87–98%)
CR rate: 79%
5-year mDOR: 60.4 months
5-year mPFS: 62.2 months
5-year OS rate: 73.9%
CR rate: 79%
5-year mDOR: 60.4 months
5-year mPFS: 62.2 months
5-year OS rate: 73.9%
Adverse events
CRS/neurologic: CRS any grade 79%, grade ≥3 7%; neurological events any grade 57%, grade ≥3 19%; one treatment-related death (CRS-related)
Hematologic: Grade ≥3 neutropenia 35%, thrombocytopenia 21%; prolonged grade ≥3 neutropenia beyond day 90 in 23%
Hematologic: Grade ≥3 neutropenia 35%, thrombocytopenia 21%; prolonged grade ≥3 neutropenia beyond day 90 in 23%
Conclusions
Axi-cel achieved exceptional long-term outcomes in R/R FL — ORR 94%, CR 79%, with a 5-year median PFS of 62.2 months — demonstrating durable remissions and potential cure in a subset of heavily pretreated FL patients.
Key Limitations
Single-arm Phase II without a randomized comparator, limiting causal interpretation versus standard salvage. Grade ≥3 neurological events (19%) and prolonged cytopenias add meaningful toxicity in an indolent disease with multiple low-toxicity options. The FL cohort was relatively small and heavily pretreated, limiting generalizability. The high cost, logistics, and lymphodepletion requirements of CAR-T restrict access compared with bispecific antibodies.
Clinical Context
ZUMA-5 led to FDA accelerated approval of axi-cel for R/R FL after ≥2 prior lines (March 2021). It was the first CAR-T approved in indolent lymphoma. Long-term ZUMA-5 data demonstrate plateau in PFS, supporting curative potential in a subset. ESMO recognizes CD19 CAR-T as an option for multiply relapsed FL. Sequencing versus the newer bispecific antibodies (mosunetuzumab, epcoritamab) and liso-cel (TRANSCEND FL) remains an open question.