Double-hit lymphoma (DHL) and triple-hit lymphoma (THL) are aggressive forms of high-grade B-cell lymphoma associated with poor prognosis. This phase 2 trial tested whether combining selinexor, an oral inhibitor of exportin 1 (XPO1), with standard R-CHOP chemotherapy (S-RCHOP) as first-line therapy could improve outcomes in newly diagnosed DHL/THL patients.
This was a single-arm, prospective phase 2 clinical trial. Thirteen patients were enrolled between May 2022 and August 2024. The cohort included nine patients with DHL and four patients with THL. The trial is registered as NCT05974085. The authors report a median follow-up of 25.4 months for outcome assessment.
Patients received up to six 21-day cycles of S-RCHOP. Selinexor was administered orally at 60 mg on days 1, 8, and 15 of each 21-day cycle. The chemotherapy backbone consisted of standard R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone). The abstract does not provide detailed reporting on dose modifications, discontinuations, or supportive-care measures beyond the planned dosing schedule.
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) of tumor or tissue samples and longitudinal monitoring of circulating cell-free DNA (cfDNA) to evaluate genomic alterations and molecular response.
The study reported an ORR of 100% across the 13-patient cohort. Of these responses, complete response (CR) was achieved in 76.9% of patients and partial response (PR) in 23.1%. At a median follow-up of 25.4 months, the 2-year PFS was 67.7% and the 2-year OS was 67.1%. One patient experienced a CNS relapse during the reported follow-up period. The authors present imaging-based confirmation of CR by PET‑CT among patients with posttreatment cfDNA negativity.
Treatment with S-RCHOP was associated with frequent hematologic toxicity. The most common all-grade adverse events reported in the abstract were:
The abstract highlights the frequency of hematologic AEs but does not provide a full breakdown of grade 3–4 events, specific management strategies, or rates of treatment discontinuation. These details were not reported in the abstract.
Exploratory NGS and baseline cfDNA analyses identified recurrent mutations, with BCL6 and IGLL5 among the most frequently observed. Longitudinal cfDNA monitoring demonstrated that 72.7% of patients achieved posttreatment cfDNA negativity; all patients with cfDNA negativity were in CR by PET‑CT at the timepoints reported. The authors also present figures showing mutation frequency across the cohort and reductions in cfDNA mutation burden over time, suggesting concordance between molecular and imaging responses.
In this small, single-arm phase 2 cohort, S-RCHOP produced high response rates (100% ORR; 76.9% CR) in newly diagnosed DHL/THL but was accompanied by frequent hematologic adverse events. cfDNA monitoring correlated with PET‑CT CR and provided additional molecular response information. The investigators conclude that combining XPO1 inhibition with R-CHOP warrants further study and emphasize the need for dose optimization of selinexor to balance efficacy and tolerability.
Limitations include the small sample size (n = 13) and the single-arm design; the abstract does not report detailed toxicity grading, dose adjustments, or long-term follow-up beyond the median 25.4 months. Those specific data elements were not provided in the source abstract and would require consultation of the full text for confirmation. Overall, these preliminary results support additional prospective evaluation of S-RCHOP in larger, controlled studies with systematic dose-finding and expanded safety reporting.