Venetoclax Dose Escalation Rapidly Activates a BAFF/BCL-2 Survival Axis in Chronic Lymphocytic Leukemia.

IF 21 1区 医学 Q1 HEMATOLOGY Blood Pub Date : 2024-10-29 DOI:10.1182/blood.2024024341
Meng-Xiao Luo, Tania Tan, Marie Trussart, Annika Poch, Minh-Hanh Thi Nguyen, Terence P Speed, Damien G Hicks, Esther Bandala-Sanchez, Hongke Peng, Stephane Chappaz, Charlotte Slade, Daniel T Utzschneider, Rachel M Koldej, David Ritchie, Andreas Strasser, Rachel Thijssen, Matthew E Ritchie, Constantine Si Lun Tam, Geoffrey J Lindeman, David Ching Siang Huang, Thomas E Lew, Mary Ann Anderson, Andrew W Roberts, Charis E Teh, Daniel H D Gray
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Abstract

Venetoclax, a first-in-class BH3 mimetic drug targeting BCL-2, has improved outcomes for 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. Yet, there are limited data concerning 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 five weeks of venetoclax monotherapy. At baseline, we resolved CLL heterogeneity at the single-cell level to define multiple subpopulations in all patients distinguished by proliferative, metabolic and cell survival proteins. Venetoclax induced significant reduction in all CLL subpopulations coincident with rapid upregulation of pro-survival BCL-2, BCL-XL and MCL-1 proteins in surviving cells, which had reduced sensitivity to the drug. Mouse models recapitulated the venetoclax-induced elevation of survival proteins in B cells and CLL-like cells that persisted in vivo, with genetic models demonstrating that extensive apoptosis and access to the B cell cytokine, BAFF, were essential. Accordingly, analysis of patients with CLL that were treated with venetoclax or the anti-CD20 antibody obinutuzumab exhibited marked elevation of BAFF and increased pro-survival proteins in leukemic cells that persisted. Overall, these data highlight the rapid adaptation of CLL cells to targeted therapies via homeostatic factors and support co-targeting of cytokine signals to achieve deeper and more durable long-term responses.

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Venetoclax剂量递增可快速激活慢性淋巴细胞白血病的BAFF/BCL-2生存轴
Venetoclax是一种靶向BCL-2的首创BH3模拟药物,它能改善慢性淋巴细胞白血病(CLL)患者的治疗效果。通过最小残留病来评估 Venetoclax 治疗反应的深度,是预测长期临床疗效的有力指标。然而,有关 Venetoclax 治疗引起的早期变化的数据却很有限,而这些数据可能为改善反应的策略提供依据。为了填补这一空白,我们在 Venetoclax 单药治疗的前五周对 CLL 患者的血细胞进行了纵向质谱分析。在基线阶段,我们在单细胞水平上解决了 CLL 的异质性,在所有患者中定义了多个亚群,这些亚群由增殖蛋白、代谢蛋白和细胞存活蛋白区分。Venetoclax 能显著减少所有 CLL 亚群的数量,同时存活细胞中促进存活的 BCL-2、BCL-XL 和 MCL-1 蛋白迅速上调,从而降低了对药物的敏感性。小鼠模型再现了 Venetoclax 诱导的 B 细胞和 CLL 样细胞中存活蛋白的升高,这种升高在体内持续存在,基因模型表明,广泛的细胞凋亡和获得 B 细胞细胞因子 BAFF 至关重要。因此,对接受 Venetoclax 或抗 CD20 抗体 obinutuzumab 治疗的 CLL 患者进行的分析表明,BAFF 明显升高,持续存在的白血病细胞中的促生存蛋白也有所增加。总之,这些数据突显了CLL细胞通过同源因子对靶向疗法的快速适应,并支持联合靶向细胞因子信号以获得更深入、更持久的长期应答。
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来源期刊
Blood
Blood 医学-血液学
CiteScore
23.60
自引率
3.90%
发文量
955
审稿时长
1 months
期刊介绍: Blood, the official journal of the American Society of Hematology, published online and in print, provides an international forum for the publication of original articles describing basic laboratory, translational, and clinical investigations in hematology. Primary research articles will be published under the following scientific categories: Clinical Trials and Observations; Gene Therapy; Hematopoiesis and Stem Cells; Immunobiology and Immunotherapy scope; Myeloid Neoplasia; Lymphoid Neoplasia; Phagocytes, Granulocytes and Myelopoiesis; Platelets and Thrombopoiesis; Red Cells, Iron and Erythropoiesis; Thrombosis and Hemostasis; Transfusion Medicine; Transplantation; and Vascular Biology. Papers can be listed under more than one category as appropriate.
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