本文由小咖机器人翻译整理

期刊来源：Lancet

原文链接：https://doi.org/10.1016/S0140-6736(24)00184-3

摘要内容如下：

背景

在标准免疫化疗中加入伊布替尼可能会改善年轻（65岁或以下）套细胞淋巴瘤患者的预后，并挑战自体干细胞移植（ASCT）。该试验旨在研究与使用aSCT的审前免疫化疗标准或不使用aSCT的含伊布替尼治疗相比，加用伊布替尼是否会产生更好的临床结果。我们还研究了使用aSCT的标准治疗是否优于添加伊布替尼但不使用aSCT的治疗。

方法

在13个欧洲国家和以色列的165个二级或三级临床中心进行了开放标签、随机、三臂、平行组、优势三角试验。根据研究组和套细胞淋巴瘤国际预后指数风险组进行分层，将既往未经治疗、年龄在18-65岁且适合aSCT的II-IV期套细胞淋巴瘤患者按1:1:1的比例随机分为对照组A或实验组A+I或I。A组的治疗包括6个交替周期的R-CHOP（第0或第1天静脉注射利妥昔单抗375 mg/m2，第1天静脉注射环磷酰胺750 mg/m2，第1天静脉注射阿霉素50 mg/m2，第1天静脉注射长春新碱1.4 mg/m2，第1-5天口服泼尼松100 mg）和R-DHAP（或R-DHAOX，第0或第1天静脉注射利妥昔单抗375 mg/m2，第1-4天静脉或口服地塞米松40 mg，第2天每12小时静脉注射阿糖胞苷2×2 G/m2，共3小时，第1天静脉注射顺铂100 mg/m2，共24小时，或者第1天静脉注射奥沙利铂130 mg/m2，然后进行aSCT。在A+I组中，在R-CHOP周期的第1-19天添加伊布替尼（每天口服560 mg），并在aSCT后作为固定持续时间的维持（每天口服560 mg，持续2年）。在I组中，伊布替尼的给药方式与A+I组相同，但省略了aSCT。对无失败生存率的主要结果进行三个成对单侧对数秩检验，并进行统计学监测。通过意向性治疗进行初步分析。在开始各自治疗的患者中，根据治疗周期评估不良事件。这项正在进行的试验已在ClinicalTrials.gov，NCT02858258上注册。

调查结果

2016年7月29日至2020年12月28日，870名患者（662名男性，208名女性）被随机分为A组（n=288）、A+I组（n=292）和I组（n=290）。中位随访31个月后，A+I组的3年无失败生存率为88%（95%CI 84-92），优于A组的72%（95%CI 67-79；危险比0.52[单侧98.3%CI 0~0.86]；单侧P=0.0008）。A组的3年无失败生存率为72%（67-79），而I组为86%（82-91；危险比1.77[单侧98.3%CI 0-3.76]；单侧P=0.9979）。A+I组与I组的比较正在进行中。接受R-CHOP/R-DHAP或伊布替尼联合R-CHOP/R-DHAP治疗的患者在诱导或aSCT期间的3-5级不良事件没有相关差异。在维持治疗或随访期间，aSCT联合伊布替尼治疗后报告了更多的3-5级血液学不良事件和感染（A+I组；血液学:231名患者中的114名[50%]；感染:231人中的58人[25%]；致命性感染:231例中的2例[1%]）与仅使用伊布替尼（组I；血液学:269人中的74人[28%]；感染:269人中的52人[19%]；致命性感染:269例中有2例[1%]）或aSCT后（A组；血液学:238人中的51人[21%]；感染:238人中的32人[13%]；致命性感染:3例（占238例的1%）。

解释

在一线治疗中加入伊布替尼，对aSCT后毒性增加的年轻套细胞淋巴瘤患者具有更好的疗效。在诱导和维持期间加用伊布替尼应作为年轻套细胞淋巴瘤患者一线治疗的一部分。aSCT是否添加到含伊布替尼的方案中尚未确定。

英文原文如下：

Abstracts

BACKGROUND  Adding ibrutinib to standard immunochemotherapy might improve outcomes and challenge autologous stem-cell transplantation (ASCT) in younger (aged 65 years or younger) mantle cell lymphoma patients. This trial aimed to investigate whether the addition of ibrutinib results in a superior clinical outcome compared with the pre-trial immunochemotherapy standard with ASCT or an ibrutinib-containing treatment without ASCT. We also investigated whether standard treatment with ASCT is superior to a treatment adding ibrutinib but without ASCT.

