Abstract 666: PIM1 and CD79b mutation status impact outcome in primary central nervous system DLBCL after high-dose methotrexate-based chemoimmunotherapy

Background: Primary central nervous system diffuse large B cell lymphoma (PCNSL) is a rare malignancy confined to the central nervous system (CNS). PCNSL has distinct molecular features,most of which harbor MYD88, CD79b and/or PIM1 mutation. Up to date,there is few study focusing on molecular classification of PCNSL. The clinicopathologic and prognostic significance of molecular classification in PCNSL remains unknown. Methods: Targeted exome sequencing covering 413 genes was conducted on 40 cases of PCNSL. The techniques of performing transcriptional sequencing on FFPE tumor tissue samples was also used following the “K.TotalRNA” protocol. All patients enrolled received high-dose methotrexate-based (HD-MTX) chemoimmunotherapy. Then, a molecular classification methodology in PCNSL patients by bioinformatic analysis was developed. Results: Targeted deep sequencing on the coding regions revealed that MYD88, CD79b and PIM1 were the three most commonly mutated genes in PCNSL patients. All cases were clustered into two molecular subgroups. Patients with PIM1 and/or CD79b mutation were clustered into the so-called CDP group; while patients without PIM1 and CD79b mutation were clustered into the so-called nonCDP group. The 2-year PFS rate was 50.0% and 29% for CDP group and nonCDP group, respectively (P=0.107). And the 2-year OS rate was 76% and 40% for CDP group and nonCDP group, respectively (P=0.037). Patients in CDP group had a prolonged long-term survival compared with those in nonCDP group. Univariate and multivariate analysis revealed that age less than 60, no Myc/Bcl2/Bcl6 double expression by immunohistochemical staining (IHC), and CDP subgroup by NGS were three independent risk factors indicating favorable OS. PyClone analysis revealed that tumor cells of nonCDP group were genetically more heterogeneous than those of CDP group. RNA sequencing analysis revealed that a total of 131 genes were significantly differentially expressed between CDP and nonCDP groups. GO enrichment analysis of these genes suggested that the major categories of biological processes that significantly altered between the two groups mainly related to drug metabolism, suggesting that tumor cells of the two groups may have different drug metabolism mechanism. Results of the PyClone analysis and RNA sequencing partially explained the different treatment sensitivity between these two groups. Conclusion: We developed a new molecular methodology to divide PCNSL into CDP and nonCDP groups, based on the mutational status of CD79b and PIM1. According to our result, PCNSL patients without PIM1 and CD79b mutation had unfavorable long-term survival after HD-MTX based chemoimmunotherapy, possibly due to their clonal heterogeneity and their different drug metabolism mechanism. Citation Format: Jihao Zhou, Min Zuo, Peng Ke, Qi Shen, Lifeng Li, Yaping Xu, Lina Hu, Guoqiang Li, Chun Feng, Xuan Gao, Yanfang Guan, Xuefeng Xia, Xinyou Zhang, Yuhua Huang. PIM1 and CD79b mutation status impact outcome in primary central nervous system DLBCL after high-dose methotrexate-based chemoimmunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 666.