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Understanding Genetic Mutations in Primary Myelofibrosis

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Published on June 8, 2021

What Are the Genetic Mutations for Primary Myelofibrosis?

When should a primary myelofibrosis patient have genetic testing to determine mutational subgroups? In this Ask the Expert program, John Mascarenhas, MD, from Mount Sinai explains the different mutations that can accompany a primary myelofibrosis diagnosis. He also explains the distinctions in outcomes for patients who are diagnosed with each type of mutation.

Support for this series has been provided by Bristol Myers-Squibb. Patient Power maintains complete editorial control and is solely responsible for program content.

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Transcript | Understanding Genetic Mutations in Primary Myelofibrosis

What Should Primary Myelofibrosis Patients Know About Genetic Mutations?

Dr. Mascarenhas: When patients are diagnosed with primary myelofibrosis, part of the workup is looking at the presence of mutations, including driver mutations and non-driver mutations. The classic driver mutations are JAK2 V617F, MPL, and calreticulin mutation. These are usually mutually exclusive, so when a patient has one, they typically don't have the other. They are often used to classify patients or subclassify patients. So, patients will be called JAK2 V617F-positive primary myelofibrosis or calreticulin-mutated myelofibrosis.

And essentially for the patient, they often don't mean all that much. However, if you look at studies where they compare outcomes, for example, in patients with these… That are in different mutational subgroups, there are some distinctions that are noticed. So, for example, patients with JAK2 V617F mutation tend to have better hemoglobins, but usually bigger spleens, and often have a clinical course that is comparable to patients with MPL, but perhaps not as good as patients with a calreticulin mutation, which is often dubbed a “favorable mutation” because their survival outcomes appear to be better. These patients are typified by lower hemoglobins, but often higher platelet counts.

What Does it Mean if a Patient Is Triple-Negative?

And then there's a category called the triple-negative. These are patients that lack a JAK2 mutation, a calreticulin mutation, and MPL mutation. And these patients tend to have a more aggressive course with a shorter survival and are considered an unmet need. So, in all, clonal mutations are part of the workup, the diagnostic criteria of myelofibrosis, but also have some prognostic implication. But they are not yet targetable. Meaning despite having a lot of information about these mutations and how they contribute to the disease – because they all, at the end of the day, contribute to one unified theme, which is hyperactivity of a signaling system within the blood cells called the JAK-STAT signaling system – they don't represent targetable lesions yet. Meaning we don't have drugs that specifically target JAK2 mutation, or calreticulin mutation, or MPL mutation. And for example, JAK inhibitors can be used across these mutations. They don't preclude patients from use of this class of agents.

So, there's still a lot to be learned. And what I'm not going to talk about is the complexity of subclonal mutations. These are mutations outside of the driver mutations like TET2 mutations or ASXL1 mutations. And some of these mutations also have prognostic significance but don't yet influence treatment decisions directly.

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