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

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.

Inclusion criteria

• Aged 18 to 75 years, regardless of gender.
• Pathologically confirmed extranodal NK/T-cell lymphoma (ENKTCL).
• Ann Arbor stage I-II disease with primary lesion located in the nasal cavity or upper aerodigestive tract (UADT).
• Eastern Cooperative Oncology Group (ECOG) performance status score of 0-2.
• Treatment-naïve patients with no prior radiotherapy, chemotherapy or targeted therapy.
• Adequate major organ function as follows:
• Hematopoietic function: absolute neutrophil count (ANC) ≥1.5×10⁹/L, platelet count (PLT) ≥100×10⁹/L, hemoglobin (Hb) ≥90 g/L.
• Hepatic function: total bilirubin (TBIL) ≤1.5×upper limit of normal (ULN), alanine transaminase (ALT) / aspartate transaminase (AST) ≤2.5×ULN.
• Renal function: serum creatinine (Cr) ≤1.5×ULN, or creatinine clearance rate ≥60 mL/min.
• Cardiac function: left ventricular ejection fraction (LVEF) ≥50%.
• Expected overall survival ≥6 months.
• Voluntarily sign the written informed consent form.

Exclusion criteria

• Non-nasal type ENKTCL, or primary lesions outside the upper aerodigestive tract (UADT), including skin, gastrointestinal tract, lung and other sites.
• Patients with Ann Arbor stage III-IV disease.
• Central nervous system involvement.
• History of prior malignant tumors, excluding non-melanoma skin cancer or cervical carcinoma in situ cured for more than 5 years.
• Active infections, including active hepatitis B virus (HBV), hepatitis C virus (HCV) and human immunodeficiency virus (HIV) infection.
• Severe complications, such as uncontrolled diabetes mellitus and severe cardiopulmonary diseases.
• Pregnant or lactating women.
• Hypersensitivity or contraindication to any investigational drugs in this study.
• Concurrent participation in other interventional clinical trials.