Selinexor Combined With Reduced-Dose Radiotherapy For Early-Stage Extranodal NK/T-Cell Lymphoma

Overview

Extranodal NK/T-cell lymphoma (ENKTCL) is an Epstein-Barr virus-associated non-Hodgkin lymphoma with high incidence in Asia and Latin America. Approximately 70% of patients present with early-stage (I-II) disease confined to the upper aerodigestive tract. Radiotherapy at 50-56 Gy is the standard curative treatment, but high-dose radiotherapy causes severe toxicities including oral mucositis and xerostomia, while radiotherapy alone yields high systemic recurrence rates. Previous studies have confirmed the efficacy of P-GEMOX induction chemotherapy, verified the feasibility of reduced-dose radiotherapy in patients achieving complete response after chemotherapy, and demonstrated the radiosensitizing effect of selinexor via inhibiting IRF3-BARD1-BRCA1-mediated DNA damage repair. Moreover, international evidence supports the efficacy of 40 Gy radiotherapy combined with chemotherapy. Accordingly, this study hypothesizes that selinexor combined with 40 Gy reduced-dose radiotherapy following P-GEMOX induction chemotherapy can achieve equivalent efficacy to standard-dose radiotherapy, while markedly decreasing radiotherapy-related toxicities. This trial innovatively applies selinexor as a radiosensitizer in ENKTCL, fulfills the unmet clinical demand for efficacy-preserving toxicity reduction, and is well supported by preliminary data.

Extranodal NK/T-cell lymphoma (ENKTCL) is a distinct subtype of Epstein-Barr virus (EBV)-associated non-Hodgkin lymphoma, which shows a prominent geographical predilection with high incidence in Asia and Latin America. Clinically, around 70% of patients are diagnosed with early-stage (stage I-II) disease, and most lesions are localized to the nasal cavity and upper aerodigestive tract (UADT). Radiotherapy at a standard dose of 50-56 Gy is recommended as the curative first-line treatment for early ENKTCL in international guidelines. Nevertheless, high-dose radiotherapy inevitably induces severe adverse events, including oral mucositis, xerostomia, hypothyroidism and dysphagia, which severely impair patients' long-term quality of life. In addition, radiotherapy alone remains unsatisfactory due to a high risk of systemic recurrence, which is the leading cause of treatment failure. Accumulating preliminary evidence supports rational treatment de-escalation for early ENKTCL. Previous research has validated the favorable efficacy and safety of the P-GEMOX chemotherapy regimen. A multicenter retrospective study including 202 early ENKTCL patients demonstrated that 4-6 cycles of P-GEMOX followed by standard-dose radiotherapy achieved an 83.2% complete response (CR) rate, with 3-year progression-free survival (PFS) of 74.6% and overall survival (OS) of 85.2%. Another retrospective cohort of 144 post-chemotherapy CR patients further confirmed the feasibility of reduced-dose radiotherapy: no significant differences in PFS and OS were observed between ≤50 Gy and \>50 Gy groups, while grade 3-4 mucositis was markedly reduced. Recent international data also verified the long-term efficacy of 40 Gy chemoradiotherapy. Our team previously identified the radiosensitizing effect of selinexor in vitro. Experiments on SNK-6 and YT cell lines showed that selinexor significantly enhances radiosensitivity by inhibiting the IRF3-BARD1-BRCA1 DNA damage repair pathway and inducing dsRNA accumulation. Based on these foundations, we hypothesize that selinexor combined with 40 Gy reduced-dose radiotherapy after P-GEMOX induction chemotherapy can achieve non-inferior efficacy compared with conventional 50-56 Gy radiotherapy, while substantially alleviating radiotherapy toxicity. This study innovatively applies XPO1 inhibitor selinexor as a radiosensitizer in ENKTCL for the first time, establishes a precision dose-reduction strategy targeting DNA damage repair, addresses the unmet clinical need of toxicity reduction without compromising efficacy, and is highly feasible with solid preclinical and clinical supporting data.