Video
Myelofibrosis: Classification, Risk Factors, and Biomarkers
Author(s):
Shared insight on classification, risk factors, and important biomarkers and pathways in myelofibrosis.
Transcript:
Aaron Gerds, MD: There are a lot of different ways we think about myelofibrosis [MF]. We think about myelofibrosis in terms of disease risk by a prognostic model such as DIPSS or MIPS. But we also think about myelofibrosis in the way a patient presents, whether they have low blood counts or high blood counts, and whether they’re anemic or their disease is more proliferative, either primary or secondary. To break that down a little bit, we think about patients with myelofibrosis as having either primary or secondary disease, with primary being myelofibrosis as the first diagnosis that they had, whereas secondary refers to patients who had prior thrombocythemia or polycythemia vera [PV] that over time progressed to myelofibrosis. And this is key. This sometimes gets confused with other versions of secondary myelofibrosis where there’s scar tissue in the bone marrow seen as a result of a rheumatologic disorder such as rheumatoid arthritis. What secondary means can be a little confusing, but often it indicates post-PV or post-ET [essential thrombocythemia] myelofibrosis.
We also think about myelofibrosis as being more cytopenic or anemic or proliferative, and this really has to go more into what the blood counts look like when on presentation. So for someone who has a high white blood cell count or preserved red cell counts or platelet counts, we think about them as more proliferative. Proliferative patients tend to be more secondary, tend to have just a JAK2 mutation or a JAK-STAT [Janus kinase and signal transducer and activator of transcription] activating mutations in few other mutations where patients with cytopenic myelofibrosis tend to present with low blood counts, anemia, thrombocytopenia, JAK2 allele burdens or CALR allele burdens and higher allele burdens of other mutations such as TAT2. It may also have other higher-risk mutations present such as ASXL1. So definitely there is a spectrum of disease in myelofibrosis, and we try to parse things out because different therapies may perform better in different segments of myelofibrosis.
Pankit Vachhani, MD: There are no major known risk factors for the development of myelofibrosis. However, a prior history of polycythemia vera or essential thrombocythemia puts one at a high risk of having secondary myelofibrosis down the line. Older age, and in particular being older than 60 years of age, can be considered a risk factor, as it is for many other hematologic and solid tumor malignancies. Last but not least, exposure to certain chemicals such as toluene and benzene as well as exposure to radiation over a long period of time has been noticed in cases to correspond or be associated with the development of myelofibrosis.
Naveen Pemmaraju, MD: In terms of myelofibrosis pathways and biomarkers, I would divide this category into essentially 3 different buckets. So bucket 1, category 1, is that of the known big driver mutations many of you are familiar with, primarily JAK2, V617F, CALR, and MPL. Among those, they represent essentially 90% or more of the driver mutations that are found in the MPNs [myeloproliferative neoplasms], including myelofibrosis. And the 10% that don’t have that are so-called triple-negative diseases. Now, interestingly, over time we’re starting to see that these biomarkers not only have diagnostic significance but also maybe even prognostic significance. There’ve been several groups that have shown prognostic significance just based on these biomarkers. And of course, there is the development of targeted therapies either for the wild-type pathways or mutation specific. I think that’s the first category, JAK2, CALR, MPL, driver mutations in 90% of patients, 10% don’t have those, and so those are termed triple negative.
No. 2 in that triple-negative, or even in the known mutated, group, we have now this series of second-generation markers. And these markers are usually seen in AML [acute myeloid leukemia], MDS [myelodysplastic syndromes], and CMML [chronic myelomonocytic leukemia], and now we’re seeing them in myelofibrosis as well upon deeper sequencing. Next-generation sequencing and other clinical tools can help you to see these in the clinic. I think importantly, some of those are starting to have prognostic implications. One of them is the ASXL1 mutation, which if present in myelofibrosis can portend for a higher risk of transformation to a higher state of myelofibrosis to AML and even worse outcomes, maybe identifying patients who may need a stem cell transplant earlier. Outside of that, you have the splicing factor mutations such as SRSF2 and others, epigenetic mutations, EZH2, other markers such as IDH1 and IDH2, and then ultimately TP53. And a lot of these markers either herald the transformation of myelofibrosis into AML or to a higher risk state within the MF.
I think the third bucket and category is the newer markers or unknown markers that the research is starting to try to elucidate. Some of these include cytokines. These are protein messengers and signals that are aberrant in myelofibrosis and other deeper markers that are not usually seen at the clinical level, but they’re being seen in the laboratory and research side. And I think one great aspect of these newer markers is we’re trying to understand and explore twin analyses in some of the ongoing clinical trials, particularly the combination studies.
I think those are the 3 categories of some of these pathways and markers. And I think in the newer marker category, there’s so much that’s being elucidated. And just to give a flavor of that, pathways such as Bcl-xL is one in particular, PI3 kinase, bromodomain, XPO1, CD123, and other pathways that are either in the malignant cell or the tumor background. And I think what this is leading to is not only the identification of better biology and understanding but also potentially identifying new markers for targeted agents that are in either preclinical development or now have entered into the clinic in phases 1, 2, and 3 clinical trials.
Transcript edited for clarity.
