Combination therapy helps reduce spleen size in myelofibrosis trial
Adding selinexor to Jakafi may improve survival, SENTRY results suggest
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An analysis of trial results shows a combination treatment may reduce spleen size.
Adding the investigational therapy selinexor to an approved regimen of Jakafi (ruxolitinib) in the Phase 3 SENTRY trial led to a greater reduction in spleen size and may have improved survival for participants with myelofibrosis, according to selinexor’s developer, Menarini Group.
“The strength of the spleen response and the encouraging early overall survival data observed in the SENTRY study creates hope for a potential new treatment option for patients suffering from this devastating disease with dismal outcomes,” Elcin Barker Ergun, CEO of the Menarini Group, said in a company press release. “Our dedication and commitment to bring transformational treatments to patients facing cancer is stronger than ever.”
The data also suggested that combining selinexor with Jakafi resulted in a similar easing of symptoms to Jakafi alone. SENTRY investigators presented the results at the European Hematology Association 2026 Congress in a presentation titled, ”Selinexor plus ruxolitinib in Janus kinase inhibitor-naïve myelofibrosis: Phase 3 SENTRY trial.”
Selinexor is approved for certain hard-to-treat blood cancers, including multiple myeloma. Outside of the U.S., the Menarini Group markets the oral medication as Nexpovio. Karyopharm Therapeutics sells it in the U.S. as Xpovio.
Myelofibrosis is a rare type of blood cancer that occurs when the precursors to blood cells grow out of control in the bone marrow. These cancerous cells often carry mutations that increase the activity of the JAK-STAT signaling pathway, which helps regulate cell growth and survival. Excessive cell growth leads to inflammation, scarring, and problems with the production of healthy blood cells. The spleen typically tries to compensate for abnormal blood cell formation, becoming abnormally large.
Spleen shrinking is a treatment goal
Reducing spleen size is one goal of myelofibrosis treatment. First-line approaches often include Jakafi and other Janus kinase (JAK) inhibitors. These medications block JAK-STAT signaling, which may help reduce spleen size and manage the disease. However, about two-thirds of people who take JAK inhibitors for myelofibrosis don’t see significant decreases in spleen size.
Karyopharm and the Menarini Group are testing selinexor as a potential add-on therapy for JAK inhibitors in myelofibrosis. Selinexor blocks the activity of the protein XPO1, an action researchers believe may reduce cancer cell growth and survival.
The SENTRY trial (NCT04562389) is examining the effects of adding selinexor to Jakafi. Participants are adults with myelofibrosis who haven’t previously used JAK inhibitors for treatment. The trial included a Phase 1 component with 39 participants that established a recommended dosing schedule for the larger Phase 3 portion.
Phase 3 participants received twice-daily oral Jakafi at a dosage determined by clinical need. A group of 235 participants also received weekly 60 mg selinexor tablets, while 118 others received a placebo. The primary goals of the study were to reduce spleen size and ease symptoms after 24 weeks (nearly six months) of treatment.
To date, researchers have analyzed data from the first 140 participants who reached the 24-week mark. Significantly more participants in the Jakafi plus selinexor group saw at least a 35% reduction in spleen size by this time (49.8% vs. 28%). Demonstrating this difference means the trial has met one of its two main goals.
“Achievement of spleen reduction is the essential goal of myelofibrosis treatment,” said Claire Harrison, MD, deputy chief medical officer at Guy’s and St. Thomas’ NHS Foundation Trust. “Importantly, the spleen reduction results seen in SENTRY were rapid, deep and durable, and associated with potential overall survival benefit for the patients receiving the combination.”
Mortality risk
Early survival statistics after a median of about one year of follow-up suggest that there is a lower risk of death among participants whose spleen size decreased by at least 35%. Additionally, the mortality risk was 57% lower in the combined Jakafi plus selinexor group compared to the Jakafi-only group. However, these results are preliminary, and more follow-up data may help clarify the effects of selinexor on survival.
Longer-term survival statistics from the small group of Phase 1 participants show a similar relationship between spleen response at week 24 and overall survival. This reflects a median follow-up period of about 2.5 years.
Change in the Absolute Total Symptom Score (Abs-TSS), a measure of myelofibrosis severity, was another primary outcome. SENTRY did not meet the goal of showing that adding selinexor had a significant effect on Abs-TSS. Symptom changes were comparable between the two treatment groups.
As an exploratory metric, investigators also compared variant allele frequency (VAF) between the two groups after 24 weeks. VAF measures the proportion of cells that carry a cancer-associated mutation. More participants in the selinexor group experienced a decrease in VAF (32% vs. 23.9% in the Jakafi-only group). This suggests that selinexor may affect underlying disease processes in myelofibrosis, according to the Menarini Group.
Safety results for participants who received selinexor plus Jakafi reflected known concerns for each medication separately, the company reported. The vast majority of participants in both groups experienced side effects. For 70.1% of the combination group and 50% of the Jakafi group, at least one side effect was severe or life-threatening.
Side effects led to treatment discontinuation in 14.5% of selinexor plus Jakafi participants and 8.6% of Jakafi participants. The rates of death related to side effects were 0.9% and 2.6%, respectively.
In both groups, 1.7% of participants converted to leukemia, an aggressive complication of myelofibrosis.
Safety and efficacy results support continued development of selinexor for myelofibrosis, according to the Menarini Group. “We are encouraged that these results represent a potential new therapeutic advance for our patients who are in dire need of better options,” Harrison said.
Karyopharm previously announced plans to meet with U.S. regulators regarding an application to approve the selinexor-Jakafi combination for myelofibrosis.
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