From the Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia (S.J.S.); the Hematopoietic Cellular Therapy Program, University of Chicago Medicine, Chicago (M.R.B.); Peter MacCallum Cancer Centre, St. Vincent's Hospital and University of Melbourne, Melbourne, VIC (C.S.T.), and the Royal Prince Alfred Hospital and Department of Medicine, University of Sydney, Sydney (P.J.H.) - both in Australia; Winship Cancer Institute of Emory University, Bone Marrow and Stem Cell Transplant Center, Atlanta (E.K.W.); the Department of Hematology and Oncology, University Hospital of Cologne, Cologne (P.B.), and the Würzburg University Medical Center, Center for Allogeneic Stem Cell Transplantation, Würzburg (S.M.) - both in Germany; the Division of Hematologic Malignancies and Cellular Therapeutics, University of Kansas Cancer Center, Kansas City (J.P.M.); the Department of Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Vienna (U.J.); James Cancer Hospital and Solove Research Institute, Ohio State University Comprehensive Cancer Center, Columbus (S.J.); the Department of Hematology and Blood and Marrow Transplant, University of California, San Francisco, Helen Diller Family Comprehensive Cancer Center, San Francisco (C.A.); the Department of Lymphoma and Myeloma, Division of Cancer Medicine, University of Texas M.D. Anderson Cancer Center, Houston (J.R.W.); Maisonneuve-Rosemont Hospital, University of Montreal, Montreal (I.F.), and the Juravinski Hospital and Cancer Centre, McMaster University, Hamilton, ON (S.R.F.) - both in Canada; the Division of Hematology, Oncology, and Transplantation, University of Minnesota, Minneapolis (V.B.); Karolinska Institutet and University Hospital, Department of Laboratory Medicine/Department of Cell Therapy and Allogeneic Stem Cell Transplantation, Stockholm (S.M.); University of Michigan Comprehensive Cancer Center, Ann Arbor (J.M.M.); the Department of Oncology, Oslo University Hospital, Oslo (H.H.); Novartis Pharma, Basel, Switzerland (S.P., O.A.); Novartis Pharmaceuticals (L.B.P., J.C.) and Novartis Institutes for BioMedical Research (R.A.), East Hanover, NJ; the Department of Hematology, Hospices Civils de Lyon, Université de Lyon, Lyon, France (G.S.); and the Center for Hematologic Malignancies, Oregon Health and Science University Knight Cancer Institute, Portland (R.T.M.).
N Engl J Med. 2019 Jan 3;380(1):45-56. doi: 10.1056/NEJMoa1804980. Epub 2018 Dec 1.
Patients with diffuse large B-cell lymphoma that is refractory to primary and second-line therapies or that has relapsed after stem-cell transplantation have a poor prognosis. The chimeric antigen receptor (CAR) T-cell therapy tisagenlecleucel targets and eliminates CD19-expressing B cells and showed efficacy against B-cell lymphomas in a single-center, phase 2a study.
We conducted an international, phase 2, pivotal study of centrally manufactured tisagenlecleucel involving adult patients with relapsed or refractory diffuse large B-cell lymphoma who were ineligible for or had disease progression after autologous hematopoietic stem-cell transplantation. The primary end point was the best overall response rate (i.e., the percentage of patients who had a complete or partial response), as judged by an independent review committee.
A total of 93 patients received an infusion and were included in the evaluation of efficacy. The median time from infusion to data cutoff was 14 months (range, 0.1 to 26). The best overall response rate was 52% (95% confidence interval, 41 to 62); 40% of the patients had complete responses, and 12% had partial responses. Response rates were consistent across prognostic subgroups. At 12 months after the initial response, the rate of relapse-free survival was estimated to be 65% (79% among patients with a complete response). The most common grade 3 or 4 adverse events of special interest included cytokine release syndrome (22%), neurologic events (12%), cytopenias lasting more than 28 days (32%), infections (20%), and febrile neutropenia (14%). Three patients died from disease progression within 30 days after infusion. No deaths were attributed to tisagenlecleucel, cytokine release syndrome, or cerebral edema. No differences between response groups in tumor expression of CD19 or immune checkpoint-related proteins were found.
In this international study of CAR T-cell therapy in relapsed or refractory diffuse large B-cell lymphoma in adults, high rates of durable responses were produced with the use of tisagenlecleucel. (Funded by Novartis; JULIET ClinicalTrials.gov number, NCT02445248 .).
原发性和二线治疗难治或干细胞移植后复发的弥漫性大 B 细胞淋巴瘤患者预后较差。嵌合抗原受体（CAR）T 细胞疗法 tisagenlecleucel 靶向并消除表达 CD19 的 B 细胞，在一项单中心、2a 期研究中显示出对 B 细胞淋巴瘤的疗效。
我们进行了一项国际、2 期、关键的 tisagenlecleucel 中心制造研究，涉及复发或难治性弥漫性大 B 细胞淋巴瘤的成年患者，这些患者不符合自体造血干细胞移植的条件，或在移植后疾病进展。主要终点是最佳总体缓解率（即完全或部分缓解患者的百分比），由独立审查委员会判断。
共有 93 例患者接受输注，并纳入疗效评估。从输注到数据截止的中位时间为 14 个月（范围为 0.1 至 26）。最佳总体缓解率为 52%（95%置信区间，41 至 62）；40%的患者完全缓解，12%部分缓解。反应率在预后亚组中是一致的。在初始反应后 12 个月，无复发生存率估计为 65%（完全缓解患者为 79%）。最常见的 3 或 4 级特别关注的不良事件包括细胞因子释放综合征（22%）、神经事件（12%）、持续超过 28 天的血细胞减少症（32%）、感染（20%）和发热性中性粒细胞减少症（14%）。三名患者在输注后 30 天内死于疾病进展。没有死亡归因于 tisagenlecleucel、细胞因子释放综合征或脑水肿。在反应组之间，没有发现肿瘤表达 CD19 或免疫检查点相关蛋白的差异。
在这项关于成人复发或难治性弥漫性大 B 细胞淋巴瘤的 CAR T 细胞治疗的国际研究中，使用 tisagenlecleucel 产生了高比例的持久反应。（由诺华公司资助；JULIET ClinicalTrials.gov 编号，NCT02445248）。
