Verstovsek Highlights Future Directions for MPN Treatments

In an interview with Targeted Oncology, Srdan Verstovsek, MD, discussed the current MPN treatment landscape and where the field is shifting.

For patients with myeloproliferative neoplasms (MPNs), JAK inhibition has become an important therapeutic approach for treatment. Particularly for patients with myelofibrosis (MF), JAK inhibitors have allowed for reduction in symptoms and better outcomes.

The first JAK inhibitor to make its debut in the MPN treatment landscape was ruxolitinib (Jakafi), followed by the FDA approval of fedratinib (Inrebic) in 2019. Since then, experts have continued to make advancements with novel therapeutic strategies.

With now over 10 ongoing phase 3 trials around the world, investigators are combining novel treatments with JAK inhibitors to develop new options to use when treating patients with MPNs, including polycythemia vera (PV), essential thrombocytopenia (ET), and myelofibrosis.

“We are looking first to see whether the combinations that are exploring enhancement of the control of the sign symptoms on top of JAK inhibitors will do that well, well enough to be approved and then considered in everyday practice. We are also looking in the near future to see whether any of these therapies can prolong life,” said Srdan Verstovsek, MD, in an interview with Targeted OncologyTM.

In the interview, Verstovsek, associate professor of medicine in the Leukemia department at the University of Texas MD Anderson Cancer Center, discussed the current MPN treatment landscape and where the field is shifting.

Targeted Oncology: Can you describe the current treatment landscape for essential thrombocytopenia?

Verstovsek: In essential thrombocythemia or ET, we worry about the thrombotic risk and our priority is to decrease it. We define the patients that are at an increased risk of blood clotting by applying certain prognostic factors. A significant change in the prognostication happened several years ago, which is now incorporated in United States based guidance, the NCCN guidelines. This is to say that in addition to historical factors of age over 60, or history of blood clotting, now, we also account for a presence or absence of a JAK2 mutation, which is present in about 60% of ET patients and it drives the disease process.

Therefore, there is a significant shift in identifying those that are at high risk of blood clotting by adding a JAK2 mutation presence to age. So, patients that are older than 60 and have a JAK2 mutation are the high-risk patients or of course, those that have a history of blood clotting. There is also an attempt to improve our management of these patients. Standard practice is to prescribe hydroxyurea, which is chemotherapy by mouth, to decrease the blood cell count. Then anagrelide is a second-line agent which inhibits the growth of the cells in the bone marrow that make platelets, so it lowers the platelets.

There is a phase 3 randomized study underway comparing anagrelide to a new agent that has the potential to be active in ET as it is in PV for which is already approved. I'm talking about ropeginterferon alfa-2b-njft [Besremi]. That study is a global randomized study comparing ropeginterferon to rusfertide, to prove the point that ropeginterferon might be better in controlling the platelets and the white cells that may be elevated sometimes in his patients. Hopefully, we are not going to have only to implement a prognostication and identification of the patients that need to be treated, otherwise, you just give them aspirin, but also more therapies to offer. Right now, it's hydrea. And for interferon if we can get it off label, this will be onlabel as a second-line choice in the near future if the study is successful.

What has recently been seen in the polycythemia vera and myelofibrosis spaces?

Where in essential thrombocythemia we worry about thrombotic risk, we phlebotomize the patients to decrease the hematocrit, which is a measure of the percent of blood made from red blood cells in polycythemia vera and we give patients aspirin to make a blood flow easier. In some patients older than 60 or those that have a history of blood clots, we give them cytoreductive therapy to decrease the red blood cells, white cells, and platelets. Again, we use hydroxyurea for ET. But now ropeginterferon was approved last November for PV. It is a long acting interferon and the guidance now says that one could consider 1 or the other meaning, hydrea or ropeginterferon as a frontline choice. Then in a second-line, we have standard practice drug ruxolitinib, a JAK inhibitor, which is actually approved for hydroxyurea-resistant, -refractory, or -intolerant patients.

