Papp, Eniko

Background: The primary analysis of the phase 1/2, single-arm, multicenter TRANSCEND CLL 004 (NCT03331198) study with a median follow-up of 21.1 mo showed that a single administration of liso-cel achieved rapid, deep, and durable responses and a manageable safety profile in pts with heavily pretreated, high-risk R/R CLL/SLL, including those with progression on a previous Bruton tyrosine kinase inhibitor (BTKi) and venetoclax failure (primary efficacy analysis set [PEAS]; Siddiqi T, et al. Lancet 2023). With 5 mo of additional follow-up (median of 23.5 mo), liso-cel continued to demonstrate durable CR/CR with incomplete marrow recovery (CRi) and high undetectable MRD (uMRD; 10−4 by next-generation sequencing) rates with no new safety signals. Median duration of response (DOR) was 35.3 mo (95% CI, 12.4-not reached [NR]), and median OS was 30.3 mo (95% CI, 15.0-NR) (Siddiqi T, et al. Blood 2023). Here, we report updated results from TRANSCEND CLL 004 with 16 mo of additional follow-up since primary analysis and a median on-study follow-up of 23.8 mo (range, 0.4-59.6). Methods: Pts must have received ≥ 2 prior lines of therapy (LOTs), including a BTKi (full population). Eligible pts 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 per independent review committee in the PEAS at DL2. Key secondary endpoints were ORR and blood uMRD rate. All pts who received liso-cel and completed or discontinued early from the study were asked to enroll in a separate long-term follow-up (LTFU) study (NCT03435796) assessing safety and OS for up to 15 y after liso-cel. Results: As of the data cutoff (01/12/2024), 118 of 137 leukapheresed pts received liso-cel (safety set), 97 (DL1, n = 9; DL2, n = 88) were efficacy evaluable, and 54 (DL1, n = 4; DL2, n = 50) were in the PEAS. A total of 22 pts were ongoing in TRANSCEND CLL 004, and 19 of 60 eligible pts enrolled to the LTFU study. In the safety set, pts had a median age of 65 y (range, 49-82), and 83% had high-risk cytogenetic markers (del[17p], 42%; TP53 mutation, 47%; unmutated immunoglobulin heavy-chain variable gene, 47%). Median prior LOTs was 5 (range, 2-14); 86% of pts had prior chemoimmunotherapy. In the PEAS at DL2, CR/CRi rate remained at 20%, ORR at 44%, blood uMRD rate at 64%, and marrow uMRD rate at 60%. Median DOR was NR (95% CI, 12.4-NR), with a median follow-up of 31.7 mo (95% CI, 21.3-35.5). Estimated 36-mo DOR rate was 61% (95% CI, 30-81). Median (95% CI) DOR was NR in pts with CR/CRi. Median (95% CI) PFS was 11.9 mo (5.7-26.2) overall, 26.2 mo (11.9-NR) in pts with blood uMRD, and 2.8 mo (0.8-3.2) in pts with detectable blood MRD. Median OS, including 19 pts in the LTFU, was 43.2 mo (95% CI, 14.5-NR). Efficacy outcomes were similar in the full population at DL2. A subgroup of 23 pts who had only prior BTKi exposure and were venetoclax naïve was less heavily pretreated, with a median of 3 prior LOTs (range, 2-11); all pts had prior chemoimmunotherapy. In the efficacy-evaluable pts of this subgroup at DL2 (n = 18), the CR/CRi rate was 22%; ORR was 61%; and median (95% CI) DOR was NR (17.1-NR), PFS was NR (18.0-NR), and OS was 52.2 mo (26.9-NR). In the safety set, rates of any-grade/grade ≥ 3 cytokine release syndrome (85%/8%), any-grade/grade ≥ 3 neurological events (45%/19%), prolonged cytopenia (grade ≥ 3 at Day 30 after liso-cel infusion [54%]), grade ≥ 3 infections (18%), and second primary malignancy (9%) remained the same as previously reported (Siddiqi T, et al. Blood 2023); most pts with prolonged cytopenia had resolution to grade ≤ 2 by Month 3. Forty-six (34%) of 137 leukapheresed pts died after CAR T cell infusion, including 1 additional pt since the previous report with an unknown cause of death at ~14.5 mo after infusion. Persistence of the liso-cel transgene was detected up to 48 months after liso-cel infusion (2/5 evaluable pts at DL2 at Month 48). Conclusions: In this updated follow-up, liso-cel continued to demonstrate durable responses with an extended median OS of 43.2 mo in pts with R/R CLL/SLL. The safety results were similar to those previously reported with no new safety signals. These data confirm the sustained clinical benefit and favorable benefit-to-risk profile of a single treatment of liso-cel in pts with R/R CLL/SLL.

7501 Background: In patients (pts) with R/R CLL/SLL that progressed on BTKi and failed venetoclax (ven)-based regimens, achieving CR with current treatment is uncommon. New therapies that achieve deep and durable responses are needed. We report the primary analysis of the phase 1/2, single-arm, multicenter TRANSCEND CLL 004 (NCT03331198) study evaluating liso-cel in pts with R/R CLL/SLL. Methods: Pts must have received at least 2 prior lines of therapy, including a BTKi. Eligible pts received liso-cel at a target dose of either 50 (DL1) or 100 (DL2) × 106 CAR+ T cells. The primary endpoint was rate of CR and CR with incomplete marrow recovery (CRi) by IRC per 2018 iwCLL criteria in the prespecified subset of efficacy-evaluable pts with disease progression on BTKi and ven failure (primary efficacy analysis set [PEAS]) at DL2 (null hypothesis [H0]: ≤ 5%). Key secondary endpoints were ORR (H0: ≤ 40%) and rate of undetectable minimal residual disease (uMRD; 10−4) in blood (H0: ≤ 5%). Results: Of 137 leukapheresed pts, 117 received liso-cel (safety set), 96 (DL1 = 9; DL2 = 87) were efficacy evaluable, and 53 (DL1 = 4; DL2 = 49) were in the PEAS. In the safety set, median (range) age was 65 y (49–82), 83% had high-risk features, median (range) lines of prior therapy was 5 (2–12), and all pts had prior BTKi. Median (range) on-study follow-up was 21.1 mo (0.4–55.6) for the safety set. In the PEAS at DL2, the primary endpoint of CR/CRi rate was met at 18.4% (95% CI, 8.8–32.0; 1-sided P = 0.0006; Table). ORR was 42.9% and was not statistically significant (95% CI, 28.8–57.8; 1-sided P = 0.3931). The uMRD rate was 63.3% in blood and 59.2% in marrow. Median (95% CI) DOR was 35.3 mo (11.01–not reached [NR]) with a median follow-up of 19.7 mo. Median duration of CR/CRi was NR. In the safety set, rate of any-grade CRS was 84.6% (gr 3, 8.5%; no gr 4/5) and neurological events (NE) was 45.3% (gr 3, 17.9%; gr 4, 0.9%; no gr 5); 69.2% received tocilizumab and/or corticosteroids for CRS/NEs. Rate of gr ≥ 3 infections, hypogammaglobulinemia, and prolonged cytopenia was 17.1%, 15.4%, and 53.8%, respectively. One death related to liso-cel was due to hemophagocytic lymphohistiocytosis. Liso-cel exhibited rapid in vivo expansion and was detected by qPCR in blood up to 36 mo after infusion. Conclusions: Liso-cel demonstrated durable CR/CRi, high uMRD rates, and a manageable safety profile in pts with heavily pretreated, high-risk R/R CLL/SLL and high unmet need. Clinical trial information: NCT03331198 . [Table: see text]