Background: Patients with relapsed or refractory chronic lymphocytic leukaemia or small lymphocytic lymphoma for whom treatment has failed with both Bruton tyrosine kinase (BTK) inhibitor and venetoclax have few treatment options and poor outcomes. We aimed to evaluate the efficacy and safety of lisocabtagene maraleucel (liso-cel) at the recommended phase 2 dose in patients with relapsed or refractory chronic lymphocytic leukaemia or small lymphocytic lymphoma., Methods: We report the primary analysis of TRANSCEND CLL 004, an open-label, single-arm, phase 1-2 study conducted in the USA. Patients aged 18 years or older with relapsed or refractory chronic lymphocytic leukaemia or small lymphocytic lymphoma and at least two previous lines of therapy, including a BTK inhibitor, received an intravenous infusion of liso-cel at one of two target dose levels: 50 × 10 6 (dose level 1) or 100 × 10 6 (dose level 2, DL2) chimeric antigen receptor-positive T cells. The primary endpoint was complete response or remission (including with incomplete marrow recovery), assessed by independent review according to the 2018 International Workshop on Chronic Lymphocytic Leukemia criteria, in efficacy-evaluable patients with previous BTK inhibitor progression and venetoclax failure (the primary efficacy analysis set) at DL2 (null hypothesis of ≤5%). This trial is registered with ClinicalTrials.gov, NCT03331198., Findings: Between Jan 2, 2018, and June 16, 2022, 137 enrolled patients underwent leukapheresis at 27 sites in the USA. 117 patients received liso-cel (median age 65 years [IQR 59-70]; 37 [32%] female and 80 [68%] male; 99 [85%] White, five [4%] Black or African American, two [2%] other races, and 11 [9%] unknown race; median of five previous lines of therapy [IQR 3-7]); all 117 participants had received and had treatment failure on a previous BTK inhibitor. A subset of patients had also experienced venetoclax failure (n=70). In the primary efficacy analysis set at DL2 (n=49), the rate of complete response or remission (including with incomplete marrow recovery) was statistically significant at 18% (n=9; 95% CI 9-32; p=0·0006). In patients treated with liso-cel, grade 3 cytokine release syndrome was reported in ten (9%) of 117 (with no grade 4 or 5 events) and grade 3 neurological events were reported in 21 (18%; one [1%] grade 4, no grade 5 events). Among 51 deaths on the study, 43 occurred after liso-cel infusion, of which five were due to treatment-emergent adverse events (within 90 days of liso-cel infusion). One death was related to liso-cel (macrophage activation syndrome-haemophagocytic lymphohistiocytosis)., Interpretation: A single infusion of liso-cel was shown to induce complete response or remission (including with incomplete marrow recovery) in patients with relapsed or refractory chronic lymphocytic leukaemia or small lymphocytic lymphoma, including patients who had experienced disease progression on a previous BTK inhibitor and venetoclax failure. The safety profile was manageable., Funding: Juno Therapeutics, a Bristol-Myers Squibb Company., Competing Interests: Declaration of interests TS discloses institutional support to conduct this study and manuscript writing support for this manuscript from Bristol Myers Squibb (BMS); fees for speakers’ bureaus from BMS, AstraZeneca, and BeiGene; participation on a data safety monitoring board for BeiGene; participation on an advisory board for AbbVie, BeiGene, BMS, Celgene, a BMS Company, AstraZeneca, and Gilead. DGM discloses institutional research funding from Kite, Juno Therapeutics, a BMS Company, Celgene, a BMS Company, Legend Biotech, and BMS; consulting fees from A2 Biotherapeutics, Navan Technologies, Chimeric Therapeutics, Genentech, BMS, ImmPACT Bio, Gilead Sciences, and Interius; rights to royalties from Fred Hutchinson Cancer Research Center for patents licensed to Juno Therapeutics, a BMS Company; advisory boards for BMS, Caribou Biosciences, Celgene, a BMS Company, Genentech, Incyte, Janssen, Juno Therapeutics, a BMS Company, Mustang Bio, MorphoSys, Kite, Lilly, Novartis, and Umoja; and stock options from A2 Biotherapeutics and Navan Technologies. SSK discloses grants or contracts from Novartis, Kite/Gilead, Juno Therapeutics, a BMS Company, Lentigen, Humanigen, MorphoSys, Tolero Pharmaceuticals, Sunesis Pharmaceuticals/Viracta Therapeutics, and LEAH Labs; royalties or licences from Novartis, Humanigen, Mettaforge Therapeutics, Sendero, and Mustang Bio; participation on a scientific advisory board for Kite, Juno Therapeutics, a BMS Company, Novartis, Humanigen, Calibr, Torque, Capstan Therapeutics, Lentigen, LEAH Labs, and Luminary Therapeutics; participation on a data safety monitoring board for Humanigen; and research funding from Novartis, Kite/Gilead, Juno Therapeutics, a BMS Company, Lentigen, Humanigen, MorphoSys, Tolero Pharmaceuticals, Sunesis Pharmaceuticals/Viracta Therapeutics, and LEAH Labs. DMB discloses grants paid to their institution (Duke University) and the role of site principal investigator for clinical trials from AbbVie, ArQule/Merck, Ascentage, Acerta, BeiGene, Catapult, DTRM