<b>Background:</b> Patients with chronic lymphocytic leukaemia and high-risk features have poorer outcomes on ibrutinib than those without high-risk features. The aim of this study was to assess the benefit of adding ublituximab, an anti-CD20 monoclonal antibody, to ibrutinib therapy in this population. <b>Methods:</b> We did a randomised, phase 3, multicentre study (GENUINE) of patients aged 18 years or older with relapsed or refractory chronic lymphocytic leukaemia with at least one of 17p deletion, 11q deletion, or TP53 mutation, at 119 clinics in the USA and Israel. Eligible patients had received at least one previous chronic lymphocytic leukaemia therapy and had an Eastern Cooperative Oncology Group performance status of 2 or lower. We randomised patients (1:1) using permuted block randomisation with a block size of four and stratified by previous lines of therapy (one vs two or more) to receive ibrutinib alone or ibrutinib in combination with ublituximab. Treatment allocation was not masked to patients or investigators. Ibrutinib was given orally daily at 420 mg for all cycles. Ublituximab was given intravenously in 28-day cycles, with increasing doses during cycle 1 (≤150 mg on day 1, 750 mg on day 2, and 900 mg on days 8 and 15) and continuing at 900 mg on day 1 of cycles 2–6. After cycle 6, ublituximab was given at 900 mg every three cycles. The study was initially designed with co-primary endpoints of progression-free survival and overall response rate but due to protracted patient accrual, the protocol was amended to have a single primary endpoint of independent review committee-assessed overall response rate (defined as the proportion of patients who had a partial response, complete response, or complete response with incomplete marrow recovery according to the 2008 International Workshop on CLL criteria) in the intention-to-treat population. Safety was evaluated in the population of patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, NCT02301156, and the final analysis is presented. <b>Findings:</b> 224 patients were assessed for eligibility, of whom 126 patients were enrolled and randomly assigned to receive ublituximab plus ibrutinib (n = 64) or ibrutinib alone (n = 62) between Feb 6, 2015, and Dec 19, 2016. After a median follow-up of 41·6 months (IQR 36·7–47·3), the overall response rate was 53 (83%) of 64 patients in the ublituximab plus ibrutinib group and 40 (65%) of 62 patients in the ibrutinib group (p = 0·020). 117 patients, including 59 in the ublituximab plus ibrutinib group and 58 in the ibrutinib group, received at least one dose of treatment and were included in safety analyses. Most adverse events were grade 1 or 2. The most common grade 3 and 4 adverse events were neutropenia (11 [19%] patients in the ublituximab plus ibrutinib group and seven [12%] in the ibrutinib group), anaemia (five [8%] and five [9%]), and diarrhoea (six [10%] and three [5%]). The most common serious adverse events were pneumonia (six [10%] in the ublituximab plus ibrutinib group and four [7%] in the ibrutinib group), atrial fibrillation (four [7%] and one [2%]), sepsis (four [7%] and one [2%]), and febrile neutropenia (three [5%] and one [2%]). Two patients in the ublituximab plus ibrutinib group died due to adverse events (one cardiac arrest and one failure to thrive), neither of which were treatment-related. Five patients in the ibrutinib group died due to adverse events, including one cardiac arrest, one cerebral infarction, one intracranial haemorrhage, one Pneumocystis jirovecii pneumonia infection, and one unexplained death; the death due to cardiac arrest was considered to be treatment-related. <b>Interpretation:</b> The addition of ublituximab to ibrutinib resulted in a statistically higher overall response rate without affecting the safety profile of ibrutinib monotherapy in patients with relapsed or refractory high-risk chronic lymphocytic leukaemia. These findings provide support for the addition of ublituximab to Bruton tyrosine kinase inhibitors for the treatment of these patients. <b>Funding:</b> TG Therapeutics.

