Lisocabtagene maraleucel for patients with relapsed or refractory large B-cell lymphomas (TRANSCEND NHL 001): a multicentre seamless design study
Lisocabtagene maraleucel for patients with relapsed or refractory large B-cell lymphomas (TRANSCEND NHL 001): a multicentre seamless design study
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DOI：
10.1016/s0140-6736(20)31366-0
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发表时间：
2020-09-19
期刊：
影响因子：
168.9
通讯作者：
Siddiqi, Tanya
中科院分区：
文献类型：
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作者：
Abramson, Jeremy S.;Palomba, M. Lia;Siddiqi, Tanya
Lisocabtagene maraleucel（liso-cel）是一种自体的、CD 19导向的嵌合抗原受体（CAR）T细胞产物。我们的目的是评估的活性和安全性的liso-cel在复发性或难治性大B细胞lymphoma.Methods的患者，我们做了一个无缝设计的研究，在14个癌症中心在美国。我们招募了患有复发性或难治性大B细胞淋巴瘤的成年患者（年龄≥ 18岁）。合格的组织学亚组包括弥漫性大B细胞淋巴瘤、伴有MYC和BCL 2、BCL 6或两者重排的高级别B细胞淋巴瘤（双重打击或三重打击淋巴瘤）、任何惰性淋巴瘤转化的弥漫性大B细胞淋巴瘤、原发性纵隔B细胞淋巴瘤和3B级滤泡性淋巴瘤。患者被分配到liso-cel的三个目标剂量水平之一，因为他们在试验中依次进行测试（50 × 10（6）CAR（+）T细胞[一个或两个剂量]、100 × 10（6）CAR（+）T细胞和150 × 10（6）CAR（+）T细胞），其以相等的目标剂量作为两种组分（CD 8（+）和CD 4（+）CAR（+）T细胞）的顺序输注施用。主要终点为不良事件、剂量限制性毒性和客观缓解率（根据Lugano标准评估）;终点由独立审查委员会在疗效可评价集中进行评估（包括所有确诊PET阳性疾病并接受至少一剂liso-cel的患者）。该试验在ClinicalTrials.gov注册，NCT 02631044。结果在2016年1月11日至2019年7月5日期间，344名患者接受了白细胞分离术以生产CAR（+）T细胞（liso-cel），其中269名患者接受了至少一剂liso-cel。患者既往接受过中位三线（范围1-8）全身治疗，260例（97%）患者至少接受过二线治疗。112例（42%）患者年龄≥ 65岁，181例（67%）患有化疗难治性疾病，7例（3%）继发性CNS受累。所有344例接受白细胞去除术的患者的中位总生存期随访时间为18.8个月（95% CI 15.0-19.3）。liso-cel的总体安全性和活性在不同剂量水平之间没有差异。推荐的目标剂量为100 × 10（6）CAR（+）T细胞（50 × 10（6）CD 8（+）和50 × 10（6）CD 4（+）CAR（+）T细胞）。在纳入疗效可评价集中的256例患者中，186例（73%，95% CI 66.8-78.0）患者达到客观缓解，136例（53%，46.8-59.4）患者达到完全缓解。最常见的3级或更严重的不良事件是161例（60%）患者的中性粒细胞减少症，101例（37%）患者的贫血和72例（27%）患者的血小板减少症。分别有113例（42%）和80例（30%）患者发生细胞因子释放综合征和神经系统事件;分别有6例（2%）和27例（10%）患者发生3级或更严重的细胞因子释放综合征和神经系统事件。9例（6%）患者出现剂量限制性毒性反应，其中1例患者在接受50 × 10（6）CAR（+）T细胞治疗后死于弥漫性肺泡损伤。解读使用liso-cel治疗复发性或难治性大B细胞淋巴瘤患者的客观缓解率较高，3级或更严重的细胞因子释放综合征和神经系统事件发生率较低，包括具有不同组织学亚型和高风险特征的那些。Liso-cel在大B细胞淋巴瘤首次复发时以及作为其他复发性或难治性B细胞恶性肿瘤的治疗方法正在接受进一步评估。版权所有（C）2020爱思唯尔有限公司保留所有权利。
Background Lisocabtagene maraleucel (liso-cel) is an autologous, CD19-directed, chimeric antigen receptor (CAR) T-cell product. We aimed to assess the activity and safety of liso-cel in patients with relapsed or refractory large B-cell lymphomas.Methods We did a seamless design study at 14 cancer centres in the USA. We enrolled adult patients (aged >= 18 years) with relapsed or refractory large B-cell lymphomas. Eligible histological subgroups included diffuse large B-cell lymphoma, high-grade B-cell lymphoma with rearrangements of MYC and either BCL2, BCL6, or both (double-hit or triple-hit lymphoma), diffuse large B-cell lymphoma transformed from any indolent lymphoma, primary mediastinal B-cell lymphoma, and follicular lymphoma grade 3B. Patients were assigned to one of three target dose levels of liso-cel as they were sequentially tested in the trial (50 x 10(6) CAR(+) T cells [one or two doses], 100 x 10(6) CAR(+) T cells, and 150 x 10(6) CAR(+) T cells), which were administered as a sequential infusion of two components (CD8(+) and CD4(+) CAR(+) T cells) at equal target doses. Primary endpoints were adverse events, dose-limiting toxicities, and the objective response rate (assessed per Lugano criteria); endpoints were assessed by an independent review committee in the efficacy-evaluable set (comprising all patients who had confirmed PET-positive disease and received at least one dose of liso-cel). This trial is registered with ClinicalTrials.gov, NCT02631044.Findings Between Jan 11, 2016, and July 5, 2019, 344 patients underwent leukapheresis for manufacture of CAR(+) T cells (liso-cel), of whom 269 patients received at least one dose of liso-cel. Patients had received a median of three (range 1-8) previous lines of systemic treatment, with 260 (97%) patients having had at least two lines. 112 (42%) patients were aged 65 years or older, 181 (67%) had chemotherapy-refractory disease, and seven (3%) had secondary CNS involvement. Median follow-up for overall survival for all 344 patients who had leukapheresis was 18.8 months (95% CI 15.0-19.3). Overall safety and activity of liso-cel did not differ by dose level. The recommended target dose was 100 x 10(6) CAR(+) T cells (50 x 10(6) CD8(+) and 50 x 10(6) CD4(+) CAR(+) T cells). Of 256 patients included in the efficacy-evaluable set, an objective response was achieved by 186 (73%, 95% CI 66.8-78.0) patients and a complete response by 136 (53%, 46.8-59.4). The most common grade 3 or worse adverse events were neutropenia in 161 (60%) patients, anaemia in 101 (37%), and thrombocytopenia in 72 (27%). Cytokine release syndrome and neurological events occurred in 113 (42%) and 80 (30%) patients, respectively; grade 3 or worse cytokine release syndrome and neurological events occurred in six (2%) and 27 (10%) patients, respectively. Nine (6%) patients had a dose-limiting toxicity, including one patient who died from diffuse alveolar damage following a dose of 50 x 10(6) CAR(+) T cells.Interpretation Use of liso-cel resulted in a high objective response rate, with a low incidence of grade 3 or worse cytokine release syndrome and neurological events in patients with relapsed or refractory large B-cell lymphomas, including those with diverse histological subtypes and high-risk features. Liso-cel is under further evaluation at first relapse in large B-cell lymphomas and as a treatment for other relapsed or refractory B-cell malignancies. Copyright (C) 2020 Elsevier Ltd. All rights reserved.