Preliminary results of first-line selinexor plus R-CHOP in TP53-mutated diffuse large B-cell lymphoma (Smart trial): A single-arm, phase II trial

Abstract Background: TP53 mutations, occurring in approximately 20% of diffuse large B-cell lymphoma (DLBCL) cases, are associated with inferior response and poor prognosis following standard first-line R-CHOP therapy. Selinexor, an oral selective inhibitor of nuclear export (SINE) targeting exportin 1 (XPO1), exerts antitumor effects in TP53-mutated DLBCL. Mechanistically, selinexor acts as a highly selective inhibitor of XPO1, correcting the mis-localization of p53 protein between the nucleus and cytoplasm and promoting nuclear accumulation of p53, p21, and p73. Concurrently, selinexor upregulates levels of the p53 downstream effectors BAX and PUMA, thereby promoting apoptosis. This phase II trial (NCT06517511) was conducted to evaluate the efficacy and safety of selinexor combined with R-CHOP regimen as first-line treatment in patients with TP53-mutated DLBCL. Methods: Newly diagnosed,untreated DLBCL patients with TP53 mutations confirmed by next-generation sequencing (NGS) were enrolled. The induction treatment consisted of six 21-day cycles of selinexor plus R-CHOP, followed by two additional cycles of selinexor plus rituximab. To reduce the risk of tumor lysis syndrome, selinexor was introduced from the second cycle at an initial dose of 60 mg, administered on days 1 and 8 of each cycle. Patients who achieved a complete response (CR) after induction treatment continued selinexor as maintenance treatment until disease progression (PD), or intolerable toxicity, or a maximum total treatment duration of two years. The primary endpoint was the CR rate of the combination regimen, assessed according to the Lugano 2014 criteria. Results: Between August 2024 and July 2025, 11 patients were enrolled, with a median age of 46 years (IQR, 44-52). Most patients (9/11, 81.8%) had stage III-IV disease, and 6 (54.4%) had an International Prognostic Index (IPI) score of ≥2. MYC/BCL-2 double expression was present in 6 patients . The median number of induction treatment cycles was 7 (range, 4-8). The CR rate was 63.6% (7/11), and the overall response rate (ORR) was 91% (10/11). Among the 7 patients who achieved CR, 5 proceeded to maintenance therapy, with one experiencing progression during maintenance phase. The remaining 2 patients are still undergoing induction treatment. At a median follow-up time of 7.4 months, the 6-month progression free survival (PFS) rate was 87.5%. No deaths were reported. The majority of adverse events (AEs) were grade 1-2. Grade 3-4 AEs included leukopenia (n=8), neutropenia (n=9), thrombocytopenia (n=2), and nausea (n=1). All AEs were manageable with supportive care and resolved. Conclusion: In this phase II trial, selinexor combined with R-CHOP as first-line treatment for TP53-mutated DLBCL demonstrated encouraging efficacy and a manageable safety profile. These preliminary results highlight the potential of selinexor to improve clinical outcomes in this high-risk DLBCL population.