Overview on Myelofibrosis: Diagnosis, Staging, and Molecular Testing


Expert hematologist-oncologist Naveen Pemmaraju, MD, highlights current strategies in diagnosing and stratifying patients with myelofibrosis.


Naveen Pemmaraju, MD: Hi, everyone. I’m Dr Naveen Pemmaraju, associate professor of leukemia at the [University of Texas] MD Anderson Cancer Center in Houston, Texas, and it’s my great honor and pleasure to be here with you for this educational program about navitoclax, a novel agent in MPNs [myeloproliferative neoplasms], myelofibrosis [MF], leukemias, and beyond.

The diagnosis for a patient with myelofibrosis, which is one of the 3 major MPNs, or myeloproliferative neoplasms, so in the same family as polycythemia vera [PV] and essential thrombocytosis [ET], the diagnosis is a complex one. It does require an expert team, including a pathologist, who helps to make the diagnosis at the level of the bone marrow, and a hematologist-oncologist, who can help to formulate a treatment plan. When we diagnose a patient with myelofibrosis, there has to be a staging process, as is common in many other tumor types. One of the most common ways to do that is to use one of the international prognostic scoring systems. There are many of them available now. The one that was created first and is used most frequently is the IPSS [International Prognostic Scoring System], which is usually used at diagnosis. In general, it helps to divide patients into 4 groups: low-risk MF, intermediate 1 and 2 MF, and then of course, high-risk MF, or myelofibrosis. Over time, we’ve been able to refine these scoring systems, there are the dynamic, molecular, and genomic scoring systems. They continue to come as we understand more about the disease biology, cytogenetics, molecular findings, platelets, anemia, and transfusion needs. All of these are incorporated.

In general, no matter what the scoring system, we’re trying to divide patients who are maybe ultra-low risk, who only may need observation, versus intermediate- to high-risk patients, who may need either JAK inhibitors, combination therapies on clinical trials, stem cell transplants, or other approaches. I think the other comment for myelofibrosis is that one way to look at it is it can either happen on its own, so from scratch, de novo myelofibrosis or primary, or importantly and interestingly, a patient can develop MF out of, or arising from essential thrombocytosis or polycythemia vera. That’s called post-ET MF, or post-PV MF. I think that’s also an important factor to know, that sometimes MPNs can transform into other MPNs.

Once a diagnosis of myelofibrosis is made and one of the traditional clinical scoring systems is applied to determine low, versus intermediate, versus high risk, very importantly in the diagnostic process is that the majority of our patients, probably 90% or more, will have what’s called a driver mutation. The big 3 driver mutations are JAK2 mutation, most notably the JAK2 V617F, which is most of our patients, followed by CALR mutation, followed by MPL. These are the 3 big driver mutations, about 90% of our patients [have one]; that means 10% will be negative for these, and those patients have so-called triple-negative myelofibrosis. Deeper sequencing, which originally was done in the laboratory, and now is clinically available, and many of our groups, including my own, use it as standard of care, is a bit more advanced genomic or molecular screening. It can be any of the commercially available NGS, next-generation sequencing, panels. They range anywhere from 20-plus genes to 80 to 400 genes. There are a lot of other gene mutations that are present in patients’ myelofibrosis, and the more you check and the deeper you sequence, the more you find. Among those most common include ASXL1, others such as EZH2, IDH1/2, splicing factor mutations in some cases were transforming to more advanced disease, TP53, etc. So, there’s an alphabet soup, if you will, of genetic mutations.

But the point is, I think, 3-fold. One is that the majority of patients will have either a JAK2, CALR, or MPL as the so-called primary or driver mutation. Two is that about 10% of patients will be negative for all 3, and that is termed triple-negative disease. Then 3, as I’m mentioning here, many of our patients will either have a comutation, or in the triple-negative group, its own mutation, one of these other serious mutations. Some of them are called HMR, or high molecular risk, mutations. What’s the implication of that? There’s a 2-fold implication. One is, especially in the latest scoring systems that incorporate molecular mutations and genomics, you can deem a patient who would have been low or intermediate risk by a traditional clinical scoring system, with the incorporation of the new molecular data, they’re upstaged to intermediate- to higher-risk disease. I think that’s important for prognosis. Two, for treatment implications, this is still an active area of research, but in the clinic right now, it may impact the treatment decision planning in a number of ways. Maybe it takes a lower-risk patient who now is higher risk because of molecular mutation status, and you may consider that patient for stem cell transplant, or earlier stem cell transplant. Another example could be a patient has the presence of a molecular mutation, and there’s a clinical trial or targeted therapy trial approach for patients with that. Then you can go there, so on and so forth.

I think there’s a lot of rationale and reason, and I advocate, if it’s available and possible, to be checking these extended gene panels on all of our patients, especially with myelofibrosis, to help determine not only prognostic information, but maybe even helping with treatment decisions now and especially in the future as more information comes about.

Transcript edited for clarity.

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