Therapeutic targeting of apoptosis with small molecule B-cell lymphoma 2 (BCL-2) inhibition with venetoclax is highly efficacious in CLL, leading to sustained deep responses, particularly among patients with treatment-naïve disease with favorable prognostic markers. Patients with unfavorable genetic characteristics such as aberration and unmutated IGHV may also derive durable benefits, but their remission duration after time-limited venetoclax-containing combination therapy is shorter, particularly in patients with relapsed/refractory disease. Emerging data indicate that the context of disease progression after initial treatment with venetoclax may define the success of re-treatment with venetoclax. Specifically, continuous venetoclax exposure may select for resistant disease due to genetic mechanisms such as mutations and functional resistance mechanisms such as hyperphosphorylation of BCL-2 family proteins, which decrease the affinity of venetoclax binding to the target or lead to increased MCL-1 dependence and concomitant decrease in BCL-2 dependence. These patients may be best served by switching to a different class of targeted agents at the time of progression. In contrast, relapsed CLL that arises while being off therapy after a period of time-limited venetoclax-based regimens maintains sensitivity to re-treatment with venetoclax for the majority of patients. Novel strategies related to therapeutic targeting of apoptosis include next-generation BCL-2 inhibitors with improved potency and pharmacokinetic profiles, direct targeting of anti-apoptotic BH3 family proteins beyond BCL-2 such as MCL-1, and indirect targeting of MCL-1 through mechanisms such as small molecule cyclin-dependent kinase 9 inhibitors.

中文翻译：

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慢性淋巴细胞白血病细胞凋亡的治疗靶向


使用 Venetoclax 抑制小分子 B 细胞淋巴瘤 2 (BCL-2) 来靶向凋亡治疗在 CLL 中非常有效，可产生持续的深度反应，特别是对于具有良好预后标志物的初治疾病患者。具有不良遗传特征（例如畸变和未突变 IGHV）的患者也可能获得持久的益处，但他们在限时含维奈托克联合治疗后的缓解持续时间较短，特别是在患有复发/难治性疾病的患者中。新数据表明，初次使用维奈托克治疗后疾病进展的情况可能决定了维奈托克再次治疗的成功与否。具体而言，持续的维奈托克暴露可能会由于遗传机制（例如突变）和功能性耐药机制（例如 BCL-2 家族蛋白的过度磷酸化）而选择耐药疾病，这会降低维奈托克与靶点结合的亲和力或导致 MCL-1 依赖性增加， BCL-2依赖性随之减少。这些患者最好在病情进展时改用不同类别的靶向药物。相比之下，对于大多数患者来说，在限时的基于维奈托克的治疗方案一段时间后停止治疗时出现的复发性慢性淋巴细胞白血病仍对再次使用维奈托克治疗敏感。与细胞凋亡治疗靶向相关的新策略包括具有改进效力和药代动力学特征的下一代 BCL-2 抑制剂、直接靶向 BCL-2 以外的抗凋亡 BH3 家族蛋白（如 MCL-1）以及通过间接靶向 MCL-1。机制，例如小分子细胞周期蛋白依赖性激酶 9 抑制剂。