A brief review of the biology of myelofibrosis, the potential for disease modification, and subsequent implications for treatment.
Naveen Pemmaraju, MD: This is amazing. John, turning it back to you, it seems like hepcidin is important. For polycythemia vera, you mentioned the rusfertide mimetic, hepcidin. Can you comment more on that?
John Mascarenhas, MD: It’s ironic because in some disease we’re trying to turn it down, but in other diseases we’re trying to turn it up; it depends on the disease and the goal. Three years ago, no one was talking about hepcidin, but now the discussions are all about hepcidin and how it regulates iron metabolism. It’s an interesting discussion. What makes it even more interesting is that it moves away from the clone. We’re not even talking about the clone anymore. We’re talking about adverse effects or consequences of the clone in terms of the inflammatory cues.
A question comes up, and I’m curious what Ruben and Stephen think. We have these JAK inhibitors, which potentially improve anemia—you can get the trifecta spleen symptom in anemia. [You get] an improvement in anemia, which is not a small thing—you get a patient who feels better with a higher hemoglobin out of the transfusion suite, and they’re thankful for that. But does improvement in anemia correlate with other outcome measures that matter, like survival?
Ruben Mesa, MD: Increasingly, we’re seeing that it likely does. It’s always tough to prove these things beyond a shadow of a doubt, but data were presented at this meeting [American Society of Hematology Annual Meeting] that transfusion independence from the momelotinib studies was correlated with a survival advantage. People ask the question, why do people live longer? This is an interesting question…. Is it improved oxygen carrying capacity? How do people pass away? It’s a range of things, but CHF [congestive heart failure] and other things are a part of that mix.
There’s a value: improved oxygen-carrying capacity, better levels of fitness, less death through the range of comorbidities. Or is it still just a surrogate? You achieve anemia independence, but let’s say you’ve improved the bone marrow microenvironment. A toxic bone marrow microenvironment is almost like a classic angiogenesis model. It’s toxic, you’re accumulating additional somatic mutations, and you have more movement of the clone toward acute leukemia. There’s nothing more definitive in lowering the life expectancy of a patient with MF [myelofibrosis] than moving toward AML [acute myeloid leukemia]. It clearly correlates, but it’s a fascinating question.
You’re right, John, as it relates to hepcidin. One, it traumatizes all of us because we have to think back to iron metabolism like hemojuvelin. I’ve got to pull out that chart. Metabolism isn’t my day job, but there’s truth there. If you dial it up, you have anemia; if you dial it down, you have an increase. It’s a real phenomenon, and we’re looking at both sides. Stephen, what do you think? How does the biology of inflammation link survival and anemia?
Stephen Oh, MD, PhD: It’s absolutely a conundrum how to interpret the data. The data with momelotinib are quite compelling, in terms of those who achieve transfusion independence associated with prolonged survival. But whether it’s the correlative or causative aspects of anemia, I don’t think we can say from the data. Anemia is a big adverse prognostic factor, but it’s ameliorating that in that sense. We don’t really know.
The other point is that we don’t know if it’s the same thing depending on which drug or mechanism we’re talking about. Does that suggest that achieving anemia benefit with any drug, any mechanism, could translate to an impact on overall survival? That’s hard to know and not necessarily the case. To speculate in terms of the biology, it’s quite plausible that this is a reflection of an overall impact on the bone marrow milieu—inflammatory microenvironments—better-functioning marrow, better-functioning disease. Does that translate to an impact on ... evolution? That’s too difficult to test in a study and in the lab, but it’s very possible.
Naveen Pemmaraju, MD: This is a wonderful discussion thus far. What I’m hearing from the panel is that our quest is about disease modification. Rather than isolated improvements, can we have linking of improvements. In the case of myelofibrosis, [can we have] overall survival benefit coupled with improvements in blood counts, spleen size, symptoms, and maybe 1 day the molecular correlate. So that’s wonderful.
Transcript edited for clarity.