Molecular pathogenesis and therapeutic development of primary central nervous system lymphoma: update and future perspectives
Molecular pathogenesis and therapeutic development of primary central nervous system lymphoma: update and future perspectives
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原发性中枢神经系统淋巴瘤的分子发病机制和治疗发展：最新进展和未来展望
DOI：
10.11406/rinketsu.63.1145
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发表时间：
2022
期刊：
影响因子：
--
通讯作者：
永根基雄
中科院分区：
文献类型：
--
作者：
見崎孝一;南部育;筒井泰史;上出智也;中田光俊;山田 茂樹;永根基雄
原发性中枢神经系统淋巴瘤(PCNSL)是一种少见的局限于中枢神经系统的结外非霍奇金淋巴瘤，具有弥漫性大B细胞淋巴瘤(DLBCL)的组织学特征，在老年患者中非常常见。全脑放射治疗(WBRT)并不能提供相当大的缓解作用；相反，它高度参与了具有迟发性神经毒性的白质脑病的发展，尤其是在老年患者中。对新诊断的PCNSL患者的标准治疗包括以大剂量甲氨蝶呤(HD-MTX)为基础的多药免疫化疗诱导，如R-MPV(利妥昔单抗、MTX、丙卡巴津、长春新碱)产生70%-75%的完全应答率，然后是HD-阿糖胞苷巩固。最近，在多个随机试验中，研究了在自体干细胞移植的支持下，以关键药物硫替巴为核心的大剂量巩固化疗，以取代WBRT，显示出不逊于WBRT，且神经毒性较小。综合的遗传学分析显示，CD79B和MYD88基因的致癌突变率很高，这是DLBCL的MCD/C5亚型的标志，导致了PCNSL中NF-κB信号通路的结构性激活。Bruton‘s酪氨酸激酶(BTK)是CD79B/MYD88下游的一种中间蛋白，已成为一种有希望的治疗靶点。此外，第二代BTK抑制剂替拉布替尼对复发/难治性PCNSL显示出显著的活性，导致其于2020年在日本获得批准。此外，其他针对PI3-激酶的新药物和免疫疗法，包括免疫调节剂、免疫检查点阻断和CAR-T，已经在临床试验中进行了积极的测试。
Primary central nervous system lymphoma (PCNSL) is a rare extra-nodal non-Hodgkin's lymphoma confined to the central nervous system with a diffuse large B-cell lymphoma (DLBCL) histology and is highly prevelant in elderly patients. Whole brain radiotherapy (WBRT) does not provide considerable remission; rather it is highly involved in the development of leukoencephalopathy with delayed neurotoxicity, notably in elderly patients. Standard care for newly diagnosed patients with PCNSL comprised induction with high-dose methotrexate (HD-MTX)-based multi-agent immunochemotherapy, such as R-MPV (rituximab, MTX, procarbazine, vincristine) yielding 70-75% complete response rate, followed by HD-cytarabine consolidation. Consolidation high-dose chemotherapy with the key drug thiotepa supported by autologous stem cell transplant has recently been investigated to replace WBRT in multiple randomized trials, demonstrating non-inferiority to WBRT with less neurotoxicity. Comprehensive genetic analyses have revealed high rates of oncogenic mutations in CD79B and MYD88 genes, the hallmarks for MCD/C5 subtype of DLBCL, leading to constitutive activation of NF-κB signaling pathways in PCNSL. Bruton's tyrosine kinase (BTK), an intermediate kinase downstream to CD79B/MYD88, has emerged as a promising therapeutic target. Furthermore, tirabrutinib, a second-generation BTK inhibitor, has shown substantial activity against relapsed/refractory PCNSL, resulting in its approval in 2020 in Japan. Additionally, other new agents against PI3-kinase and immunotherapies including immunomodulatory agents, immune checkpoint blockade, and CAR-T have been actively tested in clinical trials.