Expert Perspective on Treatment of Polycythemia Vera - Episode 11

Primary Myelofibrosis Disease State


Daniel J. DeAngelo, MD, PhD: Myelofibrosis is a member of the chronic myeloproliferative neoplasia, which also includes polycythemia vera, essential thrombocythemia, and chronic myeloid leukemia. There are other members of this class, but these are the 4 classic types. Patients who present with splenomegaly and anemia—specifically, with what we call a left-shifted, or leucoerythroblastic peripheral blood smear—should all be considered for myelofibrosis. A good review of the peripheral blood smear is warranted.

And then, these patients, in order to make a diagnosis, will need a bone marrow examination to show that there’s underlying fibrosis. An increased reticulin stain will help confirm the diagnosis. It’s important to exclude chronic myeloid leukemia in the various stages of the disease, and it’s also important to understand what the initiator of that is. A large percentage, about a third, will have a JAK2 mutation. Others will have MPL or calreticulin mutations. And there’s yet another subset, a rarer subset, which we refer to as triple-negative myelofibrosis. So, all of this needs to be incorporated in terms of the diagnosis of a patient with chronic myeloproliferative disease—specifically, chronic myelofibrosis—and differentiated from the other members of the family or from other diseases.

For patients with polycythemia vera and, especially, thrombocythemia, it’s important to differentiate patients with a central thrombocythemia from prefibrotic myelofibrosis. And here, we utilize the WHO reticulin stain grade of 0 to 3, where 0 means there’s no increase in reticulin fibers and that a patient would fit nicely into a central thrombocythemia, but a patient with a slight increase of reticulin fibers—or WHO grade 1 for a reticulin stain—has prethrombotic fibrosis. There is a worse outcome in terms of this patient, in terms of prognosis, and a higher percentage of those patients with a central thrombocythemia transforming into patients with frank myelofibrosis. In order to make the diagnosis of primary myelofibrosis or even secondary myelofibrosis, you need to have a higher WHO grade reticulin stain—typically, 2 or 3—to confirm the diagnosis.

The prognosis for primary myelofibrosis has evolved over the last few years as genetic profiling has become more available to many of us. Not just in academic centers but also for community physicians, it has become important to classify patients, not just on the driver mutations—of which there are 3: JAK2, MPL, and calreticulin—but also for additional mutations that are present. Many of these additional mutations can affect the overall prognosis in a negative fashion, and it’s important to use that in terms of classifying your patient, number 1. And number 2, as you follow patients over time, acquisitions of new mutations—specifically, mutations within the epigenetic pathway—are harbingers of disease progression. And so, these are very important factors that can be utilized not only in the academic setting but also by the community physician, in terms of accurately determining the prognosis of your patient.

Risk assessment for primary myelofibrosis is based on the patient’s karyotype, and it’s difficult to get a karyotype for many patients, because most patients—or at least many patients—will have a dry aspirate. But, if you’re able to get an aspirate, the karyotypic abnormalities within the metaphases can be very important in terms of determining those patients who have a better or worse prognosis. And what I mean by prognosis is their risk of transformation to acute myeloid leukemia. So, regarding patients with complex karyotypes—chromosome 3, chromosome 7—these are typically those mutations we see in high-risk leukemia. Not surprisingly, if they occur in patients with myelofibrosis, they tend to portend a very poor prognosis and a higher risk of leukemic transformation. In addition, the additional epigenetic modifiers—ASXL1, to name one; and many exist—also predict a higher risk of progression, specifically to acute myeloid leukemia, and, as a result, lower overall survival.

In terms of classifying a patient’s prognosis based on how they present to you clinically, when they’re in your office without a marrow exam, at the initial time, the IWG-MRT (International Working Group for Myelofibrosis Research and Treatment) criteria are a very useful prognostic scoring system. But most of us, to be honest, use the DIPSS (Dynamic International Prognostic Scoring System) score, which is a scoring system that can be used with time because it’s been validated to be used chronologically, throughout the patient’s therapy. And this incorporates the patient’s age, white blood cell count, peripheral blast count, anemia, and presence or absence of constitutional symptoms into an objective score.

Based on this scoring system, you can stratify patients who have low-risk disease with a natural history or overall survival of 200 months, which is 10 or 15 years. So, you try to leave those patients alone versus the patients who have a high-risk score, where their overall survival is measured by a year or so. Those are patients who, if they’re young, should be sent for a transplant consultation; and if they’re old, you really need to initiate some type of therapy for their myelofibrosis. And then, there are the 2 groups in the middle. But when a patient walks into my office, I typically will calculate their DIPSS score, and I will wait for the marrow examination before I can augment that DIPSS score with the karyotype and the rest of the mutational panel to really help me help the patient accurately prognosticate their outcome.

Transcript Edited for Clarity