BACKGROUND Acalabrutinib is a selective, covalent Bruton tyrosine-kinase inhibitor with activity in chronic lymphocytic leukaemia. We compare the efficacy of acalabrutinib with or without obinutuzumab against chlorambucil with obinutuzumab in patients with treatment-naive chronic lymphocytic leukaemia. METHODS ELEVATE TN is a global, phase 3, multicentre, open-label study in patients with treatment-naive chronic lymphocytic leukaemia done at 142 academic and community hospitals in 18 countries. Eligible patients had untreated chronic lymphocytic leukaemia and were aged 65 years or older, or older than 18 years and younger than 65 years with creatinine clearance of 30-69 mL/min (calculated by use of the Cockcroft-Gault equation) or Cumulative Illness Rating Scale for Geriatrics score greater than 6. Additional criteria included an Eastern Cooperative Oncology Group performance status score of 2 or less and adequate haematologic, hepatic, and renal function. Patients with significant cardiovascular disease were excluded, and concomitant treatment with warfarin or equivalent vitamin K antagonists was prohibited. Patients were randomly assigned (1:1:1) centrally via an interactive voice or web response system to receive acalabrutinib and obinutuzumab, acalabrutinib monotherapy, or obinutuzumab and oral chlorambucil. Treatments were administered in 28-day cycles. To reduce infusion-related reactions, acalabrutinib was administered for one cycle before obinutuzumab administration. Oral acalabrutinib was administered (100 mg) twice a day until progressive disease or unacceptable toxic effects occurred. In the acalabrutinib-obinutuzumab group, intravenous obinutuzumab was given on days 1 (100 mg), 2 (900 mg), 8 (1000 mg), and 15 (1000 mg) of cycle 2 and on day 1 (1000 mg) of cycles 3-7. In the obinutuzumab-chlorambucil group, intravenous obinutuzumab was given on days 1 (100 mg), 2 (900 mg), 8 (1000 mg), and 15 (1000 mg) of cycle 1 and on day 1 (1000 mg) of cycles 2-6. Oral chlorambucil was given (0·5 mg/kg) on days 1 and 15 of each cycle, for six cycles. The primary endpoint was progression-free survival between the two combination-therapy groups, assessed by independent review committee. Crossover to acalabrutinib was allowed in patients who progressed on obinutuzumab-chlorambucil. Safety was assessed in all patients who received at least one dose of treatment. Enrolment for this trial is complete, and the study is registered at ClinicalTrials.gov, NCT02475681. FINDINGS Between Sept 14, 2015, and Feb 8, 2017, we recruited 675 patients for assessment. 140 patients did not meet eligibility criteria, and 535 patients were randomly assigned to treatment. 179 patients were assigned to receive acalabrutinib-obinutuzumab, 179 patients were assigned to receive acalabrutinib monotherapy, and 177 patients were assigned to receive obinutuzumab-chlorambucil. At median follow-up of 28·3 months (IQR 25·6-33·1), median progression-free survival was longer with acalabrutinib-obinutuzumab and acalabrutinib monotherapy, compared with obinutuzumab-chlorambucil (median not reached with acalabrutinib and obinutuzumab vs 22·6 months with obinutuzumab, hazard ratio [HR] 0·1; 95% CI 0·06-0·17, p<0·0001; and not reached with acalabrutinib monotherapy vs 22·6 months with obinutuzumab, 0·20; 0·13-0·3, p<0·0001). Estimated progression-free survival at 24 months was 93% with acalabrutinib-obinutuzumab (95% CI 87-96%), 87% with acalabrutinib monotherapy (81-92%), and 47% with obinutuzumab-chlorambucil (39-55%). The most common grade 3 or higher adverse event across groups was neutropenia (53 [30%] of 178 patients in the acalabrutinib-obinutuzumab group, 17 [9%] of 179 patients in the acalabrutinib group, and 70 [41%] of 169 patients in the obinutuzumab-chlorambucil group). All-grade infusion reactions were less frequent with acalabrutinib-obinutuzumab (24 [13%] of 178 patients) than obinutuzumab-chlorambucil (67 [40%] of 169 patients). Grade 3 or higher infections occurred in 37 (21%) patients given acalabrutinib-obinutuzumab, 25 (14%) patients given acalabrutinib monotherapy, and 14 (8%) patients given obinutuzumab-chlorambucil. Deaths occurred in eight (4%) patients given acalabrutinib-obinutuzumab, 12 (7%) patients given acalabrutinib, and 15 (9%) patients given obinutuzumab-chlorambucil. INTERPRETATION Acalabrutinib with or without obinutuzumab significantly improved progression-free survival over obinutuzumab-chlorambucil chemoimmunotherapy, providing a chemotherapy-free treatment option with an acceptable side-effect profile that was consistent with previous studies. These data support the use of acalabrutinib in combination with obinutuzumab or alone as a new treatment option for patients with treatment-naive symptomatic chronic lymphocytic leukaemia. FUNDING Acerta Pharma, a member of the AstraZeneca Group, and R35 CA198183 (to JCB).

