Drug combo outperforms standard myelofibrosis treatment in trial

Combining the blood cancer therapy selinexor with Jakafi (ruxolitinib), an oral treatment approved for adults with myelofibrosis, outperformed Jakafi alone in rapidly reducing spleen size and showed promising signs of extending survival.

These are the early findings from Karyopharm Therapeutics‘ ongoing global Phase 3 trial, dubbed SENTRY (NCT04562389), which is evaluating the combination therapy against Jakafi in 353 adults with myelofibrosis who have not yet received treatment with drugs similar to Jakafi.

The company plans to meet with the U.S. Food and Drug Administration (FDA) to discuss SENTRY data and its plan to file a supplemental new drug application, which is a request to market the combination of two already-approved therapies.

“I am encouraged by the speed and magnitude of spleen response, and the promising overall survival signal and evidence of potential disease modification,” Reshma Rangwala, MD, PhD, chief medical officer and head of research at Karyopharm, said in a company press release. “These data underscore selinexor’s potential to meaningfully improve clinical outcomes for patients with myelofibrosis.”

Selinexor designed to block key enzyme

Myelofibrosis is a rare, chronic blood cancer in which bone marrow is replaced by scar tissue, disrupting normal blood cell production. While the disease may not cause symptoms at first, common signs include an enlarged spleen and anemia (low red blood cell count), which is marked by fatigue and weakness.

A common first-line treatment is Jakafi, which works by blocking JAK signaling, a biological pathway that is overactive in myelofibrosis.

Selinexor, sold as Xpovio, is a prescription oral medication for adults with certain hard-to-treat blood cancers, such as multiple myeloma and diffuse large B-cell lymphoma. It’s designed to block the enzyme XPO1, triggering cancer cell death.

“Selinexor’s differentiated mechanism provides a complementary approach to JAK inhibition and highlights the importance of targeting additional biological pathways beyond JAK signaling to further advance outcomes for patients with myelofibrosis,” Rangwala said.

Spleen reduction occurred much more quickly in combination group

SENTRY is a global, multicenter Phase 3 trial evaluating a once-weekly 60 mg dose of selinexor in combination with Jakafi against a placebo plus Jakafi in 353 adults with myelofibrosis who have not been exposed to JAK inhibitors.

Twice as many patients were randomly assigned to selinexor/Jakafi as to placebo/Jakafi. Per Jakafi’s prescribing information, its dose was determined based on the blood levels of platelets, the cell fragments that help blood clot.

The study’s two main goals are a reduction in spleen volume by at least 35% (SVR35) and a change in the average absolute total symptom score, as measured by the myelofibrosis symptom assessment form, both after 24 weeks (about 6 months) of treatment.

As of the data cutoff of Feb. 20, 2026, nearly twice as many myelofibrosis patients who received the combination of selinexor plus Jakafi achieved SVR35 by week 24 as those receiving Jakafi alone (50% vs. 28%). Spleen reduction also occurred quickly in the combination group, with more than twice as many achieving SVR35 by week 12 (49% vs. 20%).

Still, the absolute total symptom score, a patient-reported measure tracking common disease-related symptoms, was similar in both groups at week 24 (9.89 vs. 10.86 points).

Promising results were also observed in overall survival, with a 57% lower risk of death in the combination group compared with the Jakafi-alone group. The company noted that it intends to continue following overall survival to evaluate this benefit further. An analysis conducted at weeks 12 and 24 suggested that achieving SVR35 may be associated with improved overall survival.

The results from SENTRY are an important development for patients as the combination of selinexor plus [Jakafi] meaningfully improved spleen response and we observed a promising signal in overall survival.

Researchers also conducted a prespecified exploratory analysis at week 24 of the variant allele frequency (VAF), the proportion of cells carrying a disease-associated genetic mutation, such as those in the JAK2, MPL, or CALR genes. More patients who received selinexor plus Jakafi achieved a VAF reduction of at least 20% than those given Jakafi alone (32% vs. 24%), suggesting that the disease is being modified at a molecular level.

No meaningful differences were observed between the two treatment groups for other secondary and exploratory endpoints. This included progression-free survival, the length of time alive without disease progression, less bone marrow scarring, and the stabilization of hemoglobin, the protein in red blood cells that carries oxygen.

The combination of selinexor plus Jakafi was reported to have a manageable safety and tolerability profile that was consistent with what is already known about each drug individually, and no new safety signals were identified.

The most common side effects in the two groups that appeared or worsened after treatment began included low platelet counts (59% vs. 43%), anemia (57% vs. 58%), nausea (57% vs. 17%), constipation (32% vs. 36%), and low levels of neutrophils, a type of white blood cell (27% vs. 9%). Leukemic transformation, defined as progression to acute leukemia, occurred at the same rate in both groups (1.7%).

“The results from SENTRY are an important development for patients as the combination of selinexor plus [Jakafi] meaningfully improved spleen response, and we observed a promising signal in overall survival,” said John Mascarenhas, MD, a professor at the Icahn School of Medicine at Mount Sinai in New York. “Reducing spleen volume remains one of the most important treatment goals in myelofibrosis since achieving SVR35 is associated with improvement in overall survival.”

Kapila Viges, CEO of the MPN Research Foundation, was encouraged that the SENTRY data showed improved survival.

“The myelofibrosis community is waiting for new treatment options that can build upon the benefit of JAK inhibitors,” Viges said. “These results are an exciting development for the myelofibrosis community.”