Background:

Although anti-CD19 CAR-T cell therapy demonstrates high response rates in Diffuse Large B-Cell Lymphoma (DLBCL), therapeutic resistance remains a challenge in certain patient subsets due to functional impairments in CAR-T cells and an immunosuppressive tumor microenvironment. Exportin-1 (XPO-1), a nuclear export mediator for tumor suppressor proteins and growth regulators, has been associated with poor outcomes in DLBCL patients. The XPO-1 inhibitor, selinexor, has demonstrated clinical efficacy in DLBCL. Current combination strategies aim to enhance the efficacy of CAR-T therapy, with selinexor emerging as a promising candidate.

Patients and Methods

A retrospective, single-center, real-world study was conducted to assess the efficacy and safety of selinexor in combination with CD19/CD22 bispecific CAR-T cell therapy in patients with relapsed/refractory DLBCL. Adult DLBCL patients who received CD19/CD22 bispecific CAR-T cell therapy at Beijing Tongren Hospital between April 2024 and April 2025 were identified. A comparative analysis was conducted to assess the outcomes of selinexor-based regimens bridging therapy, focusing on overall response rates (ORR) at 28 day post-CAR-T cell therapy, survival outcomes, and safety profiles.

Results

A total of 54 patients were enrolled, comprising 15 patients who received selinexor-based regimens bridging CAR-T cell therapy and 39 patients who underwent alternative bridging regimens. The median ages of patients in the selinexor-based and alternative regimen groups were 58 years (range: 43-79) and 57 years (range: 16-81), respectively, with male participants accounting for 7 (46. 7%) and 19 (48.7%) in each group. Accordingly, bulky disease was present in 6 (40%) and 8 (20.5%) of the patients, ≥3 lines of therapy were administered to 5 (33.3%) and 20 (51.3%), Ann Arbor stage ≥3 was noted in 13 (86. 7%) and 32 (82.1%), Eastern Cooperative Oncology Group (ECOG) performance status ≥2 was observed in 10 (66. 7%) and 20 (51.3%), extranodal involvement ≥3 sites was reported in 8 (53. 3%) and 24 (61.5%), and International Prognostic Index (IPI) score ≥2 was found in 12 (80%) and 35 (89.7%) of the patients, respectively. Based on balanced baseline feature matching between two groups, we conducted a comparative analysis of therapeutic efficacy. The ORR were 100% for the selinexor-based group (CR%: 53.3%, 8 patients out of 15, PR%: 46.7%, 7 patients out of 15), and 84.6% for the alternative regimen group (CR%:51.3%, 20 patients out of 39, PR%:33.3%, 13 patients out of 39). Although the ORR was numerically higher in the selinexor-based group, no statistically significant difference was observed between the two groups(p=0.170). The median follow-up period was 6.57 months (range: 4.98-8.15 months). Progression-free survival (PFS) was not reached in the selinexor-based group and was 7.5 months (range: 5.33-9.68 months) in the alternative regimen group, with no significant difference between the groups (p = 0.634). Overall survival (OS) was not reached in either group, and the 1-year OS rates were 80% and 80. 6%, respectively. In the selinexor-based and alternative regimen groups, the incidence of CRS-related events was as follows: Grade 1 occurred in 9 patients (60%) and 28 patients (71.8%), respectively; Grade 2 in 1 patient (6.7%) and 4 patients (10.3%); Only one patient in the selinexor-based regimen group experienced Grade 4 (6. 7%) CRS. There is no difference between the selinexor-based group and alternative regimen groups (grade 1-4: 73.3% vs 82.1% p=0.475; grade 3 and 4: 6.7% vs 0%; p=0.278). For ICANS-related events, the selinexor-based group reported Grade 4 in 1 patient (6.7%). In the alternative regimen group, Grade 1 was observed in 3 patients (7.7%), Grade 3 in 2 patients (5.1%). There is no difference between the selinexor-based group and alternative regimen groups.

Conclusion

Our findings indicate that the addition of selinexor as bridging therapy may enhance treatment strategies for patients undergoing CAR T-cell therapy. However, extended follow-up is necessary to confirm the long-term therapeutic benefits of this combined regimen.

Keywords

Selinexor; CD19/CD22 bispecific CAR-T cell therapy; Bridging; Relapsed/Refractory DLBCL.

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2025
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