悪性リンパ腫—個別化医療の展望

Perspectives on Precision Medicine in Primary Central Nervous System Lymphoma

Point

・MYD88やCD79B遺伝子変異などによりもたらされるB細胞受容体経路およびToll様受容体シグナル伝達経路の活性化は，中枢神経系原発悪性リンパ腫（PCNSL）において重要なドライバー遺伝子異常である．

・PCNSLと全身性non-GCBびまん性大細胞型B細胞リンパ腫（DLBCL）に対して，Bruton's tyrosine kinase（BTK）を標的とする標的治療は国内外で活発な治療開発が行われている．

・メトトレキサート基盤化学療法などのPCNSLの標準治療にBTK阻害薬をどのように組み込むことが患者に利益をもたらすかは重要な検討課題である．

　Primary central nervous system lymphoma（PCNSL）is an aggressive, extranodal non-Hodgkin lymphoma that arises from the central nervous system, eyes, leptomeninges, and the spinal cord. Most PCNSLs are a type of diffuse large B-cell lymphoma（DLBCL）, and the majority are categorized as a non-germinal center B-cell（GCB）subtype. Recent genetic studies have revealed several common genetic abnormalities in PCNSL, such as MYD88 and CD79B mutations, suggesting dependence on the B-cell receptor/Toll-like receptor signaling pathway. These genetic findings have rationalized targeted therapy targeting Bruton's tyrosine kinase（BTK）, a key molecule of the B-cell receptor pathway in PCNSL and systemic non-GCB DLBCL. The first-generation BTK inhibitor ibrutinib has been widely studied in clinical trials for PCNSL and systemic non-GCB DLBCL. In Japan, a second-generation BTK inhibitor tirabrutinib was studied in a phase I/II trial and approved by the Japanese Ministry of Health and Welfare in March 2020 for relapsed and refractory PCNSL. While the current standard-of-care therapy for PCNSL is methotrexate（MTX）-based multi-agent induction immunochemotherapy like R-MPV（rituximab, MTX, procarbazine, and vincristine）followed by consolidation chemotherapy and/or radiation therapy, further investigation into the optimal use of BTK inhibitors in the standard-of-care therapy of PCNSL is warranted.