Abstract 5897: Noninvasive tumor genetic profiling and disease surveillance in mantle cell lymphoma via plasma circulating tumor DNA

Background: Mantle cell lymphoma (MCL) is an aggressive subtype of B-cell non-Hodgkin’s lymphoma. While plasma circulating tumor DNA (ctDNA) has demonstrated diagnostic and prognostic value in diffuse large B-cell lymphoma and Hodgkin lymphoma, its significance in MCL remains unclear. Methods: This study analyzed paired treatment-naïve plasma and tissue samples from 34 MCL patients with response data after first-line chemotherapy, targeting 475 genes associated with hematopoietic and lymphoid neoplasms. We assessed the ability of plasma ctDNA to detect tumor-specific genetic alterations and explored its potential as a non-invasive biomarker for predicting treatment response and prognosis. Results: The most frequently mutated genes in baseline tissues were CCND1 (93.5%), ATM (48.4%), KMT2D (25.8%), and TP53 (25.8%). Subgroup analysis showed that genetic alterations in CDKN2A (P=0.028), along with those in the B cell antigen receptor (BCR) and endosomal Toll-like receptor (TCR) signaling (P=0.004), as well as the PI3K pathway (P=0.008), were significantly enriched in the blastoid type of MCL. ATM mutations (P=0.041) were more prevalent in patients with low scores on the Mantle Cell Lymphoma International Prognostic Index (MIPI), while epigenetic chromatin remodeling pathway alterations (P=0.028) were more common in MIPI-high patients. Plasma ctDNA detected 66.3% (118/178) of tissue-based somatic variants, yielding an overall detection sensitivity of 73.3%. The highest sensitivity was observed for structural variants (96.6%), followed by mutations/indels (71.3%) and copy number variants (30.0%). At the patient level, 75% (21/28) of patients with paired tissue and plasma samples exhibited moderate to almost perfect agreement in detecting genomic variants in panel-targetable genes, achieving a kappa coefficient ≥ 0.6. Pretreatment ctDNA levels were highly specific for predicting treatment response (100%), although the sensitivity was suboptimal at 68.2%. Higher ctDNA levels were independently associated with shorter progression-free survival (PFS; P=0.002) and overall survival (OS; P=0.009). Additional genetic features associated with shorter PFS included mutations in TP53 (P=0.002), SMARCA4 (P=0.023), and TRAF2 (P=0.023). Furthermore, mutations in TP53 (P=0.006) and TERT (P=0.031) in baseline plasma ctDNA were predictive of reduced OS. Conclusions: Plasma ctDNA serves as a noninvasive approach for detecting tumor-derived genetic aberrations associated with treatment response and survival outcomes in MCL. These findings underscore its clinical utility for diagnosis, recurrence prediction, and surveillance monitoring in MCL. Citation Format: Zhou Ouyang, Ruolan Zeng, Song Wang, Xiaoying Wu, Yajun Li, Yizi He, Caiqin Wang, Chen Xia, Qiuxiang Ou, Wei Yang, Ling Xiao, Hui Zhou. Noninvasive tumor genetic profiling and disease surveillance in mantle cell lymphoma via plasma circulating tumor DNA [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5897.