Ibrutinib and Venetoclax Target Distinct Subpopulation of CLL Cells: Rationale for Drug Combination and Implication of Minimal Residual Disease Eradication

作者：Y. Lynn Lynn Wang, Carrie A. Franzen, Shengchun Wang, Girish Venkataraman, Lei Li, Nifang Niu, Madina Sukhanova, Yifan Tu, Juehua Gao, Yi-Hua Chen, Shuo Ma, Richard A. Larson, Pin Lu · 发表于：Blood · 年份：2019 · DOI：10.1182/blood-2019-125396 · 被引用次数：3 · 研究领域：Chronic Lymphocytic Leukemia Research、Phagocytosis and Immune Regulation

Ibrutinib (Ibr) is a specific inhibitor of Bruton tyrosine kinase, a component of the B-cell receptor (BCR) signaling. Venetoclax (Veneto) inhibits the anti-apoptotic protein BCL2. Both drugs are highly effective as monotherapy against chronic lymphocytic leukemia (CLL) (Byrd NEJM, Roberts, NEJM, 2015 and Roberts, Blood, 2019) and clinical trials using the combination therapy are ongoing. An interesting clinical observation is that the tumor cell sensitivity to these two drugs differ between different anatomic compartments. While lymph node-resident CLL cells are more sensitive to ibr, circulating CLL cells in the peripheral blood are more sensitive to the action of veneto. When these two drugs are used in combination to treat relapsed/refractory (Hillman ASH 2018 and Kater EHA 2019) or previously untreated CLL patients (Jain NEJM 2019), rate of complete response significantly increases compared to single drug alone. Moreover, negativity of bone marrow minimal residual disease continues to improve over time. However, the reason behind these observed compartmental responses is largely unknown, and we investigated the differential response using an ex vivo model that promotes CLL proliferation (CLL proliferation model). A better understanding of how these two drugs synergize would eventually help develop other rational combination strategies. We established the ex vivo model using fibroblasts derived from the bone marrow of a CLL patient. In this model, CLL cells closely intera...