Selinexor combined with pegaspargase and dexamethasone, followed by radiotherapy, for newly diagnosed stage I–II natural killer/T-cell lymphoma: A multicenter, single-arm, Phase I/II study

Abstract Background：Our center's DDGP regimen has significantly improved the overall prognosis of natural killer/T cell lymphoma (NKTCL). Nevertheless, for patients with early-stage disease (CA Stage I–II), which is typically localized to the nasal cavity and adjacent tissues, responds well to therapy, and rarely relapses, we further considered whether less toxic and more convenient regimens could achieve comparable efficacy. This study explores the combination of selinexor, pegaspargase and dexamethasone, followed by ntensity-modulated radiation therapy(IMRT), to improve outcomes with reduced toxicity in stage I–II NKTCL. Study Design and Methods: This multicenter, open-label, single-arm phase I/II trial evaluated the preliminary efficacy and safety of the above regimen in newly diagnosed stage I–II NKTCL(NCT 06559553). Preclinical in vitro and animal studies demonstrated a synergistic effect of selinexor and pegaspargase in inhibiting NKTCL proliferation and promoting apoptosis, providing the rationale for this clinical trial. The study included a dose-escalation phase (Ib) and a dose-expansion phase (II). A standard 3+3 design evaluated selinexor at 40, 60, and 80 mg. The primary endpoints were the complete response rate (CRR) and the objective response rate (ORR). Eligibility Criteria: Patients aged 18–70 years with ECOG 0–2, expected survival >6 months, histologically confirmed stage I–II disease with at least one measurable lesion, no prior anti-cancer therapy, no contraindications to chemotherapy, and adequate cardiac and pulmonary function were eligible. Treatment Regimen: Selinexor was administered orally on Days 1 and 8, pegaspargase (3,750 IU) given intramuscularly on Day 1, and dexamethasone (20 mg/day) orally on Days 1–5 of each cycle. IMRT was delivered sequentially at 2 Gy per fraction, totaling 50 Gy over 25 fractions. Results: At the data cutoff, 20 patients had been enrolled: 11 in phase Ib [selinexor 40 mg (n=4), 60 mg (n=4), and 80 mg (n=3)] and 9 in phase II. The median age was 51 years (range, 20–68); 15 were male and 4 were female. All had newly diagnosed CA stage I–II NKTCL. Based on phase Ib dose-escalation results, 60 mg selinexor was selected for the phase II expansion. Four patients discontinued treatment, two due to acute pancreatitis and two due to cerebrovascular events. Excluding these, the remaining 15 achieved a best CRR of 81.25% (13/16) and an ORR of 100.00% (16/16). All patients experienced ≥1 treatment-emergent adverse event, with nausea, weight loss, hypoalbuminemia, and myelosuppression being the most frequent. Notably, the two cerebrovascular events occurred in patients who discontinued treatment. Conclusion: This regimen demonstrated high preliminary efficacy in newly diagnosed stage I–II NKTCL, with simple administration and short hospitalization. While generally tolerable, vigilant monitoring and supportive care are needed to mitigate adverse events.