Background

Patients with large B-cell lymphoma (LBCL) primary refractory to or relapsed within 12 months of first-line therapy are at high risk for poor outcomes with current standard of care, platinum-based salvage immunochemotherapy and autologous haematopoietic stem cell transplantation (HSCT). Lisocabtagene maraleucel (liso-cel), an autologous, CD19-directed chimeric antigen receptor (CAR) T-cell therapy, has previously demonstrated efficacy and manageable safety in third-line or later LBCL. In this Article, we report a prespecified interim analysis of liso-cel versus standard of care as second-line treatment for primary refractory or early relapsed (within 12 months after response to initial therapy) LBCL.

Methods

TRANSFORM is a global, phase 3 study, conducted in 47 sites in the USA, Europe, and Japan, comparing liso-cel with standard of care as second-line therapy in patients with primary refractory or early (≤12 months) relapsed LBCL. Adults aged 18–75 years, Eastern Cooperative Oncology Group performance status score of 1 or less, adequate organ function, PET–positive disease per Lugano 2014 criteria, and candidates for autologous HSCT were randomly assigned (1:1), by use of interactive response technology, to liso-cel (100 × 10⁶ CAR⁺ T cells intravenously) or standard of care. Standard of care consisted of three cycles of salvage immunochemotherapy delivered intravenously—R-DHAP (rituximab 375 mg/m² on day 1, dexamethasone 40 mg on days 1–4, two infusions of cytarabine 2000 mg/m² on day 2, and cisplatin 100 mg/m² on day 1), R-ICE (rituximab 375 mg/m² on day 1, ifosfamide 5000 mg/m² on day 2, etoposide 100 mg/m² on days 1–3, and carboplatin area under the curve 5 [maximum dose of 800 mg] on day 2), or R-GDP (rituximab 375 mg/m² on day 1, dexamethasone 40 mg on days 1–4, gemcitabine 1000 mg/m² on days 1 and 8, and cisplatin 75 mg/m² on day 1)—followed by high-dose chemotherapy and autologous HSCT in responders. Primary endpoint was event-free survival, with response assessments by an independent review committee per Lugano 2014 criteria. Efficacy was assessed per intention-to-treat (ie, all randomly assigned patients) and safety in patients who received any treatment. This trial is registered with ClinicalTrials.gov, NCT03575351, and is ongoing.

Findings

Between Oct 23, 2018, and Dec 8, 2020, 232 patients were screened and 184 were assigned to the liso-cel (n=92) or standard of care (n=92) groups. At the data cutoff for this interim analysis, March 8, 2021, the median follow-up was 6·2 months (IQR 4·4–11·5). Median event-free survival was significantly improved in the liso-cel group (10·1 months [95% CI 6·1–not reached]) compared with the standard-of-care group (2·3 months [2·2–4·3]; stratified hazard ratio 0·35; 95% CI 0·23–0·53; stratified Cox proportional hazards model one-sided p<0·0001). The most common grade 3 or worse adverse events were neutropenia (74 [80%] of 92 patients in the liso-cel group vs 46 [51%] of 91 patients in the standard-of-care group), anaemia (45 [49%] vs 45 [49%]), thrombocytopenia (45 [49%] vs 58 [64%]), and prolonged cytopenia (40 [43%] vs three [3%]). Grade 3 cytokine release syndrome and neurological events, which are associated with CAR T-cell therapy, occurred in one (1%) and four (4%) of 92 patients in the liso-cel group, respectively (no grade 4 or 5 events). Serious treatment-emergent adverse events were reported in 44 (48%) patients in the liso-cel group and 44 (48%) in the standard-of-care group. No new liso-cel safety concerns were identified in the second-line setting. There were no treatment-related deaths in the liso-cel group and one treatment-related death due to sepsis in the standard-of-care group.

Interpretation

These results support liso-cel as a new second-line treatment recommendation in patients with early relapsed or refractory LBCL.

Funding

Celgene, a Bristol-Myers Squibb Company.

