Texas MPN Workshop 2021 | Factors influencing MPN progression

Yeah, I think this is an important discussion, because I think one of the biggest fears we have with MPNs is this, the potential for progression. Not everyone experiences progressive disease and progression to one person may mean something different to someone else. But largely we’re talking about changes from ET to PV, PV to MF, and then, you know, any of these can convert over to acute leukemia, which is, it raises concern. And the progressions are different from one of these diseases to another.

When we think about progression from the chronic phase, such as ET or PV, maybe to myelofibrosis, that seems like a somewhat of a more natural progression that can occur over or decades, but it’s different for every patient. This could be just an accumulation of the inflammation that develops with the ongoing disease. And you know, in our discussion of these things, we kind of talk maybe biologically what drives progression in the sense that there are, there is good evidence that inflammation, you know, which is a kind of a general term, does play a role. We know that in patients that smoke, that have certain genetic susceptibilities are more likely to develop MPNs and even in some cases, more likely to develop myelofibrosis from the chronic phase than PNs.

But in terms of risk factors, I think that that’s been somewhat harder to pin down. I think people have associated maybe JAK2 to mutant allele burdens with progression. Certain driver mutations, but it changes depending on the study, which one of those can be associated with progression. Recently, there was a study looking at different molecular abnormalities in the chronic phase. And this seemed to suggest that, you know, in the setting of the ET, maybe some splicing mutations and SF3B1, U2AF1 may be associated with an increased risk of progression. And it may differ between ET and PV as well.

So, you know, largely we’re thinking about kind of a chronic inflammatory burden, maybe some higher intensity or burden of disease, and maybe these additional mutations that contribute to the progression from chronic phase to myelofibrosis. When we think about leukemic transformation, you know this may be a little bit different. This is something that occurs more rarely, maybe it’s something around the order of 5% to 10% over the course of 20 years and from either chronic phase or from myelofibrosis. And for these risk factors, I think it largely comes down to the genetics of the disease in many cases. We know that patients that have abnormal cytogenetics, certain chromosomal abnormalities, as well as what we consider it to be high risk mutations can really influence this.

So, I think the key ones are when we think about things on the p53 axis. So, p53 mutations, very rare in the chronic phase, quite common actually in the leukemic phase and so this could be associated with an increased risk of progression. Additionally, we see things like MDM4 or MBM2 overexpression. These are key regulators of p53 pathway, and these can be associated with progressive disease phenotype. But additionally, mutations and things like IDH2, SRSF2 can be looked at as risk factors for the disease to act more unstably and in a more volatile fashion and have an increased risk of leukemic progression. That’s kind of the underlying genetics. And then when we look at the clinical factors and features, sometimes we can identify things like you know maybe thrombocytopenia or increased circulating blasts. These would also be kind of easier risk factors for disease progression to AML as well.