Selinexor-Driven Regulation of Proinflammatory Cytokines May Lead to Stabilization of Hematologic Parameters and Bone Marrow Function in Patients with Myelofibrosis: Case Study from the Phase 1 Sentry Trial
Authors: Ali Haris , Maher Keri , Kishtagari Ashwin , Mohan Sanjay R , Prchal Josef T. , Chai Yi , Walker Christopher J. , Kashyap Trinayan , Kye Steve , Tantravahi Srinivas K 
Published: December 2024

Introduction: Ineffective bone marrow (BM) erythropoiesis and associated anemia can lead to extramedullary hematopoiesis, which along with splenomegaly and constitutional symptoms are key hallmarks of myelofibrosis (MF). These disease characteristics are linked to multiple cytokines that are elevated in patients with MF. Selinexor, an investigational, first-in-class oral selective exportin 1 (XPO1) inhibitor, in combination with ruxolitinib in Janus kinase inhibitor (JAKi)-naïve MF has shown rapid, deep, and sustained spleen and symptom responses with associated reductions in proinflammatory cytokines. We present a case study of 2 patients from the Phase 1 portion of the SENTRY trial (NCT04562389). These patients received long-term treatment and showed evidence of general improvement in BM parameters, with supporting in-vitro characterization of related molecular pathways.

Methods: Patient profiles from the Phase 1 portion of SENTRY (NCT04562389) of selinexor (40/60mg once weekly ([QW]) plus ruxolitinib in patients with treatment-naïve MF include safety/tolerability, splenic and symptom responses, hematologic parameters, and cytokine plasma levels. Independent digital images of stained BM slides were evaluated with a semiquantitative cell-specific detection . TGF-β/SMAD pathway activity was assessed using HEK-Blue™ TGF-β reporter cells, and synthesis of MF-related cytokines was assessed using polarized THP-1 cells.

Results: In patients receiving selinexor (60 mg; n=14) plus ruxolitinib, mean hemoglobin was generally stable up to 72 . Hemoglobin recovery and stabilization occurred in the absence of red blood cell transfusions (). Two patients were identified who received selinexor plus ruxolitinib treatment for approximately 2 years and had evidence of potential improvement in BM . . . , hemoglobin levels recovered and remained generally stabilized. Neither patient received red blood cell transfusions throughout the study. Digital analysis of BM biopsies showed , increased CD71+ erythroid precursors (+197%/+230%), and increased CD61+ megakaryocyte nuclei distance (+40%/+66%) in both patients from baseline to Week 24. Mechanistically, in a cell-based TGF-β reporter assay selinexor-inhibited TGF-β/SMAD signaling (inhibitory concentration at 50% [IC50] of 780 nM) and in polarized THP-1 cells selinexor, but not ruxolitinib, dose-dependently inhibited TNFα (IC50 of 5.8 µM) production.

Conclusions: Improved BM parameters associated with hemoglobin stabilization were observed in 2 patients who remained on long-term selinexor plus ruxolitinib treatment. Both patients achieved SVR35 and TSS50 responses even though 1 patient received suboptimal ruxolitinib. One patient received stem cell transplantation, a potential curative therapy for MF. These results provide evidence of how XPO1 inhibition by selinexor decreases NF-κB-driven cytokine production and TGF-β/SMAD activation and supports the potential impact of selinexor-induced regulation of MF-related cytokines on BM function and hematopoiesis. These preliminary, exploratory findings must be confirmed in the larger, more robust Phase 3 portion of the SENTRY trial, which is ongoing.