University of Cologne, Faculty of Medicine and University Hospital Cologne, Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, Cologne, Germany.
Cancer Institute, University College London, London, UK.
Nat Commun. 2023 Apr 18;14(1):2147. doi: 10.1038/s41467-023-37648-w.
Data on long-term outcomes and biological drivers associated with depth of remission after BCL2 inhibition by venetoclax in the treatment of chronic lymphocytic leukemia (CLL) are limited. In this open-label parallel-group phase-3 study, 432 patients with previously untreated CLL were randomized (1:1) to receive either 1-year venetoclax-obinutuzumab (Ven-Obi, 216 patients) or chlorambucil-Obi (Clb-Obi, 216 patients) therapy (NCT02242942). The primary endpoint was investigator-assessed progression-free survival (PFS); secondary endpoints included minimal residual disease (MRD) and overall survival. RNA sequencing of CD19-enriched blood was conducted for exploratory post-hoc analyses. After a median follow-up of 65.4 months, PFS is significantly superior for Ven-Obi compared to Clb-Obi (Hazard ratio [HR] 0.35 [95% CI 0.26-0.46], p < 0.0001). At 5 years after randomization, the estimated PFS rate is 62.6% after Ven-Obi and 27.0% after Clb-Obi. In both arms, MRD status at the end of therapy is associated with longer PFS. MRD + ( ≥ 10) status is associated with increased expression of multi-drug resistance gene ABCB1 (MDR1), whereas MRD6 (< 10) is associated with BCL2L11 (BIM) expression. Inflammatory response pathways are enriched in MRD+ patient solely in the Ven-Obi arm. These data indicate sustained long-term efficacy of fixed-duration Ven-Obi in patients with previously untreated CLL. The distinct transcriptomic profile of MRD+ status suggests possible biological vulnerabilities.
关于 Venetoclax 通过 B 细胞淋巴瘤 2 抑制（BCL2 抑制）治疗慢性淋巴细胞白血病（CLL）后深度缓解相关的长期结果和生物学驱动因素的数据有限。在这项开放标签、平行组、3 期研究中，432 例未经治疗的 CLL 患者被随机（1:1）分为 Venetoclax-奥滨尤妥珠单抗（Ven-Obi，216 例）或苯丁酸氮芥-奥滨尤妥珠单抗（Clb-Obi，216 例）治疗组（NCT02242942）。主要终点是研究者评估的无进展生存期（PFS）；次要终点包括微小残留病灶（MRD）和总生存期。对 CD19 富集的血液进行 RNA 测序，进行探索性事后分析。中位随访 65.4 个月后，与 Clb-Obi 相比，Ven-Obi 的 PFS 显著改善（风险比 [HR] 0.35 [95%CI 0.26-0.46]，p<0.0001）。随机分组后 5 年，Ven-Obi 组的估计 PFS 率为 62.6%，Clb-Obi 组为 27.0%。在两个治疗组中，治疗结束时的 MRD 状态与更长的 PFS 相关。MRD+（≥10）状态与多药耐药基因 ABCB1（MDR1）的过度表达相关，而 MRD6（<10）与 BCL2L11（BIM）的表达相关。在 Ven-Obi 组中，仅在 MRD+患者中富集了炎症反应途径。这些数据表明，固定疗程 Ven-Obi 在未经治疗的 CLL 患者中具有持续的长期疗效。MRD+状态的独特转录组谱表明可能存在生物学脆弱性。
