Background
Phase II single-arm pivotal trial. 93 infused patients with relapsed or refractory DLBCL (including transformed FL) after ≥2 prior lines of therapy including anti-CD20. Conducted across 27 sites in 10 countries. Pivotal trial supporting FDA approval of tisagenlecleucel (tisa-cel) for R/R DLBCL in May 2018. Bridging therapy was permitted; 92 patients received bridging before infusion.
Interventions and follow up
Regimen: Tisagenlecleucel (tisa-cel) single IV infusion (median 3.0×10⁸ CAR+ cells) after lymphodepleting chemotherapy (fludarabine + cyclophosphamide or bendamustine)
Primary endpoint: Overall response rate (ORR) at 3 months by independent review committee (IRC) per Lugano criteria
Median follow-up: 14 months
Primary endpoint: Overall response rate (ORR) at 3 months by independent review committee (IRC) per Lugano criteria
Median follow-up: 14 months
Results
ORR: 52% (48/93 patients)
CR rate: 40%
12-month relapse-free survival (responders): 65%
12-month OS: 49%
CR rate: 40%
12-month relapse-free survival (responders): 65%
12-month OS: 49%
Adverse events
Immune effector toxicities: CRS any grade 57%, grade ≥3 22%; ICANS any grade 21%, grade ≥3 12%; HLH/macrophage activation 1 patient
Cytopenias (grade ≥3): neutropenia 82%, thrombocytopenia 51%, anemia 49%
Management/mortality: tocilizumab in 51%, corticosteroids in 24%; 3 treatment-related deaths (2 CRS-related, 1 HLH)
Cytopenias (grade ≥3): neutropenia 82%, thrombocytopenia 51%, anemia 49%
Management/mortality: tocilizumab in 51%, corticosteroids in 24%; 3 treatment-related deaths (2 CRS-related, 1 HLH)
Conclusions
Tisa-cel produced durable responses in heavily pretreated R/R DLBCL, with a 40% CR rate and 65% sustained responses at 12 months in responders. These results supported the approval of the second CAR-T product in LBCL, providing an alternative to axi-cel with a different manufacturing and toxicity profile.
Key Limitations
Single-arm design without a comparator limits efficacy interpretation. Substantial attrition between enrollment and infusion (manufacturing failures, rapid progression) means intention-to-treat outcomes are less favorable than infused-population results. ORR (52%) and CR (40%) are numerically lower than ZUMA-1 (axi-cel), although cross-trial comparison is confounded by differing eligibility, bridging, and patient mix. No central comparison of long-term durability beyond the reported window.
Clinical Context
FDA approved tisagenlecleucel for R/R DLBCL after ≥2 prior lines in May 2018; EMA approval followed in 2018. Tisa-cel is one of three anti-CD19 CAR-T products used in R/R LBCL alongside axicabtagene ciloleucel and lisocabtagene maraleucel. The subsequent BELINDA trial failed to show benefit of tisa-cel over standard salvage in the second-line setting, in contrast to ZUMA-7 (axi-cel) and TRANSFORM (liso-cel), which restricted tisa-cel's role largely to third-line and later.