Overview of Myeloproliferative Disorders

Srdan Verstovsek, MD, PhD

Today, ahead of the International Congress on Hematologic Malignancies, being held February 23–25 in Sunny Isles, Florida, we are discussing chronic myeloproliferative disorders with Srdan Verstovsek, MD, PhD, professor in the department of leukemia at the University of Texas MD Anderson Cancer Center in Houston. Dr. Verstovsek will provide an overview of the latest clinical developments in myeloproliferative disorders at the meeting.

 -Interviewed by Anna Azvolinsky 

Cancer Network: First, could you provide an overview of the different types of myeloproliferative disorders. Are these generally similar in their biologies?

Dr. Verstovsek: When we talk about myeloproliferative neoplasms (MPN), we talk about essential thrombocythemia (ET), polycythemia vera (PV), and myelofibrosis. These are inter-related Philadelphia chromosome-negative MPNs. And indeed, the biology of these three entities, ET, PV, and myelofibrosis is connected by the common underlying biological problem, which is hyperactivity of intracellular signaling pathway, the JAK/STAT pathway. In ET, PV, or myelofibrosis the pathway may be activated for different reasons. For example, in PV there are in many patients, mutations in the JAK2 gene, the V617F JAK2 mutation or JAK exon 12 mutations. In ET and myelofibrosis there are three mutations, usually exclusive of each other that activate the JAK/STAT pathway which are called JAK2 V617F and MPL mutation or calreticulin mutations. So biologically they are connected, but clinically they do really present in different ways. And therefore we have criteria to diagnose either PV or ET or myelofibrosis. There is no one single test to do that and as you know, clinical outcome is different and there are different therapies for these conditions. Knowing that patients who receive these therapies can evolve from one condition to another, it is not very common but it can happen, from ET to PV or from ET or PV to myelofibrosis.

Cancer Network: The diagnostic criteria for these myeloproliferative disorders, they were modified last year. Can you talk about what the major changes were?

Dr. Verstovsek: So, for ET, PV, and myelofibrosis, now we have, for sure, a need to do genetic testing. The recommendation to do genetic testing has been added for each of these three entities, as part of the diagnostic process, to test for the mutations that activate the JAK/STAT pathway. So these are the JAK2 mutations for PV or JAK2 mutations, calreticulin, and MPL mutations for ET and myelofibrosis. So, genetics are part of the diagnostic process but again, this is not the only factor. And the biggest change in how we make a diagnosis of one of the three MPNs is a change for PV. Here, traditionally, we always wonder about a need for very high red blood cell counting, it’s a disease that makes all of the cells grow, particularly red blood cells. And in that case, we would look at hematocrit or hemoglobin. But, what happened is that we realized some patients with PV do not present with extraordinary red blood counts so the level or grade of hemoglobin or hematocrit needed for diagnosis of PV has been lowered, by 2 g, for example, for hemoglobin, from 18.5 to 16.5. This is very important because patients with PV already present with iron deficiency which is very common in PV and that would cause lower red blood cell counts and therefore, they do not have those extraordinarily high red blood cell counts.

The other very important part of change for PV is addition of a requirement for a bone marrow biopsy; that is one of the mandatory tests. Of course, perhaps not in every single case, that this is needed. My take is that if you have very high red blood cell count, very low erythropoietin, which is the only preserved minor criteria for PV and you have a JAK2 mutation, which is number 3 on the major criteria, if you have all three of these factors, do you really need a bone marrow biopsy? Perhaps not, but the biopsy has been elevated to a major criteria to make sure that we think about it and in the cases where we are not sure of the diagnosis, that we do it to make sure we really have a PV case.

And then just briefly, there was also a change in the diagnostic process for myelofibrosis. We now have two types of myelofibrosis, prefibrotic myelofibrosis and overt myelofibrosis, meaning that there is an abundance of fibers in the bone marrow where in prefibrotic myelofibrosis there are not too many fibers at all. There are some questions on how to distinguish prefibrotic myelofibrosis from ET, and that is in hands of hematopathologist in many cases. This is an evolving field, we are evolving the diagnosis criteria as we learn about the biology of the disease more and more and every 8 years or so we see a change. This is not the last update, but we need the community to be aware that there are new findings that are applicable for the everyday management of these patients.

Cancer Network: What are some of the major approaches to treatment for these disorders?

Dr. Verstovsek: We have known since 2011 that for the most aggressive of these three conditions, of ET, PV, and myelofibrosis, myelofibrosis is the most aggressive because lifespan is affected, the quality of life is very bad; life expectancy is 5 to 7 years. For this condition, since 2011, we have approved one medication, ruxolitinib, a JAK/STAT pathway inhibitor, it inhibits this active intracellular signaling so it provides antiproliferative and anti-inflammatory signals and makes patients feel better. The spleen which is commonly enlarged in these people shrinks and people, on average, we know from data presented at the last American Society of Hematology (ASH) meeting, that when we have a very long follow-up of these patients in the study that led to approval of ruxolitinib, we now know that the median extension of life in patients with myelofibrosis is about 3 years. So no doubt about it, we can, by controlling signs and symptoms of the disease we can make people live longer, but there is no cure. So, there are many other studies that have been done recently for myelofibrosis and one that I want to highlight is for a medication called sotatercept, which appears to be very active for anemia in these patients and we will need to see whether in a larger study is real or not because we do need antianemia medications.

Now, in ET and PV, major other approaches that are very well-established are therapies with hydroxyurea or in some cases, with interferon, biological agents injected under the skin. In community clinical practice, hydroxyurea has been very popular. Most patients receive hydroxyurea, but now there were studies done and two studies were reported that were presented at the American Society of Hematology meeting in December, where hydroxyurea was compared with a long-acting interferon in the frontline setting in patients with PV and ET. This was done by the Myeloproliferative Neoplasm Consortium, data from a number of academic centers in the United States and Europe were combined together in an effort to compare one drug to the other and the interim analysis was presented at ASH showing that there was no difference in activity between the two drugs. There were some differences in the toxicity profile. As we know, long-acting interferon, a peginterferon called Pegasys was the one used, given under the skin once a week, still had some toxicity issues when compared to hydroxyurea.

However, the other phase III study from Europe paired a novel long-acting interferon, called ROG peginterferon, might come to the United States in the form of clinical studies. This was a frontline study comparing ROG peginterferon to hydroxyurea and again, there was no difference in efficacy; it was the same efficacy in terms of controlling red blood cell count. But there was a sense that peginterferon-which is given every 2 weeks-might be better in terms of the toxicity profile. We will see what happens in these studies as we follow these patients longer. There is an attempt in Europe to get ROG peginterferon approved for PV and certainly these studies are very important for everyday management of patients to give us a better sense of potential of interferon to be provided to our patients in a safer way and for a longer period of time because after all, there is a sense that these biological agents can actually manage the underlying biology and perhaps the disease to a greater extent in a fraction of patients.

Cancer Network: Thank you so much for joining us today, Dr. Verstovsek.

Dr. Verstovsek: It was a pleasure, thank you so much for the opportunity.