Biopharma, Genentech, Celgene, a BMS Company, Juno Therapeutics, a BMS Company, BMS, MEI Pharma, Newave, Novartis, and TG Therapeutics; consulting fees from Genentech, AbbVie, and Pharmacyclics; participation on a panel of the National Comprehensive Cancer Network for chronic lymphocytic leukaemia or small lymphocytic lymphoma and hairy cell leukaemia, a registry steering committee for informCLL (Pharmacyclics) and CORE (AbbVie), and an expert medical council for Chronic Lymphocytic Leukemia Society (unpaid), and being a leukaemia committee member and trial champion of S1925 for Alliance in Clinical Trials (unpaid); and writing support for abstracts or manuscripts from AbbVie, BeiGene, Pharmacyclics, and TG Therapeutics. KD discloses institutional research funding for this study from BMS; institutional grants or contracts from BMS, Kite/Gilead, and Genmab; consulting fees for participation on an advisory board for BMS; and honoraria for participation in American Society of Hematology Congress Connect. JS discloses consulting fees from AbbVie, AstraZeneca, BeiGene, BMS, Roche, Seattle Genetics, and TG Therapeutics; and research funding paid to their institution from Adaptive Biotechnologies, BeiGene, BostonGene, Genentech/Roche, GlaxoSmithKline, Moderna, Takeda, and TG Therapeutics. PAR discloses consulting fees from AbbVie, BMS, Janssen, Novartis, BeiGene, Kite/Gilead, Intellia Therapeutics, Sana Biotechnology, CVS Caremark, Genmab, Pharmacyclics, Takeda, Karyopharm Therapeutics, Nektar Therapeutics, Nurix Therapeutics, and ADC Therapeutics; honoraria from Kite/Gilead; and support for attending meetings or travel from Nektar Therapeutics. NNS discloses support for this manuscript from Juno Therapeutics, a BMS Company; research funding from Loxo@Lilly and Miltenyi Biotec; consulting fees from Loxo@Lilly and Miltenyi Biotec; participation on a data safety monitoring board for Incyte; participation on an advisory board for Epizyme, Janssen, Kite Pharma, Incyte, Seattle Genetics, Novartis, Juno Therapeutics, a BMS Company, TG Therapeutics, and Umoja Biopharma; travel support from Loxo@Lilly and Miltenyi Biotec; stock or stock options from Tundra Targeted Therapeutics; and is a scientific advisory board member and founder of Tundra Targeted Therapeutics. RN discloses consulting fees from Actinium Pharmaceuticals; consulting fees for participation on an advisory board for Incyte; and stock or stock options from Pfizer. BF discloses research funding from BMS; consulting fees from AbbVie, Adaptive Biotechnologies, AstraZeneca, BeiGene, BMS, Genentech, Genmab, Loxo@Lilly, Pharmacyclics, and TG Therapeutics; honoraria from Curio Science and Medscape; support for attending meetings or travel from AbbVie and Loxo@Lilly; and participation on a guideline panel for chronic lymphocytic leukaemia and hairy cell leukaemia for the National Comprehensive Cancer Network (unpaid). DMS discloses grants or contracts from Celgene, a BMS Company, Novartis, AstraZeneca, Merck, MingSight Pharmaceuticals, and Newave; consulting fees from Lilly, Genentech, Pharmacyclics/Janssen, Karyopharm Therapeutics, BeiGene, Innate Pharma, AstraZeneca, AbbVie, CSL Behring, Celgene, a BMS Company, TG Therapeutics, and Innate Pharma; and research funding from Acerta Pharma, Gilead Sciences, Karyopharm Therapeutics, MingSight Pharmaceuticals, ArQule, Novartis, Verastem Oncology, and Juno Therapeutics, a BMS Company. SM discloses institutional funding from Juno Therapeutics, a BMS Company, BeiGene, Loxo@Lilly, AstraZeneca, and AbbVie; consulting fees from TG Therapeutics; honoraria from AstraZeneca, BeiGene, Janssen, Lilly, and Pharmacyclics; and participation on a data safety monitoring board or advisory board for AbbVie, AstraZeneca, BeiGene, BMS, Genentech, and Janssen. TF discloses consulting fees from Seattle Genetics, BMS, Genmab, ADC Therapeutics, and AstraZeneca; speakers’ bureau fees from Seattle Genetics and Kite; travel expenses from Seattle Genetics and Takeda; honoraria from Seattle Genetics, Pharmacyclics/Janssen, AbbVie, BMS, Kite, Bayer, and Takeda; and research funding from BMS, Seattle Genetics, Portola Pharmaceuticals, Eisai, Kyowa Kirin, Amgen, Viracta Therapeutics, Cell Medica, Roche, Trillium Therapeutics, and Pfizer. SJS discloses consulting fees from Caribou Biosciences, Genentech/Roche, Genmab, Kite Pharma, Incyte, Legend Biotech, MorphoSys, Mustang Bio, Nordic Nanovector, and Novartis; honoraria from Novartis and Takeda; a patent for combination therapies of chimeric antigen receptor and programmed cell death protein-1 inhibitors licensed to Novartis; research funding from Merck and Genentech/Roche; and travel accommodations from Genentech/Roche and Novartis. SKP is an employee of BMS and a shareholder of BMS and Autolus. SAT, S-SO, EP, LP, and YC are employees and shareholders of BMS. WGW discloses travel expenses from AbbVie, Genentech, and Eli Lilly; and research funding from AbbVie, Acerta Pharma, BMS, Cyclacel Pharmaceuticals, Genentech, Gilead Sciences, GlaxoSmithKline, Loxo@Lilly, Novartis, and Oncternal Therapeutics. SRS declares no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)