{"doi":"10.1002/hon.70094_188","title":"188 | INFLUENCE OF TP53 GENE ALTERATIONS IN PATIENTS WITH RELAPSED/REFRACTORY LARGE B‐CELL LYMPHOMA TREATED WITH BISPECIFIC ANTIBODIES","abstract":"Introduction: BsAbs have become a pivotal treatment option for patients with R/R LBCLs. However, disease relapses occur in approximately 70% of patients. In the context of immunochemotherapy, TP53 aberrations associate poor outcomes due to impaired DNA damage response. Additionally, TP53 alterations are an adverse prognostic feature for chimeric antigen receptor T-cell therapy by promoting B-cell proliferation, downregulating MHC-II expression, and depleting tumor microenvironment; mechanisms facilitating T-cell immune evasion. Despite these insights, the impact of TP53 alterations on BsAb therapy outcomes remains unexplored. Methods: Patients diagnosed with LBCL and an available biopsy prior to BsAb treatment were included. TP53 mutations and copy number alterations were analyzed by targeted Next Generation Sequencing with a coverage of 1.000x and a limit of detection of 1%. TP53 mutations were curated to report mutation type (missense, nonsense, frameshift, or splicing) and hotspot designation. A compound group of TP53 alteration (Combined-TP53) was defined when more than 1 allele was mutated, or a single deletion was present. Association with overall response rate (ORR) was assessed using Fisher’s exact test, while survivals were analyzed using Cox proportional-hazards regression. Prognostic variables were included in a multivariable Cox regression. Results: A total of 42 LBCL patients with a median age of 68.1 years, two median number of prior treatments, and 24% classified as HGBCL were included in the study. Twenty-four patients (57%) had TP53 aberrations: 25 TP53 mutations were identified across 21 patients (2 patients had 2 TP53 mutations and a single patient had 3 mutations), 8 patients had co-occurring TP53 mutation and deletion, and 3 patients had isolated TP53 deletions. In total, 14 patients were classified into the Combined-TP53 subgroup. The presence of TP53 deletion (n = 11) was associated with a significant impact on overall survival (OS) (HR = 3.2 p = 0.01). Notably, the Combined-TP53 group (n = 14) exhibited poorer BsAbs outcomes, with significantly shorter progression-free survival (PFS) (median 15.4 vs. 5.1 months; HR = 2.1 p = 0.05) and OS (median not reached vs. 7.6 months; HR = 2.9 p = 0.01). No significant differences in ORR, PFS, or OS were observed when comparing wild-type and mutated TP53, hotspot designation, or among TP53 mutation types. In a multivariable analysis adjusting for age, LBCL histology (HGBCL vs. DLBCL), stratified IPI (0–2 vs. 3–5), and Combined-TP53 status; Combined-TP53 remained a statistically significant predictor in OS (HR 2.7 p = 0.03) and demonstrated a trend toward significance for PFS (HR = 2 p = 0.08) in patients receiving BsAb. Conclusions: TP53 alterations impact outcomes in LBCL patients receiving BsAb when multiple mutations or a deletion result in a TP53 loss-of-function, defining a previously unrecognized high-risk subgroup associated with shorter OS and a trend toward shorter PFS under BsAbs therapy. Research funding declaration: This project has been funded by Instituto de Salud Carlos III (ISCIII), through the project PI22/01204 and co-funded by the European Union. Keywords: tumor biology and heterogeneity; aggressive B-cell non-Hodgkin lymphoma; diagnostic and prognostic biomarkers No potential sources of conflict of interest.","journal":"Hematological Oncology","year":2025,"id":568583,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9568,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1473430,"name":"M. 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