Small molecule inhibitors, including B-cell receptor antagonists and B-cell lymphoma - 2 inhibitors, have revolutionized the treatment of chronic lymphocytic leukemia (CLL). These agents have improved outcomes for patients of all prognostic backgrounds, thus securing their role in the frontline setting. Impressive activity has been demonstrated both with monotherapy and in combination with other targeted therapeutics. The most important remaining question is whether to administer small molecule inhibitors in a sequential fashion or in combination with each other and/or anti-CD20-directed therapy. Together, a number of retrospective and prospective clinical trials have provided insight into patient outcomes with different sequencing and combination strategies. While rituximab does not appear to provide significant additional benefit to ibrutinib, the incorporation of venetoclax appears to enable a deeper response and allow for a shorter duration of therapy. How durable of a response this produces and whether patients can be effectively retreated with venetoclax remain unclear. As various targeted therapy doublets and triplets are explored, it is important to investigate whether they produce significant long-term benefits over monotherapy and whether these approaches are appropriate for all patients.

中文翻译：

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慢性淋巴细胞白血病的靶向治疗：2（或3）好于1？

小分子抑制剂，包括B细胞受体拮抗剂和B细胞淋巴瘤-2抑制剂，彻底改变了慢性淋巴细胞白血病（CLL）的治疗方法。这些药物可改善所有预后背景的患者的预后，从而确保其在前线治疗中的作用。单一疗法以及与其他靶向疗法的结合均已证明了令人印象深刻的活性。剩下的最重要的问题是是否要以顺序方式或相互结合和/或抗CD20定向疗法联合使用小分子抑制剂。在一起，许多回顾性和前瞻性临床试验通过不同的测序和组合策略，为患者的预后提供了见识。尽管利妥昔单抗似乎并未为依鲁替尼提供明显的额外益处，Venetoclax的掺入似乎可以实现更深的反应并缩短治疗时间。尚不清楚这种反应产生多长时间持久，以及是否可以使用Venetoclax有效治疗患者。随着各种靶向疗法的双重治疗和三联疗法的研究，重要的是要研究它们是否比单一疗法产生长期的显着益处，以及这些方法是否适合所有患者。