Background: Splenic Marginal Zone Lymphoma (SMZL) is a rare B-cell lymphoma with heterogeneous clinical behavior. Although typically indolent, survival outcomes are modestly inferior to those of other indolent lymphomas, with 5-year overall survival (OS) rates of 70–80% compared to 85–95% in follicular or nodal marginal zone lymphoma. Additionally, 5–10% of patients present with aggressive disease, highlighting the need for better prognostic tools and treatment strategies. While rituximab (RTX) has become central to SMZL management, often replacing splenectomy as first-line therapy, it remains unclear whether survival outcomes have improved during this era of increased RTX use. We conducted a national analysis to characterize treatment patterns, prognostic factors, and survival trends over time.

Methods: We conducted a retrospective cohort study of SMZL cases diagnosed between 2004 and 2020 using the National Cancer Database (NCDB). Descriptive statistics characterized baseline features. OS was estimated via Kaplan-Meier methods and compared using log-rank tests. Cox proportional hazards models assessed prognostic factors. To evaluate changes in survival over time, we stratified cases by year of diagnosis into early (2004–2009), mid (2010–2014), and recent (2015–2020) RTX-era cohorts. Differences in survival between eras were compared using the log-rank (Mantel–Cox) test.

Results: Among 7,228 patients with SMZL, treatment data were available for 7,176 (99.2%). Median age at diagnosis was 69 years (IQR: 60 to 77), with 4.9% identifying as African American. Of 4,167 patients with stage data, 64% had advanced-stage (III or IV) disease. Among patients with available risk scores, 37% were classified as high-risk by IPI (4-5) and 43% had a Charlson-Deyo (CD) comorbidity score of 3 or higher.

Treatment patterns included splenectomy alone in 1,381 patients (19%), RTX monotherapy in 2,068 (28.5%), and combined RTX and splenectomy in 3,727 (51.9%). Chemotherapy was administered to 1,834 patients (25%), radiation to 29 (0.4%), and autologous transplant to 3. Treatment modalities overlapped due to multimodal approaches; Patients undergoing splenectomy tended to be younger (≤65 years), have earlier-stage disease, lower CD scores, and low-risk IPI (all p < 0.001). Sixty-eight percent received care at academic centers.

Median follow-up was 130 months (95% CI: 123.2 to 136.4). Three- and five-year OS rates were 81.5% and 73.6%, respectively. Despite increased RTX use over time, no significant improvement in OS was observed across eras (log-rank p = 0.35). Survival varied significantly by treatment strategy (p < 0.001). Patients who received neither RTX nor splenectomy had the poorest outcomes, with a median OS of 19.3 months (95% CI not estimable to 70.7). Splenectomy alone was associated with the longest median OS of 148.8 months (95% CI: 137.9 to 159.7), though this likely reflects favorable patient selection. Median OS was not reached for RTX monotherapy patients, suggesting similarly favorable, if not superior long-term outcomes. Combined RTX and splenectomy were associated with similarly prolonged survival (median OS 119.4 to 120.6 months). Addition of chemotherapy in sequential treatment did not significantly affect OS (121 vs. 131 months; p = 0.07).

On multivariable analysis, factors independently associated with inferior OS included older age at diagnosis (HR 1.07; 95% CI: 1.06–1.08; p < 0.001) and higher CD comorbidity score (HR 1.29; 95% CI: 1.18–1.42; p < 0.001). In contrast, female sex (HR 0.66; 95% CI: 0.56–0.78; p < 0.001), treatment at an academic center (HR 0.84; 95% CI: 0.71–0.99; p = 0.04), and receipt of RTX (HR 0.48; 95% CI: 0.32–0.74; p < 0.001) were associated with prolonged OS.

Conclusion:

In this large national cohort of SMZL, receipt of RTX, alone or with splenectomy, was associated with improved OS. Favorable prognostic factors included younger age, female sex, lower comorbidity burden, and treatment at academic centers. However, despite greater RTX use over time, population-level survival in the recent RTX era has not significantly improved, likely reflecting poor outcomes in relapsed or refractory disease. These findings highlight the need to optimize frontline therapy and develop novel strategies to improve long-term outcomes in SMZL.

This content is only available as a PDF.
2025
Sign in via your Institution