Selinexor Plus Ruxolitinib Reduces Symptom Burden in Myelofibrosis

Selinexor plus ruxolitinib was well tolerated, reduced symptom burden, and led to spleen volume reduction in patients with myelofibrosis (MF) by inhibiting NF-κB and activating p53 pathways, according to a recent study. The study was led by Srinivas K. Tantravahi, MBBS, MRCP, of the University of Utah Huntsman Cancer Institute, and presented at the Twelfth Annual Meeting of the Society of Hematologic Oncology.

The researchers assessed adverse events (AEs), symptom burden (total symptom score reduction of ≥50%, or TSS50), and spleen volume reduction of ≥35% (SVR35) following selinexor plus ruxolitinib therapy in the phase I portion of the SENTRY trial. Fourteen patients received at least one dose of selinexor 60 mg.

The most common AEs were nausea (79%), fatigue (57%), anemia (64%), and thrombocytopenia (64%). At week 24, most patients (79%) achieved SVR35, 58% achieved TSS50, and 50% achieved both SVR35 and TSS50. Seventy-five percent achieved both SVR35 and TSS50 at any time. The mean absolute change in total symptom score from baseline to week 24 was –19.

Compared with single agents, selinexor plus ruxolitinib “induced cell cycle arrest and showed greater loss of cell viability,” the researchers noted. “Selinexor plus ruxolitinib reduced CDK4 and CdC25A levels and increased nuclear localization of p53.”

Selinexor also induces nuclear localization of IkBa, therefore inhibiting NF-kB transcriptional activity, the researchers explained. This mechanism was enhanced in combination with ruxolitinib (50% [selinexor plus ruxolitinib] vs 30% [selinexor monotherapy]). Selinexor also negatively regulated the expression of MF-related cytokines such as interleukin-6, a main activator of the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling pathway.

“The in vitro results point to a potential mechanism of action in which XPO1 inhibition targets multiple oncogenic pathways beyond JAK/STAT, including inhibition of NF-kB−driven proinflammatory cytokine production and p53-mediated apoptosis,” the researchers concluded.

Reference

Tantravahi SK, Kishtagari A, Maher K, et al. Selinexor and ruxolitinib impact on symptom burden in patients with myelofibrosis is potentially driven by inhibition of NF-κB and activation of P53 pathways. Abstract # MPN-527. Presented at the Twelfth Annual Meeting of the Society of Hematologic Oncology. September 4-7, 2024; Houston, Texas.