Department of Hematology, Cancer Center Amsterdam, Lymphoma and Myeloma Center Amsterdam, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.
Department of Hematology, Faculty of Medicine, Ankara University, Ankara, Turkey.
Lancet Oncol. 2024 Apr;25(4):463-473. doi: 10.1016/S1470-2045(24)00070-6. Epub 2024 Mar 8.
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 TP53 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 ClinicalTrials.gov, NCT02756611, 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.
大多数慢性淋巴细胞白血病患者在接受靶向治疗或化疗免疫治疗后或复发后进展，后续治疗选择有限。 Venetoclax 单药治疗在复发环境中的反应水平尚不清楚。我们旨在评估 Venetoclax 在有或没有先前 B 细胞受体相关激酶抑制剂（BCRi）治疗的患者中的活性。
这项多中心、开放标签、单臂、3b 期试验（VENICE-1）评估了 Venetoclax 单药治疗有或没有先前 BCRi 治疗的复发或难治性慢性淋巴细胞白血病成人患者的活性和安全性。合格的参与者年龄在 18 岁或以上，且患有先前治疗的复发或难治性慢性淋巴细胞白血病。允许存在 del(17p)或 TP53 异常和先前的 BCRi 治疗。患者接受 5 周的 ramp-up 至每天口服 400mg 的 Venetoclax，并接受最多 108 周的治疗，停药后随访 2 年或可选的延长访问。主要活动终点是 BCRi 初治患者的完全缓解率（完全缓解或完全缓解伴不完全骨髓恢复）。分析使用意向治疗（即，所有入组患者，与至少接受一次 Venetoclax 治疗的患者一致）。这项研究在 ClinicalTrials.gov 上注册，NCT02756611，现已完成。
2016 年 6 月 22 日至 2022 年 3 月 11 日期间，我们招募了 258 例复发或难治性慢性淋巴细胞白血病患者（180 例[70%]为男性；252 例[98%]为白人；191 例为 BCRi 初治患者，67 例为 BCRi 预处理患者）。在整个队列中，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），BCRi 预处理组为 49.7 个月（47.4-54.3）。在 191 例 BCRi 初治患者中，66 例（35%；95%CI 27.8-41.8）达到完全缓解或不完全骨髓恢复的完全缓解。在 67 例 BCRi 预处理患者中，18 例（27%；95%CI 16.8-39.1）达到完全缓解或不完全骨髓恢复的完全缓解。在整个队列的 258 例患者中，203 例（79%）报告了 3 级或更高级别的治疗后出现的不良事件，136 例（53%）报告了严重不良事件。最常见的治疗后出现的不良事件是中性粒细胞减少症（96 [37%]），最常见和最严重的不良事件是肺炎（21 [8%]）。有 13 例（5%）患者因不良事件死亡；其中一例（自身免疫性溶血性贫血）可能与 Venetoclax 有关。未发现新的安全信号。
这些数据表明，Venetoclax 单药治疗在复发或难治性慢性淋巴细胞白血病患者中具有深度和持久的反应，包括 BCRi 预处理患者，这表明 Venetoclax 单药治疗是治疗 BCRi 初治和 BCRi 预处理患者的有效策略。
艾伯维。
