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Background: In the primary analysis of the pivotal JULIET trial of tisagenlecleucel, an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, the best overall response rate was 52% and the complete response rate was 40% in 93 evaluable adult patients with relapsed or refractory aggressive B-cell lymphomas. We aimed to do a long-term follow-up analysis of the clinical outcomes and correlative analyses of activity and safety in the full adult cohort., Methods: In this multicentre, open-label, single-arm, phase 2 trial (JULIET) done at 27 treatment sites in ten countries (Australia, Austria, Canada, France, Germany, Italy, Japan, the Netherlands, Norway, and the USA), adult patients (≥18 years) with histologically confirmed relapsed or refractory large B-cell lymphomas who were ineligible for, did not consent to, or had disease progression after autologous haematopoietic stem-cell transplantation, with an Eastern Cooperative Oncology Group performance status of 0-1 at screening, were enrolled. Patients received a single intravenous infusion of tisagenlecleucel (target dose 5 × 10 8 viable transduced CAR T cells). The primary endpoint was overall response rate (ie, the proportion of patients with a best overall disease response of a complete response or partial response using the Lugano classification, as assessed by an independent review committee) at any time post-infusion and was analysed in all patients who received tisagenlecleucel (the full analysis set). Safety was analysed in all patients who received tisagenlecleucel. JULIET is registered with ClinialTrials.gov, NCT02445248, and is ongoing., Findings: Between July 29, 2015, and Nov 2, 2017, 167 patients were enrolled. As of Feb 20, 2020, 115 patients had received tisagenlecleucel infusion and were included in the full analysis set. At a median follow-up of 40·3 months (IQR 37·8-43·8), the overall response rate was 53·0% (95% CI 43·5-62·4; 61 of 115 patients), with 45 (39%) patients having a complete response as their best overall response. The most common grade 3-4 adverse events were anaemia (45 [39%]), decreased neutrophil count (39 [34%]), decreased white blood cell count (37 [32%]), decreased platelet count (32 [28%]), cytokine release syndrome (26 [23%]), neutropenia (23 [20%]), febrile neutropenia (19 [17%]), hypophosphataemia (15 [13%]), and thrombocytopenia (14 [12%]). The most common treatment-related serious adverse events were cytokine release syndrome (31 [27%]), febrile neutropenia (seven [6%]), pyrexia (six [5%]), pancytopenia (three [3%]), and pneumonia (three [3%]). No treatment-related deaths were reported., Interpretation: Tisagenlecleucel shows durable activity and manageable safety profiles in adult patients with relapsed or refractory aggressive B-cell lymphomas. For patients with large B-cell lymphomas that are refractory to chemoimmunotherapy or relapsing after second-line therapies, tisagenlecleucel compares favourably with respect to risk-benefit relative to conventional therapeutic approaches (eg, salvage chemotherapy)., Funding: Novartis Pharmaceuticals., Competing Interests: Declaration of interests SJS is an adviser or consultant for Acerta, AlloGene, AstraZeneca, BeiGene, Celgene (Juno), Genentech (Roche), LoxoOncology, Novartis, and Tessa Therapeutics; reports honoraria from Acerta, AlloGene, AstraZeneca, BeiGene, Celgene, Genentech (Roche), LoxoOncology, Novartis, Nordic Nanovector, Pfizer, and Tessa Therapeutics; reports steering committee participation for AbbVie, Celgene, Novartis, Juno, Nordic Nanovector, and Pfizer; reports research support from AbbVie, Acerta, Celgene (Juno), DTRM Bio, Genentech, Incyte, Merck, Novartis, Portola, and TG Therapeutics; and reports a patent with Novartis. CST reports honoraria from AbbVie, BeiGene, Janssen, Novartis, and Roche, and research support from AbbVie and Janssen. NW reports personal fees from Celgene (Bristol Myers Squibb), Kite (Gilead), and Novartis, and travel support from Celgene and Novartis. JPM is a consultant for Juno; reports honoraria from AlloVir, Juno, and Kite; reports research support from AlloVir, Astellas, Bellicum, Fresenius Biotech, Gamida Cell, Juno, Kite, Novartis, and