Ruben Mesa, MD: As we monitor these diseases, there are several potential outcomes. I share with many patients with MPN [myeloproliferative neoplasm] that with ET [essential thrombocythemia] and PV [polycythemia vera], if the disease doesn’t progress, hopefully most of them will live out their normal life span, and that it’s the minority who will progress. Probably more patients with PV progress than with ET. Clearly, it’s 1 of our great unmet needs: how do we understand progression, and how do we help avoid it?

We’ll talk a little later about the progression we’re most fearful of, which is a progression into acute leukemia. First, Angela and Stephen, why don’t we finish this section focusing on why patients progress from ET or PV into myelofibrosis? What have we learned? Do our therapies have any impact? Angela, you’ve had a great interest in the pathogenesis of MPNs, why they progress, and even the role of inflammation. Why do you think these patients progress?

Angela Fleischman, MD, PhD: That’s a good question. I don’t think I can answer that. I can try to give you some of my thoughts. I clearly believe that inflammation plays a big role in myeloproliferative neoplasms in ET and PV and in particular myelofibrosis. We all know that myelofibrosis is a very inflammatory disease. It drives a lot of the symptoms that people are feeling. I do believe it plays a critical role in the pathogenesis of the disease.

High inflammation may also be playing a role in the anemia that’s seen in myelofibrosis, somewhat similar to anemia of chronic inflammation and other diseases. It’s multifactorial—inflammation plays a role in many features of the disease.

If we knew why people progressed from PV or ET to myelofibrosis, that would be great. I don’t think we know that. The best we can do is watch somebody very carefully and, as hematologists, hope we can identify the warning signs quicker than the patient would realize it or another practitioner would realize it. I’m not answering the question, but if we knew why people progressed, then we could start to do something about it.

Ruben Mesa, MD: I share with many folks that that truly is 1 of the greatest unmet needs. Once we understand that better, we may be able to target it more efficiently. Stephen, you’re clearly our deep expert in terms of the mutations associated with pathogenesis but also with progression. What role do you think the bone marrow microenvironment—the inflammatory milieu—may play a role. Maybe it’s even conducive to changes. In cancer we’ve certainly had this somewhat historical model of almost stepwise sequential accumulation of genetic events leading to progressive disease. What do you think is that step with ET and PV to MF? Do you think it’s the accumulation of additional genetic damage?

Stephen Oh, MD, PhD: Yes. On the 1 hand, we view the progression of MPNs—for instance, from PV or ET to MF and, potentially directly, to secondary MF as driven in large part by acquisition of additional genetic mutations. Certain mutations are stronger or confer an increased risk of transformation. In many ways, the stepwise progression of additional mutations that you describe is a big factor. We know, for instance, that patients with myelofibrosis tend to have more driver mutations than patients with PV and ET.

On the other hand, it’s certainly more complicated than that. I’d echo that inflammation is likely an important player in that regard, and I view it as both a cause and a consequence. It’s well established from a number of studies that mutations such as JAK2 that are commonly found in these diseases can, by themselves, produce abnormal inflammatory cytokines and things like that. The malignant clone is probably more sensitive or more susceptible to coronal outgrowth in that inflammatory setting. There’s been growing literature in that regard, including presentations from ASH [American Society of Hematology Annual Meeting] supporting that concept. It’s a feed-forward loop over time. The malignant clone is going to acquire additional mutations, and as that inflammatory milieu worsens, it can contribute or be conducive to that progression.

Ruben Mesa, MD: Wonderful. There’s much more to come as we try to get a sense of what’s going on with that clonal mutational pressure as well as with the patient and the microenvironment.

This transcript has been edited for clarity.