Clinical Summary: 

• Design/Population: The phase 3 SENTRY trial randomized JAK inhibitor–naïve patients with intermediate-1–risk or higher myelofibrosis to receive selinexor plus ruxolitinib or placebo plus ruxolitinib in a double-blind, placebo-controlled study.
• Key Outcomes: Selinexor plus ruxolitinib significantly improved spleen volume responses compared with ruxolitinib alone and was associated with an early overall survival benefit. The combination also demonstrated evidence of disease modification, including reductions in driver mutation allele burden and circulating blasts, while maintaining a manageable safety profile.
• Clinical Relevance: These findings support selinexor plus ruxolitinib as a promising frontline combination strategy that may improve both disease control and survival in patients with myelofibrosis.

Claire Harrison, MD, Guy's and St Thomas' NHS Foundation Trust, London, United Kingdom, discusses results from the phase 3 SENTRY trial evaluating selinexor in combination with ruxolitinib for patients with JAK inhibitor–naïve myelofibrosis. Selinexor, an XPO1 inhibitor, was combined with ruxolitinib to enhance disease control by targeting complementary biologic pathways involved in myelofibrosis.

The combination produced deeper spleen responses than ruxolitinib alone while maintaining symptom control and a safety profile consistent with the known toxicities of both agents. The observed overall survival benefit and molecular responses suggest that selinexor may enhance the disease-modifying effects of JAK inhibition and support further adoption of combination therapy in the frontline setting.

Dr Harrison presented these results at the European Hematology Association (EHA) Congress in Stockholm, Sweden.

Transcript: 

Hi, my name is Claire Harrison, I'm a professor of hematology at Guy's Hospital in London, UK. Now I want to talk about selinexor, an XPO1 inhibitor, in combination with ruxolitinib in JAK inhibitor–naïve myelofibrosis, and the results of the phase 3 SENTRY study. 

Just as a reminder, our current JAK inhibitors still leave a number of unmet needs for our patients. Most patients do not achieve a 35% reduction in spleen volume, and many ultimately progress with persistent residual disease. 

Selinexor is a drug that has been administered to more than 40,000 patients worldwide across a variety of hematologic malignancies, including multiple myeloma. As an XPO1-mediated nuclear export inhibitor, it has the potential to enhance the depth of response to JAK inhibitors by reducing cell proliferation, inhibiting NF-κB activity, increasing apoptosis, and modulating JAK-STAT signaling. So it represents a very logical partner for ruxolitinib.

In the SENTRY study, we enrolled JAK inhibitor–naïve patients with intermediate-1 risk or higher myelofibrosis who had measurable splenomegaly and symptoms. Patients were randomized in a double-blind, placebo-controlled study with a 2:1 randomization. A total of 235 patients received selinexor plus ruxolitinib and 118 received placebo plus ruxolitinib.

At the week 24 data cutoff that we presented, treatment discontinuation rates were remarkably similar—36% in the selinexor arm and 35% in the ruxolitinib-alone arm. 

The reasons for discontinuation differed somewhat. More patients discontinued because of physician decision or splenic progression in the ruxolitinib-alone arm, whereas more patient withdrawals occurred in the selinexor arm. Importantly, transformation to acute myeloid leukemia, which has been imbalanced in some previous studies, was well balanced between the two treatment groups.

Interestingly, the median weekly doses of both selinexor and ruxolitinib were actually somewhat lower in the combination arm. The median follow-up at the time of analysis was approximately 11 to 12 months. So, cutting to the chase, what were the results?

At week 24, 49.8% of patients treated with selinexor plus ruxolitinib achieved SVR35 compared with 28% of patients treated with ruxolitinib alone—the same approximate response rate we originally reported with ruxolitinib monotherapy nearly 15 years ago. So we essentially increased the SVR35 rate from 28% to almost 50%. These spleen responses occurred rapidly. Separation between the treatment arms was already evident by week 12, and the benefit was sustained through week 36, although longer follow-up is still needed. The results were highly statistically significant.

Subgroup analyses demonstrated consistent benefit across all patient groups evaluated. Importantly, despite the somewhat lower median dose of ruxolitinib in the combination arm, spleen responses remained superior with selinexor across all ruxolitinib dose levels. 

Symptom response was also a co-primary end point. There was no significant difference in symptom improvement between the selinexor and placebo arms. I think this is particularly important because we are adding a drug with known side effects, yet patients still experienced comparable symptom improvement.

Perhaps the most striking finding was the overall survival analysis. Despite only 11 to 12 months of follow-up, we observed a statistically significant survival advantage for patients treated with selinexor plus ruxolitinib. This is the first time we have seen an overall survival benefit demonstrated in this setting. The hazard ratio for overall survival was 0.43.

Interestingly, we had already seen a similar trend in the earlier phase I study, where survival appeared closely linked to achievement of SVR35, and that relationship was again observed in the SENTRY study. 

We also saw findings consistent with disease modification. Reductions in driver mutation variant allele frequency were more common with selinexor plus ruxolitinib, occurring in 32% of patients compared with 23.9% of patients receiving ruxolitinib alone.  We also observed reductions in circulating blast counts. 

Turning to safety, we know that selinexor can cause cytopenias, nausea, and fatigue, and these were the principal differences observed between the treatment groups. There were no unexpected adverse events. As I mentioned earlier, rates of leukemic transformation were balanced between both arms.

So overall, this is a frontline combination study in JAK inhibitor–naïve myelofibrosis demonstrating that selinexor plus ruxolitinib produces rapid, deep, and sustained spleen volume reductions, with significantly more patients achieving SVR35. This was associated with an overall survival benefit, with a hazard ratio of 0.43. Symptom improvement was maintained, and the safety profile was manageable and consistent with the known safety profiles of both agents. 

Finally, I think it is important to acknowledge all of the patients who participated in this study. They have made a major contribution to advancing research in myelofibrosis. I'd also like to thank all of the investigators and study teams involved. And please look out for the full manuscript, which is now available online in the Journal of Clinical Oncology.

Source: 

Harrison C, Al-Ali HK, Gutierrez VC, et al. Selinexor plus ruxolitinib in janus kinase inhibitor-naive myelofibrosis: Phase 3 SENTRY trial. Presented at EHA 2026 Congress; June 11-14, 2026; Stockholm, Sweden. LB5002.