Selinexor Combined With R-CHOP Achieved a High Response Rate in Newly Diagnosed Double/Triple Hit Lymphoma

Double-hit or triple-hit lymphoma (DH/THL) is an aggressive subtype 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 (S-RCHOP) as first-line therapy for newly diagnosed DH/THL. This single-arm, prospective phase Ⅱ trial (NCT 05974085) enrolled 13 patients between May 2022 and August 2024. Patients received up to six 21-day cycles of S-RCHOP (selinexor 60 mg on days 1, 8, 15). The primary endpoint was overall response rate (ORR). Secondary endpoints 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. 13 patients (9 DHL, 4 THL) were enrolled. The ORR was 100% (CR: 76.9%, PR: 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/neutropenia (55.1% each), febrile neutropenia and fatigue (43.5% each), and thrombocytopenia (33.7%). NGS and cfDNA revealed frequent BCL6 and IGLL5 mutations. Post-treatment cfDNA negativity was achieved in 72.7% of patients, all in CR by PET-CT. In this exploratory phase Ⅱ study, S-RCHOP achieved high response rates in newly diagnosed DH/THL but was associated with frequent hematologic AEs. cfDNA monitoring provided valuable insights into treatment response. These preliminary findings support further investigation of XPO-1 inhibition with R-CHOP, with priority given to dose optimization. NCT05974085