Background: The germinal center B-cell-like (GCB) subtype represents the most prevalent molecular classification of diffuse large B-cell lymphoma (DLBCL), predominantly affecting pediatric and young adult populations. Approximately 30% of patients with GCB-DLBCL exhibit resistance to R-CHOP therapy. An International Prognostic Index (IPI) score of 3-5 is recognized as one of the high-risk factors in this population. Currently, therapeutic strategies for high-risk GCB-DLBCL remain insufficiently defined, underscoring a critical unmet need in first-line treatment approaches. Selinexor, an oral selective inhibitor of nuclear export (SINE), targets exportin 1 (XPO1), thereby,inducing nuclear retention and reactivation of tumor suppressor proteins. The SADAL trial demonstrated that single-agent oral selinexor elicited a durable response in patients with relapsed or refractory DLBCL, and the adverse events were manageable. The combination of selinexor with the R-CHOP regimen has demonstrated encouraging efficacy and manageable safety in the treatment of newly diagnosed double- and triple-hit (DH/TH) DLBCL. This phase II trial (NCT05422066) aims to evaluate the efficacy and safety of selinexor in combination with the R-CHOP regimen as a first-line treatment for patients with high-risk (IPI 3-5) GCB-DLBCL. This report provides updated data on efficacy.

Methods: Patients newly diagnosed with untreated GCB-DLBCL and IPI 3-5 were enrolled in this study. Patients will be treated with six cyclesof R-CHOP and selinexor (60 mg qw), with each cycle lasting three weeks. Treatment continued for six cycles, or until intolerability, inadequate response, disease progression, consent withdrawal or death. Efficacy was evaluated according to the Lugano 2014 criteria. The primary endpoint was the complete response (CR) rate, and the secondary endpoints included the objective response rate (ORR), progression-free survival (PFS), disease-free survival (DFS), overall survival (OS), as well as safety and tolerability.

Results: Between August 2022 and July 2025, a totle of 44 patients were enrolled, with a median age of 59 years (range, 26-79). The majority of patients (97.7%) presented with stage III-IV disease, and 45.5% were aged 60 years or older. Additionally, 68.2% of the patients had exhibited two or more extranodal lesions, and 50.0% had elevated lactate dehydrogenase levels. The dual expression of MYC and BCL2 was observed in 18.2% of patients. Among the patients, 84.1% had an IPI score of 3, while 13.6% had an IPI score of 4. The median follow-up period was 17.2 months (95% CI: 12.6 - 21.8), during which 37 patients were evaluable for response.The CR rate was 73.0%, and the ORR was 100.0%. The 1-year PFS rate and DFS rate were 81.4% (95% CI:69%-96%) and 100%. The 2-year PFS and DFS rate were 67.3% (95% CI: 48%-94%) and 77.8% (95% CI: 55%-100%), respectively. The median PFS, DFS and OS have not yet been reached.

Conclusions: The combination of Selinexor (60 mg qw) with the R-CHOP as a first-line treatment for high-risk (IPI 3-5) GCB-DLBCL demonstrates encouraging efficacy. Detailed data on adverse events (AE) data will be reported in the subsequent research.

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2025
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