泽布替尼、奥妥珠单抗和维奈克拉用于CLL：长期随访、MRD动力学、再治疗、T细胞分析、药代动力学
Zanubrutinib, Obinutuzumab, and Venetoclax in CLL: Long-Term Follow Up, MRD Kinetics, Retreatment, T-Cell Profiling, PKs.
摘要(中文译文)
三药联合方案在初治慢性淋巴细胞白血病（CLL）中可诱导高比例的≤10⁻⁴不可检测微小残留病（uMRD4），并似可延长无进展生存期（PFS），但将中性粒细胞减少/感染风险降至最低的最佳治疗持续时间尚不明确。在这项2期试验中，我们评估了泽布替尼、奥妥珠单抗和维奈克拉（BOVen）方案在初治CLL中的疗效（NCT03824483）。我们这项由MRD驱动的治疗/再治疗研究旨在优化治疗持续时间，在疗效与延长治疗暴露相关毒性之间取得平衡，并评估泽布替尼-维奈克拉（Z+V）再治疗。中位观察时间为69个月，中位治疗持续时间为10个周期，96%的患者达到血液uMRD4，92%的患者在血液和骨髓中均达到uMRD4（主要终点）。BOVen耐受性良好，3-4级中性粒细胞减少发生率为25%，感染发生率为9.6%（无5级事件）。中位无MRD4生存期为34.1个月（95% CI 23.1-50.5），48个月PFS率为79.7%（95% CI 68.6-92.5）。ΔMRD400（第4个月时经免疫测序检测血液MRD较基线下降≥400倍）可识别出更早达到骨髓uMRD4的患者（6个月 vs 12个月，p<0.001），以及尽管治疗持续时间更短（8个月 vs 13个月，p<0.001）但无MRD4生存期更长的患者（50.5个月 vs 18.1个月，p<0.001）。本文还报告了Z+V再治疗的安全性/疗效，并描述了药代动力学和T细胞谱分析研究。总之，BOVen耐受性良好，在初治CLL中以较短的治疗持续时间（中位10个月）实现了频繁的早期uMRD4和持久缓解。目前正在两项基于维奈克拉和sonrotoclax的三药联合方案治疗初治CLL的前瞻性试验中评估ΔMRD400作为指导治疗持续时间的预测性生物标志物。
Abstract
Triplet regimens induce high rates of undetectable MRD at ≤10-4 (uMRD4) and appear to prolong progression-free survival (PFS) in treatment-naïve (TN) CLL, but the optimal treatment duration to minimize the risk of neutropenia/infections is unknown. In this phase 2 trial, we evaluated zanubrutinib, obinutuzumab, and venetoclax (BOVen) in TN CLL (NCT03824483). Our MRD-driven treatment/retreatment study was designed to optimize treatment duration balancing efficacy against toxicities associated with extended treatment exposure, and evaluate zanubrutinib-venetoclax (Z+V) retreatment. With a median observation time of 69 months and median treatment duration of 10 cycles, 96% achieved blood uMRD4, and 92% achieved uMRD4 in both blood and bone marrow (primary endpoint). BOVen was well-tolerated with low rates of grade 3-4 neutropenia (25%) and infections (9.6%; none grade 5). Median MRD4-free survival was 34.1 months (95% CI 23.1-50.5) and 48-month PFS was 79.7% (95% CI 68.6-92.5). ΔMRD400 (≥400-fold reduction in blood MRD by immunosequencing at 4 months) identified patients with earlier bone marrow uMRD4 (6 vs 12 months, p<0.001), and longer MRD4-free survival (50.5 vs 18.1 months, p<0.001) despite a shorter treatment duration (8 vs 13 mo, p<0.001). This manuscript also reports on the safety/efficacy of Z+V retreatment and describes pharmacokinetic and T-cell profiling studies. In summary, BOVen was well-tolerated and resulted in frequent, early uMRD4 and durable remissions in TN CLL with a short treatment duration (median 10 months). ΔMRD400 is undergoing evaluation for use as a predictive biomarker to guide treatment duration in two prospective trials of venetoclax- and sonrotoclax-based triplets in TN CLL.
如何引用
AMA
Jacob D Soumerai, Meghan C Thompson, Ahmet Dogan, Venkatraman E Seshan, Kelsey Flaherty, Natalie Slupe, et al. Zanubrutinib, Obinutuzumab, and Venetoclax in CLL: Long-Term Follow Up, MRD Kinetics, Retreatment, T-Cell Profiling, PKs.. Blood advances. 2026; doi:10.1182/bloodadvances.2026020221.
APA
Jacob D Soumerai, Meghan C Thompson, Ahmet Dogan, Venkatraman E Seshan, Kelsey Flaherty, Natalie Slupe, et al (2026). Zanubrutinib, Obinutuzumab, and Venetoclax in CLL: Long-Term Follow Up, MRD Kinetics, Retreatment, T-Cell Profiling, PKs.. Blood advances. https://doi.org/10.1182/bloodadvances.2026020221
GB/T 7714
Jacob D Soumerai, Meghan C Thompson, Ahmet Dogan, Venkatraman E Seshan, Kelsey Flaherty, Natalie Slupe, et al. Zanubrutinib, Obinutuzumab, and Venetoclax in CLL: Long-Term Follow Up, MRD Kinetics, Retreatment, T-Cell Profiling, PKs.[J]. Blood advances, 2026 doi:10.1182/bloodadvances.2026020221.
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