Momelotinib: Considerations for Patient Selection in the Front-Line Setting

Andrew Kuykendall

Which new patients would you consider to be candidates for front-line momelotinib over ruxolitinib?

Natasha L. Johnson

In my opinion, any patient who is experiencing anemia. If that's what they come in with, and we can offer them some benefit—because that benefit was seen in over 30% of patients who received momelotinib on study—then why not try that option?

Andrew Kuykendall

I agree with you. In my opinion, for this kind of patient, we can rely on the data from SIMPLIFY-1, where there's a head-to-head comparison of ruxolitinib vs momelotinib.¹ The two agents are pretty much equivalent in that trial in terms of spleen volume responses; the caveat is that momelotinib was not noninferior to ruxolitinib in terms of symptoms. What gives me some peace there is that the trial enrolled a largely nonanemic population, most of whom—three-quarters of patients—were transfusion-independent.

What we don't really know is whether momelotinib is better, the same, or worse than ruxolitinib in terms of symptom and spleen responses in patients who are anemic in the front-line setting. How do you weigh two agents that have overlapping benefits, but with different degrees of benefit? We know in all-comers (anemic and nonanemic, as enrolled on SIMPLIFY-1), momelotinib is about the same for spleen response and maybe a little bit worse for symptoms. But in anemic patients, I'd argue that from all the data we have, momelotinib is probably just as good, if not maybe slightly better, than ruxolitinib, but we don't have that question prospectively answered. So, I agree with you: that is the patient population I would consider momelotinib for in the front line, especially the more anemic they are, because the last thing you want to do is make them more transfusion-dependent or push them into transfusion dependency. But I think it's a good question, especially as we now have combination therapies coming down the pipeline or clinical trials.

Natasha L. Johnson

So, if you have a patient come in who has mild anemia but no splenomegaly and no symptoms, what would you do?

Andrew Kuykendall

It's so rare, right? Historically, in the NCCN Clinical Practice Guidelines in Oncology, what’s been recommended for myelofibrosis-related anemia is erythropoiesis-stimulating agents, and if their erythropoietin levels are less than 500 mU/mL (preferably less than 125 mU/mL), we've used danazol, lenalidomide, and thalidomide for those patients.² The question now is: would you still use those non–disease-specific, anemia-targeting agents vs an agent like momelotinib, which has been compared to at least one of these choices and danazol and was shown to result in better rates of transfusion independence on the MOMENTUM study?³

I certainly would have the discussion of using momelotinib in the purely anemic population, perhaps considering using an erythropoiesis-stimulating agent first. I think we often forget to mention to consider alternative reasons for anemia. Anemia is quite multifactorial within myelofibrosis—certainly we've talked about hepcidin, this anemia of chronic inflammation. You also have ineffective erythropoiesis with intravascular or intramedullary hemolysis, or you can have splenic sequestration from splenomegaly. We also often see splicing mutations that cause ineffective erythropoiesis as well. You also have to think about nutritional deficiencies that could be corrected immediately. Then, lastly, I think cost is an issue. It's nice to say, “Hey, let's use momelotinib or pacritinib for anemia because it has some benefit there,” but these drugs are not cheap—even with good insurance, they can be quite challenging financially. In that case, maybe erythropoiesis-stimulating agents provide a better ‘bang for the buck’ to try first and see if we can get a response; if that doesn't work, maybe then you move down the algorithm to considering some of these newer agents. Unfortunately, as much as we'd love to talk about what's empirically the best choice for the patient, I think cost actually ends up driving the decision many times.

Natasha L. Johnson

Absolutely, I agree.