Tisagenlecleucel 二线治疗或侵袭性 B 细胞淋巴瘤的标准治疗。
Second-Line Tisagenlecleucel or Standard Care in Aggressive B-Cell Lymphoma.
机构信息
From the David and Etta Jonas Center for Cellular Therapy, University of Chicago, Chicago (M.R.B.); Peter MacCallum Cancer Centre and Royal Melbourne Hospital, Melbourne, VIC (M. Dickinson), Fiona Stanley Hospital, Murdoch, WA (D.P.), and the Department of Haematology, St. Vincent's Hospital Sydney, and St. Vincent's Clinical School, University of New South Wales, Sydney (N.H.) - all in Australia; Hospital Universitari Vall d'Hebron and Universitat Autònoma de Barcelona (P. Barba) and the Clinical Hematology Department, Institut Català d'Oncologia-Hospitalet de Llobregat (A. Sureda), Barcelona, and the Hematology Department, Hospital 12 de Octubre, Complutense University, Instituto de Investigación Hospital 12 de Octubre, Centro Nacional de Investigaciones Oncológicas, Madrid (J.M.-L.) - all in Spain; the Department of Biomedical Sciences, Humanitas University and IRCCS Humanitas Research Hospital-Humanitas Cancer Center, Milan (A. Santoro); the Department of Hematology, Oncology, and Cardiovascular Medicine, Kyushu University Hospital, Fukuoka (K.K.), and Tohoku University Hospital, Sendai (H. Harigae) - both in Japan; the Third Medical Department, Paracelsus Medical University, Salzburg Cancer Research Institute-Center for Clinical Cancer and Immunology Trials and Cancer Cluster Salzburg, Salzburg (R.G.), and Internal Medicine I, Bone Marrow Transplant Unit (W.R.), and the Clinical Division of Hematology and Hemostaseology, Department of Medicine I (U.J.), Vienna General Hospital-Medical University of Vienna, Vienna - both in Austria; Assistance Publique-Hôpitaux de Paris, Hemato-Oncology, Hôpital Saint-Louis, Paris (C.T.), Centre Hospitalier Régional Universitaire de Lille, Lille (F.M.), Hospices Civils de Lyon and Université Claude Bernard Lyon 1, Lyon (E.B.), and Centre de Recherche en Cancérologie et Immunologie Nantes-Angers, INSERM, and Nantes Medical University, Nantes (S.L.G.) - all in France; the Department of Hematology, Oncology, and Tumorimmunology, Charité-University Hospital Berlin, Campus Benjamin Franklin, and the Experimental and Clinical Research Center of the Max Delbrück Center for Molecular Medicine and Charité Berlin, Berlin (M.J.), Medizinische Klinik III, LMU Klinikum, Munich (M. Dreyling), and Clinic I for Internal Medicine, University Hospital Cologne, Cologne (P. Borchmann) - all in Germany; Sarah Cannon Research Institute-Tennessee Oncology, Nashville (I.F., P.M.); the Department of Medicine, Queen Mary Hospital, Hong Kong (Y.-L.K.); the Department of Hematology, Amsterdam UMC, University of Amsterdam, Amsterdam (M.J.K.), and Universitair Medisch Centrum Utrecht, Department of Medical Oncology, Utrecht (M.C.M.) - both in the Netherlands; the Department of Oncology, Oslo University Hospital, and K.G. Jebsen Center for B-Cell Malignancies - both in Oslo (H. Holte); the National University Cancer Institute Singapore, Singapore (E.H.L.C.); the Department of Medical Oncology and Hematology, University Hospital, Zurich (A.M.S.M.), and Novartis Pharma, Basel (S.N., E.D., G.A.) - both in Switzerland; the Center for Hematologic Malignancies, Knight Cancer Institute, Oregon Health and Science University, Portland (R.T.M.); the Division of Hematologic Malignancies and Cellular Therapeutics, University of Kansas Cancer Center, Westwood (J.P.M.); Ohio State University, Columbus (D.B.); Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco (C.A.); the Division of Hematology-Oncology and Blood and Marrow Transplantation and Cellular Therapy Program, Mayo Clinic, Jacksonville, FL (M.K.-D.); Novartis Pharmaceuticals, East Hanover, NJ (R.A., C.C., A.M.); the Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia (S.J.S.); and the Department of Lymphoma and Myeloma, M.D. Anderson Cancer Center, Houston (J.R.W.).
出版信息
N Engl J Med. 2022 Feb 17;386(7):629-639. doi: 10.1056/NEJMoa2116596. Epub 2021 Dec 14.
