Targeting JAK2 in Myeloproliferative Neoplasms - Episode 4

Disease Progression in MPN

The progression of disease in MPNs and how genetic testing may inform therapy.

Srdan Verstovsek, MD: One needs to appreciate that this is a process that takes time. It is not that [transformation to acute myeloid leukemia] happens overnight. There is a need for fulfillment of certain diagnostic criteria for transformation. For transformation to acute myeloid leukemia [AML], it is relatively simple; one must have 20% myeloblasts. For progression from ET [essential thrombocythemia] or PV [polycythemia vera] to myelofibrosis [MF], it is not that simple at all; 20% of patients with PV already have a high degree of fibrosis at the beginning of the journey.

I think that is really confusing for the practicing doctors, because they do bone marrow biopsies, and there are some fibers and they say, “You have myelofibrosis,” but nothing else is really changing. How do you go about that when advising doctors? I have to call the doctors and explain, “Look, the fibers are fibers, but that doesn’t mean a different disease entity.”

Andrew Kuykendall, MD: I think there are a couple points to make here. First, it is one of the reasons we stress getting a baseline bone marrow biopsy for patients with polycythemia vera and ET because you can see, even in the early stages of the disease, that fibrosis may be there in a moderate or marked fashion right from the diagnosis, but the phenotype looks exactly like polycythemia vera.

The fibrosis is critical to the diagnosis of post-ET and post-PV MF, but it is not the end-all be-all. There certainly have to be other disease-related features that have to be associated with it. When you have that baseline, and you can see that over time nothing has really changed, and the numbers look the same, it is pretty clear that the disease itself has not changed. But myelofibrosis really represents the deterioration of functional hematopoiesis, right?

You are often seeing progressive anemia. You are seeing immature blood cells being spit out. You are seeing progressive splenomegaly. In the setting of ET, you are seeing an increased LDH [lactate dehydrogenase], constitutional symptoms are worsening. This usually is not a very mild transition—although it can occur over a year, so it seems more mild—but you are really seeing a change in the disease from a proliferative disease to a disease that is becoming more dysfunctional.

Srdan Verstovsek, MD: After all, one needs to reassure the patient that the risk of progression is low. People read about it; patients read about it and say, “Oh my God, I am going to transform from having PV to myelofibrosis.” And the fear here is of having a short life expectancy, 5 to 7 years for patients with myelofibrosis and maybe 15 or more years or so for patients with PV.

The risk is not extraordinary high. Of course, there is a risk, 20% to 25% of patients transform from PV to myelofibrosis, but the odds are, at the time of the diagnosis, that is not going to happen. There are even fewer patients with ET who transform to having myelofibrosis. I think understanding of that transition is crucial. The diagnostic criteria are there; it is not just about the fibers, but anemia, big spleen, and high LDH, like you said, but after all, it is not that common. The clarification is needed for everyday practice that that is a possibility, but it is not that common.

Andrew Kuykendall, MD: Yes, as you said, most patients will not transform, so I think that that needs to be stressed.

Srdan Verstovsek, MD: The same applies to transformation from myelofibrosis to acute myeloid leukemia. Again, 25% is not everybody. Of course, if they do transform to having AML, that is usually detrimental; there is a short-life expectancy, but it is myelofibrosis for most of them for the rest of their lives.

Andrew Kuykendall, MD: When I look at the transformation to AML, I look at it a little differently than the transformation to myelofibrosis. With the transformation to myelofibrosis, overwhelming inflammation over years can predict or influence that and lead to an inhospitable bone marrow environment. But with transformation to AML, often what we are seeing is new genetic lesions that are occurring. It is really the disease acquiring new mutations or new abnormalities that are driving that process and not so much the end result of a process.

Srdan Verstovsek, MD: Yes, you make a very good distinction between them because the fibrotic transformation is much slower, and it is not easy to explain why it does happen in some patients and not in others. You are right, there are not too many mutations that people acquire. There are some abnormalities in chromosomes, but the percentage is very low, even within those that transform.

That is one aspect that we are not analyzing or understanding much at all: the fibrotic transformation. We are focused on what is critical for a patient’s outcome. That is AML. AML is deadly, and people who have it live for a short time, usually less than a year. The mechanism is clonal evolution most of the time, abnormalities in chromosomes or genetic abnormalities. This is a good question for us. Should we test our patients with myelofibrosis, for example, periodically for new genetic or karyotypic abnormalities to predict or prevent certain conditions or introduce new therapies in those that show the clonal evolution? That would be, I think, enhancing the practical approach to therapy, if we get that information ahead of the clinical progression.

Andrew Kuykendall, MD: Yes, we often will check for these genetic abnormalities early in the diagnostic work-up, but when to test for them after that isunclear. Certainly, if there are changes in the blood counts that can’t be explained, you will often do another bone marrow test and check for it.

Hopefully we will increasingly have therapies emerge that are targeted to some of these genetic abnormalities that we can utilize earlier rather than later. Right now, the few therapies we do have that target these are used in the later stages of treatment of the disease as a salvage effort.

Transcript edited for clarity.