Addition of autologous stem-cell transplantation to an ibrutinib-containing first-line treatment in patients aged 18-65 years with mantle cell lymphoma (TRIANGLE): 4·5-year follow-up of a three-arm, randomised, open-label, phase 3 superiority trial of the European MCL Network.

Methods

We conducted a three-arm, randomised, open-label, phase 3 superiority trial (TRIANGLE) in 165 secondary or tertiary clinical centres, with experience in mantle cell lymphoma treatment and the capability to perform ASCT or an association with such a centre, in 13 European countries and Israel.

我们在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TRIANGLE试验，这些中心在套细胞淋巴瘤治疗方面有经验，并且能够进行自体干细胞移植（ASCT）或与这样的中心合作，这是一个三臂、随机、开放标签的III期优势试验。

Patients aged 18-65 years with untreated, stage II-IV mantle cell lymphoma and suitable for ASCT were randomly assigned (1:1:1) to control group A or experimental groups A + I or I.

年龄在18-65岁之间，未接受治疗的II-IV期套细胞淋巴瘤患者，且适合进行自体干细胞移植（ASCT）的患者被随机分配（1:1:1）至对照组A或实验组A+I或I。

Randomisation was done using computer-generated random numbers and stratified by study groups and Mantle Cell Lymphoma International Prognostic Index risk groups.

随机分配是使用计算机生成的随机数进行的，并根据研究组和套细胞淋巴瘤国际预后指数（MCL-IPI）风险组进行分层。

Treatment in group A consisted of six alternating, 21-day cycles of R-CHOP (intravenous rituximab 375 mg/m2 on day 0 or 1, cyclophosphamide 750 mg/m2 on day 1, doxorubicin 50 mg/m2 on day 1, vincristine 1·4 mg/m2 on day 1 [up to a maximum of 2 mg], 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, high-dose intravenous cytarabine 2 × 2 g/m2 for 3 h every 12 h on day 2, plus either intravenous cisplatin 100 mg/m2 over 24 h on day 1 [R-DHAP] or intravenous oxaliplatin 130 mg/m2 on day 1 [R-DHAOx]), followed by ASCT.

A组的治疗包括六个交替的21天周期的R-CHOP（静脉注射利妥昔单抗375 mg/m2在第0天或第1天，环磷酰胺750 mg/m2在第1天，多柔比星50 mg/m2在第1天，长春新碱1·4 mg/m2在第1天[最大不超过2 mg]，以及口服泼尼松100 mg在第1-5天）和R-DHAP或R-DHAOx（静脉注射利妥昔单抗375 mg/m2在第0天或第1天，静脉注射或口服地塞米松40 mg在第1-4天，高剂量静脉注射阿糖胞苷2 × 2 g/m2，每12小时一次，持续3小时，在第2天进行，加上静脉注射顺铂100 mg/m2在24小时内完成在第1天[R-DHAP]或静脉注射奥沙利铂130 mg/m2在第1天[R-DHAOx]），随后进行自体干细胞移植（ASCT）。

In group A + I, oral ibrutinib (560 mg daily) was added on days 1-19 of R-CHOP cycles and as 2-year maintenance after ASCT.

在A+I组中，口服伊布替尼（每日560 mg）在R-CHOP周期的第1-19天添加，并作为ASCT后的2年维持治疗。

In group I, ibrutinib was given the same way, but ASCT was omitted.

在I组中，伊布替尼的给药方式相同，但省略了自体干细胞移植（ASCT）。

Rituximab maintenance was allowed in all treatment groups according to national guidelines.

根据国家指南，所有治疗组均允许使用利妥昔单抗维持治疗。

Three pairwise, one-sided, log-rank tests for the primary outcome (failure-free survival) were statistically monitored.

对主要结果（无失败生存）进行了三次成对的一侧对数秩检验，并进行了统计监测。

The primary analysis was by intention to treat and included all randomly assigned patients, ignoring protocol deviations.

主要分析是按治疗意向进行的，包括所有随机分配的患者，忽略了方案偏离。

Safety was assessed in randomly assigned patients who started any trial treatment component of the respective treatment phase.

安全性评估是在开始相应治疗阶段的任何试验治疗组分的随机分配患者中进行的。

The trial is registered with ClinicalTrials.gov (NCT02858258) and is complete.

该试验已在ClinicalTrials.gov注册（NCT02858258），并已完成。

Results

Between July 29, 2016, and Dec 28, 2020, 870 patients (662 [76%] were male, 208 [24%] were female) were randomly assigned to group A (n=288), group A + I (n=292), or group I (n=290).

