In an interview with Targeted Oncology, Srdan Verstovsek, MD, spoke about the current MPN treatment landscape and where the field is shifting.
JAK inhibition has become an important therapeutic approach for patients with myeloproliferative neoplasias (MPNs). In particular, in patients with myelofibrosis (MF), JAK inhibitors have enabled a reduction in symptoms and better outcomes.
The first JAK inhibitor to make its debut in the MPN treatment landscape was ruxolitinib (Jakafi), followed by FDA approval of fedratinib (Inrebic) in 2019. Since then, experts have made further advances with novel therapeutic strategies.
With now over 10 ongoing Phase 3 trials around the world, researchers are combining novel treatments with JAK inhibitors to develop new options for use in treating patients with MPN, including polycythemia vera (PV), essential thrombocytopenia (ET ) and myelofibrosis.
“We are first looking at whether the combinations investigating improvement in sign symptom control in addition to JAK inhibitors are doing it well, well enough to be approved and then considered in daily practice. We are also exploring whether any of these therapies can prolong life in the near future,” said Srdan Verstovsek, MD, in an interview with Targeted OncologyTM.
In the interview, Verstovsek, Associate Professor of Medicine in the Leukemia Division at the University of Texas MD Anderson Cancer Center, spoke about the current MPN treatment landscape and where the field is shifting.
Targeted Oncology: Can you describe the current treatment landscape for essential thrombocytopenia?
Verstovskek: With essential thrombocythemia or ET, we are concerned about the risk of thrombosis and our priority is to reduce it. We define the patients who are at increased risk of blood clotting by applying certain prognostic factors. A few years ago there was a significant change in prognosis, which has now been incorporated into US guidelines, the NCCN guidelines. This means that in addition to the historical factors of age over 60 or history of blood clotting, we now also consider the presence or absence of a JAK2 Mutation present in about 60% of ET patients that drives the disease process.
Therefore, there is a significant shift in identifying people who are at high risk of blood clotting by adding a JAK2 mutation presence with age. So, patients older than 60 and a JAK2 Mutation are the high risk patients or of course those who have a history of blood clots. There is also an attempt to improve our management of these patients. Standard practice is to prescribe hydroxyurea, an oral chemotherapy regimen to reduce blood cell counts. Then anagrelide is a drug of second choice, which inhibits the growth of blood platelet-forming cells in the bone marrow, i.e. reduces the blood platelet count.
A phase 3 randomized trial is currently underway comparing anagrelide to a new drug that has the potential to be as active in ET as in PV that has already been approved. I’m talking about ropeginterferon alfa-2b-njft [Besremi]. This study is a global randomized trial comparing ropeginterferon with rusfertide to show that ropeginterferon may be better at controlling platelets and white blood cells, which can sometimes be elevated in its patients. Hopefully, not only do we have to do prognosis and identify patients to treat, otherwise just give them aspirin, but also offer more therapies. For now it’s Hydrea. And for interferon, if we can get it off-label, it will be on-label as a second-line choice in the near future if the trial is successful.
What has been observed recently in the areas of polycythemia vera and myelofibrosis?
Where we are concerned about the risk of thrombosis in essential thrombocythemia, we bleed the patient to lower the hematocrit, which is a measure of the percentage of blood made up of red blood cells in polycythemia vera, and we give the patient aspirin to lower the to facilitate blood flow. Some people who are older than 60 years or who have a history of blood clots are given cytoreductive therapy to reduce the number of red blood cells, white blood cells, and platelets. Again, we use hydroxyurea for ET. But now ropeginterferon was approved for PV last November. It’s a long-acting interferon and the instructions now say you might consider one meaning or the other, hydrea or ropeginterferon, as your first choice. Then, secondarily, we have the standard-of-care drug ruxolitinib, a JAK inhibitor that’s actually approved for hydroxyurea-resistant, refractory, or intolerant patients.
Against this background, there is another drug that is being developed in a randomized phase 3 study for possible approval. It’s called the Russet tide. It is a hepcidin mimetic and hepcidin is an important protein in the blood that modulates iron metabolism. This drug would mimic what it does and keep the iron in, for example, the liver or spleen or a lining of the liver [gastrointestinal] tract. This is called a radical endothelial system in the body. That would decrease the availability of iron to the red blood cells and eliminate the need for phlebotomy, which is very important, and people could feel better. A randomized, placebo-controlled phase 3 study is ongoing in patients who require too many phlebotomies with the aim of approving Rusfertide as an additional agent for these patients with PV in the near future.
Then myelofibrosis is the most aggressive MPN with a shorter life expectancy. Here we have a plethora of different studies underway. Most importantly, this year, in addition to ruxolitinib and fedratinib, we also approved pacritinib, another JAK inhibitor that can be given to patients with low platelet counts. Then there’s the recent filing for a possible approval of another JAK inhibitor called mometinib, which is very different from the others. It can improve anemia and eliminate the need for transfusions. The randomized phase 3 study of mometinib vs. danazol has been completed with good results and an application for approval is pending. By next summer we may have momelotinib, the fourth approved drug for myelofibrosis, which will be perfect for patients who have suffered from anemia.
Can you elaborate on ruxolitinib and its mechanism of action?
Ruxolitinib inhibits JAK1 and JAK2, 2 of 4 members of the JAK enzymes that are important in the body for function related to blood-forming 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 heavily involved in inflammation. Ruxolitinib inhibits proliferation and inflammation. For example, people with myelofibrosis have a smaller spleen as a result of the therapy and therefore people feel much better because it is anti-inflammatory. On the other hand, it can lower platelets through myelosuppression and so we need to balance when we can give it. We like to give it as early as possible in patients’ lives and when the patients are not too ill. It’s easier to administer, it’s a good dose, and the results are much better with earlier intervention.
In polycythemia vera, ruxolitinib is valuable as a second-line therapy when hydroxyurea is not going well. Patients then have a much higher white blood cell count, may have a large spleen, and of course need a phlebotomy. In this regard, it was demonstrated in 2 randomized studies that ruxolitinib provides a significant clinical benefit in normalizing blood cell count, improving quality of life and reducing spleen in patients with large spleen. After many years of follow-up, this appears to be very permanent and potentially reduce the risk of early death from the complications of uncontrolled polycythemia vera. We often use it in the second line setting and it is the first choice in Primary.
What are the unmet needs related to MPNs?
In each of these three conditions, ET, PV or myelofibrosis, we are talking about reducing the risk of thrombosis, controlling blood cell counts, improving quality of life and reducing spleen. We don’t really have drugs that would eliminate disease or make it controllable forever. More effective drugs that are much more durable and can perhaps be achieved through combinations [are needed]. For example, in myelofibrosis, we’re seeing a spate of randomized phase 3 trials combining novel agents with the JAK inhibitor ruxolitinib to make it even better, and perhaps longer lasting, at controlling signs and symptoms. I would like to see drugs like interferon that have the potential to reduce and maybe even eliminate bad clones.
What are the future directions in this area?
We first look at whether the combinations investigating improvement in sign symptom control, in addition to JAK inhibitors, actually do it well or well enough to be approved and considered daily practice. We are also investigating whether one of these therapies can prolong life in the near future. Overall survival is already a primary goal in 1 potential approval trial of a drug called Imetelstat, which is a telomerase inhibitor. This is a randomized phase 3 study in a second-line setting.
Then, maybe not in a year, but in 3-5 years, to amplify that effect of the potential targeted agents to evoke the molecular response, and that would possibly mean a full response and a partial response. We are at the beginning of the new phase of drug development, not only to talk about improving the number or size of the spleen or the number of blood cells, but also to influence the malicious clone.