Selinexor combined with R-CHOP achieved a high response rate in newly diagnosed double/triple-hit lymphoma.

Double-hit lymphoma (DHL) and triple-hit lymphoma (THL) are aggressive subtypes of high-grade B-cell lymphoma with poor prognosis. This study evaluated the efficacy and safety of selinexor, a first-in-class oral inhibitor of exportin 1 (XPO1), combined with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone; S-RCHOP) as first-line therapy for DHL/THL. This single-arm, prospective phase 2 study enrolled 13 patients from May 2022 to August 2024. Patients received up to 6 21-day cycles of S-RCHOP (selinexor 60 mg on days 1, 8, 15). The primary end point was overall response rate (ORR). Secondary end points included progression-free survival (PFS), overall survival (OS), central nervous system (CNS) relapse rate within 2 years, and adverse events (AEs). Exploratory analyses included next-generation sequencing (NGS) and circulating cell-free DNA (cfDNA) monitoring. Thirteen patients (9 DHL and 4 THL) were enrolled. ORR was 100% (complete response [CR], 76.9%; partial response, 23.1%). At a median follow-up of 25.4 months, the 2-year PFS and OS were 67.7% and 67.1%, respectively. One patient developed CNS relapse. The most common all-grade AEs included leukopenia and neutropenia (55.1% each), febrile neutropenia and fatigue (43.5% each), and thrombocytopenia (33.7%). NGS and cfDNA revealed frequent BCL6 and IGLL5 mutations. Posttreatment cfDNA negativity was achieved in 72.7% of patients, all of whom were in CR by positron emission tomography-computed tomography. In this study, S-RCHOP achieved high response rates in DHL/THL but was associated with frequent hematologic AEs. cfDNA monitoring provided valuable insights into treatment response. These preliminary findings support further investigation of XPO1 inhibition combined with R-CHOP, with priority given to dose optimization. This trial was registered at www.clinicaltrials.gov as NCT05974085.