Abstract：
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.
RESULTS: 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).
CONCLUSIONS: 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.
BACKGROUND: Janssen and Leukemia & Lymphoma Society.
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.
RESULTS: 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).
CONCLUSIONS: 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.
BACKGROUND: Janssen and Leukemia & Lymphoma Society.
摘要：
背景：在标准免疫化学疗法中加入依鲁替尼可能会改善年轻（65岁或更年轻）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或不使用ASCT的含依鲁替尼的治疗相比，添加依鲁替尼是否会导致更好的临床结果。我们还研究了使用ASCT的标准治疗是否优于添加依鲁替尼但不使用ASCT的治疗。
方法：开放标签，随机化，三臂,平行组，优势TRIANGLE试验在13个欧洲国家和以色列的165个二级或三级临床中心进行.以前未经治疗的患者，II-IV期套细胞淋巴瘤,年龄18-65岁，适合ASCT的患者被随机分配1:1:1到对照组A或实验组A+I或I，按研究组和套细胞淋巴瘤国际预后指数风险组进行分层。A组的治疗包括R-CHOP（第0天或第1天静脉注射利妥昔单抗375mg/m2，第1天静脉注射环磷酰胺750mg/m2，第1天静脉注射阿霉素50mg/m2，第1天静脉注射长春新碱1·4mg/m2，第1-5天口服泼尼松100mg）和R-DHAP（或R-DHOx，第0天或第1天静脉注射利妥昔单抗375mg/m2，第1-4天静脉注射或口服地塞米松40mg，第2天静脉注射阿糖胞苷2×2g/m2，每12小时3h，第1天静脉注射顺铂100mg/m2超过24h，或第1天静脉注射奥沙利铂130mg/m2），然后进行ASCT。在A+I组中,在R-CHOP周期的第1-19天加入依鲁替尼(560mg/天口服),并作为ASCT后的固定持续时间维持(560mg/天,持续2年).在第一组中,伊布替尼的给药方式与A+I组相同，但ASCT被省略了。对无失败生存的主要结局进行了三个成对单侧对数秩检验。主要分析是通过意向治疗进行的。在开始相应治疗的患者中，通过治疗期评估不良事件。这项正在进行的试验已在ClinicalTrials.gov注册，NCT02858258。
结果：2016年7月29日至2020年12月28日，870名患者（662名男性，208名妇女）被随机分配到A组（n=288），A+I组（n=292），和I组(n=290)。经过31个月的中位随访，A+I组优于A组，3年无失败生存率为88%(95%CI84-92)，而非72%(67-79；风险比0·52[单侧98·3%CI0-0·86]；单侧p=0·0008)。未显示A组优于I组，3年无失败生存率为72％（67-79）对86％（82-91；风险比1·77[单侧98·3％CI0-3·76]；单侧p=0·9979）。正在进行A+I组与I组的比较。使用R-CHOP/R-DHAP或依鲁替尼联合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。在维护或随访期间，与仅伊布替尼相比，ASCT加伊布替尼后报告的3-5级血液学不良事件和感染明显更多（A+I组；血液学：231例患者中的114[50%]；感染：231例患者中的58[25%]；致命性感染：231例患者中的2[1%]）；与仅伊布替尼相比（I组；血液学：269例的74[28%]；
结论：在接受ASCT治疗后，将依鲁替尼添加到一线治疗中，对年轻套细胞淋巴瘤患者的疗效更佳，且毒性增加。在诱导和维持期间添加依鲁替尼应该是年轻套细胞淋巴瘤患者一线治疗的一部分。尚未确定ASCT是否添加到含依鲁替尼的方案中。
背景：Janssen和白血病和淋巴瘤协会。
方法：开放标签，随机化，三臂,平行组，优势TRIANGLE试验在13个欧洲国家和以色列的165个二级或三级临床中心进行.以前未经治疗的患者，II-IV期套细胞淋巴瘤,年龄18-65岁，适合ASCT的患者被随机分配1:1:1到对照组A或实验组A+I或I，按研究组和套细胞淋巴瘤国际预后指数风险组进行分层。A组的治疗包括R-CHOP（第0天或第1天静脉注射利妥昔单抗375mg/m2，第1天静脉注射环磷酰胺750mg/m2，第1天静脉注射阿霉素50mg/m2，第1天静脉注射长春新碱1·4mg/m2，第1-5天口服泼尼松100mg）和R-DHAP（或R-DHOx，第0天或第1天静脉注射利妥昔单抗375mg/m2，第1-4天静脉注射或口服地塞米松40mg，第2天静脉注射阿糖胞苷2×2g/m2，每12小时3h，第1天静脉注射顺铂100mg/m2超过24h，或第1天静脉注射奥沙利铂130mg/m2），然后进行ASCT。在A+I组中,在R-CHOP周期的第1-19天加入依鲁替尼(560mg/天口服),并作为ASCT后的固定持续时间维持(560mg/天,持续2年).在第一组中,伊布替尼的给药方式与A+I组相同，但ASCT被省略了。对无失败生存的主要结局进行了三个成对单侧对数秩检验。主要分析是通过意向治疗进行的。在开始相应治疗的患者中，通过治疗期评估不良事件。这项正在进行的试验已在ClinicalTrials.gov注册，NCT02858258。
结果：2016年7月29日至2020年12月28日，870名患者（662名男性，208名妇女）被随机分配到A组（n=288），A+I组（n=292），和I组(n=290)。经过31个月的中位随访，A+I组优于A组，3年无失败生存率为88%(95%CI84-92)，而非72%(67-79；风险比0·52[单侧98·3%CI0-0·86]；单侧p=0·0008)。未显示A组优于I组，3年无失败生存率为72％（67-79）对86％（82-91；风险比1·77[单侧98·3％CI0-3·76]；单侧p=0·9979）。正在进行A+I组与I组的比较。使用R-CHOP/R-DHAP或依鲁替尼联合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。在维护或随访期间，与仅伊布替尼相比，ASCT加伊布替尼后报告的3-5级血液学不良事件和感染明显更多（A+I组；血液学：231例患者中的114[50%]；感染：231例患者中的58[25%]；致命性感染：231例患者中的2[1%]）；与仅伊布替尼相比（I组；血液学：269例的74[28%]；
结论：在接受ASCT治疗后，将依鲁替尼添加到一线治疗中，对年轻套细胞淋巴瘤患者的疗效更佳，且毒性增加。在诱导和维持期间添加依鲁替尼应该是年轻套细胞淋巴瘤患者一线治疗的一部分。尚未确定ASCT是否添加到含依鲁替尼的方案中。
背景：Janssen和白血病和淋巴瘤协会。
