Abstract

BACKGROUND: CTL019 (tisagenlecleucel) is an investigational chimeric antigen receptor (CAR) T-cell therapy that identifies and eliminates CD19-expressing B cells. JULIET (NCT02445248) is a single-arm, open-label, multicenter, global, pivotal phase 2 trial of CTL019 in adults with relapsed/refractory (r/r) diffuse large B-cell lymphoma (DLBCL). The primary objective was met at the interim analysis, with the best overall response (ORR) of 59% (complete response [CR], 43%; partial response [PR], 16%). Here, we report the results of the primary analysis of the JULIET study.

METHODS: Eligible patients were 18 years or older with r/r DLBCL and had progressed after receiving ≥2 lines of chemotherapy, and were ineligible for or failed autologous stem cell transplant (auto-SCT). Centrally manufactured CAR T cells were provided to patients at 27 study centers in 10 countries on 4 continents using cryopreserved apheresis, central production facilities and a global supply chain. CTL019 was manufactured at 2 sites (United States and Germany). Autologous T cells were transduced with a lentiviral vector encoding an anti-CD19 scFv-CD3ζ-4-1BB CAR, expanded ex vivo, cryopreserved, shipped, and infused at study centers. The primary endpoint was best ORR (CR + PR) per independent review committee.

RESULTS: As of data cutoff (8 March 2017), 147 patients were enrolled and 99 were infused with a single dose of CTL019 transduced cells (median, 3.1 × 108 [range, 0.1-6.0 × 108] cells). 90% of patients received bridging therapy. Prior to infusion, patients underwent restaging, and 93% received lymphodepleting chemotherapy (73% received fludarabine 25 mg/m2/cyclophosphamide 250 mg/m2/day × 3 days and 19% received bendamustine 90 mg/m2/day × 2 days). Median time from infusion to data cutoff was 5.6 months. The median age was 56 years (range, 22-76); 77% of patients had stage III or IV disease at study entry. The median number of prior lines of antineoplastic therapy was 3 (range, 1-6; 95% received ≥2 and 51% received ≥3 prior lines); 47% of patients had prior auto-SCT.

In this primary analysis of patients who received CTL019 from the US manufacturing site, among 81 infused patients with ≥3 months follow-up or earlier discontinuation the best ORR was 53.1% (95% CI, 42% to 64%; P <.0001) with 39.5% CR and 13.6% PR. At month 3, the CR rate was 32% and the PR rate 6%. Among patients evaluable at 6 months (n=46), the CR rate was 30% and PR rate was 7%. Response rates were consistent across prognostic subgroups (including those who received prior auto-SCT and those with double-hit lymphoma). Median duration of response was not reached; the 6-month probability of being relapse free was 73.5% (95% CI, 52.0% to 86.6%). Median overall survival was not reached; the 6-month probability of overall survival was 64.5% (95% CI, 51.5% to 74.8%). No patient who achieved a response (CR or PR) proceeded to allogenic- or auto-SCT. CTL019 was detected in peripheral blood by quantitative PCR for up to 367 days in responders.

Overall, 86% of patients had grade 3 or 4 adverse events (AEs). Cytokine release syndrome (CRS) occurred in 58% of infused patients, with 15% grade 3 and 8% grade 4 using the Penn grading scale and managed by a protocol-specific algorithm. 15% of patients received anti-IL6 therapy, tocilizumab, for CRS management with good response and 11% of patients received corticosteroids. Other grade 3 or 4 AEs of special interest included neurologic AEs (12%, managed with supportive care), cytopenias lasting >28 days (27%), infections (20%), and febrile neutropenia (13%). Three patients died within 30 days of infusion, all due to disease progression. No deaths were attributed to CTL019. No CRS or neurologic event associated deaths occurred.

CONCLUSIONS: CTL019 produces high response rates with 95% of CRs at 3 months being sustained at 6 months in a cohort of highly pretreated adult patients with r/r DLBCL, results which confirm the findings of our earlier interim analysis. Centralized manufacturing was feasible in the first global study of CAR T cell therapy in DLBCL. CRS and other AEs could be effectively and reproducibly managed by appropriately trained investigators without treatment-related mortality.

