Most patients with chronic lymphocytic leukaemia progress after treatment or retreatment with targeted therapy or chemoimmunotherapy and have limited subsequent treatment options. Response levels to the single-agent venetoclax in the relapsed setting is unknown. We aimed to assess venetoclax activity in patients with or without previous B-cell receptor-associated kinase inhibitor (BCRi) treatment. This multicentre, open-label, single-arm, phase 3b trial (VENICE-1) assessed activity and safety of venetoclax monotherapy in adults with relapsed or refractory chronic lymphocytic leukaemia, stratified by previous exposure to a BCRi. Eligible participants were aged 18 years or older with previously treated relapsed or refractory chronic lymphocytic leukaemia. Presence of del(17p) or aberrations and previous BCRi treatment were permitted. Patients received 5-week ramp-up to 400 mg of oral venetoclax once daily and were treated for up to 108 weeks, with 2 years follow-up after discontinuation, or optional extended access. The primary activity endpoint was complete remission rate (complete remission or complete remission with incomplete marrow recovery) in BCRi-naive patients. Analyses used the intent-to-treat (ie, all enrolled patients, which coincided with those who received at least one dose of venetoclax). This study was registered with , , and is complete. Between June 22, 2016, and March 11, 2022, we enrolled 258 patients with relapsed or refractory chronic lymphocytic leukaemia (180 [70%] were male; 252 [98%] were White; 191 were BCRi-naive and 67 were BCRi-pretreated). Median follow-up in the overall cohort was 49·5 months (IQR 47·2–54·1), 49·2 months (47·2–53·2) in the BCRi-naive group, and 49·7 months (47·4–54·3) in the BCRi-pretreated group. Of 191 BCRi-naive patients, 66 (35%; 95% CI 27·8−41·8) had complete remission or complete remission with incomplete marrow recovery. 18 (27%; 95% CI 16·8–39·1) of 67 patients in the BCRi-pretreated group had complete remission or complete remission with incomplete marrow recovery. Grade 3 or worse treatment-emergent adverse events were reported in 203 (79%) and serious adverse events were reported in 136 (53%) of 258 patients in the overall cohort. The most common treatment-emergent adverse event was neutropenia (96 [37%]) and the most common and serious adverse event was pneumonia (21 [8%]). There were 13 (5%) deaths reported due to adverse events; one of these deaths (autoimmune haemolytic anaemia) was possibly related to venetoclax. No new safety signals were identified. These data demonstrate deep and durable responses with venetoclax monotherapy in patients with relapsed or refractory chronic lymphocytic leukaemia, including BCRi-pretreated patients, suggesting that venetoclax monotherapy is an effective strategy for treating BCRi-naive and BCRi-pretreated patients. AbbVie.

中文翻译：

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Venetoclax 在复发或难治性慢性淋巴细胞白血病患者中的活性：VENICE-1 多中心、开放标签、单臂、3b 期试验分析


大多数慢性淋巴细胞白血病患者在接受靶向治疗或化学免疫疗法治疗或复治后病情进展，后续治疗选择有限。复发环境中对单药维奈托克的反应水平尚不清楚。我们的目的是评估既往接受或未接受 B 细胞受体相关激酶抑制剂 (BCRi) 治疗的患者的 Venetoclax 活性。这项多中心、开放标签、单组 3b 期试验 (VENICE-1) 评估了 Venetoclax 单药治疗成人复发性或难治性慢性淋巴细胞白血病的活性和安全性，并根据既往 BCRi 暴露情况进行分层。符合资格的参与者年龄为 18 岁或以上，患有既往治疗过的复发性或难治性慢性淋巴细胞白血病。 del(17p) 或畸变的存在以及之前的 BCRi 治疗是允许的。患者每天一次口服维奈托克，为期 5 周，剂量递增至 400 毫克，治疗时间长达 108 周，停药后随访 2 年，或可选择延长治疗时间。主要活动终点是未接受过 BCRi 治疗的患者的完全缓解率（完全缓解或完全缓解但骨髓恢复不完全）。分析使用意向治疗（即所有入组患者，与接受至少一剂维奈托克的患者一致）。这项研究已在 、 、 注册，并且已完成。 2016 年 6 月 22 日至 2022 年 3 月 11 日期间，我们招募了 258 名复发或难治性慢性淋巴细胞白血病患者（180 名 [70%] 为男性；252 名 [98%] 为白人；191 名未接受过 BCRi 治疗的患者，67 名接受过 BCRi 治疗的患者。预处理）。整个队列的中位随访时间为 49·5 个月 (IQR 47·2–54·1)，BCRi 初治组为 49·2 个月 (47·2–53·2)，未经治疗组为 49·7 个月 (IQR 47·2–54·1)。 47·4–54·3) 在 BCRi 预处理组中。 在 191 名未接受过 BCRi 治疗的患者中，66 名（35%；95% CI 27·8−41·8）获得完全缓解或完全缓解但骨髓恢复不完全。 BCRi 预处理组的 67 名患者中有 18 名（27%；95% CI 16·8–39·1）获得完全缓解或完全缓解但骨髓恢复不完全。整个队列中 258 名患者中有 203 名 (79%) 报告了 3 级或更严重的治疗引起的不良事件，136 名 (53%) 报告了严重不良事件。最常见的治疗中出现的不良事件是中性粒细胞减少症（96 [37%]），最常见和严重的不良事件是肺炎（21 [8%]）。据报告，有 13 人 (5%) 因不良事件死亡；其中一例死亡（自身免疫性溶血性贫血）可能与维奈托克有关。没有发现新的安全信号。这些数据表明，对于复发或难治性慢性淋巴细胞白血病患者（包括接受过 BCRi 治疗的患者），维奈托克单药疗法具有深度且持久的疗效，表明维奈托克单药疗法是治疗未接受过 BCRi 治疗和接受过 BCRi 治疗的患者的有效策略。艾伯维.