Dose-reduced (24 Gy) involved-site radiotherapy combined with rituximab in early-stage non-gastric mucosa-associated lymphoid tissue lymphoma: a prospective phase II trial.

While involved-site radiotherapy (ISRT) is the standard first-line treatment in localized non-gastric mucosa-associated lymphoid tissue (MALT) lymphoma, the cumulative risk of distant relapse poses a persistent clinical challenge. We conducted a prospective phase II trial evaluating rituximab with 24 Gy ISRT, aiming to reduce distant relapse and enhance long-term survival. By October 2025, 60 patients with early-stage non-gastric MALT lymphoma were enrolled. Among the per-protocol efficacy-evaluable cohort (n = 55), the combined immunoradiotherapy regimen achieved a complete response rate of 100%. At a median follow-up of 30.2 months, only one distant recurrence was observed (estimated 5-year distant recurrence: 1.9%). In the full analysis set, 2- and 4-year progression-free survival rates were 98.0% and 92.9%, respectively, improving to 100% and 94.4% in the per-protocol set. Treatment-related hematologic toxicity was frequent but manageable. Infections were reported in 23.3%, including one grade 4 respiratory infection that necessitated treatment discontinuation. Immunophenotypic profiling revealed that parotid, thyroid, or mediastinal involvement correlated with higher lymphocyte proportions (39.5% ± 16.4%, P = 0.012). Post-treatment immunologic changes featured near-complete B-cell depletion and a compensatory expansion of NK cells. Overall, the combined immunoradiotherapy regimen demonstrated durable disease control in localized non-gastric MALT lymphoma, with potential synergistic benefit from NK cell-mediated immune activation. Trial registration: Chinese Clinical Trials Registry, ChiCTR2000036318; registered on Aug 22, 2020 (prospective).