Papp, Eniko

Patients in the liso-cel plus ibrutinib cohort of the phase 1/2, open-label TRANSCEND CLL 004 study had relapsed/refractory chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) and received liso-cel (50×106 [dose level (DL)1] or 100×106 [DL2] chimeric antigen receptor-positive T cells) with concurrent ibrutinib from enrollment through 90 days after liso-cel infusion or longer per investigator discretion. Primary end point was complete response/remission (CR)/CR with incomplete marrow recovery (CRi) by investigator assessment. Among 56 patients who received ibrutinib plus liso-cel (DL1, n=5; DL2, n=51), median (range) age was 64.5 years (44‒77), 98% had high-risk cytogenetics, 55% had progression on Bruton tyrosine kinase inhibitor and venetoclax failure, and median (range) number of prior therapies was 5 (1‒13). Median (range) follow-up was 24.8 months (3.1‒51.8). At DL2, CR/CRi rate was 45% (95% confidence interval [CI], 31‒60) and overall response rate was 86% (95% CI, 74‒94). Median (95% CI) duration of response was not reached (NR; 28.7‒NR) for patients with CR/CRi and 41.4 months (23.3‒NR) for all responders. Median (95% CI) progression-free survival was 31.4 months (20.1‒NR). In DL1+DL2, most common grade ≥3 treatment-emergent adverse events (TEAE) were neutropenia (52%) and anemia (41%). Cytokine release syndrome was reported in 80% of patients (grade 3, 4%; no grade 4/5), and neurological events in 41% (grade 3/4, 11%; no grade 5). Ibrutinib-related TEAEs were reported in 68% of patients (grade 3/4, 43%; no grade 5). Liso-cel plus ibrutinib demonstrated notable efficacy in patients with relapsed/refractory CLL/SLL with predictable and manageable safety. Clinicaltrials.gov: NCT03331198; NCT03435796.

Background: In TRANSCEND CLL 004 (NCT03331198),monotherapy with liso-cel, an autologous, CD19-directed CAR T cell product (100 × 106 CAR+ T cells [dose level (DL) 2]), resulted in 43% ORR and 18% CR/CR with incomplete marrow recovery (CRi) rate per IRC in pts with third-line or later R/R CLL/SLL who had PD on Bruton tyrosine kinase inhibitor (BTKi) and failed venetoclax (Siddiqi T, et al. Lancet 2023). Ibr + other CAR T cell therapies has shown high ORR and reduced cytokine release syndrome (CRS) severity in pts with R/R CLL/SLL. In the phase 1 dose-escalation ibr combination cohort, DL2 was the recommended dose of liso-cel for expansion (Wierda WG, et al. Blood 2020). Here, we report results of liso-cel + ibr in pts with R/R CLL/SLL from TRANSCEND CLL 004. Methods: Eligible pts ≥ 18 y of age with CLL/SLL had ≥ 1 of the following: 1) receiving BTKi with PD at entry, 2) high-risk disease and < CR after ≥ 6 mo on BTKi, 3) BTK/PLCγ2 mutation ± ibr PD, 4) prior BTKi with no contraindications to ibr, and 5) (per amendment) PD on BTKi and received prior venetoclax. At enrollment, pts started or continued ibr (420 mg daily or less for toxicity) through leukapheresis and for up to 90 d (or longer per investigator [inv]) after liso-cel (target dose of 50 × 106 CAR+ T cells [DL1] or DL2). Response was per inv by 2018 iwCLL criteria. Primary endpoint was CR/CRi rate at DL2; secondary endpoints included safety, ORR, duration of response (DOR), duration of CR/CRi (DOCR), time to response, time to CR/CRi, PFS, OS, and undetectable MRD (uMRD) rate in blood. Cellular kinetics was exploratory. Efficacy analyses were at DL2 and safety at DL1 + DL2. Treatment-emergent AEs (TEAE) occurred the latter of ≤ 90 days after liso-cel or ≤ 30 days of ibr completion. Liso-cel-treated pts who completed or withdrew from study could enroll in a separate long-term follow-up (LTFU) study (NCT03435796) for safety and OS ≤ 15 y after liso-cel. Results: A total of 65 pts underwent leukapheresis; 56 received ibr + liso-cel (DL1, n = 5; DL2, n = 51). At data cutoff (01/12/2024), 28 of 56 (50%) pts had discontinued the study, 11 (20%) completed the study, and 17 (30%) were ongoing; 5 of 28 (18%) eligible pts enrolled in LTFU. Median (IQR) on-study follow-up (including LTFU) was 24.8 mo (14.2-34.6). Median (range) age was 65 y (44-77); 55 (98%) pts had high-risk cytogenetics, such as del(17p) (n = 25), TP53 mutation (n = 24), and unmutated IGHV (n = 39); 43% had LDH ≥ ULN; and median (range) SPD was 27 cm2 (1-218). Pts had a median (range) of 5 (1-13) prior therapies (≤ 2, n = 13 [23%]). Median (range) time from leukapheresis to liso-cel availability was 25 d (17-79). Median (range) ibr exposure was 34 d (15-188) before and 94.5 d (6-1517) after liso-cel. At DL2, ORR (95% CI) was 86% (73.7-94.3), median (range) time to first response was 1.0 mo (0.9-6.0), and median (95% CI) DOR was 41.4 mo (23.3-not reached [NR]). CR/CRi rate (95% CI; primary endpoint) was 45% (31.1-59.7), median (range) time to first CR/CRi was 3.1 mo (0.9-12.1), and median (95% CI) DOCR was NR (26.6-NR). Median (95% CI) PFS and OS was 31.4 mo (20.1-NR) and NR (27.5-NR), respectively. uMRD rate (95% CI) in blood and marrow was 86% (73.7-94.3) and 84% (71.4-93.0), respectively. Grade (gr) ≥ 3 TEAEs occurred in 48 (86%) pts (most commonly neutropenia [52%] and anemia [41%]) with no gr 5 TEAEs. Liso-cel-related gr ≥ 3 TEAEs occurred in 32 (57%) pts and ibr-related gr ≥ 3 TEAEs in 24 (43%) pts including cardiovascular events of hypertension (7%) and atrial fibrillation (2%). Any-gr CRS occurred in 45 (80%) pts (gr ≥ 3, n = 2 [4%]) and any-gr neurological events (NE) in 23 (41%) pts (gr ≥ 3, n = 6 [11%]). Eight (14%) pts had gr ≥ 3 infections and 5 (9%) had second primary malignancies. Twenty-five (45%) pts had prolonged cytopenias (gr ≥ 3 at D30); most recovered to gr ≤ 2 by D90. Sixteen pts died after infusion (PD, n = 6; unknown, n = 6; COVID-19, n = 3; mixed septic/cardiogenic shock, n = 1). Liso-cel showed rapid expansion (median tmax, 10 d) and was detected up to 42 mo after infusion. Conclusions: Combined liso-cel + ibr demonstrated substantial efficacy with deep remissions (86% ORR, 45% CR rate, and 86% blood uMRD rate) and manageable safety in pts with R/R CLL/SLL. Though comparisons should be made with caution and there were differences in disease characteristics between cohorts, liso-cel + ibr showed a numerically higher ORR/CR rate and lower gr ≥ 3 CRS/NE rates vs liso-cel monotherapy, supporting the combination as a promising new therapeutic strategy for pts with R/R CLL/SLL.

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]