Mutations, Diagnosis, and Prognosis in Myelofibrosis

Transcript:Srdan Verstovsek, MD, PhD: Myelofibrosis is a disease of the bone marrow, where there is a reaction to the presence of malignant cells by developing fibers. Therefore, the bone marrow biopsy is a cornerstone of the diagnostic process for myelofibrosis. However, you cannot really diagnose myelofibrosis only based on a bone marrow biopsy. In fact, there is no one test that will diagnose myelofibrosis; there are criteria that need to be fulfilled. This includes looking at the blood cell count, presence of anemia, presence of leukoerythroblastic reaction—meaning blasts, metamyelocytes, and promyelocytes—bone marrow cells in blood, presence of systemic symptoms, and presence of increase in lactate dehydrogenase. So, one would need to have a complex knowledge about the bone marrow, clinical presentation, enlargement of the spleen, chemistry, and a blood cell count to know whether the patient has myelofibrosis. This is a task that a clinician needs to undertake: putting things together and having a final diagnosis of myelofibrosis.

Furthermore, just the presence of fibers in the bone marrow is now known not to be mandatory for presence of myelofibrosis as a disease. In a new edition of the WHO classification of the myeloproliferative neoplasms, published in April of this year, we have witnessed the vision of a myelofibrosis diagnostic presence in two parts: more aggressive advanced disease with lots of fibers in the bone marrow—high-grade fibrosis—and the earlier-stage myelofibrosis with hardly any fibers in the bone marrow, but with the presence of all these other factors. So, our ways of making diagnosis of myelofibrosis is evolving. As we learn about the genetic complexity, we also learn about different aspects of other parts of the disease; fibrosis grade, in particular.

Daniel J. DeAngelo, MD, PhD: Myelofibrosis is a chronic disorder, and there are patients who will develop or transform into acute myeloid leukemia. Interestingly, the International Working Group looked at several prognostic factors and looked at outcomes, specifically death. About 15% of those patients who had a known identifiable death died of transformation to acute leukemia. Now, there are those patients where death was unclassified or just wasn’t known. But of the patients who had a known cause of death, about 15% of those were due to acute leukemia. The rest were due to a myriad of problems, including infection, bleeding risk, and complications from their own disease. Remember, these patients are often older patients. So, they die of things that older patients die of: coronary vessel disease, cerebrovascular disease. It’s a multitude of issues. Acute leukemia is the big problem. Because once acute leukemia develops in patients with a history of chronic myeloproliferative diseases, including myelofibrosis, current treatment strategies are really ineffective. So, it’s a multitude of issues: 15% or so about acute leukemia and the rest including infection, bleeding, and then other problems associated with age.

Srdan Verstovsek, MD, PhD: The watershed for our understanding of the biology of the disease, talking about myelofibrosis and for development of a new therapy, was a discovery of a mutation called JAK2 V617F in 2005. At that point in time, that was the new completely novel discovery of a first-ever genetic mutation in myeloproliferative neoplasms that led to a development of JAK inhibitors, further looking into what is the consequence of that mutation and if there are any others. And, yes, there are many others. To start with the biology part, there is a calreticulin and a MPL mutation. These are two other mutations that, along with the JAK2 mutation, leads to activation of the JAK/STAT pathway. That is the underlying biological problem in myelofibrosis. And since then, there are many other mutations that have nothing to do with the JAK/STAT pathway that have been discovered in patients with myelofibrosis. I’m talking about 25, 30 mutations; the number keeps enlarging. These other mutations, like in epigenetic control and other aspects of the biology of the disease, are present in addition to the three driver mutations: the JAK2, MPL, and calreticulin mutations.

The presence of these other mutations can influence the outcome of the patients. In addition to prognostication of the patients based on the traditional factors like age, symptoms, and blood cell count, it can certainly ask the question of whether one or the other of the driver mutation, or one or the other of a number of the additional mutations, matter for the outcome of the patients. For example, if we analyze patient’s outcome based on the presence of calreticulin versus MPL versus JAK2 mutation, or having none of the three, we now know that patients with calreticulin mutations have better outcomes than patients with triple-negative disease. And the JAK2 and MPL mutations presence is in the middle for the outcome. However, the additional 25 or 30 other mutations, if they’re present, they can also influence the outcome of the patients. The number of them, or the type of them, can identify patients at the high risk of progression, or even transformation, to myeloid leukemia. It’s becoming very complicated.

Transcript Edited for Clarity