DP072 | IGHV AND TP53 MUTATIONAL STATUS AT DIAGNOSIS: IMPACT ON OUTCOME IN PATIENTS WITH SPLENIC MARGINAL ZONE LYMPHOMA

Introduction: Splenic Marginal Zone Lymphoma (SMZL) is an rare, indolent B-cell non-Hodgkin Lymphoma (NHL). Limited data are available on the impact of immunogenetics and TP53 mutations on SMZL outcomes. Methods: We explored the Immunoglobulin Heavy Chain Variable (IGHV) rearrangement status and TP53 alterations in 164 patients (pts) diagnosed with SMZL between April 1987 and December 2024 at our institution. SMZL diagnosis was based on flow cytometry, histology, and clinical findings. IGHV rearrangements were assessed using Sanger sequencing, while TP53 status with Next-Generation Sequencing. Primary endpoints were Event-Free Survival (EFS; events included: progression, histological transformation [HT] and death) and Overall Survival (OS) based on molecular data. Results: Median age at diagnosis was 64 years (range 28.8-97.8) and 51% were female. With a median follow-up of 97.6 months (mo) (95% Confidence Interval [CI]: 66.3–124.9), 84% of pts received a first-line treatment (chemoimmunotherapy [CIT] 38%, chemotherapy 25%, splenectomy 19%, rituximab 4%, splenectomy plus chemotherapy 4%, other 10%). Of 98 pts with productive IGHV, 13 (13%) were truly unmutated (100% germline identity), 30 (31%) borderline/minimally mutated (98–99.9% germline identity), and 55 (56%) significantly mutated (<98% germline identity). TP53 status was available for 96 pts, with mutations detected in 12 (12.5%) pts. Truly unmutated IGHV status was significantly associated with shorter OS (median OS: 5.1 vs 12.4 and 18.6 years respectively; Hazard Ratio (HR): 3.16, 95% CI: 1.29–7.77; p=0.012) and EFS (median EFS: 8.6 vs 62 and 64 mo, respectively; HR: 3.58, 95% CI: 1.75–7.30; p<0.001) compared to borderline/minimally mutated and significantly mutated statuses. TP53 mutations at diagnosis did not impact OS, but patients with TP53 mutations had significantly shorter EFS (median EFS: 29.7 vs 75.9 months; HR: 2.62, 95% CI: 1.06–6.5; p=0.038). TP53 mutated pts who received CIT as first-line treatment had a markedly inferior EFS (median EFS: 7.3 vs 159 mo in wild-type pts; HR: 12.99, 95% CI: 2.85–59.22; p<0.001). Conclusion: IGHV and TP53 status in SMZL may serve as prognostic and predictive biomarkers and could be incorporated into the baseline evaluation. In our analysis, SMZL pts with TP53 mutations who received first-line CIT had poorer outcomes. This unfavorable genomic profile could potentially be overcome by targeted therapies, such as Bruton tyrosine kinase inhibitors.