Disclosures

Schuster: Novartis Pharmaceuticals Corporation: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Janssen R&D: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; Seattle Genetics: Consultancy; Nordic Nanovector: Consultancy; Merck: Research Funding. Tam: Janssen Cilag: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; Roche: Honoraria, Research Funding. Waller: Katz Foundation: Research Funding; Novartis Pharmaceuticals Corporation: Consultancy, Honoraria, Research Funding; Cambium Medical Technologies: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties; Celldex: Consultancy; Helocyte: Consultancy; Coulter Foundation: Research Funding; AMGEN: Consultancy; Chimerix: Equity Ownership; Cerus: Equity Ownership; PRA: Consultancy; National Institutes of Health: Research Funding. Borchmann: Novartis Pharmaceuticals Corporation: Honoraria. Jaeger: Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis Pharmaceuticals Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Jaglowski: Novartis Pharmaceuticals Corporation: Consultancy, Research Funding; Kite Pharma: Consultancy, Research Funding; Unum Therapeutics: Research Funding; Pharmacyclics Inc: Research Funding. Andreadis: Astellas: Honoraria; Pharmacyclics: Research Funding; Incyte Pharmaceuticals: Research Funding; Amgen: Research Funding; Seattle Genetics: Honoraria; Genentech Inc.: Employment, Equity Ownership, Honoraria; Cellerant Therapeutics: Research Funding; Novartis Pharmaceuticals Corporation: Honoraria, Research Funding; Gilead Sciences: Honoraria. Westin: Novartis Pharmaceuticals Corporation: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Apotex: Membership on an entity's Board of Directors or advisory committees; Kite Pharma: Membership on an entity's Board of Directors or advisory committees. Fleury: Amgen: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Lundbeck: Consultancy, Honoraria; Merck: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria. Bachanova: Novartis Pharmaceuticals Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding; Zymogen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Seattle-Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Juno: Membership on an entity's Board of Directors or advisory committees; Oxis: Membership on an entity's Board of Directors or advisory committees, Research Funding. Foley: Novartis Pharmaceuticals Corporation: Consultancy. Ho: Amgen, Bristol-Myers Squibb, Celgene, Novartis, Janssen, Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. Mielke: KIADIS Pharma: Other: Travel grants; Jazz Pharma: Speakers Bureau; Novartis: Consultancy; Celgene: Other: Travel grants, Speakers Bureau; MSD: Consultancy, Other: Travel grants; Gilead: Other: Travel grants; Cellex GmbH: Other: Travel grants, Speakers Bureau; DGHO: Other: Travel support; ISCT: Other: Travel support. Holte: Novartis Pharmaceuticals Corporation: Membership on an entity's Board of Directors or advisory committees; Oslo University Hospital: Employment; Nordic Nanovector: Consultancy. Kersten: MSD: Honoraria; BMS: Honoraria; Gilead Sciences: Honoraria; Mundipharma: Honoraria; Milennium/Takeda: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Kite Pharma: Honoraria; Novartis Pharmaceuticals Corporation: Honoraria; Amgen: Honoraria. Teshima: Bristol-Myers Squibb: Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Research Funding; Kyowa-Hakko Kirin: Research Funding; Pfeizer: Research Funding; Chugai: Research Funding. Tobinai: Janssen: Honoraria, Research Funding; Servier: Research Funding; Zenyaku Kogyo: Honoraria; Eisai: Honoraria, Research Funding; Chugai: Honoraria, Research Funding; Kyowa Hakko Kirin: Honoraria, Research Funding; Mundipharma: Honoraria, Research Funding; Ono Pharmaceutical: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; AbbVie: Research Funding; HUYA Bioscience: Honoraria; Daiichi Sankyo Co., Ltd: Consultancy, Honoraria; GlaxoSmithKline: Research Funding; Celgene: Consultancy, Honoraria, Research Funding. Corradini: Takeda: Honoraria; Novartis: Honoraria; Sanofi: Honoraria; Roche: Honoraria; Janssen: Honoraria; Celgene: Honoraria; Gilead: Honoraria; Amgen: Honoraria. Anak: Novartis Pharma AG: Employment. Bubuteishvili Pacaud: Novartis Pharma AG: Employment. del Corral: Novartis Pharmaceuticals Corporation: Employment. Awasthi: Novartis Pharmaceuticals Corporation: Employment. Tai: Novartis Pharmaceuticals Corporation: Employment. Salles: Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Morphosys: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Kite: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; MSD: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Maziarz: Novartis Pharmaceuticals Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Consultancy, Honoraria; Juno Therapeutics: Honoraria; Kite Therapeutics: Honoraria; Athersys, Inc: Patents & Royalties.

Author notes

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Asterisk with author names denotes non-ASH members.