Neurological Surgery 脳神経外科50巻1号

2022年01月発行

特集 Precision Medicine—個別化医療を目指した遺伝子診断と新治療の知見 Ⅰ悪性脳腫瘍

悪性リンパ腫—個別化医療の展望

著者： 佐々木重嘉¹ 永根基雄¹

所属機関： ¹杏林大学医学部脳神経外科

ページ範囲：P.51 - P.60

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．

参考文献

1）Brain tumor registry of Japan（2005-2008）. Neurol Med Chir（Tokyo）57（Suppl 1）：9-102, 2017

2）成田善孝：脳腫瘍（1）脳腫瘍の分類と疫学．日本臨牀 79（増刊号1）：187-193, 2021

3）Shiels MS, et al：Trends in primary central nervous system lymphoma incidence and survival in the U.S. Br J Haematol 174：417-424, 2016

4）Hayabuchi N, et al：Primary central nervous system lymphoma in Japan：a nationwide survey. Int J Radiat Oncol Biol Phys 44：265-272, 1999

5）Deckert M PW, et al：Lymphomas. Louis DN, et al（eds）：WHO classification of tumours of the central nervous system（ed Revised 4th Edition）. Lyon, IARC Press, 2016, pp. 270-277

6）Shah GD, et al：Combined immunochemotherapy with reduced whole-brain radiotherapy for newly diagnosed primary CNS lymphoma. J Clin Oncol 25：4730-4735, 2007

7）Morris PG, et al：Rituximab, methotrexate, procarbazine, and vincristine followed by consolidation reduced-dose whole-brain radiotherapy and cytarabine in newly diagnosed primary CNS lymphoma：final results and long-term outcome. J Clin Oncol 31：3971-3979, 2013

8）Sasaki N, et al：Consecutive single-institution case series of primary central nervous system lymphoma treated by R-MPV or high-dose methotrexate monotherapy. Jpn J Clin Oncol 50：999-1008, 2020

9）Bromberg JEC, et al：Rituximab in patients with primary CNS lymphoma（HOVON 105/ALLG NHL 24）：a randomised, open-label, phase 3 intergroup study. Lancet Oncol 20：216-228, 2019

10）Kasenda B, et al：First-line treatment and outcome of elderly patients with primary central nervous system lymphoma（PCNSL）-a systematic review and individual patient data meta-analysis. Ann Oncol 26：1305-1313, 2015

11）Basso K, Dalla-Favera R：Germinal centres and B cell lymphomagenesis. Nat Rev Immunol 15：172-184, 2015

12）Alizadeh AA, et al：Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Nature 403：503-511, 2000

13）Rosenwald A, et al；Lymphoma/Leukemia Molecular Profiling Project：The use of molecular profiling to predict survival after chemotherapy for diffuse large-B-cell lymphoma. N Engl J Med 346：1937-1947, 2002

14）Hans CP, et al：Confirmation of the molecular classification of diffuse large B-cell lymphoma by immunohistochemistry using a tissue microarray. Blood 103：275-282, 2004

15）Scott DW, et al：Determining cell-of-origin subtypes of diffuse large B-cell lymphoma using gene expression in formalin-fixed paraffin-embedded tissue. Blood 123：1214-1217, 2014

16）Nowakowski GS, et al：ROBUST：a phase Ⅲ study of lenalidomide plus R-CHOP versus placebo plus R-CHOP in previously untreated patients with ABC-type diffuse large B-cell lymphoma. J Clin Oncol 39：1317-1328, 2021

17）Wilson WH, et al：Targeting B cell receptor signaling with ibrutinib in diffuse large B cell lymphoma. Nat Med 21：922-926, 2015

18）Younes A, et al；PHOENIX investigators：Randomized phase Ⅲ trial of ibrutinib and rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone in non-germinal center B-cell diffuse large B-cell lymphoma. J Clin Oncol 37：1285-1295, 2019

19）Nowakowski GS, et al：Lenalidomide combined with R-CHOP overcomes negative prognostic impact of non-germinal center B-cell phenotype in newly diagnosed diffuse large B-Cell lymphoma：a phase Ⅱ study. J Clin Oncol 33：251-257, 2015

