Introduction: The prognosis of relapsed or refractory (R/R) Peripheral T-cell lymphomas (PTCL) is very poor, except for CD30+ ALK positive PTCLs patients treated with brentuximab-vedotin and chemotherapy. Selinexor is an oral, first in class, potent selective inhibitor of nuclear exportin (SINE), that is overexpressed in many malignancies, including PTCLs. In a small phase I study, selinexor in combination with high-dose dexamethasone, ifosfamide, carboplatin and etoposide (D-ICE) has shown promising overall response rate (ORR, 91%) and complete response (CR, 82%) in R/R PTCLs, (Tang et al. Haematologica 2021). On these bases, we designed the pilot phase II study PTCL S-IDE (selinexor, ifosfamide, etoposide, dexamethasone, without carboplatin to reduce hematologic toxicity), EudraCT number 2021-006229-23.

Methods: Key inclusion criteria were: age 18-75 years, R/R histologically confirmed PTCL (PTCL-NOS, angioimmunoblastic T cell lymphoma - AITL, anaplastic large cell ALK negative - ALK neg, T-helper follicular - TFH) after at least one course of anthracycline containing regimen chemotherapy (including or not high dose chemotherapy and stem cell transplantation [SCT]), PS ECOG <=2, adequate organ function. All patients received S-IDE on a 21-day cycle: Selinexor (40 mg on day 3, 5 and 7); Ifosfamide 5g/mq on day 2; Etoposide 100 mg/mq on days 1-3; Dexamethasone 20 mg/day on days 3-7. Patient in CR at the end of the 4 courses received a maintenance with 60 mg selinexor weekly, until progression or unacceptable toxicity, or proceeded to allo-SCT or auto-SCT according to donor availability, previous SCT, patient age and comorbidities. The primary endpoint was ORR at the end of 4 courses of S-IDE; the secondary endpoints were duration of response, 18-months progression-free survival (PFS) and overall survival (OS) and safety. Exploratory biological analyses have been planned to evaluate the role of GATA3 and TBX21 expression; loss of tumor suppressor genes on the CDKN2A/B-TP3 axis and PTEN-PI3K pathways as well as genetic gains and amplification of STAT3 and MYC; the presence of mutations described as associated with a poor prognosis, including CD28 mutations in AITL; TP63 rearrangement, loss of TP53, and loss of PRDM1 in ALK− ALCL; GATA3 , TP53, and/or CDKN2A in ALK− ALCL; and alterations in histone methyltransferase genes KMT2A, KMT2B, or KDM6A and FAT1 in PTCL-NOS; XPO1 expression; circulating tumor DNA (ctDNA). A sample size of 30 patients was calculated to achieve a statistical power of more than 90% (94%) to test an increase of 30% of ORR (from 50% under null hypothesis to 80% under the alternative one) using a two-sided one sample binomial test with alpha = 5%.

Results: From August 2022 to April 2025, 30 patients were enrolled in 9 Italian centers; one patient was a screening failure and 29 were eligible and evaluable for response. Median age was 66 years (IQR 60;70); 22 (76%) had stage III-IV and 6 (21%) PIT score >2. Histological subgroups were: 14 (48%) PTCL-NOS, 8 (28%) ALK negative and 7 (24%) AITL/THF. All patients received one prior line of therapy and 48% (14/29) were primary refractory; 24% (7/29) failed a prior auto-SCT. All patients were evaluable for response after 2 courses of S-IDE: ORR 48% (14/29), with 21% CR. At the end of induction, ORR was 41% (12/29), with 31% (9/29) patients in metabolic CR. Considering the 9 patients in CR at the end of therapy, one elderly patient not eligible for transplant received selinexor maintenance; 6 out of 9 patients received allo-SCT as consolidation, one patient did not for donor unavailability, and one patient developed a West Nile infection. At a median follow-up of 10.1 months (IQR: 5.1, 13.09), the 12-months PFS was 30% (95% CI: 15.3%-58.7%) and the 12-months OS was 40.7% (95% CI: 23.7%-69.7%). Hematological adverse events were reported in 31% (9/29) patients; 3 patients died during induction, one due to West Nile infection not related to the treatment, and 2 due to pulmonary infection.Conclusions: In the pilot phase II study S-IDE, the primary end-point was not met, with ORR of 41% at the end of induction. The addition of selinexor to ifosfamide, etoposide, dexamethasone did not ameliorate prognosis in relapsed/refractory PTCLs, the clinical outcome is similar to standard therapies available in this setting. Biological analyses are ongoing.

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2025
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