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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.)

Purpose: Combined-modality treatment (CMT) with 2× ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) and small-field radiotherapy is standard of care for patients with early-stage favorable Hodgkin lymphoma (HL). However, the role of radiotherapy has been challenged. Positron emission tomography (PET) after 2× ABVD (PET-2) might help to predict individual outcomes and guide treatment., Methods: Between November 2009 and December 2015, we recruited patients age 18 to 75 years with newly diagnosed, early-stage favorable HL for this international randomized phase III trial. Patients were assigned to standard CMT of 2× ABVD and 20-Gy involved-field radiotherapy or PET-guided treatment, omitting involved-field radiotherapy after negative PET-2 (Deauville score < 3). Primary objectives were to exclude inferiority of 10% or more in 5-year progression-free survival (PFS) of ABVD alone compared with CMT in a per-protocol analysis among PET-2-negative patients (noninferiority margin for hazard ratio, 3.01) and to confirm PET-2 positivity (Deauville score ≥ 3) as a risk factor for PFS among CMT-treated patients., Results: We enrolled 1,150 patients. Median follow-up was 45 months. Among 628 PET-2-negative, per-protocol-treated patients, 5-year PFS was 93.4% (95% CI, 90.4% to 96.5%) with CMT and 86.1% (95% CI, 81.4% to 90.9%) with ABVD (difference 7.3% [95% CI, 1.6% to 13.0%]; hazard ratio, 1.78 [95% CI, 1.02 to 3.12]). Five-year overall survival was 98.1% (95% CI, 96.5% to 99.8%) with CMT and 98.4% (95% CI, 96.5% to 100.0%) with ABVD. Among 693 patients who were assigned to CMT, 5-year PFS was 93.2% (95% CI, 90.2% to 96.2%) among PET-2-negative patients and 88.4% (95% CI, 84.2% to 92.6%) in PET-2-positive patients ( P = .047). When using the more common liver cutoff (Deauville score, 4) for PET-2 positivity, the difference was more pronounced (5-year PFS, 93.1% [95% CI, 90.7% to 95.5%] v 80.9% [95% CI, 72.2% to 89.7%]; P = .0011)., Conclusion: In early-stage favorable HL, a positive PET after two cycles ABVD indicates a high risk for treatment failure, particularly when a Deauville score of 4 is used as a cutoff for positivity. In PET-2-negative patients, radiotherapy cannot be omitted from CMT without clinically relevant loss of tumor control.

Purpose: Combined-modality treatment consisting of four to six cycles of chemotherapy followed by involved-field radiotherapy (IFRT) is the standard of care for patients with early unfavorable Hodgkin's lymphoma (HL). It is unclear whether treatment results can be improved with more intensive chemotherapy and which radiation dose needs to be applied., Patients and Methods: Patients age 16 to 75 years with newly diagnosed early unfavorable HL were randomly assigned in a 2 × 2 factorial design to one of the following treatment arms: four cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) + 30 Gy of IFRT; four cycles of ABVD + 20 Gy of IFRT; four cycles of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP(baseline)) + 30 Gy of IFRT; or four cycles of BEACOPP(baseline) + 20 Gy of IFRT., Results: With a total of 1,395 patients included, the freedom from treatment failure (FFTF) at 5 years was 85.0%, overall survival was 94.5%, and progression-free survival was 86.0%. BEACOPP(baseline) was more effective than ABVD when followed by 20 Gy of IFRT (5-year FFTF difference, 5.7%; 95% CI, 0.1% to 11.3%). However, there was no difference between BEACOPP(baseline) and ABVD when followed by 30 Gy of IFRT (5-year FFTF difference, 1.6%; 95% CI, -3.6% to 6.9%). Similar results were observed for the radiotherapy question; after four cycles of BEACOPP(baseline), 20 Gy was not inferior to 30 Gy (5-year FFTF difference, -0.8%; 95% CI, -5.8% to 4.2%), whereas inferiority of 20 Gy cannot be excluded after four cycles of ABVD (5-year FFTF difference, -4.7%; 95% CI, -10.3% to 0.8%). Treatment-related toxicity occurred more often in the arms with more intensive therapy., Conclusion: Moderate dose escalation using BEACOPP(baseline) did not significantly improve outcome in early unfavorable HL. Four cycles of ABVD should be followed by 30 Gy of IFRT.