Pluristem; reports participation on a speakers bureau for Kite; and reports assistance with manuscript preparation from ArticulateScience. HH is an adviser or consultant for Gilead, Roche, Nordic Nanovector, Novartis, and Takeda, and reports honoraria from Novartis. EKW is an adviser or consultant for Cambium Medical Technologies, Celldex, Novartis, Partner Therapeutics, cyclics, and Verastem; reports research support from Amgen, Celldex, Juno, Novartis, and Partner Therapeutics; and owns stocks in Cambium Medical Technologies and Cambium Oncology. SJ reports research support from Kite and Novartis, and personal fees from Juno, Kite, and CRISPR Therapeutics. MRB is a consultant for Celgene, CRISPR Therapeutics, Juno, Kite, and Novartis; reports research support from Novartis; and reports participation on speakers bureaus for Celgene and Kite. SRF reports personal fees from Novartis. JRW is an adviser or consultant for Celgene, Curis, Genentech, Janssen, Juno, Kite, MorphoSys, and Novartis, and reports research support from Celgene, Curis, Forty Seven, Genentech, Janssen, Kite, Novartis, and Unum. IF is an adviser or consultant for AbbVie, AstraZeneca, Gilead, Janssen, Novartis, Roche, and Seattle Genetics, and reports honoraria from AbbVie, Gilead, Janssen, Novartis, Roche, and Seattle Genetics. PJH reports travel support from Celgene, Janssen, La Jolla, and Novartis. SM is an adviser or consultant for Merck and Novartis; reports research support from Kiadis Pharma; reports speaker fees from Celgene, Cellex, DNA Prime, Jazz Pharma, Kiadis Pharma, Miltenyi Biotec, and Novartis; reports participation in an expert panel for Bellicum and Kite (Gilead); reports participation in a data and safety monitoring board for Miltenyi Biotec; and reports travel support from Celgene, Cellex, the European Hematology Association and the European Society for Blood and Marrow Transplantation, the German Society of Hematology and Medical Oncology, the International Society for Cellular Therapy, Kiadis Pharma, Kite (Gilead), Merck, and Miltenyi Biotec. TT is an adviser or consultant for Merck, Novartis, and Takeda; reports honoraria from Bristol Myers Squibb, Fuji Pharma, Kyowa Kirin, Merck, Nippon Shinyaku, Pfizer, Takeda, and Teijin Pharma; reports research support from Astellas, Chugai, Kyowa Kirin, Novartis, and Sanofi; reports grants from the Japan Society for the Promotion of Science and the Japan Science and Technology Agency; and reports assistance with manuscript preparation from Janssen and Novartis. GS is an adviser or consultant for AbbVie, Allogene, Autolus, BeiGene, Celgene, Epizyme, Genmab, Janssen, Kite (Gilead), Merck, MorphoSys, Novartis, Roche, and VelosBio, and reports honoraria from AbbVie, Amgen, Bristol Myers Squibb, Celgene, Epizyme, Janssen, Kite (Gilead), Merck, MorphoSys, Novartis, and Roche. KI reports grants from Celgene, Daiichi Sankyo, and Novartis, and personal fees from Celgene and Novartis. MJK is an adviser or consultant for, and reports travel support from, Amgen, Bristol Myers Squibb, Celgene, Janssen, Kite (Gilead), Merck, Miltenyi Biotec, Novartis, and Roche, and reports research support from Celgene, Roche, and Takeda. NW-J is an adviser or consultant for ADC Therapeutics, Bayer, Epizyme, Gilead, Grünenthal, Janssen, Karyopharm, and Regeneron, and reports research support from ADC Therapeutics, Astex, Juno, and Regeneron. KK is an adviser or consultant for AbbVie, AstraZeneca, Celgene, Chugai, Eisai, Janssen, and Novartis; reports honoraria from Celgene, Chugai, Janssen, Kyowa Kirin, Merck, Mundi, Novartis, Ono, Sumitomo Dainippon, and Takeda; and reports research support from AbbVie, Celgene, Chugai, Eisai, Janssen, Kyowa Kirin, Ono, Novartis, and Takeda. MM-P, XH, and RT are employees of Novartis. RTM is an adviser or consultant for AlloVir, Artiva, CRISPR Therapeutics, CytoDyn, Incyte, and Novartis; reports honoraria from Bristol Myers Squibb (Celgene), Incyte, Intellia, Kite, Omeros, Orca BioSystems, and PACT Pharma; reports research support from Juno and Novartis; reports participation in a data and safety monitoring board for Athersys and Novartis; and has a patent with Athersys. All other authors declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)