Plasma Cell Dyscrasias Unit, Department of Clinical Therapeutics, National and Kapodistrian University of Athens , Athens, Greece.
Expert Rev Anticancer Ther. 2020 Aug;20(8):663-674. doi: 10.1080/14737140.2020.1791705. Epub 2020 Jul 13.
Waldenstrom's Macroglobulinemia (WM) is a rare, indolent lymphoplasmacytic lymphoma characterized by heterogeneous clinical and genomic profile. Bruton's tyrosine kinase (BTK) is central to the signaling pathways required for clonal WM cell survival, and BTK inhibitors currently have an imperative role in the treatment of WM.
The central role of BTK in WM will be described, and the rationale behind the development of BTKi. Clinical trial data that led to the approval of ibrutinib (the first-in-class BTKi) will be reviewed. Despite its potency and safe toxicity profile, ibrutinib does not induce deep remissions, and responses are mutational-status dependent. The mechanisms that lead to resistance to this agent are being investigated. Ibrutinib treatment has to be continuous; consequently, patients face the effects of long-term toxicity. In that context, second-generation inhibitors are in clinical development with fewer off-target effects and an efficacy profile, which will be determined based on long-term follow-up data.
The optimal therapeutic approach for WM patients remains to be established. The question of whether a combinatory (or synergistic) regimen to overcome resistance and allow for a fixed treatment duration will allow for deep and durable response is being addressed in ongoing clinical trials.
华氏巨球蛋白血症（WM）是一种罕见的惰性淋巴浆细胞淋巴瘤，其临床和基因组特征具有异质性。布鲁顿酪氨酸激酶（BTK）是克隆性 WM 细胞存活所需信号通路的核心，BTK 抑制剂目前在 WM 的治疗中具有重要作用。
BTK 在 WM 中的核心作用将被描述，以及开发 BTKi 的基本原理。将回顾导致伊布替尼（首个 BTKi）获批的临床试验数据。尽管伊布替尼具有强大的疗效和安全的毒性特征，但它并不能诱导深度缓解，且反应依赖于突变状态。正在研究导致对该药物产生耐药性的机制。伊布替尼治疗必须是连续的；因此，患者面临长期毒性的影响。在这种情况下，第二代抑制剂正在临床开发中，具有更少的脱靶效应和疗效特征，这将根据长期随访数据来确定。
WM 患者的最佳治疗方法仍有待确定。正在进行中的临床试验正在探讨联合（或协同）方案是否能够克服耐药性，并允许固定的治疗持续时间，从而实现深度和持久的缓解。