METHODS  The open-label, randomised, three-arm, parallel-group, superiority TRIANGLE trial was performed in 165 secondary or tertiary clinical centres in 13 European countries and Israel. Patients with previously untreated, stage II-IV mantle cell lymphoma, aged 18-65 years and suitable for ASCT were randomly assigned 1:1:1 to control group A or experimental groups A+I or I, stratified by study group and mantle cell lymphoma international prognostic index risk groups. Treatment in group A consisted of six alternating cycles of R-CHOP (intravenous rituximab 375 mg/m2 on day 0 or 1, intravenous cyclophosphamide 750 mg/m2 on day 1, intravenous doxorubicin 50 mg/m2 on day 1, intravenous vincristine 1·4 mg/m2 on day 1, and oral prednisone 100 mg on days 1-5) and R-DHAP (or R-DHAOx, intravenous rituximab 375 mg/m2 on day 0 or 1, intravenous or oral dexamethasone 40 mg on days 1-4, intravenous cytarabine 2 × 2 g/m2 for 3 h every 12 h on day 2, and intravenous cisplatin 100 mg/m2 over 24 h on day 1 or alternatively intravenous oxaliplatin 130 mg/m2 on day 1) followed by ASCT. In group A+I, ibrutinib (560 mg orally each day) was added on days 1-19 of R-CHOP cycles and as fixed-duration maintenance (560 mg orally each day for 2 years) after ASCT. In group I, ibrutinib was given the same way as in group A+I, but ASCT was omitted. Three pairwise one-sided log-rank tests for the primary outcome of failure-free survival were statistically monitored. The primary analysis was done by intention-to-treat. Adverse events were evaluated by treatment period among patients who started the respective treatment. This ongoing trial is registered with ClinicalTrials.gov, NCT02858258.

FINDINGS  Between July 29, 2016 and Dec 28, 2020, 870 patients (662 men, 208 women) were randomly assigned to group A (n=288), group A+I (n=292), and group I (n=290). After 31 months median follow-up, group A+I was superior to group A with 3-year failure-free survival of 88% (95% CI 84-92) versus 72% (67-79; hazard ratio 0·52 [one-sided 98·3% CI 0-0·86]; one-sided p=0·0008). Superiority of group A over group I was not shown with 3-year failure-free survival 72% (67-79) versus 86% (82-91; hazard ratio 1·77 [one-sided 98·3% CI 0-3·76]; one-sided p=0·9979). The comparison of group A+I versus group I is ongoing. There were no relevant differences in grade 3-5 adverse events during induction or ASCT between patients treated with R-CHOP/R-DHAP or ibrutinib combined with R-CHOP/R-DHAP. During maintenance or follow-up, substantially more grade 3-5 haematological adverse events and infections were reported after ASCT plus ibrutinib (group A+I; haematological: 114 [50%] of 231 patients; infections: 58 [25%] of 231; fatal infections: two [1%] of 231) compared with ibrutinib only (group I; haematological: 74 [28%] of 269; infections: 52 [19%] of 269; fatal infections: two [1%] of 269) or after ASCT (group A; haematological: 51 [21%] of 238; infections: 32 [13%] of 238; fatal infections: three [1%] of 238).

INTERPRETATION  Adding ibrutinib to first-line treatment resulted in superior efficacy in younger mantle cell lymphoma patients with increased toxicity when given after ASCT. Adding ibrutinib during induction and as maintenance should be part of first-line treatment of younger mantle cell lymphoma patients. Whether ASCT adds to an ibrutinib-containing regimen is not yet determined.

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