In this setting, there is another drug that is being developed in a phase 3 randomized study for possible approval. It's called rusfertide. It's a hepcidin mimetic and hepcidin is an important protein in the blood that modulates the iron metabolism. That medication would mimic what it does and keep the iron inside the liver, for example, or spleen, or a lining of the [gastrointestinal] tract. That's called a radical endothelial system in the body. That would decrease the iron availability for the red blood cells and that would lead to elimination of the need for phlebotomy, which is very important, and people may feel better. At the moment, there is a phase 3 randomized placebo-controlled study in patients that need too many phlebotomies with a goal to approve rusfertide in the near future as another agent for these patients with PV.

Then, myelofibrosis is the most aggressive of MPNs with a shorter life expectancy. Here we have a plethora of different studies underway. The most important part is that in addition to ruxolitinib and fedratinib, this year, we have also pacritinib approved which is another JAK inhibitor and it can be given to patients with low platelets. Then, there is the recent application for possible approval of another JAK inhibitor called momelotinib, which is quite different from the others. It can improve anemia and eliminate the need for transfusions. The phase 3 randomized study of momelotinib vs danazol has completed and the results are good, and an application for approval is in place. By next summer, we may have momelotinib the fourth drug approved from myelofibrosis which will be perfect for patients who have suffered from anemia.

Can you further explain ruxolitinib and its mechanism of action?

Ruxolitinib inhibits JAK1 and JAK2, 2 of 4 members of JAK enzymes that are important in the body for function relative to blood making inflammation in the immune system. In particular, the JAK2 enzyme is associated with the growth factors and mechanisms of cell growth for red blood cells and platelets. JAK1 and JAK2 are also involved heavily in inflammation.Ruxolitinib will inhibit the proliferation and inflammation. People with myelofibrosis, for example, have a smaller spleen because of therapy, and that is why people feel much better, because it's anti-inflammatory. On the other hand, it can lower the platelets through myelosuppression and that's why we need to balance when we can give it. We like to give it as early as possible in the life of the patients and when the patients are not too sick. It's easier to give it, it is a good dose, and the results are much better with earlier intervention.


In polycythemia vera, ruxolitinib is valuable as a second-line choice when things don't go well with hydroxyurea. Patients then have much higher white blood cell counts, may have a big spleen, and of course, require phlebotomy. In that setting, it has been proven in 2 randomized studies that ruxolitinib provides a significant clinical benefit in normalizing blood cell count, improving quality of life, and decreasing spleen in those that have a big spleen. It appears after many years of follow-up that this is very durable, and possibly decreases the risk of early death from the complications of uncontrolled polycythemia vera. We use it often in the second-line setting, and it is a number 1 choice in PV.

What unmet needs still exist regarding MPNs?

In any of these three conditions, ET, PV, or myelofibrosis, we are talking about decreasing thrombotic risk, controlling the blood cell count, improving the quality of life, and decreasing the spleen. We don't really have drugs that would eliminate disease or make it controllable forever. More active drugs that will be much more durable and perhaps that can be achieved by combinations [are needed]. For example, in myelofibrosis, we're witnessing a flurry of phase 3 randomized studies where novel agents are combined with the JAK inhibitor ruxolitinib to make it even better and perhaps longer lasting in controlling signs and symptoms. I would like to see agents like interferon that have a potential that can lower, and perhaps eliminate malignant clones.

What are the future directions in this space?

We are looking first to see whether the combinations that are exploring enhancement of the control of the sign symptoms, on top of JAK inhibitors, will actually do that well or well enough to be approved and considered everyday practice. We are also looking in the very near future to see whether any of these therapies can prolong life. Overall survival is already in 1 study with a possible approval with the drug called imetelstat, which is a telomerase inhibitor, a primary goal. This is a phase 3 randomized study in a second-line setting.

Then to enhance that, perhaps not in a year but in 3-5 years, that effect of the potential targeted agents to bring about the molecular response, and that would mean possibly a complete response and partial response. We are at the beginning of the new phase in developing the drugs, not just to talk about improvement in the number or the size of the spleen or a blood cell count, but also to talk about affecting the malignant clone.