中文翻译：

---

Lisocabtagene maraleucel 与挽救性化疗后自体干细胞移植作为二线治疗复发或难治性大 B 细胞淋巴瘤 (TRANSFORM) 患者的标准护理：开放标签、随机、3 期的中期分析结果审判

背景

大 B 细胞淋巴瘤 (LBCL) 原发性难治性或在一线治疗 12 个月内复发的患者在目前的护理标准、基于铂的挽救性免疫化疗和自体造血干细胞移植 (HSCT) 下预后不良的风险很高. Lisocabtagene maraleucel (liso-cel) 是一种自体、CD19 导向的嵌合抗原受体 (CAR) T 细胞疗法，此前已在三线或晚期 LBCL 中证明了疗效和可控的安全性。在本文中，我们报告了一项预先指定的中期分析，即利索赛尔与标准护理作为原发性难治性或早期复发（初始治疗反应后 12 个月内）LBCL 的二线治疗。

方法

TRANSFORM 是一项全球性的 3 期研究，在美国、欧洲和日本的 47 个地点进行，比较了 liso-cel 与标准护理作为原发性难治性或早期（≤12 个月）复发性 LBCL 患者的二线治疗。18-75 岁的成年人、东部肿瘤协作组体能状态评分为 1 分或更低、器官功能充足、符合 Lugano 2014 标准的 PET 阳性疾病以及自体 HSCT 的候选人被随机分配 (1:1)，通过使用交互式响应技术、liso-cel（100 × 10 ⁶ CAR ⁺ T 细胞静脉注射）或护理标准。护理标准包括三个周期的静脉内挽救性免疫化疗——R-DHAP（利妥昔单抗 375 mg/m ²第 1 天，第 1-4 天地塞米松 40 mg，第 2 天两次输注阿糖胞苷 2000 mg/m ² ，第 1天 100 mg/m ²顺铂），R-ICE（第 1 天 rituximab 375 mg/ m ² 1，异环磷酰胺 5000 mg/m ²第 2 天，依托泊苷 100 mg/m ²第 1-3 天，卡铂曲线下面积 5 [最大剂量 800 mg] 第 2 天），或 R-GDP（利妥昔单抗 375第 1 天mg/m ²，第 1-4 天地塞米松 40 mg，第 1 天和第 8 天吉西他滨 1000 mg/m ²，顺铂 75 mg/m ²第 1 天）——随后对应答者进行大剂量化疗和自体 HSCT。主要终点是无事件生存，由独立审查委员会根据 Lugano 2014 标准进行反应评估。根据意向治疗（即所有随机分配的患者）评估疗效和接受任何治疗的患者的安全性。该试验已在 ClinicalTrials.gov 注册，NCT03575351，并且正在进行中。

发现

在 2018 年 10 月 23 日至 2020 年 12 月 8 日期间，筛查了 232 名患者，其中 184 名被分配到 liso-cel (n=92) 或标准护理 (n=92) 组。在此中期分析的数据截止日期为 2021 年 3 月 8 日，中位随访时间为 6·2 个月（IQR 4·4–11·5）。与护理标准组（2·3 个月 [2·2- 4·3]；分层风险比 0·35；95% CI 0·23–0·53；分层 Cox 比例风险模型单侧 p<0·0001)。最常见的 3 级或更严重的不良事件是中性粒细胞减少症（liso-cel 组 92 名患者中的 74 [80%] vs标准护理组 91 名患者中的 46 [51%]）、贫血（45 [49 %] vs 45 [49%])，血小板减少症 (45 [49%] vs58 [64%]）和长期血细胞减少（40 [43%]对3 [3%]）。与 CAR T 细胞治疗相关的 3 级细胞因子释放综合征和神经系统事件分别发生在 liso-cel 组的 92 名患者中的 1 名 (1%) 和 4 名 (4%) 中（无 4 级或 5 级事件）。liso-cel 组 44 例 (48%) 患者和标准护理组 44 例 (48%) 患者报告了严重的治疗紧急不良事件。在二线治疗中未发现新的 Liso-cel 安全问题。liso-cel 组没有与治疗相关的死亡，标准护理组中有 1 例因败血症导致的治疗相关死亡。

解释

这些结果支持 liso-cel 作为早期复发或难治性 LBCL 患者的新二线治疗推荐。

资金

Celgene，百时美施贵宝公司。