Myelofibrosis: Diagnosis and Prognostic Risk Assessment


Comprehensive discussion highlighting diagnostic and molecular testing involved in the diagnosis of myelofibrosis, challenges related to early diagnosis, and consideration factors for assessing prognostic risk.


Aaron Gerds, MD: The diagnosis of myelofibrosis can sometimes be tricky. It’s on a spectrum of diseases with essential thrombocythemia. Within myelofibrosis, there are prefibrotic and overt fibrotic myelofibrosis categories. Key pieces of information that you need to make the diagnosis are blood counts, and you want to take a good history along with those blood counts, looking for things like fever, night sweats, weight loss, and splenomegaly to cue you into the diagnosis.

At the heart of the diagnosis of getting a good bone marrow biopsy, specifically the biopsy portion. Patients on biopsy are inaspirable, meaning you can’t suck out the bone marrow. You have to get the core to take a good look and make the diagnosis. Cytogenetics is also quite valuable in determining prognosis, but ultimately next-generation sequencing of the marrow sample is considered standard of care, for not only diagnosing and identifying a JAK-STAT driving mutation but also looking at other mutations that could help inform prognosis.

Pankit Vachhani, MD: There are several challenges to the diagnosis of myelofibrosis, particularly an early diagnosis. Let’s start with what happens when someone gets latched up. Sometimes we notice abnormal lab testing abnormal white blood cell count or hemoglobin or platelet levels. These get attributed to an alternative diagnosis or get ignored sometimes because they’re not severely abnormal.

For example, iron deficiency might be the reason for a slight or mild thrombocythemia, or anemia or white blood cell abnormalities may be attributed to autoimmune diseases. That could be a challenge. On the other hand, signs or symptoms could be attributed to alternative diagnoses as well. Fatigue, for example, could be from a vast area of comorbidities—sweats, flushing, or pleuritis could be attributed to medications or alternative conditions. Even splenomegaly doesn’t get identified on examination frequently. Sometimes it’s found only when imaging is performed for completely unrelated reasons. Even then, if the splenomegaly isn’t massive, sometimes it doesn’t get referred or investigated further, and a potential diagnosis of myelofibrosis may have been missed or delayed.

These items are related to lab abnormalities or examination findings, or signs and symptoms, but there are additional things that may delay diagnosis. For example, if 1 were to suspect a myeloproliferative neoplasm, and a physician checked for JAK2, and the JAK2 gene mutation was found to not be mutated, or at least a classic V617F mutation was not found, 1 may erroneously make the mistake of assuming that there’s no myeloproliferative neoplasm or myelofibrosis. However, 40% to 45% of patients with myelofibrosis have a CALR gene mutation or an MPL gene mutation or are negative for all 3 classic driver genes: JAK2, CALR, and MPL. It’s a very important point because even patients with myelofibrosis who have these other gene mutations—CALR, MPL, or none of the above—benefit from JAK inhibitors. It’s important to test with a broad, next-generation sequencing panel, which tests for all 3 driver gene mutations and beyond.

Beyond that, sometimes a bone marrow biopsy is performed. If a reticulin or collagen staining isn’t performed by a pathologist, a potential diagnosis of myelofibrosis may be missed. Sometimes, lack of fibrosis may be mistaken for no myelofibrosis. However, that may be a case of prefibrotic myelofibrosis. Sometimes, light dysplasia is thought to be related to myelodysplastic syndrome with fibrosis. An incorrect diagnosis may be rendered in cases where the diagnosis may have been myelofibrosis.

Naveen Pemmaraju, MD: Prognostication in myelofibrosis has evolved over time. The first prognostic scoring system, now a decade old was known as the IPSS, the International Prognostic Scoring System. It had 5 clinical factors: age, constitutional symptoms, white blood cell count, anemia, and circulating blast count. This was very nice. It was validated in over 1000 patients just prior to the JAK inhibitor era. It was designed to be done at diagnosis. You could prognosticate patients into 4 categories: low, intermediate 1, intermediate 2, and high risk. That’s valuable even today.

But over time, other factors have been incorporated. The next scoring system generation was dynamic. That’s called DIPSS [Dynamic International Prognostic Scoring System], or DIPS+, which added new factors, such as cytogenetics, thrombocytopenia, and transfusion dependency, and also elevated the anemia a bit more, recognizing the prognostic significance of anemia. Believe it or not, in our disease myelofibrosis area, further scoring systems have continued to refine these prognostic factors over time. We started out with IPSS, then DIPS, and now we have MIPS [Mutation-enhanced International Prognostic Scoring System] and MIPS-70+, but the M now stands for molecular. That’s trying to incorporate these new aspects that we’re all discussing.

If you have high-risk molecular mutations, bone marrow fibrosis, and old factors such as circulating blasts and anemia, you’re trying to put the whole package together—cytogenetics, molecular features for prognosticating patients. This is not only to determine the risk of transformation leukemia and overall survival but also to help you identify which patients to go for stem cell transplant.

Transcript edited for clarity.

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