The therapeutic landscape for myelofibrosis is rapidly expanding beyond traditional JAK inhibitor monotherapy to include novel agents that target specific disease-driving pathways, manage associated anemia, and combine to improve durability of response. Data presented at the 2026 ASCO Annual Meeting provided information on recent advances and investigational agents for myelofibrosis.

Following these presentations, featured expert Raajit K. Rampal, MD, PhD, was interviewed by Conference Reporter Associate Editor-in-Chief Rick Davis, MS, RPh. Clinical perspectives from Dr Rampal on these findings are presented here.

The SENTRY trial is one of the more important studies in myelofibrosis from the last year. Presented at ASCO 2026 by John Mascarenhas, MD, this randomized phase 3 trial compared the JAK inhibitor ruxolitinib vs ruxolitinib plus selinexor, an inhibitor of XPO1-mediated nuclear support (abstract LBA6500). The co-primary end points were spleen volume reduction by 35% or greater (SVR35) and absolute mean change in total symptom score. The trial population included untreated patients with myelofibrosis who were intermediate-1 or higher according to the Dynamic International Prognostic Scoring System (DIPSS) score. These are all patients with symptoms and splenomegaly.

The 6-month data showed that the combination therapy resulted in a significantly higher proportion of patients achieving SVR35 (49.8% vs 28%). There is a dose-response curve with ruxolitinib in terms of spleen volume response, meaning that higher doses are needed to get better spleen volume reduction responses. However, this did not seem to be the case with combination therapy in the SENTRY trial. A fairly flat dose-response curve was observed, meaning that a lot of the spleen volume reduction activity was coming from the addition of selinexor, and this was a very interesting observation.

Additionally, there was no difference in symptoms between the 2 arms, which has been a problem with this end point in myelofibrosis trials. It is hard to beat ruxolitinib for symptom control, and many combination studies have shown this to be the case. You cannot get better than what you get with ruxolitinib alone. Selinexor can have gastrointestinal side effects, so patients in SENTRY were given antiemetic prophylaxis. There were still higher rates of gastrointestinal toxicity seen in the combination arm, but, fortunately, these were not high-level grade 3 or 4 events.

There were 2 pieces of data in the SENTRY trial that were highly provocative from this presentation by Dr Mascarenhas at ASCO 2026. First, there were data showing a potential overall survival (OS) difference between the arms in favor of the combination therapy. The hazard ratio touched 1, so we cannot really say that yet for sure, but there is, perhaps, the early hint of some survival difference, which would be very interesting for the field. This also reinforces the idea that we need to follow these types of patients for longer periods while they are on these types of therapies.

Second, the survival difference was based on spleen volume response, meaning that those who had an SVR35 reduction lived longer than those who did not. When we think about an end point in a study, we want it to have clinical meaning, such as improvements in OS or progression-free survival. The fact that we saw an association between SVR35 and improvement in OS reinforces the idea that perhaps spleen volume reduction as a primary end point may actually be meaningful, and maybe it is the more important end point that we see here.

RALLY-MF was a study of DISC-0974, an HJV-blocking antibody, for the treatment of anemia and myelofibrosis presented at ASCO 2026 by Naseema Gangat, MBBS (abstract 6501). This was a study of patients who had anemia with either no transfusion dependence, a low transfusion burden, or a high transfusion burden. The results showed clear activity with DISC-0974, and a number of patients experienced an increase in their hemoglobin level. There was both a conversion of patients to transfusion independence and a proportion of patients who had a 50% or greater reduction in their transfusion needs.

A problem with anemia studies is that there tends to be a lot of subjectivity in the sense that, in a non–transfusion-dependent patient, if their hemoglobin level goes up, does that make a big difference? It depends on the patient. Another problem is that transfusion dependence or transfusion threshold is an individual thing for each patient. This is not something that is mandated by any guidelines. In other words, you do not transfuse a patient just because of the number. It depends on whether the patient needs it. So, it is sometimes hard to interpret these types of data, but I would say that the conversion from transfusion dependence to independence is meaningful.

I would also say that reducing the transfusion burden by cutting the transfusion needs by 50% or greater, which was reported in the RALLY-MF study, is also a clinically meaningful outcome. A patient who goes from 4 transfusions per month to 2 gains 10 to 12 hours of their life back. I think that we clearly see activity with DISC-0974, which has a different mechanism of action than some of the current drugs that we use to treat anemia, potentially making it another interesting tool in the toolkit for anemia in myelofibrosis.