Myeloproliferative Neoplasms - Episode 6

Case 1: The Diagnosis of Myelofibrosis

May 14, 2020
Targeted Oncology

Srdan Verstovsek, MD, PhD: Let’s all together discuss from the beginning, the diagnosis first because diagnosis appears to be problematic in some cases, particularly when the sampling of the bone marrow is not good enough, when the molecular testing for the driver mutations is not good enough. We have to understand that the diagnosis actually combines different aspects of what one sees in a patient. It’s not just the bone marrow. Perhaps Prithviraj, you can help us here. What does it actually entail to get the diagnosis of myelofibrosis? What needs to be ruled out that we wonder when we have fibrosis in the bone marrow? Is it always myelofibrosis or can it be something else? What are the diagnostic criteria and what needs to be ruled out?

Prithviraj Bose, MD: Sure, Srdan, thank you. The primary myelofibrosis diagnostic criteria, there’s quite a few. There’s major and minor criteria. But 1 point I’d really like to make is you’re looking for megakaryocytic atypia. You’re not just looking for proliferation, because you see that in ET [essential thrombocythemia] as well. But the atypia is really, in my view, the hallmark of primary myelofibrosis. Of course, you have several minor criteria such as anemia, splenomegaly, increased LDH[lactate dehydrogenase], leukoerythroblastosis, etc. But you certainly need the clonal marker, and you touched on this, sometimes we don’t have a driver mutation. In about 10% of patients, we don’t have JAK2, MPL, or CALR mutated, and that’s what we call triple-negative primary myelofibrosis. But there, too, using a myeloid mutation panel, an NGS [next-generation sequencing] panel, which is getting increasingly prevalent nowadays, can really help because you find these nondriver mutations—mostly epigenetic and splicing mutations, ASXL1, TEK2, EZH2, DNMT3A, SRSF2, and SF3B1—which can really help you show that this is, in fact, a clonal disease.

Other diseases, sure, can cause myelofibrosis without being clonal—infections, autoimmune conditions, certain drugs even, certain recreational drug toxicities. But those are not going to have a clonal marker. So, yes, it’s really a combination of a lot of factors, pathologic, genetic, laboratory, as well as clinical.

Srdan Verstovsek, MD, PhD: So it seems that it is a clinician who actually makes a final decision, because you have to combine the bone marrow exam, including the molecular and cytogenetics, you combine the physical exam, you have a chemistry such as LDH [lactate dehydrogenase], and you have a blood count. All this needs to come together and the clinician many times is the one who makes the final decision. But you already mentioned the mutation analysis beyond the driver mutations, testing for the JAK2 mutations, calreticulin or MPL mutations is part of the diagnostic process and it’s 1 of the factors accounted for. But other mutations you already mentioned have a role in a differential diagnosis if there are questions. Andrew, the mutation analysis gets handed up only in these borderline cases but also for prognostication. Is this something that we should be doing quite often, expensive molecular testing? What’s your take on this—where there is a question of diagnostic differential? Where else should we do it and how often?

Andrew Kuykendall, MD: I think that certainly the NGS has allowed us to do molecular panels much more easily than we were able to do in the past. Certainly, with diseases like myelofibrosis, we typically do broad molecular panels on virtually every patient that comes in. I think that they provide a lot of information, diagnostics, and we touched on prognostics as well. Increasingly, we’re starting to have the potential for providing some therapeutic benefit as well.

I think Dr. Komrokji talked a little bit about some of the prognostic gene mutations such as ASXL1, SRSF2, EZH2, U2AF1, and IDH1/2. Certainly, I think those are helpful and give us a sense of where exactly we think this disease might go, and it may act a little bit more aggressively than we would have thought otherwise. But diagnostically, you may suggest or think you’re seeing something like myelofibrosis, but you could see some combination of the CSF3R mutation or a combination of tattoo, ASXL1, SRSF2, that makes you rethink the diagnosis and maybe consider something like chronic neutrophilic leukemia or atypical CML [chronic myelogenous leukemia] or CMML[chronic myelomonocytic leukemia], which can sometimes present some overlapping features with myelofibrosis.

I think the idea of potentially being able to use these as therapeutic is really where we need to get to and where we’re kind of going, and certainly with the IDH-1 and -2 inhibitors, there becomes the potential to use that. And increasingly, we’re starting to come out with more molecular-targeted treatments that could be used in some of these cases.

Transcript edited for clarity.