Selinexor in Combination with R-GDP/R-ICE Regimen for Refractory Aggressive Large B-Cell Lymphoma Patients with TP53 Alterations

BackgroundTP53 has been identified as one of the most frequently altered gene in large B-cell lymphoma (LBCL). The prognosis of LBCL patients (pts) with TP53 mutations is poor in R-CHOP era, even treated with autologous stem-cell transplantation (ASCT) or anti-CD19 chimeric antigen receptor T-cell (CAR-T) therapy. Furthermore, TP53 mutation rate was much higher in LBCL pts who acquired relapsed or refractory (R/R) disease and associated with therapeutic resistance. Selinexor is a selective inhibitor of nuclear export with promising anti-cancer properties. Several clinical studies have proved selinexor in combination with R-GDP/R-ICE was effective in relapsed/refractory LBCL and preclinical studies reported that selinexor could suppress tumor cells with TP53 mutations.

Method Relapsed/refractory LBCL pts with TP53 alterations (including TP53 mutation and/or deletion) were enrolled to be treated with selinexor plus R-GDP/R-ICE since November 2021 in our center. Selinexor was administered orally (40 mg day 1, 8, 15) plus R-GDP (R 375mg/m2 d0, gemcitabine 1g/m2×d1, cisplatin 25mg/m2 d1-d3, dexamethasone 40mg d1-d4) or R-ICE (R 375mg/m2 d0, ifosfamide 1.5g/m2×3d, carboplatin (AUC 5) and etoposide 100mg/m2×3d) 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.

Results In total, eleven patients treated with at least 3 cycles of selinexor plus R-GDP/R-ICE and were eligible for initial efficacy evaluation. The median age of the 11 pts was 63 years (range 18 to 77), 7 pts (63.6%) were male, 5 pts (45.5%) had stage III-IV disease, 63.6% of patients with IPI intermediate to high risk. The median number of prior regimen was 2 (range, 1-4), with 2 patients (3 L) and 1 patient (4L). 9 pts were refractory to the last regimen. The mutational profile was presented in Figure 1 (7 patients with TP53 mutation, 3 patients with TP53 mutation and deletion, 1 patient with TP53 deletion). Pts received a median of four cycles (range, 3-6) of selinexor 40mg once a week combined with R-GDP/R-ICE (9 patients received selinexor plus R-GDP and 2 received selinexor plus R-ICE) (Table 1).

The most common treatment-related adverse events were grade 1 or 2, including nausea (81.8%), fatigue (81.8%), and anorexia (27.3%) and the most common grade 3 or 4 adverse events were hematological toxicities including neutropenia (63.6%), thrombocytopenia (45.5%)，anemia (9.0%). 2 pts after interim evaluation with PR stopped treatment for one month due to gastrointestinal toxicities and had disease progression. Both of them continued to receive their prior regimen (selinexor-RGDP and selinexor-RICE regimen, respectively). Of the ten evaluable patients, the overall and complete response rates at interim evaluation were 100% and 20%, respectively (the left patient will have interim evaluation at the mid of August).

ConclusionsTP53 alterations are an established poor outcome marker in LBCL. To our knowledge, this is the first report on TP53-altered relapsed/refractory aggressive B-cell lymphomas treated upon the combination of selinexor and chemotherapy. The new exploration showed promising response rates in patients with relapsed/refractory TP53-altered LBCL and was well tolerated. In addition, clinicians should be cautious to its GI toxicities with more proactive prevention and management measures. Selinexor (40mg qw) with R-GDP/R-ICE is worthy of further study based on the preliminary efficacy results.

No relevant conflicts of interest to declare.