BACKGROUND
Patient outcomes are poor for aggressive B-cell non-Hodgkin's lymphomas not responding to or progressing within 12 months after first-line therapy. Tisagenlecleucel is an anti-CD19 chimeric antigen receptor T-cell therapy approved for diffuse large B-cell lymphoma after at least two treatment lines.
METHODS
We conducted an international phase 3 trial involving patients with aggressive lymphoma that was refractory to or progressing within 12 months after first-line therapy. Patients were randomly assigned to receive tisagenlecleucel with optional bridging therapy (tisagenlecleucel group) or salvage chemotherapy and autologous hematopoietic stem-cell transplantation (HSCT) (standard-care group). The primary end point was event-free survival, defined as the time from randomization to stable or progressive disease at or after the week 12 assessment or death. Crossover to receive tisagenlecleucel was allowed if a defined event occurred at or after the week 12 assessment. Other end points included response and safety.
RESULTS
A total of 322 patients underwent randomization. At baseline, the percentage of patients with high-grade lymphomas was higher in the tisagenlecleucel group than in the standard-care group (24.1% vs. 16.9%), as was the percentage with an International Prognostic Index score (range, 0 to 5, with higher scores indicating a worse prognosis) of 2 or higher (65.4% vs. 57.5%). A total of 95.7% of the patients in the tisagenlecleucel group received tisagenlecleucel; 32.5% of the patients in the standard-care group received autologous HSCT. The median time from leukapheresis to tisagenlecleucel infusion was 52 days. A total of 25.9% of the patients in the tisagenlecleucel group had lymphoma progression at week 6, as compared with 13.8% of those in the standard-care group. The median event-free survival in both groups was 3.0 months (hazard ratio for event or death in the tisagenlecleucel group, 1.07; 95% confidence interval, 0.82 to 1.40; P = 0.61). A response occurred in 46.3% of the patients in the tisagenlecleucel group and in 42.5% in the standard-care group. Ten patients in the tisagenlecleucel group and 13 in the standard-care group died from adverse events.
CONCLUSIONS
Tisagenlecleucel was not superior to standard salvage therapy in this trial. Additional studies are needed to assess which patients may obtain the most benefit from each approach. (Funded by Novartis; BELINDA ClinicalTrials.gov number, NCT03570892.).
背景
对于一线治疗后 12 个月内无应答或进展的侵袭性 B 细胞非霍奇金淋巴瘤患者，其预后较差。Tisagenlecleucel 是一种抗 CD19 嵌合抗原受体 T 细胞疗法，适用于至少接受过两线治疗的弥漫性大 B 细胞淋巴瘤。
方法
我们进行了一项国际性的 3 期临床试验，纳入了对一线治疗无反应或在一线治疗后 12 个月内进展的侵袭性淋巴瘤患者。患者被随机分配接受 tisagenlecleucel 联合可选桥接治疗（tisagenlecleucel 组）或挽救性化疗和自体造血干细胞移植（HSCT）（标准治疗组）。主要终点是无事件生存，定义为从随机分组到 12 周评估时或之后稳定或进展性疾病或死亡的时间。如果在 12 周评估时或之后发生了规定的事件，则允许交叉接受 tisagenlecleucel 治疗。其他终点包括反应和安全性。
结果
共 322 名患者接受了随机分组。在基线时，tisagenlecleucel 组中高级别淋巴瘤的比例高于标准治疗组（24.1% vs. 16.9%），国际预后指数评分（范围为 0 至 5，评分越高表示预后越差）为 2 或更高的比例也高于标准治疗组（65.4% vs. 57.5%）。tisagenlecleucel 组 95.7%的患者接受了 tisagenlecleucel 治疗；标准治疗组 32.5%的患者接受了自体 HSCT。从白细胞分离到 tisagenlecleucel 输注的中位时间为 52 天。tisagenlecleucel 组有 25.9%的患者在第 6 周时发生淋巴瘤进展，而标准治疗组有 13.8%的患者发生淋巴瘤进展。两组的中位无事件生存时间均为 3.0 个月（tisagenlecleucel 组的事件或死亡风险比为 1.07；95%置信区间为 0.82 至 1.40；P=0.61）。tisagenlecleucel 组的反应率为 46.3%，标准治疗组为 42.5%。tisagenlecleucel 组有 10 例患者和标准治疗组有 13 例患者因不良事件死亡。
结论
在这项试验中，tisagenlecleucel 并不优于标准的挽救性治疗。需要进一步的研究来评估哪些患者可能从每种治疗方法中获益最大。（由诺华公司资助；BELINDA 临床试验.gov 编号，NCT03570892）。
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