Expert Insights into the Treatment of Myelofibrosis - Episode 3

The JAK/STAT Pathway and Myelofibrosis

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Raajit Rampal, MD, describes the JAK-STAT pathway and how it’s fundamental to all types of myelofibrosis.

John Mascarenhas, MD: Keeping on the theme of the pathophysiology underlying the disease biology and the clinical phenotypes, Raajit, can you comment on the JAK-STAT pathway and how this fits into the treatment landscape for patients with myelofibrosis [MF]?

Raajit Rampal, MD, PhD: We’ve painted an interesting portrait of the disease thus far with the comments from Srdan and Aaron. As Aaron said, this isn’t a monolithic entity. This is a spectrum of disease. We have to think about myelofibrosis as a spectrum of disease. But one of the things that does unite it in all of its manifestations is activation of the JAK-STAT pathway. This is fundamental to the pathobiology of the disease. There are data from a number of groups that looked at this on a gene expression level, where regardless of what drives the disease—Srdan talked about the 3 main driver mutations: JAK, MPL, and calreticulin—regardless of what mutation you see, you still see activation of this pathway. That’s the hallmark of myelofibrosis as a disease.

As Aaron pointed out, we see different manifestations. We see patients who have a more cytopenic phenotype, patients with a more proliferative phenotype, and patients who may have had disease that occurs secondary to ET [essential thrombocythemia] or PV [polycythemia vera]. Clinically, we see that these patients manifest in a different way. Some of this is secondary to some of the other mutations that can occur in these patients. When we think about MPNs [myeloproliferative neoplasms] in general, it’s the minority of patients that have more than a JAK-STAT driver mutation in terms of ET and PV. But with MF, it’s much more. There’s a higher percentage of patients who have other mutations.

It’s clear to us from preclinical studies and studies of patients that those other mutations can make a difference in how the disease manifests and the likelihood of that disease to progress. Importantly, in this context, at least with regard to ruxolitinib, work from Srdan’s team showed that this may also predict how durable of a response a patient is going to have to a JAK inhibitor like ruxolitinib. I don’t think we’re at the point where we can robustly say with a given patient that if we do next-generation sequencing that we can predict this patient’s path or what type of disease they’re going to have. That’s where we’re going to move in the future. We aren’t there, but at least we have some hints from the work that has been done thus far that the information can at least give us some hint of the patient’s likely course and response to therapy.

John Mascarenhas, MD: Fantastic. To close this section out, can you highlight 2 or 3 mutations that are clinically meaningful outside of the JAK-STAT pathway in myelofibrosis?

Raajit Rampal, MD, PhD: There are a couple of them that we worry about. We often consider mutations in ASXL1 to pose an increased risk of the patient progressing. That has been our central dogma since 2013, although there are recent data that have challenged that assertion a little and indicated that it may be different in primary myelofibrosis versus post-ET or post-PV myelofibrosis. More data is needed there, but either way, that’s a mutation that brings some concern.

Splicing factor mutations like SRSF2 and U2AF1 also seem to be associated with a higher risk of disease progression. U2AF1 is interesting because it looks like it’s associated with anemia—in particular in patients with myelofibrosis. There are others, like EZH2 and RAS pathway mutations, which all seem to be associated with an increased risk of disease progression. Work from Srdan’s group showed that ASXL1 or having 3 or more mutations seems to predict an earlier time to treatment failure with ruxolitinib. Aside from pure prognostication of a patient’s course, it may have implications in terms of how a patient is going to do on therapy.

John Mascarenhas, MD: Excellent. Srdan, to end this part of the discussion, how about TP53 mutations? Is there any consideration when you see those in patients with myelofibrosis?

Srdan Verstovsek, MD, PhD: That’s a good question, because we always worry whenever there’s TP53 involvement with myeloid neoplasms. Luckily, in chronic phase myelofibrosis, it isn’t present too often. The percentage is very low: 1% to 2% at the worst. In the study, it was difficult to pinpoint whether this means anything because it’s so rare. However, it has been much more common—present 20% or 25% of the time in people who have progressed to accelerated or blastic phase. Work by Raajit and colleagues has shown that if you have a good-enough test and go back to the chronic phase, you’ll find TP53 there at a very low level, which progresses over time. Overall, I’d worry about TP53 whenever it’s present. I can’t pinpoint and say how bad that is, but it’s bad.

Transcript edited for clarity.