Long-term clinical outcomes of tisagenlecleucel in patients with relapsed or refractory aggressive B-cell lymphomas (JULIET): a multicentre, open-label, single-arm, phase 2 study,The Lancet Oncology

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Long-term clinical outcomes of tisagenlecleucel in patients with relapsed or refractory aggressive B-cell lymphomas (JULIET): a multicentre, open-label, single-arm, phase 2 study
The Lancet Oncology ( IF 51.1 ) Pub Date : 2021-09-10 , DOI: 10.1016/s1470-2045(21)00375-2
Stephen J Schuster ₁ , Constantine S Tam ₂ , Peter Borchmann ₃ , Nina Worel ₄ , Joseph P McGuirk ₅ , Harald Holte ₆ , Edmund K Waller ₇ , Samantha Jaglowski ₈ , Michael R Bishop ₉ , Lloyd E Damon ₁₀ , Stephen Ronan Foley ₁₁ , Jason R Westin ₁₂ , Isabelle Fleury ₁₃ , P Joy Ho ₁₄ , Stephan Mielke ₁₅ , Takanori Teshima ₁₆ , Murali Janakiram ₁₇ , Jing-Mei Hsu ₁₈ , Koji Izutsu ₁₉ , Marie José Kersten ₂₀ , Monalisa Ghosh ₂₁ , Nina Wagner-Johnston ₂₂ , Koji Kato ₂₃ , Paolo Corradini ₂₄ , Marcela Martinez-Prieto ₂₅ , Xia Han ₂₅ , Ranjan Tiwari ₂₆ , Gilles Salles ₂₇ , Richard T Maziarz ₂₈

Affiliation

Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA.
Peter MacCallum Cancer Center, Royal Melbourne Hospital and University of Melbourne, Melbourne, VIC, Australia.
Clinic I for Internal Medicine, University Hospital of Cologne, Cologne, Germany.
Department of Blood Group Serology and Transfusion Medicine, Medical University of Vienna, Vienna, Austria.
Department of Internal Medicine, The University of Kansas Health System, Kansas City, KS, USA.
Department of Oncology, Oslo University Hospital, Oslo, Norway.
Bone Marrow and Stem Cell Transplant Center, Emory University Winship Cancer Institute, Atlanta, GA, USA.
Blood and Marrow Transplant Program, James Cancer Hospital and Solove Research Institute, Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.
Hematopoietic Cellular Therapy Program, Section of Hematology/Oncology, University of Chicago, Chicago, IL, USA.
Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA.
Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON, Canada.
Department of Lymphoma and Myeloma, MD Anderson Cancer Center, Houston, TX, USA.
Department of Lymphoma and Myeloma, Maisonneuve-Rosement Hospital, University of Montreal, Montreal, QC, Canada.
Institute of Haematology, Royal Prince Alfred Hospital and University of Sydney, Camperdown, NSW, Australia.
Department of Medicine II, University of Würzburg Medical Center, Würzburg, Germany; Department of Laboratory Medicine, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden; Department of Medicine, Huddinge, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.
Department of Hematology, Hokkaido University Hospital, Sapporo, Japan.
Division of Hematology, Oncology, and Transplantation, University of Minnesota, Minneapolis, MN, USA.
Department of Medicine, Weill Cornell Medicine, NewYork-Presbyterian Hospital, New York, NY, USA.
Department of Hematology, National Cancer Center Hospital, Tokyo, Japan.
Department of Hematology, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands.
Department of Internal Medicine, Michigan Medicine, University of Michigan, Ann Arbor, MI, USA.
Department of Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA.
Department of Hematology, Oncology, and Cardiovascular Medicine, Kyushu University Hospital, Fukuoka, Japan.
Fondazione IRCCS Istituto Nazionale dei Tumori, University of Milan, Milan, Italy.
Novartis Pharmaceuticals, East Hanover, NJ, USA.
Novartis Healthcare, Hyderabad, India.
Department of Hematology, Hospices Civils de Lyon, Lyon-Sud Hospital, Pierre-Bénite, France.
Center for Hematologic Malignancies, Oregon Health and Science University Knight Cancer Institute, Portland, OR, USA.

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 × 10⁸ 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.

中文翻译：

tisagenlecleucel 在复发或难治性侵袭性 B 细胞淋巴瘤 (JULIET) 患者中的长期临床结果：一项多中心、开放标签、单臂、2 期研究

背景

在 tisagenlecleucel 的关键 JULIET 试验（一种自体抗 CD19 嵌合抗原受体 (CAR) T 细胞疗法）的主要分析中，在 93 名可评估的成年患者中，最佳总体缓解率为 52%，完全缓解率为 40%复发或难治性侵袭性 B 细胞淋巴瘤。我们旨在对整个成人队列的临床结果和活动性和安全性的相关分析进行长期随访分析。

方法

在这项多中心、开放标签、单臂、2 期试验 (JULIET) 中，在 10 个国家（澳大利亚、奥地利、加拿大、法国、德国、意大利、日本、荷兰、挪威和美国）的 27 个治疗点进行, 组织学确诊的复发性或难治性大 B 细胞淋巴瘤的成年患者（≥18 岁）不适合、不同意自体造血干细胞移植或在自体造血干细胞移植后疾病进展，东部肿瘤协作组的体能状态为筛选时为 0-1 人。患者接受单次静脉输注 tisagenlecleucel（目标剂量 5 × 10 ⁸活转导的 CAR T 细胞）。主要终点是输注后任何时间的总体缓解率（即，使用 Lugano 分类获得完全缓解或部分缓解的最佳总体疾病缓解的患者比例，由独立审查委员会评估），并在输注后的任何时间进行分析。所有接受 tisagenlecleucel（完整分析集）的患者。在所有接受 tisagenlecleucel 的患者中分析了安全性。JULIET 在 ClinialTrials.gov 注册，NCT02445248，并且正在进行中。

发现

2015 年 7 月 29 日至 2017 年 11 月 2 日期间，共招募了 167 名患者。截至 2020 年 2 月 20 日，115 名患者接受了 tisagenlecleucel 输注，并被纳入全分析集。中位随访 40·3 个月 (IQR 37·8–43·8)，总体反应率为 53·0%（95% CI 43·5-62·4；115 名患者中的 61 名）， 45 (39%) 名患者的完全反应是他们的最佳总体反应。最常见的 3-4 级不良事件是贫血 (45 [39%])、中性粒细胞计数减少 (39 [34%])、白细胞计数减少 (37 [32%])、血小板计数减少 (32 [28 %])、细胞因子释放综合征 (26 [23%])、中性粒细胞减少 (23 [20%])、发热性中性粒细胞减少 (19 [17%])、低磷酸盐血症 (15 [13%]) 和血小板减少 (14 [12%] ]）。最常见的治疗相关严重不良事件是细胞因子释放综合征（31 [27%]），发热性中性粒细胞减少症（7 [6%]）、发热（6 [5%]）、全血细胞减少症（3 [3%]）和肺炎（3 [3%]）。没有报告与治疗相关的死亡。