Abstract 172: Molecular predictors of central nervous system (CNS) recurrence in diffuse large B-cell lymphoma (DLBCL)
Authors: Ollila Thomas , Kurt Habibe , Waroich Jozal , Vatkevich John , Sturtevant Ashlee , Patel Nimesh , Olszewski Adam 
Published: September 2020

Abstract
CNS recurrence is a devastating outcome after systemic treatment of DLBCL. Clinical features are poor at predicting CNS recurrence or guiding prophylactic therapy. However, emerging data suggest that specific mutational profiles in DLBCL may correlate with primary extranodal involvement, including primary CNS lymphoma (Ollila et al, Curr Treat Options Oncol. 2018). We evaluated DLBCL tumors from patients who experienced either isolated CNS or systemic recurrence (not involving the CNS) using a 592 gene next generation sequencing (NGS) assay (Illumina NextSeq platform, average coverage depth &gt;750x; Caris Life Sciences) performed on formalin-fixed tissue. We additionally examined clinicopathologic data, including cell of origin (COO) determined by immunohistochemistry; MYC, BCL2 and/or BCL6 rearrangements detected by FISH, and complex karyotype. The study included 26 cases of DLBCL with CNS-only recurrence (n=13) or systemic recurrence without CNS involvement (n=13). We observed no significant difference between those two groups in any clinicopathologic characteristics, including COO, FISH, or karyotype, and no significant difference for mutations in any specific gene (using Fisher's exact test adjusted for multiple testing). We then identified 3 common molecular subtypes of DLBCL using a simplified classification: (1) the MCD subtype (defined as MYD88L265P or &gt;2 other mutations in CD79B, PIM1, ETV6, BTG1, TBL1XR1, or PRDM1), (2) the subtype characterized by TP53 mutations (and often complex karyotype with multiple structural variants), and (3) the GCB subtype characterized by ≥2 mutations in BCL2, CREBBP, EZH2, KMT2D, TNFRSF14, GNA13, MEF2B, or PTEN. We compared prevalence of these subtypes between our groups and unselected DLBCL datasets by Chapuy et al. (Nat Medicine, 2018; n=135; dbGaP phs000450) and Reddy et al. (Cell, 2018; n=1001; EGA: EGAS00001002606). The MCD subtype was more frequent among patients with CNS recurrence (46%) compared with non-CNS systemic recurrence (31%), and it was statistically significantly more frequent in our CNS recurrence group than in the unselected DLBCL datasets by Reddy (18%, P=0.017) or Chapuy (19%, P=0.030). In contrast, we observed no difference between groups with CNS or systemic recurrence for the TP53 subtype (23% in both groups) or the GCB subtype (15% in both groups), and these proportions were not significantly different compared with the unselected DLBCL datasets (P&gt;0.05). In-depth molecular classification of DLBCL requires integration of single nucleotide, structural chromosomal variants, and copy alteration, unfeasible in clinical practice. Our data demonstrate that a clinically meaningful molecular predictor signature for future CNS recurrence can be obtained from widely available NGS assays using a simplified classification. If validated, this signature may prove useful for selecting patients for CNS-directed prophylactic therapy.
Citation Format: Thomas Ollila, Habibe Kurt, Jozal Waroich, John Vatkevich, Ashlee Sturtevant, Nimesh Patel, Adam Olszewski. Molecular predictors of central nervous system (CNS) recurrence in diffuse large B-cell lymphoma (DLBCL) [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 172.