美国马萨诸塞州总医院Jeremy S Abramson团队研究了Lisocabtagene maraleucel治疗复发或难治性大B细胞淋巴瘤的疗效。2020年9月1日，该研究发表在《柳叶刀》杂志上。

Lisocabtagene maraleucel（liso-cel）是CD19定向的自体嵌合抗原受体（CAR）T细胞产物。

为了评估liso-cel治疗复发性或难治性大B细胞淋巴瘤患者的活性和安全性，研究组在美国的14个癌症中心进行了一项无缝设计研究。2016年1月11日至2019年7月5日，研究组共招募了344例复发性或难治性大B细胞淋巴瘤的成年患者（≥18岁），均接受白细胞分离术以制造CAR⁺ T细胞。将其随机分组，分别接受liso-cel剂量为50×10⁶、100×10⁶、150×10⁶ CAR⁺ T细胞治疗。主要终点为不良事件、剂量限制性毒性和客观缓解率。

有269例患者至少接受了一剂liso-cel。患者此前平均接受过3种系统治疗，其中260名（占97％）至少接受了两种治疗。112例（42％）为65岁及以上的患者有，181例（67％）有化疗难治性疾病，7例（3％）继发中枢神经系统受累。344例白细胞分离术患者的总生存期中位随访时间为18.8个月。

Liso-cel的总体安全性和活性在剂量水平上没有显著差异。推荐的目标剂量为100×10⁶个CAR⁺ T细胞。在接受疗效评估的256名患者中，有186名（73%）客观缓解，136名完全缓解（53%）。最常见的3级及以上严重不良事件是161例（60％）中性粒细胞减少、101例（37％）贫血和72例（27％）血小板减少。

分别有113例（42％）和80例（30％）患者发生细胞因子风暴和神经系统事件，其中6例（2％）和27例（10％）患者发生3级及以上细胞因子风暴和神经系统事件。9例（6％）发生剂量限制性毒性，1例在接受50×10⁶ CAR⁺ T细胞剂量治疗后死于弥漫性肺泡损伤。

总之，使用liso-cel治疗复发或难治性大B细胞淋巴瘤可获得较高的客观缓解率，且3级及以上细胞因子风暴和神经事件的发生率较低。

附：英文原文

Title: Lisocabtagene maraleucel for patients with relapsed or refractory large B-cell lymphomas (TRANSCEND NHL 001): a multicentre seamless design study

Author: Jeremy S Abramson, M Lia Palomba, Leo I Gordon, Matthew A Lunning, Michael Wang, Jon Arnason, Amitkumar Mehta, Enkhtsetseg Purev, David G Maloney, Charalambos Andreadis, Alison Sehgal, Scott R Solomon, Nilanjan Ghosh, Tina M Albertson, Jacob Garcia, Ana Kostic, Mary Mallaney, Ken Ogasawara, Kathryn Newhall, Yeonhee Kim, Daniel Li, Tanya Siddiqi

Issue&Volume: 2020-09-01

Abstract: 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 (50×10 6 CAR + T cells [one or two doses], 100×10 6 CAR + T cells, and 150×10 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 100×10 6 CAR + T cells (50×10 6 CD8 + and 50×10 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 50×10 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.

DOI: 10.1016/S0140-6736(20)31366-0

Source: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)31366-0/fulltext