Abstract 171: Genomic and phenotypic analysis of post-transplant plasmablastic lymphomas

Abstract

Abstract Introduction: Plasmablastic lymphoma (PBL), a rare and aggressive type of B-cell non-Hodgkin lymphoma, typically occurs in immunocompromised individuals, including a subset of patients who have undergone solid-organ transplantation. The pathogenesis of these lymphomas is not well understood and the underlying genetic alterations have not been characterized. In this study, we evaluated the genomic and pathologic features of PT-PBL to gain insights into disease biology. Methods: We searched our departmental database to identify PT-PBL diagnosed over the last 19 years. The pathologic features of each case and any prior lymphoproliferations were reviewed. A panel of 465 cancer-associated genes was sequenced using DNA extracted from each specimen and corresponding non-tumor tissue. Chromosomal aberrations involving CMYC and/or TP53 were assessed by fluorescence in situ hybridization (FISH). PCR analysis was performed to detect clonal immunoglobulin heavy chain (IGH) gene rearrangements. Results: Eighteen PT-lymphoproliferations from 11 solid organ allograft recipients (3 lung, 4 cardiac, 3 renal, and 1 combined liver and renal) with PT-PBL were identified. The median time to PBL development after transplant was 9.6 years (range 0.5 - 11.9 years). All PT-PBL occurred at extranodal sites and 4/11 (36%) were EBV+. Eight of 11 patients (73%) developed de novo PT-PBL, while in 3 cases, the PT-PBL was preceded by a clonally-related plasmacytoma-like lesion, a monomorphic PTLD, and a polymorphic PTLD. All cases showed plasmablastic morphology, with 7/11 (64%) showing variable degrees of plasmacytic differentiation. Nine of 11 (82%) PT-PBL expressed CD138. IgG, IgA or IgM was expressed by 4, 2, and 2 cases. CD56 or CD10 expression was noted in 2 and 5 cases, respectively. CMYC rearrangements were detected in 5/11 (45%) cases, 3 at the time of diagnosis and 2 upon disease progression. Next-generation sequencing revealed mutations in chromatin modifying genes (e.g. MLL2, MLL3, TET2) in 8/11 (73%) cases, RAS/MAP kinase pathway (e.g. KRAS, NRAS, HRAS) in 7/11 (64%) cases, JAK/STAT pathway (STAT3, STAT6, JAK3, SOCS1) in 4/11 (36%) cases, and the NOTCH pathway (e.g. NOTCH1, NOTCH3, SPEN) in 4/11 (36%) cases. DNA damage repair defects were seen in 8/11 (73%) cases, with 2/11 harboring mutations in DNA mismatch repair genes and showing microsatellite instability. Five of 11 (45%) PT-PBL had TP53 alterations; TP53 mutations at diagnosis (n=3), including 1 also exhibiting monosomy 17 (biallelic inactivation), an additional case with monosomy 17 at diagnosis, and one with TP53 deletion detected at relapse. Conclusions: Our results demonstrate different pathways of PT-PBL pathogenesis as well as immunophenotypic and genomic heterogeneity of these neoplasms. Furthermore, the observation of recurrent genetic alterations in PT-PBL that overlap with those described in diffuse large B-cell lymphomas and plasma cell neoplasms has implications for the design of effective therapies for these aggressive malignancies. Citation Format: Rebecca J. Leeman-Neill, Craig Soderquist, Murty Vundavalli, David Park, Susan Hsiao, Mahesh Mansukhani, Bachir Alobeid, Govind Bhagat. Genomic and phenotypic analysis of post-transplant plasmablastic lymphomas [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 171.