Mechanism and Updated Results of Selinexor in Combination with Salvage Regimen for Refractory Diffuse Large B-Cell Lymphoma (DLBCL) Patients with TP53 Alterations
Authors: Fang Ying , Zhao Weili , Li Wang 
Published: December 2024

BACKGROUND
Alterations in TP53 are found in 20% to 25% of diffuse large B-cell lymphoma (DLBCL) and are unfavorable biomarker of DLBCL progression. In addition, the prevalence of TP53 alterations increases at relapse and is associated with chemoresistance, novel approach to overcome chemoresistance and to improve prognosis is an unmet need in TP53-altered DLBCL. Our previous study suggested that selinexor, a first-in-class highly selective inhibitor of XPO1, in combination with salvage regimen was effective in refractory DLBCL with TP53 alterations (2023 ASH abstract #1745). Here we present updated clinical results and explore the pivotal role of selinexor in modulating cell cycle arrest in response to DNA damage in DLBCL accompanied by TP53 alterations.
METHOD
The study enrolled relapsed/refractory DLBCL (R/R DLBCL) patients with TP53 alterations (including TP53 mutation and/or deletion) for treatment with selinexor in combination with salvage regimens (R-GDP/R-ICE/R-Gemox) since November 2021 in our center. The treatment was administered orally as 40 mg of selinexor on days 1, 8, and 15, combined with one of the following regimens: R-GDP (R 375mg/m2 d0, gemcitabine 1g/m2*d1, cisplatin 25mg/m2 d1-d3, dexamethasone 40 mg d1-d4). R-ICE (R 375 mg/m2 d0, ifosfamide 1.5g/m2*3d, carboplatin (AUC 5) and etoposide 100mg/m2*3d). R-Gemox (R 375mg/m2 d0, gemcitabine 1g/m2*d1, oxaliplatin 100mg/m2*d1) every 3 weeks as per physician's choice. Objective response rate (ORR) was evaluated every 3 cycles based on Lugano 2014 criteria and Adverse events (AE) were rated according to the NCI CTCAE 5.0. In vitro experiments were performed using the B-lymphoma cell line DB, which harbored the TP53R248Q mutation. The cells were exposed to selinexor at a concentration of 0.05uM for 48 hours, and cell viability was assessed using the cell counting kit-8. Cell apoptosis and the cell cycle were analyzed by flow cytometry. Direct data independent acquisition (DIA)-based proteomics was conducted to study the correlated signal transductions associated with selinexor treatment of DB cells.
RESULTS 48 patients with TP53 alterations (mutation/deletion) were treated with selinexor plus salvage regimen in this study and received at least two cycles of treatment, including 29 patients with TP53 mutation, 16 patients with TP53 mutation and deletion, 3 with TP53 deletion.The median age was 58 years (range 17 to 83), of these patients, 27 (56.3%) were male, 30 (62.5%) patients had disease stage III-IV at screening, and 70.8% with IPI&gt;2. The median number of prior regimen was 2 (range, 1-4). All patients were refractory to the last line of treatment.The patients received a median of three cycles (range, 2-6) of selinexor 40mg once a week combined with salvage regimen (30 patients received selinexor plus R-GDP, 7 with Selinexor plus R-ICE, 11 with selinexor plus R-Gemox).The best overall and complete response rates were 60.4% and 14.6%, respectively.
Our preliminary in vitro experiments showed selinexor had a synergistic effect with cisplatin in DB cell lines with which carried TP53R248Q mutation. DIA-based proteomics demonstrated that selinexor effectively impeded the export of multiple nuclear proteins, including those associated with DNA damage related pathways and cell cycle checkpoints (such as S, G2/M phase checkpoints). In response to DNA damage, TP53-altered cancer cells exhibit a heightened reliance on S and G2 arrest for DNA repair, underscoring the pivotal role of p53 in cell cycle regulation. Hence, we speculated that the augmentation of chemotherapy sensitivity is facilitated by cell cycle arrest which increased by selinexor, leading to accumulation of unpaired DNA. This accumulation subsequently heightens sensitivity to DNA-damaging chemotherapeutic agents such as cisplatin, thereby aiding in inhibiting TP53-altered tumor growth.

CONCLUSION
Our ongoing mechanism research are focused on a deeper understanding of the synergistic effect of selinexor combination treatment. The updated findings demonstrate comparable effectiveness to our previous study, and the positive clinical outcome indicates that the selinexor combination could be a potential treatment option for R/R TP53-altered DLBCL