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.

Disclosures

Siddiqi:BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Beigene: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Gilead: Other: Ad board; Astra Zeneca: Speakers Bureau. Gauthier:Sobi, Legend Biotech, Janssen, Kite Pharma, MorphoSys: Honoraria; Sobi, Juno Therapeutics (a BMS company), Celgene (a BMS company), Angiocrine Bioscience, Faron Pharmaceuticals, CARGO therapeutics: Research Funding; Century Therapeutics: Other: Independent Data Review Committee. Kenderian:Novartis, Kite/Gilead, Juno/BMS, Capstan, Humanigen, Carisma: Membership on an entity's Board of Directors or advisory committees; Kite/Gilead, Novartis, Carisma, Juno/BMS, Humanigen, Luminary: Consultancy; Novartis, Humanigen, MustangBio,: Patents & Royalties; Novartis, Kite/Gilead, Juno/BMS, Lentigen, Humanigen, Morphosys, Tolero, LeahLabs, InCyte, Viracta: Research Funding. Brander:BeiGene: Consultancy, Other: site PI clinical trial (grant paid to institution); Catapult: Other: site PI clinical trial (grant paid to institution); DTRM: Other: site PI clinical trial (grant paid to institution); Genentech: Consultancy, Other: site PI clinical trial (grant paid to institution); Juno/Celegene/BMS: Other: site PI clinical trial (grant paid to institution); NeWave: Other: site PI clinical trial (grant paid to institution); Nurix: Other: site PI clinical trial (grant paid to institution); Pharmacyclics: Consultancy, Other: site PI clinical trial (grant paid to institution); TG therapeutics: Other: site PI clinical trial (grant paid to institution); BMS: Other; AstraZeneca/Acereta: Other: site PI clinical trial (grant paid to institution); ArQule/Merck: Other: site PI clinical trial (grant paid to institution); AbbVie: Consultancy, Other: site PI clinical trial (grant paid to institution). Dorritie:Janssen: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Genmab: Research Funding; Kite-Gilead: Research Funding; Hoffman La-Roche: Research Funding. Soumerai:Takeda: Research Funding; Moderna: Research Funding; TG Therapeutics: Research Funding; LOXO@Lilly: Consultancy; Adaptive Biotechnologies: Research Funding; Roche/Genentech: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy; BostonGene: Research Funding; Beigene: Consultancy, Research Funding; GlaxoSmithKline: Research Funding; AstraZeneca: Consultancy, Honoraria, Research Funding. Riedell:Genmab: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Nektar Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; BeiGene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Intellia Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Cellectis: Research Funding; Sana Biotechnology: Consultancy, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Fate Therapeutics: Research Funding; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Tessa Therapeutics: Research Funding; Cargo Therapeutics: Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech/Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kite/Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; CRISPR Therapeutics: Research Funding; Calibr: Research Funding; CVS Caremark: Consultancy, Membership on an entity's Board of Directors or advisory committees; Xencor: Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Honoraria. Shah:Tundra Therapeutics: Current holder of stock options in a privately-held company; Miltenyi Biomedicine, Lilly Oncology: Research Funding; Gilead-Kite, BMS-Juno, Miltenyi, Lilly Onclogy, Novartis, Seattle Genetics, Janssen, Abbvie, Cargo, Beigene, Galapagos, AstraZeneca: Honoraria. Nath:Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy, Honoraria; Bristol Myers Squib: Consultancy, Honoraria; Autolus: Consultancy, Honoraria; Allogene: Consultancy, Honoraria; ADC Therapeutics: Consultancy, Honoraria; Actinium: Membership on an entity's Board of Directors or advisory committees. Andreadis:Novartis: Research Funding; Merck: Research Funding; Astra Zeneca: Consultancy; Gilead/Kite: Consultancy; Genmab: Research Funding; Abbvie: Consultancy; BMS: Consultancy; Seattle Genetics: Consultancy; Roche: Research Funding. Ermann:AstraZeneca: Speakers Bureau; Beigene, ADC therapeutics: Consultancy. Ma:Juno: Research Funding; Janssen: Consultancy; Lilly: Research Funding, Speakers Bureau; BeiGene: Consultancy, Research Funding, Speakers Bureau; AstraZeneca: Consultancy, Research Funding, Speakers Bureau; AbbVie: Consultancy, Honoraria, Research Funding. Feldman:Seagen: Consultancy, Speakers Bureau; AbbVie, AstraZeneca, Epizyme, Genmab, Gilead/Kite, Karyopharm, Takeda: Consultancy. Schuster:AbbVie: Consultancy; Pharmacyclics: Consultancy, Research Funding; Nordic Nanovector: Honoraria, Membership on an entity's Board of Directors or advisory committees; Kite Pharmaceuticals: Consultancy; Janssen: Consultancy, Honoraria, Research Funding; Gilead: Research Funding; Celgene/Juno Therapeutics: Consultancy, Honoraria, Research Funding; Genentech/Roche: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; viTToria biotherapeutics: Consultancy; AstraZeneca: Consultancy, Honoraria; Caribou Biosciences: Consultancy, Membership on an entity's Board of Directors or advisory committees; BioNTech: Consultancy; BeiGene: Consultancy, Honoraria; Genmab: Consultancy; Legend Biotech: Consultancy, Honoraria; Merck: Research Funding; Acerta: Consultancy. Tuazon:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Perna:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Ou:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Rane:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Papp:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Chen:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Wierda:BMS: Research Funding; Nurix Therapeutics: Research Funding; Kite: Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; Cyclacel Pharmaceuticals Inc: Research Funding; Loxo Oncology: Research Funding; Oncternal Therapeutics: Research Funding; AbbVie: Research Funding; Janssen: Research Funding; Eli Lilly: Research Funding; Oncternal Therapeutics: Research Funding; AstraZeneca: Research Funding; Accutar Biotechnology: Research Funding; GSK: Research Funding; Gilead Sciences: Research Funding; Genentech, Inc.: Research Funding; Numab Therapeutics: Research Funding; Juno Therapeutics: Research Funding; Novartis: Research Funding; Acerta Pharma: Research Funding; F. Hoffmann-La Roche Ltd.: Research Funding; National Comprehensive Care Center (NCCN): Other: Financial relationship (Chair, CLL).

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2024
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