Background
Phase I single-arm pivotal trial (dose-escalation + expansion). 269 patients treated across dose levels; primary efficacy analysis at dose level 2 (DL2, 100×10⁶ CAR+ T-cells) in relapsed or refractory large B-cell lymphoma (DLBCL NOS, HGBCL, PMBCL, FL3B, DLBCL-TFL) after ≥2 prior lines. Pivotal trial leading to FDA approval of lisocabtagene maraleucel (liso-cel) in February 2021. Bridging therapy permitted. Notably, liso-cel uses a defined 1:1 CD4:CD8 CAR-T ratio.
Interventions and follow up
Regimen: Lisocabtagene maraleucel (liso-cel) at dose level 2 (100×10⁶ CAR+ cells, 1:1 CD4:CD8) IV after fludarabine/cyclophosphamide lymphodepletion
Primary endpoint: Incidence and severity of adverse events (phase I); ORR per IRC (DL2 pivotal cohort)
Median follow-up: 12 months (primary); 24 months (updated)
Primary endpoint: Incidence and severity of adverse events (phase I); ORR per IRC (DL2 pivotal cohort)
Median follow-up: 12 months (primary); 24 months (updated)
Results
ORR (DL2, LBCL): 73%
CR rate: 53%
Median DOR: 12.1 months
12-month OS: 58%
CR rate: 53%
Median DOR: 12.1 months
12-month OS: 58%
Adverse events
Immune effector toxicities: CRS any grade 42%, grade ≥3 2% (notably low); ICANS any grade 30%, grade ≥3 10%
Cytopenias/infection (grade ≥3): neutropenia 60%, anemia 37%, thrombocytopenia 27%, infection 12%
Management/mortality: tocilizumab in 19%, corticosteroids in 21%; no treatment-related deaths from CRS or ICANS in pivotal cohort
Cytopenias/infection (grade ≥3): neutropenia 60%, anemia 37%, thrombocytopenia 27%, infection 12%
Management/mortality: tocilizumab in 19%, corticosteroids in 21%; no treatment-related deaths from CRS or ICANS in pivotal cohort
Conclusions
Liso-cel produced high response rates with a markedly lower CRS rate (grade ≥3: 2%) compared with other approved CAR-T products in LBCL. The defined CD4:CD8 ratio and lower conditioning intensity may contribute to the favorable safety profile, making liso-cel more suitable for older or frailer patients.
Key Limitations
Single-arm, non-randomized phase I design; favorable CRS/ICANS rates derive partly from a defined cell composition and slower expansion but cannot be directly compared with other CAR-T products absent head-to-head trials. Outcomes reported in the infused population overstate intention-to-treat efficacy given manufacturing and progression-related attrition. Heterogeneous histologies and multiple dose levels complicate interpretation, and longer-term durability beyond the reported follow-up is limited.
Clinical Context
FDA approved liso-cel for R/R LBCL after ≥2 prior lines in February 2021; EMA approval followed in 2022. Liso-cel is one of three anti-CD19 CAR-T products for R/R LBCL alongside axi-cel and tisa-cel. The subsequent TRANSFORM trial established liso-cel superiority over standard salvage chemotherapy plus ASCT in second-line transplant-eligible patients, broadening its role to earlier lines. Its favorable CRS profile supports outpatient administration in selected settings.