目的:Waldenström巨球蛋白血症(WM)的治疗在过去十年中不断发展。随着MYD88和CXCR疣的开创性发现,低球蛋白血症,感染,和WM细胞中的髓核变性(WHIM)突变,我们对疾病生物学和治疗的认识有所提高。一类新的代理人的发展,布鲁顿酪氨酸激酶抑制剂(BTKi),严重影响了WM的治疗模式。在这里,我们回顾了当前和新兴的BTKi及其在WM中使用的证据。
结果:临床试验已经确定了共价BTKi在WM治疗中的作用。在携带CXCR4WHIM突变或MYD88WT基因型的患者中,其疗效受损。BTKC481突变介导的对共价BTKi的抗性的发展可能导致疾病难治性。小说,非共价的,下一代BTKi正在出现,早期临床试验的初步结果显示,在WM中具有有希望的活性,甚至在难以共价BTKi的患者中。共价BTK抑制剂在治疗初期(TN)和复发难治性(R/R)WM中显示出有意义的结果,特别是那些有MYD88L265P突变的人。下一代BTKi显示出改进的选择性,导致更有利的毒性。在WM中,给予BTKi直至进展或发展为不可耐受的毒性。因此,获得性抵抗的潜力,累积毒性的出现,与治疗相关的经济负担是与持续治疗方法相关的关键挑战.通过规避BTKC481突变,将结合位点改变为共价BTKi,在获得性耐药的情况下,非共价BTKi可作为替代药物.缺乏与常规化学免疫疗法的头对头比较试验。RAINBOW试验的结果(NCT046152),比较地塞米松,利妥昔单抗,和环磷酰胺(DRC)方案到第一代,等待伊布替尼,但需要更多的研究来得出关于化学免疫疗法和BTKi疗效比较的明确结论.完整的反应是难以捉摸的BTKi,在WM中也正在评估改善疗效和限制治疗持续时间的组合方案。
The treatment of Waldenström macroglobulinemia (WM) has evolved over the past decade. With the seminal discoveries of MYD88 and CXCR warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) mutations in WM cells, our understanding of the disease biology and treatment has improved. The development of a new class of agents, Bruton tyrosine kinase inhibitors (BTKi), has substantially impacted the treatment paradigm of WM. Herein, we review the current and emerging BTKi and the evidence for their use in WM.
Clinical trials have established the role of covalent BTKi in the treatment of WM. Their efficacy is compromised among patients who harbor CXCR4WHIM mutation or MYD88WT genotype. The development of BTKC481 mutation-mediated resistance to covalent BTKi may lead to disease refractoriness. Novel, non-covalent, next-generation BTKi are emerging, and preliminary results of the early phase clinical trials show promising activity in WM, even among patients refractory to a covalent BTKi. Covalent BTK inhibitors have demonstrated meaningful outcomes in treatment-naïve (TN) and relapsed refractory (R/R) WM, particularly among those harboring the MYD88L265P mutation. The next-generation BTKi demonstrate improved selectivity, resulting in a more favorable toxicity profile. In WM, BTKi are administered until progression or the development of intolerable toxicity. Consequently, the potential for acquired resistance, the emergence of cumulative toxicities, and treatment-related financial burden are critical challenges associated with the continuous therapy approach. By circumventing BTK C481 mutations that alter the binding site to covalent BTKi, the non-covalent BTKi serve as alternative agents in the event of acquired resistance. Head-to-head comparative trials with the conventional chemoimmunotherapies are lacking. The findings of the RAINBOW trial (NCT046152), comparing the dexamethasone, rituximab, and cyclophosphamide (DRC) regimen to the first-generation, ibrutinib are awaited, but more studies are needed to draw definitive conclusions on the comparative efficacy of chemoimmunotherapy and BTKi. Complete response is elusive with BTKi, and combination regimens to improve upon the efficacy and limit the treatment duration are also under evaluation in WM.