中文翻译：

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高危 CLL：靶向联合治疗可提高生存率

<b>背景：</b> 患有慢性淋巴细胞白血病和高危特征的患者在使用依鲁替尼时的结果比没有高危特征的患者差。本研究的目的是评估在该人群中将抗 CD20 单克隆抗体 ublituximab 添加到依鲁替尼治疗中的益处。<b>方法：</b> 我们对 18 岁或以上患有复发或难治性慢性淋巴细胞白血病且至少有 17p 缺失、11q 缺失或 TP53 突变之一的患者进行了一项随机、3 期、多中心研究 (GENUINE) ，在美国和以色列的 119 家诊所。符合条件的患者至少接受过一种既往慢性淋巴细胞白血病治疗，并且东部肿瘤协作组的体能状态为 2 或更低。我们随机分配患者（1：1) 使用排列块随机化，块大小为 4，并按之前的治疗线（1 对 2 或更多）分层，单独接受依鲁替尼或依鲁替尼联合 ublituximab。治疗分配没有向患者或研究人员隐藏。依鲁替尼在所有周期中每天口服 420 mg。Ublituximab 以 28 天为一个周期静脉给药，在第 1 周期增加剂量（第 1 天≤150 mg，第 2 天 750 mg，第 8 天和第 15 天 900 mg）并在第 2 周期的第 1 天继续 900 mg –6。第 6 周期后，每三个周期给予 900 mg ublituximab。该研究最初设计有无进展生存期和总体反应率的共同主要终点，但由于长期的患者招募，该方案被修改为具有独立审查委员会评估的总体反应率的单一主要终点（根据 2008 年国际 CLL 研讨会，定义为部分反应、完全反应或完全反应但骨髓恢复不完全的患者比例标准）在意向治疗人群中。在接受至少一剂研究治疗的患者群体中评估了安全性。该试验已在 ClinicalTrials.gov 注册，NCT02301156，并提供最终分析。<b>研究结果：</b> 224 名患者接受了资格评估，其中 126 名患者在 2015 年 2 月 6 日和2016 年 12 月 19 日。中位随访 41 6 个月 (IQR 36 7–47 3) 后，ublituximab 加依鲁替尼组 64 名患者中的 53 名 (83%) 和依鲁替尼组 62 名患者中的 40 名 (65%)组（p = 0 020）。117 名患者（包括 ublituximab 加依鲁替尼组 59 名和依鲁替尼组 58 名）接受了至少一剂治疗并被纳入安全性分析。大多数不良事件为 1 级或 2 级。最常见的 3 级和 4 级不良事件是中性粒细胞减少症（ublituximab 加依鲁替尼组 11 名 [19%] 患者和依鲁替尼组 7 名 [12%] 患者）、贫血（5 名 [8 %] 和五个 [9%])，以及腹泻 (六个 [10%] 和三个 [5%])。最常见的严重不良事件是肺炎（ublituximab加依鲁替尼组6例[10%]和依鲁替尼组4例[7%]）、心房颤动（4例[7%]和1例[2%]）、败血症（4 例 [7%] 和 1 例 [2%]）和发热性中性粒细胞减少症（3 例 [5%] 和 1 例 [2%]）。ublituximab 加依鲁替尼组的两名患者死于不良事件（一名心脏骤停和一名无法茁壮成长），这两者均与治疗无关。依鲁替尼组5例患者因不良事件死亡，包括1例心脏骤停、1例脑梗死、1例颅内出血、1例耶氏肺孢子菌肺炎感染、1例原因不明的死亡；心脏骤停导致的死亡被认为与治疗有关。<b>解读：</b> 将 ublituximab 添加到 ibrutinib 后，总体缓解率在统计学上更高，而不会影响 ibrutinib 单药治疗复发或难治性高危慢性淋巴细胞白血病患者的安全性。这些发现为将 ublituximab 添加到 Bruton 酪氨酸激酶抑制剂治疗这些患者提供了支持。<b>资金：</b> TG Therapeutics。