中文翻译：

---

Acalabrutinib联合或不联合obinutuzumab与苯丁酸氮芥和obinutuzmab联合治疗未治疗的慢性淋巴细胞性白血病（ELEVATE TN）：一项随机，对照，3期试验。

背景技术Acalabrutinib是一种选择性的，共价的Bruton酪氨酸激酶抑制剂，在慢性淋巴细胞性白血病中具有活性。我们比较了未经治疗的慢性淋巴细胞性白血病患者中acalabrutinib联合或不联合obinutuzumab对苯丁酸氮芥与obinutuzumab的疗效。方法ELEVATE TN是一项全球性的，三阶段，多中心，开放标签的研究，研究对象是18个国家的142家学术和社区医院进行的未经治疗的慢性淋巴细胞白血病患者。符合条件的患者患有未经治疗的慢性淋巴细胞性白血病，年龄在65岁或以上，或大于18岁且小于65岁，肌酐清除率为30-69 mL / min（通过使用Cockcroft-Gault方程计算）或累积疾病评分老年医学量表的得分大于6。其他标准包括东部合作肿瘤小组的表现状态评分为2或更低，以及血液学，肝功能和肾功能均足够。排除患有严重心血管疾病的患者，并禁止与华法林或同等维生素K拮抗剂同时治疗。通过交互式语音或网络响应系统将患者随机分配到中心（1：1：1），以接受acalabrutinib和obinutuzumab，acalabrutinib单药治疗或obinutuzumab和口服苯丁酸氮芥。治疗为期28天。为了减少与输注相关的反应，在服用obinutuzumab之前将acalabrutinib给药一个周期。每天两次口服acalabrutinib（100 mg），直到出现疾病进展或出现不可接受的毒性作用。在acalabrutinib-obinutuzumab组中，在第2周期的第1天（100 mg），第2天（900 mg），第8天（1000 mg）和第15天（1000 mg）以及第3-7周期的第1天（1000 mg）静脉给予obinutuzumab。在obinutuzumab-chlorambucil组中，在第1周期的第1天（100 mg），第2天（900 mg），第8（1000 mg）和15（1000 mg）和第1周期（1000 mg）静脉给予obinutuzumab 2-6。在每个周期的第1天和第15天给予口服苯丁酸氮芥（0·5 mg / kg），共六个周期。主要终点是两个独立治疗委员会评估的两个联合治疗组之间的无进展生存期。接受obinutuzumab-chlorambucil进展的患者允许转用acalabrutinib。在接受至少一剂治疗的所有患者中评估安全性。该试验的研究已经完成，该研究已在ClinicalTrials.gov上注册，编号NCT02475681。结果在2015年9月14日至2017年2月8日之间，我们招募了675名患者进行评估。140名患者不符合入选标准，其中535名患者被随机分配接受治疗。179例患者被分配接受acalabrutinib-obinutuzumab，179例患者被分配接受acalabrutinib单药治疗，177例患者被分配接受obinutuzumab-chlorambucil治疗。在中位随访28·3个月（IQR 25·6-33·1）时，与obinutuzumab-chlorambucil单药治疗相比，acalabrutinib-obinutuzumab和aacalabrutinib单药治疗的中位无进展生存期更长（acalabrutinib和obinutuzumab与未接受vs奥比妥珠单抗22·6个月，危险比[HR] 0·1； 95％CI 0·06-0·17，p <0·0001；与acalabrutinib单药治疗未达到相比，奥比妥珠单抗22·6个月，0·20 ; 0·13-0·3，p <0·0001）。