Lisocabtagene Maraleucel (liso-cel) in R/R CLL/SLL: 24-Month Median Follow-up of TRANSCEND CLL 004

Background: Patients with R/R CLL/SLL who experience intolerance to or disease progression after Bruton tyrosine kinase inhibitor (BTKi) and venetoclax treatment have no established standard of care and poor outcomes, indicating a critical unmet need. Liso-cel, an autologous, CD19-directed, 4-1BB CAR T cell product, has demonstrated efficacy in large B-cell lymphoma and CLL/SLL. In the primary analysis of the phase 1/2, single-arm, multicenter TRANSCEND CLL 004 (NCT03331198) study, a single administration of liso-cel demonstrated rapid, deep, and durable responses and a manageable safety profile in patients with R/R CLL/SLL, including those with progression on previous BTKi and venetoclax failure (Siddiqi T, et al. Lancet 2023). The primary endpoint was met in the prespecified subset of efficacy-evaluable patients with disease progression on BTKi and venetoclax failure (primary efficacy analysis set [PEAS]) at a target dose of 100 × 10⁶ CAR⁺ T cells (null hypothesis: ≤ 5%) with the rate of complete response/remission (CR) and CR with incomplete marrow recovery (CRi) by an independent review committee (IRC) per 2018 International Workshop on CLL (iwCLL) criteria at 18.4% (P = 0.0006). Here we report results from TRANSCEND CLL 004 with a median follow-up of 23.5 months.

Methods: Patients must have received ≥ 2 prior lines of therapy, including a BTKi. Eligible patients received liso-cel at a target dose of either 50 × 10⁶ (dose level [DL] 1) or 100 × 10⁶ (DL2) CAR⁺ T cells after lymphodepleting chemotherapy. The primary endpoint was CR/CRi in the PEAS at DL2. Key secondary endpoints were ORR and rate of undetectable MRD (uMRD; 10⁻⁴ by next-generation sequencing) in blood. All null hypotheses were tested at the primary analysis and not retested in this analysis.

Results: Of 137 leukapheresed patients, 118 received liso-cel (safety set), 97 (DL1 = 9; DL2 = 88) were efficacy evaluable, and 54 (DL1 = 4; DL2 = 50) were in the PEAS. In the safety set, median (range) age was 65 years (49–82), 83% had high-risk cytogenetics (del[17p], 42%; TP53 mutation, 47%; unmuted immunoglobulin heavy-chain variable gene, 47%; ≥ 3 chromosomal aberrations, 61%), median (range) lines of prior therapy was 5 (2–14), and all patients had prior BTKi. As of data cutoff (February 28, 2023), median (range) on-study follow-up was 23.5 months (0.4–59.6) for the safety set. In the PEAS at DL2, CR/CRi rate was 20% (95% CI, 10.0–33.7; Table 1). ORR was 44% (95% CI, 30.0–58.7). One patient who had best overall response (BOR) of partial response/remission (PR) at primary analysis had deepened to CR/CRi at 18 months without any additional therapy. Of 9 patients who had BOR of CR/CRi at the primary analysis, 8 had ongoing CR/CRi and 1 completed the study with the last assessment as CR/CRi. The uMRD rate was 64% (95% CI, 49.2–77.1) in blood and 60% (95% CI, 45.2–73.6) in marrow. Median (95% CI) duration of response was 35.3 months (12.4–not reached [NR]) and median duration of CR/CRi was NR. Median (95% CI) PFS was 11.9 months (5.7–26.2). Median (95% CI) OS was 30.3 months (15.0–NR). The efficacy outcomes were similar in the full population at DL2. Of 16 patients who had BOR of CR/CRi at primary analysis, 10 had ongoing CR/CRi. In the safety set, rates of any-grade and grade ≥ 3 treatment-emergent AEs were similar across age groups (Table 2). The rate of any-grade cytokine release syndrome (CRS) was 85% (grade 3, 8%; no grade 4/5) and neurological events (NE) was 45% (grade 3, 18%; grade 4, 1%; no grade 5); 69% received tocilizumab and/or corticosteroids for CRS/NEs. Median (range) time to onset and resolution was 4 days (1–18) and 6 days (2–37) for CRS and 7 days (1–21) and 7 days (1–83) for NEs, respectively. Prolonged cytopenia (grade ≥ 3 at Day 30 after liso-cel infusion), grade ≥ 3 infections, hypogammaglobulinemia, tumor lysis syndrome, second primary malignancy, and macrophage activation syndrome occurred in 54%, 18%, 15%, 11%, 9%, and 3%, respectively. Forty-five (33%) of 137 leukapheresed patients died after liso-cel infusion (disease progression, n = 27 [20%]; AE, n = 6 [4%]; other reasons, n = 12 [9%]).

Conclusions: With longer follow-up, liso-cel continued to demonstrate durable CR/CRi, high uMRD rates, and a manageable safety profile in patients with heavily pretreated, high-risk R/R CLL/SLL. The safety results from longer follow-up were similar to those reported in the primary analysis with no new safety signals and were consistent across age groups.