BTK抑制剂治疗原发免疫豁免部位大B细胞淋巴瘤的研究进展

Research on Bruton’s tyrosine kinase inhibitor for the treatment of primary immuneprivileged site large B-cell lymphoma

原发免疫豁免部位大B细胞淋巴瘤(primary immune-privileged site large B-cell lymphoma,IP-DLBCLs)是世界卫生组织(WHO)淋巴样肿瘤分类第5版新的类别总称,指一组原发于免疫功能正常患者的免疫屏障之后部位的侵袭性B细胞淋巴瘤,起源于各自的解剖结构(如血脑、血网膜和血睾丸屏障)和各自原发部位的免疫调节系统所形成的免疫庇护所,并具有相同的免疫表型和分子特征,目前包括原发性中枢神经系统大B细胞淋巴瘤(primary central nervous system lymphoma,PCNSL)、原发睾丸大B细胞淋巴瘤(primary testicular large B-cell lymphoma,PTL)和原发玻璃体视网膜大B细胞淋巴瘤(primary vitreoretinal large B-cell lymphoma,PVRL)。该类疾病预后相对较差,目前尚无标准的治疗方案。Toll样受体(TLR)信号(通过MYD88突变)和B细胞受体(BCR)信号(通过CD79B突变)通路介导的NF-κB激活是三者发病的核心机制。该共同属性为这一类疾病的治疗提供了通用的靶点。BTK(Bruton’s tyrosine kinase,BTK)是上述信号通路的中心分子。因此,BTK抑制剂可能是这类疾病合理的治疗药物选择。本文将就BTK抑制剂治疗原发免疫豁免部位大B细胞淋巴瘤的作用机制、临床研究、不良反应及耐药问题进行综述。

Primary immune-privileged site large B-cell lymphoma(IP-DLBCLs)is a general term introduced in the 5th edition of the World Health Organization(WHO)Classification of Lymphoid Tumors and refers to a group of aggressive B-cell lymphomas that originate in sites behind the immune barrier in immunocompetent patients.Anatomical-derived immune sanctuaries(such as the blood-brain,blood-retinal,and blood-testicular barriers)and immunomodulatory systems that share the same immunophenotype and molecular characteristics currently include the central nervous,vitreoretinal,and testes systems and large B-cell lymphomas.The primary immune-privileged site large Bcell lymphoma prognosis is relatively poor,with no standard treatment plan.Toll-like receptor-mediated nuclear factor kappa B(NF-κB)(via MYD88 mutation)and B-cell receptor(BCR)(via CD79B mutation)pathway activation was the core pathogenesis mechanism in all three systems(central nervous,vitreoretinal,and testes),presenting a potential common treatment target.Bruton's tyrosine kinase(BTK)is a central molecule in the above signaling pathway,thus BTK inhibitors present a reasonable therapeutic drug choice for such diseases.This article reviews the mechanism of action,clinical studies,adverse reactions,and drug resistance of BTK inhibitors in primary immune-priviledged site large B-cell lymphoma treatment.