Background
Phase 1/2, open-label, single-arm study (TRANSCEND CLL 004). N=117 patients with R/R CLL/SLL. Heavily pretreated: all had prior BTK inhibitor, 62% had prior venetoclax. Lisocabtagene maraleucel (liso-cel) is a CD19-directed, 4-1BB costimulatory CAR-T cell product with a defined CD4:CD8 ratio. First pivotal CAR-T trial in CLL to demonstrate high uMRD rates; registrational trial supporting FDA approval of liso-cel for R/R CLL.
Interventions and follow up
Regimen: Lisocabtagene maraleucel (liso-cel) 50–100 × 10⁶ CAR-T cells IV (single infusion) after lymphodepleting chemotherapy — R/R CLL/SLL with prior BTKi and venetoclax
Primary endpoint: CR/CRi rate (per iwCLL 2018) in the primary efficacy set
mFollow up: 21.1 months
Primary endpoint: CR/CRi rate (per iwCLL 2018) in the primary efficacy set
mFollow up: 21.1 months
Results
ORR (CLL cohort, N=89): 45%
CR/CRi: 20%
uMRD4 (peripheral blood): 63%
uMRD4 (bone marrow): 60%
mDOR (responders): Not reached
18-mo PFS: 45% (uMRD-negative) vs 19% (uMRD-positive)
ORR (Richter subset, N=23): 65%, CR 46%
CR/CRi: 20%
uMRD4 (peripheral blood): 63%
uMRD4 (bone marrow): 60%
mDOR (responders): Not reached
18-mo PFS: 45% (uMRD-negative) vs 19% (uMRD-positive)
ORR (Richter subset, N=23): 65%, CR 46%
Adverse events
CRS/Neurologic: Cytokine release syndrome any grade 85%, grade ≥3 9%; ICANS any grade 45%, grade ≥3 25%
Hematologic: Day-29 grade ≥3 cytopenias — neutropenia 69%, thrombocytopenia 44%, anemia 30%; B-cell aplasia in responders
Infections: Grade ≥3 infections 27%; one treatment-related death (infection)
Hematologic: Day-29 grade ≥3 cytopenias — neutropenia 69%, thrombocytopenia 44%, anemia 30%; B-cell aplasia in responders
Infections: Grade ≥3 infections 27%; one treatment-related death (infection)
Conclusions
Liso-cel achieved a 20% CR/CRi rate and high uMRD rates (63% peripheral blood) in heavily pretreated R/R CLL/SLL, with impressive activity in Richter transformation (65% ORR, 46% CR). Patients achieving uMRD negativity had markedly superior PFS, suggesting CAR-T can induce deep, potentially durable remissions in a subset double-exposed to BTKi and venetoclax.
Key Limitations
Single-arm design: No randomized comparator in a heterogeneous R/R population
Modest overall ORR/CR: Responses concentrated in uMRD-negative patients; CR rate 20%
Toxicity: High rates of grade ≥3 neurologic events and prolonged cytopenias limit applicability in frail patients
Modest overall ORR/CR: Responses concentrated in uMRD-negative patients; CR rate 20%
Toxicity: High rates of grade ≥3 neurologic events and prolonged cytopenias limit applicability in frail patients
Clinical Context
On the basis of TRANSCEND CLL 004, the FDA approved liso-cel (Breyanzi) in March 2024 for R/R CLL/SLL after ≥2 prior lines including a BTKi and a BCL-2 inhibitor — the first CAR-T approval in CLL. iwCLL increasingly recognizes uMRD as a deep-response endpoint. Liso-cel offers a one-time, potentially durable option for double-refractory CLL where treatment choices are limited.