Luo Meng-Xiao, Tan Tania, Trussart Marie, Poch Annika, Nguyen Thi Minh Hanh, Speed Terence P, Hicks Damien G, Bandala-Sanchez Esther, Peng Hongke, Chappaz Stéphane, Slade Charlotte, Utzschneider Daniel T, Koldej Rachel M, Ritchie David, Strasser Andreas, Thijssen Rachel, Ritchie Matthew E, Tam Constantine S, Lindeman Geoffrey J, Huang David C S, Lew Thomas E, Anderson Mary Ann, Roberts Andrew W, Teh Charis E, Gray Daniel H D
The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia.
Department of Medical Biology, The University of Melbourne, Melbourne, VIC, Australia.
Blood. 2024 Dec 26;144(26):2748-2761. doi: 10.1182/blood.2024024341.
Venetoclax, a first-in-class BH3 mimetic drug that targets B-cell lymphoma-2 (BCL-2), has improved the outcomes of patients with chronic lymphocytic leukemia (CLL). Early measurements of the depth of the venetoclax treatment response, assessed by minimal residual disease, are strong predictors of long-term clinical outcomes. However, there are limited data on the early changes induced by venetoclax treatment that might inform strategies to improve responses. To address this gap, we conducted longitudinal mass cytometric profiling of blood cells from patients with CLL during the first 5 weeks of venetoclax monotherapy. At baseline, we resolved CLL heterogeneity at the single-cell level to define multiple subpopulations in all patients based on proliferative, metabolic, and cell survival proteins. Venetoclax induced a significant reduction in all CLL subpopulations and caused rapid upregulation of the prosurvival BCL-2, BCL-extra large, and mantle cell lymphoma-1 proteins in surviving cells, which had reduced sensitivity to the drug. In mouse models, the venetoclax-induced elevation of survival proteins in B cells and CLL-like cells that persisted was recapitulated, and genetic models demonstrated that extensive apoptosis and access to the B-cell cytokine, B-cell activating factor (BAFF), were essential. Accordingly, in patients with CLL who were treated with venetoclax or the anti-CD20 antibody obinutuzumab there was marked elevation in BAFF and an increase in prosurvival proteins in leukemic cells that persisted. Overall, these data highlight the rapid adaptation of CLL cells to targeted therapies through homeostatic factors and support cotargeting of cytokine signals to achieve deeper and more durable long-term responses.
维奈托克是一种靶向B细胞淋巴瘤-2（BCL-2）的首创BH3模拟药物，改善了慢性淋巴细胞白血病（CLL）患者的治疗结局。通过微小残留病评估的维奈托克治疗反应深度的早期测量是长期临床结局的有力预测指标。然而，关于维奈托克治疗引起的早期变化的数据有限，这些变化可能为改善反应的策略提供信息。为了填补这一空白，我们在维奈托克单药治疗的前5周对CLL患者的血细胞进行了纵向质谱细胞分析。在基线时，我们在单细胞水平解析了CLL异质性，以根据增殖、代谢和细胞存活蛋白在所有患者中定义多个亚群。维奈托克导致所有CLL亚群显著减少，并使存活细胞中促存活的BCL-2、BCL-超大和套细胞淋巴瘤-1蛋白迅速上调，这些细胞对该药物的敏感性降低。在小鼠模型中，维奈托克诱导的B细胞和CLL样细胞中存活蛋白的持续升高得到了重现，遗传模型表明广泛的细胞凋亡和获得B细胞细胞因子B细胞活化因子（BAFF）至关重要。因此，在用维奈托克或抗CD20抗体奥滨尤妥珠单抗治疗的CLL患者中，BAFF显著升高，白血病细胞中促存活蛋白持续增加。总体而言，这些数据突出了CLL细胞通过稳态因子对靶向治疗的快速适应性，并支持对细胞因子信号进行联合靶向以实现更深、更持久的长期反应。
