Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX.
Weill Cornell Medicine, New York, NY.
J Clin Oncol. 2021 Dec 1;39(34):3853-3865. doi: 10.1200/JCO.21.00807. Epub 2021 Oct 7.
CAPTIVATE (NCT02910583), a randomized phase II study, evaluates minimal residual disease (MRD)-guided treatment discontinuation following completion of first-line ibrutinib plus venetoclax treatment in patients with chronic lymphocytic leukemia (CLL).
Previously untreated CLL patients age < 70 years received three cycles of ibrutinib and then 12 cycles of combined ibrutinib plus venetoclax. Patients in the MRD cohort who met the stringent random assignment criteria for confirmed undetectable MRD (Confirmed uMRD) were randomly assigned 1:1 to double-blind placebo or ibrutinib; patients without Confirmed uMRD (uMRD Not Confirmed) were randomly assigned 1:1 to open-label ibrutinib or ibrutinib plus venetoclax. Primary end point was 1-year disease-free survival (DFS) rate with placebo versus ibrutinib in the Confirmed uMRD population. Secondary end points included response rates, uMRD, and safety.
One hundred sixty-four patients initiated three cycles of ibrutinib lead-in. After 12 cycles of ibrutinib plus venetoclax, best uMRD response rates were 75% (peripheral blood) and 68% (bone marrow). Patients with Confirmed uMRD were randomly assigned to receive placebo (n = 43) or ibrutinib (n = 43); patients with uMRD Not Confirmed were randomly assigned to ibrutinib (n = 31) or ibrutinib plus venetoclax (n = 32). Median follow-up was 31.3 months. One-year DFS rate was not significantly different between placebo (95%) and ibrutinib (100%; arm difference: 4.7% [95% CI, -1.6 to 10.9]; = .15) in the Confirmed uMRD population. After ibrutinib lead-in tumor debulking, 36 of 40 patients (90%) with high tumor lysis syndrome risk at baseline shifted to medium or low tumor lysis syndrome risk categories. Adverse events were most frequent during the first 6 months of ibrutinib plus venetoclax and generally decreased over time.
The 1-year DFS rate of 95% in placebo-randomly assigned patients with Confirmed uMRD suggests the potential for fixed-duration treatment with this all-oral, once-daily, chemotherapy-free regimen in first-line CLL.
CAPTIVATE（NCT02910583）是一项随机的 II 期研究，评估了在慢性淋巴细胞白血病（CLL）患者中完成一线伊布替尼联合维奈托克治疗后，微小残留病（MRD）指导的治疗停药。
年龄<70 岁的未经治疗的 CLL 患者接受三个周期的伊布替尼治疗，然后接受 12 个周期的联合伊布替尼加维奈托克治疗。MRD 队列中符合严格随机分配标准的确认不可检测 MRD（Confirmed uMRD）患者被随机分配 1:1 接受双盲安慰剂或伊布替尼；未达到 Confirmed uMRD（uMRD Not Confirmed）的患者被随机分配 1:1 接受开放标签伊布替尼或伊布替尼加维奈托克。主要终点是确认 uMRD 人群中安慰剂与伊布替尼的 1 年无病生存率（DFS）率。次要终点包括缓解率、uMRD 和安全性。
164 例患者开始了三个周期的伊布替尼导入治疗。接受 12 个周期伊布替尼加维奈托克治疗后，最佳 uMRD 缓解率分别为外周血 75%和骨髓 68%。达到 Confirmed uMRD 的患者被随机分配接受安慰剂（n=43）或伊布替尼（n=43）；未达到 uMRD Not Confirmed 的患者被随机分配接受伊布替尼（n=31）或伊布替尼加维奈托克（n=32）。中位随访时间为 31.3 个月。在确认 uMRD 人群中，安慰剂（95%）和伊布替尼（100%；手臂差异：4.7%[95%CI，-1.6 至 10.9]；=0.15）的 1 年 DFS 率无显著差异。在伊布替尼导入肿瘤减瘤后，基线时有高肿瘤溶解综合征风险的 40 例患者中的 36 例转移到中或低肿瘤溶解综合征风险类别。伊布替尼加维奈托克治疗的前 6 个月最常发生不良事件，并且随着时间的推移通常会减少。
在确认 uMRD 的安慰剂随机分配患者中，1 年 DFS 率为 95%，提示在一线 CLL 中使用这种口服、每日一次、无化疗的固定疗程治疗方案具有潜在可能性。
