Historic Challenges and New Options in the Treatment of Patients With Myelofibrosis

Andrew Kuykendall

What would you say is the biggest challenge for you in treating patients who are currently receiving ruxolitinib? What have been the biggest unmet needs or issues facing your patients?

Natasha L. Johnson

The greatest challenge that stands out is the development of anemia. Unfortunately, we see many patients who present with anemia. Before we had these two newer agents, we were trying to dose-reduce ruxolitinib to not make their anemia worse, or once they started, we’d support them with transfusions in an effort to help them stay on ruxolitinib and even increase their dosage. But if they’re on ruxolitinib and they’re feeling well, but they get worsening anemia that requires transfusions, it makes treatment really difficult. Momelotinib is a drug that we’ve been anticipating for a long time, and patients are really excited to have it available now.

Andrew Kuykendall

Please tell me about the two new agents that have been approved by the U.S. Food and Drug Administration (FDA) over the past 2 years or so for patients with myelofibrosis.

Natasha L. Johnson

Pacritinib was approved on the basis of findings from the PERSIST-1¹ and PERSIST-2² studies, and it specifically benefits patients with thrombocytopenia. Just like we were talking about with ruxolitinib, it can get to a point where, per prescriber or manufacturer instructions, you can’t prescribe a treatment when platelets are below a certain count; pacritinib offers an option for patients who have platelet counts less than 50,000. Essentially, it makes a JAK inhibitor available to patients who are more severely thrombocytopenic. Unfortunately, because it also inhibits FLT3, pacritinib does come with more gastrointestinal side effects. It seems like in the clinical setting, these side effects do seem to improve, but you don’t want to give patients who already don’t feel well a drug that can also cause more gastrointestinal symptoms.

The second, more recently approved agent is momelotinib. We have data on this drug from the SIMPLIFY-1³ and SIMPLIFY-2⁴ trials. In SIMPLFY-1, momelotinib was compared to ruxolitinib, and in SIMPLIFY-2, it was compared to best available therapy. Also, in 2023, results of the MOMENTUM study were published, where it was compared head-to-head to danazol and led to an improvement in hemoglobin and transfusion independence. On the basis of these findings, momelotinib was approved by the FDA for patients with intermediate- or high-risk myelofibrosis who are also experiencing anemia.⁵

Andrew Kuykendall

These are two options that had both been in development for a long time before they were approved, so we knew a lot about them by the time they did receive regulatory approval.

As you mentioned earlier, pacritinib was approved by the FDA in February 2022 for patients with intermediate- or high-risk primary or secondary myelofibrosis who have platelet counts less than 50,000, which is a unique approval, but certainly speaks to what we lacked in the treatment armamentarium for that patient population. When you look at the PERSIST-2 study, however, it compared two different dose levels of pacritinib vs best available therapy in patients with thrombocytopenia who could have received a prior JAK inhibitor. So these patients had platelet counts of less than 100,000, but the trial did not require them to have a platelet count of less than 50,000, although about 50% of patients did. Pacritinib was able to improve spleen volume responses as well as symptom responses compared to best available therapy. The reason it didn’t get approved right away for this indication of less than 100,000 platelets was largely because it actually didn’t meet the symptom endpoint based on the way that the trial was designed statistically. The trial compared the pooled pacritinib arms, both dosing levels, with best available therapy, and it missed that very narrowly with a P value of .08, so it didn’t lead to approval. Interestingly, if you just look at the 200-mg twice-daily arm of that study, with statistical significance, it beat best available therapy. 

We now have the ongoing PACIFICA study for pacritinib (ClinicalTrials.gov identifier NCT03165734), which has completed accrual and is looking at patients with primary myelofibrosis, post–polycythemia vera myelofibrosis, or post–essential thrombocythemia myelofibrosis who have platelet counts of less than 50,000. We also have the NCCN Clinical Practice Guidelines in Oncology that say yes, in the first-line setting, we can use pacritinib in patients with platelet counts of less than 50,000, but it’s also an option for patients in the second-line setting regardless of platelet count because we do have a preponderance of data that suggest that it’s active there.

As you mentioned, I think the challenge or concern with pacritinib is the gastrointestinal side effects. They’re usually mild, grade 1 or 2—but we know that grade 1 or 2 diarrhea or grade 1 or 2 nausea can be life-changing and challenging for patients. Because we’ve used it in the clinic, we do see some patients who have zero gastrointestinal side effects; we’ve had others who have had significant gastrointestinal side effects; and we’ve had others who have mild effects—it’s all across the board, and you don’t exactly know which patients are going to experience them and to what degree. It is something we have to think about and counsel patients on, and we may prophylactically give them antiemetics or antidiarrheals.

Then we have momelotinib. As you referenced, it went through the SIMPLIFY-1, SIMPLIFY-2, and MOMENTUM studies. People always wonder, “Well, why did it go through so many phase III studies before its approval?” Well, again, it wasn’t simple.

SIMPLIFY-1 compared momelotinib head-to-head to ruxolitinib—a very aspirational trial, we get a head-to-head comparison of two JAK inhibitors. It was designed as a noninferiority study. Momelotinib was found to be noninferior to ruxolitinib in terms of splenomegaly, so they were about the same in terms of spleen volume responses. But it was shown to not be noninferior to ruxolitinib in terms of symptoms—so somewhat worse. This has been subsequently debated, but these data ultimately hindered the agent’s development at that stage.

This led to the SIMPLIFY-2 study, which was a second-line trial in patients who had previously been on a JAK inhibitor. Patients were randomly assigned to either immediately switch to momelotinib or receive best available therapy, which, for 90% of them, was just staying on ruxolitinib. The problem there is if you go from one JAK inhibitor and switch to another immediately, without a washout, you don’t really achieve better spleen volume reduction; the spleens largely stayed the same. In SIMPLIFY-2, which was designed as a superiority trial, the spleen volume responses were 7% in the momelotinib arm and 6% in the ruxolitinib arm, which was not very surprising, retrospectively. Interestingly, patients who switched to momelotinib had a much better symptom response compared with patients who stayed on ruxolitinib. So there’s something different about momelotinib there, at least in the open-label setting, because patients did know they were switching treatments and still felt better, even though some bias can be found when patients are aware of switches.

Finally, we had the MOMENTUM study, which was conducted in patients who had been on ruxolitinib and who were anemic. MOMENTUM compared momelotinib vs danazol and, obviously, momelotinib met all of its endpoints there in terms of symptom response and spleen response, and the trial led to its ultimate approval.