Diagnosis of Myelofibrosis

Moshe Talpaz, MD: Myelofibrosis is characterized first by typical features. I would say generally the patient with myelofibrosis is a sick patient because he has symptoms of weight loss, splenic pain, bone pain, night sweats, lack of energy, severe fatigue, and at times anemia. As far as laboratory findings, the typical findings of myelofibrosis are a typical blood picture of anemia, although not all patients have anemia, and the appearance of immature red and white cells in the blood, a phenomenon known as leukoerythroblastic reaction. Simply, it implies immature cells of the red series and of the white series showing up in the blood where normally they are not supposed to show up. The abnormal appearance of red cells in the blood is also part of the features of this disease.

This, taken together with an enlarged spleen and other symptoms, is fairly typical for the diagnosis of this condition. For a complete diagnosis, patients are required to have a bone marrow test—in other words, a bone marrow biopsy. Unlike polycythemia vera and essential thrombocythemia, the bone marrow typically shows the development of excessive fiber in the bone marrow, known as fibrosis. We tend to grade the fiber development by a scoring known as the myelofibrosis scoring. And although patients with essential thrombocythemia and polycythemia tend to have no fibrosis at all or, at the most, a stage known as MF-1, patients with myelofibrosis have more extensive fibrosis ranging from MF-2 to MF-3. Typically, it implies the development of reticular fibers in the bone marrow, and when the fibrosis is more advanced, reticular fiber is replaced by collagen fibers and, sometimes in the very advanced disease, even new bone formation.

There are typical molecular markers for the myeloproliferative neoplasia. Collectively for these 3 diseases—conditions that I repeat mentioning, essential thrombocythemia, polycythemia vera, myelofibrosis, and maybe we should also mention the prefibrotic myelofibrosis—there are very common mutations. The most common one is mutation in the JAK2 gene, a mutation known as V617F, and in some patients, it can be a mutation in exon 12 of the JAK2 gene. This particular mutation is extremely common in polycythemia vera and may be present in up to 98% of patients with polycythemia vera. Other mutations include an MPL mutation, and a seed mutation is a mutation in a gene known as calreticulin. In conditions such as essential thrombocythemia and myelofibrosis, the mutations of calreticulin and MPL are present, whereas they are very uncommon in polycythemia vera. So that allows a nice distinction as far as the mutation profile in the 3 conditions.

Additional mutations on top of this are founder mutations, and they are essentially mutually exclusive, which means that a patient who has a mutation in JAK2 is not going to have a mutation in MPL or in calreticulin. In addition to those mutations, when we do more extensive studies of DNA analysis, especially with what we call next-generation sequencing, we have identified repeat mutations in genes such as ASXL2 and so forth, which may have prognostic significance in the course of disease progression.

We stated that myelofibrosis is an uncommon disease. Actually, there are not even very accurate numbers of how many patients are diagnosed every year with this condition in the United States. It can be as few as 1500 and as many as 4000 to 5000. But the prevalence of patients alive with myelofibrosis represents a much higher number because the disease is chronic in nature and some people can live a long time with this disease. It’s very possible that some patients go undiagnosed with this condition, so it’s important to emphasize the characteristics of this disease and the fact that there is a very extensive differential diagnosis.

The presence of fiber in the bone marrow is…by itself not sufficient to call it myelofibrosis. Fiber in the bone marrow can be secondary to an inflammatory condition, can be secondary to other malignancies, can be secondary to leukemias, myelodysplastic syndrome, and so forth. So the diagnosis of myelofibrosis requires the molecular testing, the presence of splenomegaly, the abnormal blood features, and the abnormal clinical features in order to come up with the diagnosis. Granted, this is a relatively rare disease, and personally I prefer that this disease be managed in major centers. But because of availability of established treatment for this disease, it should be a basis for exchange between practicing physicians and academic centers.