2016年7月29日至2020年12月28日期间，共有870名患者（男性662名[76%]，女性208名[24%]）被随机分配到A组（n=288），A+I组（n=292）或I组（n=290）。

After median follow-up of 54·9 months (95% CI 54·4-56·0), group A + I did not show superiority over group I, with 4-year failure-free survival of 82% (95% CI 78-87) versus 81% (76-86; hazard ratio[HR] 0·86 [one-sided 98·33% CI 0·00-1·27]; one-sided p=0·21).

经过中位随访54.9个月（95%置信区间54.4-56.0），A+I组与I组相比未显示出优越性，4年无失败生存率为82%（95%置信区间78-87）对比81%（76-86；风险比[HR] 0.86 [单侧98.33%置信区间0.00-1.27]；单侧p=0.21）。

Group A + I remained superior to group A (82% [78-87] vs 70% [65-76]; HR 0·63 [one-sided 98·33% CI 0·00-0·89]; one-sided p=0·0026) and, as before, group A did not show superiority over group I (70% [65-76] vs 81% [76-86]; HR 1·45 [one-sided 98·33% CI 0·00-2·02]; one-sided p=0·99). 4-year overall survivalwas 88% (95% CI 84-92) in group A + I versus 81% (76-85) in group A (HR 0·59 [95% CI 0·38-0·92], p=0·0036) and 90% (87-94) in group I versus 81% (76-85) in group A (0·57 [0·36-0·90], p=0·0019).

A + I 组的效果仍然优于 A 组 (82% [78-87] vs 70% [65-76]; HR 0·63 [单侧 98·33% 置信区间 0·00-0·89]; 单侧 p=0·0026)，并且，如之前所述，A 组并不优于 I 组 (70% [65-76] vs 81% [76-86]; HR 1·45 [单侧 98·33% 置信区间 0·00-2·02]; 单侧 p=0·99)。4年总生存率为 A + I 组的 88% (95% 置信区间 84-92) 与 A 组的 81% (76-85) (HR 0·59 [95% 置信区间 0·38-0·92], p=0·0036)，以及 I 组的 90% (87-94) 与 A 组的 81% (76-85) (0·57 [0·36-0·90], p=0·0019)。

During maintenance or follow-up, the most common grade 3-5 adverse events were haematological disorders, reported in 127 (54%) of 234 patients in group A + I versus 74 (28%) of 269 in group I and 56 (23%) of 240 patients in group A, and infections, reported in 80 (34%) of 234 patients in group A + I versus 71 (26%) of 269 in group I and 37 (15%) of 240 patients in group A.

在维持治疗或随访期间，最常见的3-5级不良事件是血液系统疾病，A + I 组有 127 (54%) 名患者出现此症状，而 I 组有 74 (28%) 名患者，A 组有 56 (23%) 名患者。感染是第二常见的不良事件，A + I 组有 80 (34%) 名患者，I 组有 71 (26%) 名患者，A 组有 37 (15%) 名患者。

Infections and infestations were the most common fatal adverse events during maintenance or follow-up, occurring in four (2%) of 234 patients in group A + I and five (2%) of 269 patients in group I.

在维持治疗或随访期间，感染和寄生虫病是最常见的致命不良事件，A+I组234名患者中有4名（2%）发生，I组269名患者中有5名（2%）发生。

interpretation

After a prolonged follow-up of 55 months, both ibrutinib-containing groups showed relevant improvements not only in failure-free survival-a modified form of progression-free survival-but also in overall survival. In contrast, the addition of ASCT to an ibrutinib-containing regimen had no supplementary benefit but increased toxicity.

经过长达55个月的长期随访，含有伊布替尼的两组不仅在无进展生存期（一种改良的无进展生存形式）上显示出相关改善，而且在总生存期上也有所改善。相比之下，将自体干细胞移植（ASCT）添加到含有伊布替尼的方案中并没有额外的益处，但增加了毒性。

Induction treatment with ibrutinib and R-CHOP plus R-DHAP (or R-DHAOx), followed by 2 years of maintenance treatment with ibrutinib, should be considered as a new standard of care for younger patients with mantle cell lymphoma.

对于年轻患者，使用伊布替尼和R-CHOP联合R-DHAP（或R-DHAOx）的诱导治疗，随后进行2年的伊布替尼维持治疗，应被视为套细胞淋巴瘤治疗的新标准。

funding

Janssen.

杨森制药。