Targeting JAK2 in Myeloproliferative Neoplasms - Episode 1

Defining Myeloproliferative Neoplasms

Experts discuss the differences between essential thrombocythemia [ET], polycythemia vera [PV], and myelofibrosis [MF] and refinement of diagnosis.

Srdan Verstovsek, MD: Hello and thank you for joining this Targeted Oncology™presentation titled, “Targeting JAK2 in Myeloproliferative Neoplasms.” The treatment of myeloproliferative neoplasms, such as polycythemia vera [PV], essential thrombocythemia [ET], and myelofibrosis [MF], has undergone a transformation over the last several years, driven by the approval of several targeted therapies. The availability of these therapies has allowed hematologist-oncologists treating these conditions to use a precision medicine approach that was previously out of reach. Our discussion today will focus on JAK2-directed therapies, their roles in treatment, and the key clinical trials guiding their use. We will also discuss some relevant data recently presented at ASCO [American Society of Clinical Oncology annual meeting].My name is Srdan Verstovsek. I am a professor of medicine in the leukemia department at the MD Anderson Cancer Center in Houston, Texas. Joining me today is my good friend and colleague, Dr Andrew Kuykendall, a hematologist-oncologist at the Moffitt Cancer Center in Tampa, Florida.

Andrew Kuykendall, MD:It is great to be here.

Srdan Verstovsek, MD: Thank you so much for joining me today, and thank you, everybody, for joining us together for this lively discussion. Let’s begin. Let’s first try to objectivize what we are talking about. We are going to talk about myeloproliferative neoplasms, or MPNs. We typically talk about ET, essential thrombocythemia; PV, polycythemia vera; or MF, myelofibrosis. How do they relate to each other, and what is the typical course of these conditions? Andrew, can you give us a brief summary? This is probably very well known, but let’s have this as an introduction to the topic.

Andrew Kuykendall, MD:Absolutely; we are talking about, for the most part, there are 3 classical myeloproliferative neoplasms, and those are ET, PV and myelofibrosis. I tend to look at these on a spectrum of disease, from ET at the lower end of the spectrum, up to myelofibrosis. They typically share pathogenesis as far as driver mutations go, and they both lead to upregulation of blood cell production in the bone marrow. They are related, but they are different. They tend to share driver mutations, these JAK2, MPL, and CALR mutations. With ET, we see more overproduction of platelets. The bone marrow looks more normal. We have megakaryocytes, which are platelet producing cells that are a little more overproduced, but everything looks relatively intact.

When we talk about polycythemia vera, we start to see more cell lines involved. Red blood cells are elevated. Sometimes, white blood cells and platelets are also elevated. With myelofibrosis, you get a more complex disease, with a little more atypia. We talk about weird looking megakaryocytes, more scar tissue in the bone marrow. It is a spectrum of disease, and with that we also see that ET can then become over time more like PV, or transform into myelofibrosis. Similarly, polycythemia vera can transform into myelofibrosis. They are interrelated, but there are different stages of the disease to some extent.

Srdan Verstovsek, MD:There are some interesting points here to make along the trajectory of the most benign ET to PV to myelofibrosis. There are cases that are not that easy to pin or diagnose properly, because for each condition there is a need for fulfillment of the diagnostic criteria, among which is the presence of the driver mutations, those that activate the JAK-STAT pathway, which is an underlying biological problem in all of them, including in the majority of the cases the JAK2 V617Fmutation.

There is overlap, as you say, so there are patients who have masked PV, for example. They present with high platelets. The red blood cell count may not be obviously high, but if you look carefully, they have hypercellularity of the bone marrow, low erythropoietin, and low iron. One needs to be careful in looking at factors other than just the cell lines. Or a prefibrotic early myelofibrosis; this is something that was carved out of ET, the megakaryocytes look different in the bone marrow. The outcome might be a little worse than ET, with a median survival of 15 years, but it is not a death sentence. We manage the prefibrotic myelofibrosis, typically, as we manage ET.

The refinement and the new developments have taken part in the realization of the disease entities and introduction of the new entities like prefibrotic myelofibrosis. It is not only in the development of the therapies; it is also in the diagnostic process and a separation of the disease entities for the therapeutic purposes practically.

Transcript edited for clarity.