Molecular Markers and Subsets of Myelofibrosis

Transcript:

James K. McCloskey II, MD: Danielle, could you talk more about any other biomarker testing that’s important to these patients?

Danielle E. Marcotulli, APN: We’re typically doing biomarker testing during diagnosis initially for a baseline, and that can help us with further treatment planning. Again, we usually do this at diagnosis. And then if we’re ever concerned about progression of disease, we would again do these to see if we were coming up with different biomarkers that weren’t there initially, if something had gone away … We continuously monitor our patients and decide on a case-by-case basis when to do them, but certainly [doing them] at initial diagnosis or any point of progression is really important. And I think we usually are telling our patients that these will help us determine more about their disease. Patients always want to know what their prognosis is. Is this good or is this bad? And I think this helps us to have that conversation with them and give them more information about how we think their disease will behave.

James K. McCloskey II, MD: Absolutely. And I think in addition to that, like Danielle mentioned [with] these biomarkers, something else we’re often doing as well is monitoring allele frequency. While I would say that this is … ahead of the curve in terms of its current use in day-to-day clinical practice, it is something that we watch. We have shown that changes in variant allele frequency are associated with both response to the therapies that we use in these patients, but also increase in allele frequency associated with the risk of progression. So that’s something we’re monitoring as well. I think that Danielle mentioned that initial approach. I think important one to keep a lookout for is ASXL1. When you see this on your next-gen panel, this is always a worrisome mutation, particularly in other patients who might be negative for the 3 classic mutations that we see in myelofibrosis [MF]. Which you all know includes primarily JAK2, but also CALR and MPL. These are important mutations. But when we see the ASXL1, that always confers a more adverse prognosis. And P53 as well … These tend to be bad actors, just like we see in other disease diseases in the myeloid space, especially if there’s a high TP53 disease burden or biallelic mutation.

Danielle E. Marcotulli, APN: Dr McCloskey, can you tell us about the different types of myelofibrosis?

James K. McCloskey II, MD: We talked about … the molecular heterogeneity of the disease. And I think that in the average clinic, this is a disease that oncologists probably aren’t seeing every single day. At Hackensack, we see this every day, and we probably have multiple patients each day that we see. And [although] we tell everyone they have myelofibrosis, in reality many of these patients have different diseases. And I think we are making strides and improving our understanding of this just like we have in AML [acute myeloid leukemia] and MDS [myelodysplastic syndromes]. A lot of this starts with understanding what’s going on at a molecular level. And clearly we understand that, molecularly, not all diseases are the same. I think that we all have those patients who are triple negative for those classic 3 mutations that I mentioned. And clearly, they probably have a different disease than a patient who might be more commonly seen with a high JAK2 allele burden as the solitary abnormality.

And so, there’s a variety of ways we can kind of look at these patients. One discussion we’re having right now is … separating patients into proliferative and cytopenic myelofibrosis. And it’s important to understand that patients may start proliferative and can progress later to be cytopenic. But [patients with] cytopenic myelofibrosis tend to be patients who, as the term would imply, have cytopenias. At a molecular level, this disease tends to be signified by being JAK2 negative or having a low allele burden, and additionally will often come to us with other mutations. So [it means] having more complexity from a molecular standpoint with mutations being seen in epigenetic modifiers, in the spliceosome genes. And not surprisingly, these patients tend to have disease that behaves more poorly. That’s why in the DIPSS calculator, cytopenias are one of the factors that weigh heavily into your risk stratification. These patients with cytopenic MF tend to have disease that is more progressive. And also, as we’re going to see, they have disease that can be more difficult to manage because the therapies that we’ve had until recently often worsened those cytopenias.

And when we see these patients, I think the other thing that can be difficult is that it can be hard to decide … We start a JAK inhibitor and then their counts are a lot lower. Is that disease related or is it drug related? And sometimes it’s … impossible to tell. At some level, in my opinion, it’s always disease related. So if we can’t treat them on adequate doses of the drugs that we have because of cytopenias, it really just indicates us now that we need to switch to other options. But historically, this has been a big problem for us is because the treatments we’ve had [for] cytopenias often limit dosing of drugs that otherwise [might be] really effective.

Transcript is AI-generated and edited for clarity and readability.