使用acalabrutinib-obinutuzumab估计的24个月无进展生存率为93％（95％CI 87-96％），使用alablabrutinib单药治疗的87％（81-92％）和使用obinutuzumab-chlorambucil（39-55％）的47％ 。各组中最常见的3级或更高级别不良事件是中性粒细胞减少（acalabrutinib-obinutuzumab组中178例患者中有53 [30％]，acalabrutinib组中179例患者中有17 [9％]，而169中有70 [41％]） obinutuzumab-chlorambucil组的患者）。相较于obinutuzumab-苯丁酸氮芥（169例患者中的67 [40％]），acalabrutinib-obinutuzumab（178例中的24例[13％]）全等级输注反应的发生率较低。使用acalabrutinib-obinutuzumab的37例（21％）患者，使用alablabrutinib单药治疗的25（14％）例和使用obinutuzumab-chlorambucil的14（8％）患者发生3级或更高级别的感染。接受acalabrutinib-obinutuzumab的患者有8（4％）人死亡，接受aacalabrutinib的患者有12（7％）患者，接受obinutuzumab-chlorambucil的患者为15（9％）。解释与奥比妥单抗-苯丁酸氮芥化学免疫疗法相比，有或没有奥比妥单抗的阿巴拉鲁替尼显着改善了无进展生存期，提供了无化学疗法的治疗选择，其副作用与以前的研究一致。这些数据支持acalabrutinib与obinutuzumab联合使用或单独使用，作为初治性有症状慢性淋巴细胞性白血病患者的新治疗选择。资金AstraZeneca集团成员Acerta Pharma和R35 CA198183（致JCB）。15例（9％）患者接受了obinutuzumab-chlorambucil治疗。解释与奥比妥单抗-苯丁酸氮芥化学免疫疗法相比，有或没有奥比妥单抗的阿巴拉鲁替尼显着改善了无进展生存期，提供了无化学疗法的治疗选择，其副作用与以前的研究一致。这些数据支持acalabrutinib与obinutuzumab联合使用或单独使用，作为初治性有症状慢性淋巴细胞性白血病患者的新治疗选择。资金AstraZeneca集团成员Acerta Pharma和R35 CA198183（致JCB）。15例（9％）患者接受了obinutuzumab-chlorambucil治疗。解释与奥比妥单抗-苯丁酸氮芥化学免疫疗法相比，有或没有奥比妥单抗的阿巴拉鲁替尼显着改善了无进展生存期，提供了无化学疗法的治疗选择，其副作用与以前的研究一致。这些数据支持acalabrutinib与obinutuzumab联合使用或单独使用，作为初治性有症状慢性淋巴细胞性白血病患者的新治疗选择。资金AstraZeneca集团成员Acerta Pharma和R35 CA198183（致JCB）。提供一种无化学疗法的治疗选择，其副作用可以接受，这与以前的研究一致。这些数据支持acalabrutinib与obinutuzumab联合使用或单独使用，作为初治性有症状慢性淋巴细胞性白血病患者的新治疗选择。资金AstraZeneca集团成员Acerta Pharma和R35 CA198183（致JCB）。提供一种无化学疗法的治疗方案，其副作用可以接受，这与以前的研究一致。这些数据支持acalabrutinib与obinutuzumab联合使用或单独使用，作为初治性有症状慢性淋巴细胞性白血病患者的新治疗选择。资金AstraZeneca集团成员Acerta Pharma和R35 CA198183（致JCB）。