New cancer drug shows some promise in resistant myelofibrosis

Adults with myelofibrosis whose disease no longer responded to or who could not tolerate Jakafi (ruxolitinib) or other Janus kinase (JAK) inhibitors showed signs of clinical benefit with the investigational therapy selinexor in a small Phase 2 study.

The therapy also proved safe and well tolerated. The researchers saw clinically meaningful reductions in spleen size and easing of disease symptoms in a small subset of participants, indicating modest clinical activity.

The findings helped researchers identify the optimal selinexor dose for the later, ongoing Phase 3 SENTRY trial (NCT04562389), which showed that adding selinexor to Jakafi resulted in a greater reduction in spleen size than Jakafi alone in participants with myelofibrosis.

The study, “Single agent selinexor is active in patients with myelofibrosis refractory or intolerant to JAK inhibitors,” was published as a letter to the editor in the Blood Cancer Journal.

Myelofibrosis is a rare blood cancer in which blood-forming stem cells in the bone marrow grow out of control, causing scar tissue (fibrosis) to build. As the bone marrow becomes less able to produce healthy blood cells, people can develop anemia, marked by fatigue and weakness, among other myelofibrosis symptoms. The spleen also grows abnormally large in an attempt to compensate for poor blood cell formation.

Recommended Reading

June 29, 2026 by Ruth Fein

How to manage expectations about advances in myelofibrosis treatment

JAK inhibitors

In many patients, the cancerous growth of blood-forming cells is driven by mutations that keep the JAK-STAT signaling pathway permanently switched on. This pathway normally regulates cell growth, division, and inflammatory responses, but its persistent activation drives uncontrolled cell production and abnormal tissue scarring in the bone marrow. A common first-line treatment relies on JAK inhibitors, including Jakafi, which block the overactive JAK-STAT signaling with the main goal of reducing spleen size and easing symptoms.

While Jakafi can shrink the spleen and ease symptoms in about 40% of patients, these responses are often temporary. JAK inhibitors also generally do not eliminate the abnormal cells driving the disease, prompting researchers to explore therapies that target other disease mechanisms.

One such therapy is selinexor, sold in the U.S. by Karyopharm Therapeutics as Xpovio. Approved for certain difficult-to-treat blood cancers, including multiple myeloma, selinexor blocks exportin 1, a protein involved in transporting certain proteins and RNA molecules out of the cell nucleus. In a mouse model of myelofibrosis, selinexor selectively killed cancerous cells while sparing normal blood cells.

To determine whether selinexor could benefit people whose disease had become resistant to or who could not tolerate JAK inhibitors, a team of researchers in the U.S. launched the Phase 2 ESSENTIAL trial (NCT03627403). The study was funded by Karyopharm.

The study enrolled 17 adults — nine men and eight women — with a median age of 66 between May 2019 and March 2023. All participants had previously received Jakafi, and two had also been treated with other JAK inhibitors. They had been on JAK inhibitor therapy for a median of 13 months, with treatment durations ranging from about two weeks to eight years. Fifteen participants had a disease that no longer responded to JAK inhibitors, while two had stopped treatment because of side effects.

Six participants started selinexor at 80 mg once weekly, another six at 60 mg, and five at 40 mg. One person initially assigned to 40 mg had the dose increased to 60 mg after 12 weeks.

By week 24, three of the 17 participants (17%) achieved the study’s main goal of at least a 35% reduction in spleen volume. Four participants (23%) reached that threshold at some point during the study, and three remained on treatment for up to 96 weeks (about 22 months), maintaining their spleen responses throughout that time.

The therapy also eased symptoms in some participants. Overall, 29% achieved at least a 50% reduction in total symptom score (TSS), as measured using the Myelofibrosis Symptom Assessment Form (MF-SAF), excluding fatigue, while 11% reached that threshold by week 24.

The treatment’s safety profile was generally consistent with that reported for selinexor in other blood cancers. The most common side effects included nausea, fatigue, loss of appetite, diarrhea, and weight loss. Blood cell counts remained stable throughout the study, and no participants discontinued treatment because of blood-related side effects.

Exploratory analyses also suggested that selinexor may have influenced the underlying disease. Bone marrow scarring decreased in six of the 14 participants whose samples could be evaluated, while two participants also experienced reductions in the proportion of blood cells carrying disease-causing mutations.

“The ESSENTIAL study suggests that selinexor is safe and tolerable in JAK [inhibitors]-resistant [myelofibrosis] patients, with modest clinical activity,” the researchers concluded, noting that selinexor’s efficacy seems to be within the range of JAK inhibitors approved for second-line therapy and novel single-agent therapies currently under development.