Background
Phase I/II single-arm pivotal trial. 101 patients with relapsed or refractory large B-cell lymphoma (DLBCL, PMBCL, transformed FL) after ≥2 prior lines who were refractory to last therapy or relapsed within 12 months of ASCT. Patients were ineligible for or had failed ASCT. Pivotal trial leading to FDA approval of axicabtagene ciloleucel (axi-cel) in October 2017, the first CAR-T approved for LBCL. Bridging therapy was not permitted.
Interventions and follow up
Regimen: Axicabtagene ciloleucel (axi-cel) 2×10⁶ CAR+ cells/kg IV after conditioning with fludarabine 30 mg/m² + cyclophosphamide 500 mg/m² × 3 days
Bridging therapy: Not permitted
Primary endpoint: Objective response rate (ORR) at 3 months per Lugano criteria
Median follow up: 27.1 months (primary); 5 years (long-term)
Bridging therapy: Not permitted
Primary endpoint: Objective response rate (ORR) at 3 months per Lugano criteria
Median follow up: 27.1 months (primary); 5 years (long-term)
Results
ORR (primary): 82% (83/101 patients)
CR rate (3 months): 54%
5-year PFS: 31%
5-year OS: 43%
CR rate (3 months): 54%
5-year PFS: 31%
5-year OS: 43%
Adverse events
CRS: Any grade 93%; grade ≥3: 13%; tocilizumab used in 43%, corticosteroids in 27%
ICANS: Any grade 64%; grade ≥3: 28%; ICU admission ~42%
Hematologic/infection (grade ≥3): Neutropenia 78%, anemia 43%, thrombocytopenia 38%; infection 23%; manufacturing failure 9% of enrolled
ICANS: Any grade 64%; grade ≥3: 28%; ICU admission ~42%
Hematologic/infection (grade ≥3): Neutropenia 78%, anemia 43%, thrombocytopenia 38%; infection 23%; manufacturing failure 9% of enrolled
Conclusions
Axi-cel produced high response rates in multiply relapsed/refractory LBCL, with ~54% CR and ~31% of patients remaining progression-free at 5 years, supporting curative potential. This landmark trial established CD19-directed CAR-T therapy as an effective treatment in relapsed LBCL.
Key Limitations
Single-arm phase I/II without a randomized comparator, precluding direct comparison with standard salvage therapy. Small sample (n=101) limits subgroup precision. High-grade CRS and ICANS require management at specialized centers. No bridging therapy was permitted, potentially excluding rapidly progressive patients. Manufacturing failure (9%) and ~4-week vein-to-vein time limit real-world access; long-term toxicity (prolonged cytopenias, B-cell aplasia) requires ongoing monitoring.
Clinical Context
FDA approved axi-cel (Yescarta) in October 2017 and EMA in 2018 for R/R LBCL after ≥2 lines — the first CAR-T for LBCL. ESMO recognizes CD19 CAR-T as standard for relapsed/refractory LBCL. The subsequent ZUMA-7 trial moved axi-cel into the second-line setting, demonstrating superiority over salvage chemotherapy plus ASCT in early-relapsing/refractory disease. Liso-cel (TRANSCEND, TRANSFORM) and tisa-cel (JULIET) are alternative CD19 CAR-T products.