Ibrutinib and venetoclax in combination for chronic lymphocytic leukemia: synergy in practice

Natalia Timofeeva , Nitin Jain , Varsha Gandhi
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Abstract

The combination of ibrutinib and venetoclax has emerged as a promising therapeutic strategy for patients with chronic lymphocytic leukemia (CLL). Preclinical investigations demonstrated a synergistic antitumor effect through multiple mechanisms, providing a robust foundation for translating this regimen into clinical trials. Beyond the dual inhibition by 2 small molecules, another innovative concept being tested with this combination is the use of measurable residual disease (MRD)–driven treatment vs fixed-duration treatment to meet the escalating demand for oral, convenient, cost-effective, and time-limited therapeutic approaches. The clinical translation of this combination has yielded remarkable outcomes with significant improvements in the progression-free survival and overall survival rates for both treatment-naïve patients and those with relapsed/refractory CLL. Notably, a substantial proportion of patients achieved undetectable MRD. Clinical trial updates following the initial published results have shown consistency and durability of responses over time. In this review, the initial investigator-initiated trial results for ibrutinib and venetoclax are discussed, several multicenter clinical trial designs and outcomes are examined, variables such as chromosome 17p deletion that influence treatment responses are addressed, and the safety of the regimen is discussed. In addition, we reviewed the usage of this combination in other B-cell malignancies and discussed how current knowledge can be used for shaping the future CLL treatment regimens.

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伊布替尼和 venetoclax 联合治疗慢性淋巴细胞白血病:实践中的协同作用
摘要 ibrutinib和venetoclax联合治疗慢性淋巴细胞白血病(CLL)已成为一种很有前景的治疗策略。临床前研究表明,这两种药物通过多种机制产生协同抗肿瘤作用,为将这一治疗方案转化为临床试验奠定了坚实的基础。除了两种小分子的双重抑制作用外,这种组合疗法的另一个创新理念是使用可测量残留疾病(MRD)驱动的治疗与固定疗程的治疗,以满足对口服、方便、经济、有时限的治疗方法不断升级的需求。这种组合疗法的临床应用取得了显著成果,治疗无效患者和复发/难治性 CLL 患者的无进展生存率和总生存率都得到了明显改善。值得注意的是,相当一部分患者的MRD检测不到。在首次公布结果后,临床试验更新显示,随着时间的推移,反应具有一致性和持久性。在这篇综述中,我们讨论了研究者发起的伊布替尼和 venetoclax 最初的试验结果,研究了几项多中心临床试验的设计和结果,探讨了影响治疗反应的染色体 17p 缺失等变量,并讨论了治疗方案的安全性。此外,我们还回顾了这一联合疗法在其他 B 细胞恶性肿瘤中的应用,并讨论了如何利用现有知识制定未来的 CLL 治疗方案。
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