Evolving Treatment Landscape for Myelofibrosis: Where Are We Headed?

Natasha Johnson

Hi Katie, I am so glad to be talking to you today about myelofibrosis. When you and I started our careers as advanced practitioners, there really was only one myelofibrosis treatment approved by the U.S. Food and Drug Administration (FDA), and that was the JAK1/2 inhibitor ruxolitinib.¹ It’s been so exciting to see how the treatment landscape has evolved over the past 15 years!

Kathryn Herricks

Absolutely. There are now a total of four FDA-approved agents for myelofibrosis. In addition to ruxolitinib, we also have fedratinib, pacritinib, and most recently momelotinib, which was approved in 2023.^2-4

The growth in the myelofibrosis space has been amazing to watch, and it’s been wonderful to have so many different options on the table. But even though we have all these new JAK inhibitors, they each have their own niche of what they are able to do—Ruxolitinib, for example, is excellent at reducing spleen size and managing the symptoms of myelofibrosis, but can cause cytopenias; anemia in particular is very common.⁵ Similarly, fedratinib is beneficial for symptom management but can also lead to cytopenias and has been known to cause Wernicke's encephalopathy, a potentially fatal side effect.⁶ On the other hand, pacritinib and momelotinib benefit patients with thrombocytopenia and anemia, but are not as effective for symptom management—and both come with their own side effects.^3,4

So, we’re still trying to implement new strategies for our patients and make things better. In a way, I think we can never truly have enough options for our patients with myelofibrosis. Do you want to talk about some of the clinical trials that are currently underway, and the new agents coming down the pipeline?

Natasha Johnson

Sure. I’ve been particularly interested in a new JAK2 inhibitor being developed by Ajax, AJ1-11095. This is a first-in-class type II JAK2 inhibitor that aims to provide better efficacy with disease modification compared with our current type I JAK2 inhibitors. In preclinical studies, this novel agent has shown that it can reverse fibrosis, reduce the mutation allele burden, and maintain efficacy against myeloproliferative neoplasm cells that have become resistant to chronic type I JAK2 inhibition. We have this trial at our center, and we have seen some good spleen responses there (NCT06343805).

I know it’s early on, but it’s exciting to potentially have this as an option. A great thing about this trial specifically—and I think you share this sentiment—is that historically our myelofibrosis trials have really focused on spleen and symptoms, rather than disease modification. But that is finally changing. Now, in addition to improving spleen and symptoms, we are seeing more trials that ask the question of whether these treatments can be disease modifying.

Katie, what are some other trials in this space that you’re excited about?

Kathryn Herricks

I agree, Natasha. To have something on the table that could potentially be disease modifying—that’s what we all strive for.

As to your question, there are a couple other ongoing trials that I’ve found interesting. The first is RALLY-MF, a phase Ib/IIa trial (NCT05320198) targeting hemojuvelin, which is a protein that modulates hepcidin to free up iron. The investigational agent in question, DISC-0974, has been showing a positive anemia response in patients with myelofibrosis.

In addition, right now at Moffitt, we also have a phase II trial evaluating canakinumab (NCT05467800), which is a monoclonal antibody that has shown both anemia and spleen response. I think this is something that will be particularly important in this arena; we really need something like it at the moment.

And finally, another regimen that we’re studying is imetelstat in combination with ruxolitinib (NCT05371964). Unfortunately, so far, we haven’t seen the positive responses with that combination that we saw in our patients with myelodysplastic syndromes who received imetelstat in the phase III IMerge trial.⁷

Natasha Johnson

Thanks for that rundown, Katie. Both of us were involved in the confirmatory trials for the current JAK inhibitors, and it was great to be a part of that process and see them get approved. But as you said earlier, even though they have definitely led to improvements for our patients in the way that symptoms feel, we still continue to struggle with cytopenias and disease progression. Having new trials come out that focus on these issues is very encouraging, and I hope that more patients will continue to take advantage of them at cancer centers where they are offered.