文章：

伊布替尼联合方案在慢性淋巴细胞白血病治疗中的科学依据与临床结果

Ibrutinib combinations in CLL therapy: scientific rationale and clinical results

原文发布日期：2021-04-29

DOI: 10.1038/s41408-021-00467-7

类型: Review Article

开放获取: 是

英文摘要：

Ibrutinib has revolutionized the treatment of chronic lymphocytic leukemia (CLL). This drug irreversibly inhibits Bruton tyrosine kinase (BTK) by covalently binding to the C481 residue in the BTK kinase domain. BTK is a pivotal protein for B cell receptor signaling and tissue homing of CLL cells. Preclinical investigations have established the importance of the B cell receptor pathway in the maintenance and survival of normal and malignant B cells, underscoring the importance of targeting this axis for CLL. Clinical trials demonstrated overall and progression-free survival benefit with ibrutinib in multiple CLL subgroups, including patients with relapsed or refractory disease, patients with 17p deletion, elderly patients, and treatment-naïve patients. Consequently, ibrutinib was approved by the US Food and Drug Administration for newly diagnosed and relapsed disease. Ibrutinib has transformed the treatment of CLL; however, several limitations have been identified, including low complete remission rates, development of resistance, and uncommon substantial toxicities. Further, ibrutinib must be used until disease progression, which imposes a financial burden on patients and society. These limitations were the impetus for the development of ibrutinib combinations. Four strategies have been tested in recent years: combinations of ibrutinib with immunotherapy, chemoimmunotherapy, cell therapy, and other targeted therapy. Here, we review the scientific rationale for and clinical outcome of each strategy. Among these strategies, ibrutinib with targeted agent venetoclax results in high complete response rates and, importantly, high rates of undetectable minimal residual disease. Although we concentrate here on ibrutinib, similar combinations are expected or ongoing with acalabrutinib, tirabrutinib, and zanubrutinib, second-generation BTK inhibitors. Future investigations will focus on the feasibility of discontinuing ibrutinib combinations after a defined time; the therapeutic benefit of adding a third agent to ibrutinib-containing combinations; and profiling of resistant clones that develop after combination treatment. A new standard of care for CLL is expected to emerge from these investigations.
 

摘要翻译： 

伊布替尼革新了慢性淋巴细胞白血病（CLL）的治疗模式。该药物通过与BTK激酶结构域中的C481残基共价结合，不可逆地抑制布鲁顿酪氨酸激酶（BTK）。BTK是B细胞受体信号传导及CLL细胞组织归巢的关键蛋白。临床前研究已证实B细胞受体通路在正常和恶性B细胞的维持与存活中的重要作用，突显了靶向该通路对于CLL治疗的重要意义。临床试验表明，伊布替尼在多个CLL亚组中均显示出总生存期和无进展生存期的获益，这些亚组包括复发或难治性疾病患者、17p缺失患者、老年患者以及初治患者。因此，美国食品药品监督管理局批准伊布替尼用于新诊断及复发CLL的治疗。

尽管伊布替尼改变了CLL的治疗格局，但其局限性也逐渐显现，包括完全缓解率较低、耐药性的产生以及不常见的严重毒性反应。此外，伊布替尼需持续使用至疾病进展，这给患者和社会带来了经济负担。这些局限性推动了伊布替尼联合疗法的研发。近年来已测试四种联合策略：伊布替尼与免疫疗法、化学免疫疗法、细胞疗法及其他靶向疗法的联合。本文综述了各策略的科学依据及临床结果。其中，伊布替尼与靶向药物维奈托克的联合方案实现了较高的完全缓解率，更重要的是，带来了高比例的可检测不到微小残留病。虽然本文聚焦于伊布替尼，但类似联合方案预计或正在第二代BTK抑制剂（如阿卡替尼、替拉鲁替尼和泽布替尼）中进行探索。

未来的研究将重点关注：限定疗程后停用伊布替尼联合方案的可行性；在含伊布替尼的联合方案中加入第三种药物的治疗获益；以及对联合治疗后出现的耐药克隆进行特征分析。这些研究有望为CLL确立新的标准治疗方案。

原文链接：

Ibrutinib combinations in CLL therapy: scientific rationale and clinical results