20）Westin JR, et al：Smart start：rituximab, lenalidomide, and ibrutinib alone and in combination with standard chemotherapy for patients with newly diagnosed diffuse large B-cell lymphoma：final phase Ⅱ results. Blood 134：1581, 2019

21）Schmitz R, et al：Genetics and pathogenesis of diffuse large B-cell lymphoma. N Engl J Med 378：1396-1407, 2018

22）Chapuy B, et al：Molecular subtypes of diffuse large B cell lymphoma are associated with distinct pathogenic mechanisms and outcomes. Nat Med 24：679-690, 2018

23）Zhang M, et al：Genetic subtype guided rituximab-based immunochemotherapy improves outcome in newly diagnosed diffuse large B-cell lymphoma：first report of a randomized phase Ⅱ study. Hematol Oncol 39：56-57, 2021

24）Lee JH, et al：Clinicopathologic significance of MYD88 L265P mutation in diffuse large B-cell lymphoma：a meta-analysis. Sci Rep 7：1785, 2017

25）Nakamura T, et al：Recurrent mutations of CD79B and MYD88 are the hallmark of primary central nervous system lymphomas. Neuropathol Appl Neurobiol 42：279-290, 2016

26）Tateishi K, et al：A hyperactive RelA/p65-Hexokinase 2 signaling axis drives primary central nervous system lymphoma. Cancer Res 80：5330-5343, 2020

27）Watanabe J, et al：Comparison of circulating tumor DNA between body fluids in patients with primary central nervous system lymphoma. Leuk Lymphoma 60：3587-3589, 2019

28）Yamagishi Y, et al：Liquid biopsy of cerebrospinal fluid for MYD88 L265P mutation is useful for diagnosis of central nervous system lymphoma. Cancer Sci 112：4702-4710, 2021

29）Fukumura K, et al：Genomic characterization of primary central nervous system lymphoma. Acta Neuropathol 131：865-875, 2016

30）Nayyar N, et al：MYD88 L265P mutation and CDKN2A loss are early mutational events in primary central nervous system diffuse large B-cell lymphomas. Blood Adv 3：375-383, 2019

31）Chapuy B, et al：Targetable genetic features of primary testicular and primary central nervous system lymphomas. Blood 127：869-881, 2016

32）Fangazio M, et al：Genetic mechanisms of HLA-I loss and immune escape in diffuse large B cell lymphoma. Proc Natl Acad Sci U S A 118：e2104504118, 2021

33）Nayak L, et al：PD-1 blockade with nivolumab in relapsed/refractory primary central nervous system and testicular lymphoma. Blood 129：3071-3073, 2017

34）Grommes C, et al：Ibrutinib unmasks critical role of Bruton tyrosine kinase in primary CNS lymphoma. Cancer Discov 7：1018-1029, 2017

35）Soussain C, et al：Ibrutinib monotherapy for relapse or refractory primary CNS lymphoma and primary vitreoretinal lymphoma：final analysis of the phase Ⅱ ‘proof-of-concept’ iLOC study by the Lymphoma study association（LYSA）and the French oculo-cerebral lymphoma（LOC）network. Eur J Cancer 117：121-130, 2019

36）Lionakis MS, et al：Inhibition of B cell receptor signaling by ibrutinib in primary CNS lymphoma. Cancer Cell 31：833-843. e835, 2017

37）Grommes C, et al：Phase 1b trial of an ibrutinib-based combination therapy in recurrent/refractory CNS lymphoma. Blood 133：436-445, 2019

38）Yasuhiro T, et al：Anti-tumor efficacy study of the Bruton's tyrosine kinase（BTK）inhibitor, ONO/GS-4059, in combination with the glycoengineered type Ⅱ anti-CD20 monoclonal antibody obinutuzumab（GA101）demonstrates superior in vivo efficacy compared to ONO/GS-4059 in combination with rituximab. Leuk Lymphoma 58：699-707, 2017

39）Kaptein A, et al：Potency and selectivity of BTK inhibitors in clinical development for B-cell malignancies. Blood 132：1871, 2018

40）Narita Y, et al：Phase Ⅰ/Ⅱ study of tirabrutinib, a second-generation Bruton's tyrosine kinase inhibitor, in relapsed/refractory primary central nervous system lymphoma. Neuro Oncol 23：122-133, 2021