Challenges Remain in MPN Diagnosis and Drug Development

Andrew T. Kuykendall, MD

Drug development in myeloproliferative neoplasms (MPNs), specifically polycythemia vera (PV) and myelofibrosis, have both remained similar to their diagnosis: difficult, explained Andrew T. Kuykendall, MD.

Regarding therapeutic advances, the FDA approved ruxolitinib (Jakafi) for the treatment of patients with myelofibrosis and polycythemia vera in 2011 and 2014, respectively. However, researchers are diligently working to bring more novel agents to the field.

The JAK2/FLT3 inhibitor pacritinib, though put on a clinical hold in 2016, is back on trial. The agent is being tested in patients with primary or secondary myelofibrosis who did not benefit from ruxolitinib or were not eligible to receive the agent in the ongoing PAC203 study (NCT03165734). Though momelotinib has been explored, it has demonstrated mixed findings in clinical trials, Kuykendall explained.

“Trying to get additional agents on board especially for different phenotypes of [myelofibrosis] is where I see the field going,” said Kuykendall, an assistant member of Moffitt Cancer Center. “In PV, we need to make some strides in understanding how to better treat the disease overall. We also have to understand what it means when we decrease the JAK2-mutant allele burden.”

OncLive^®: How do these neoplasms typically present?

In an interview during the 2018 OncLive^® State of the Science Summit^TM on Hematologic Malignancies, Kuykendall discussed the presentation of these neoplasms, novel agents in development, and the overall outlook of these diseases.Kuykendall: The first challenge with diagnosing PV is ruling out primary PV from other causes that lead to erythrocytosis. The JAK mutation has been extremely helpful because it identifies patients who have this disease. The new World Health Organization criteria has relaxed the hemoglobin thresholds that we used to have, so that has allowed us to capture an increased volume of patients who otherwise weren't meeting the criteria.

The challenge has become how to differentiate PV from some of the other related MPNs. We typically like to do bone marrow biopsies. Those aren't always mandated but are in the vast majority of cases. They can be extremely helpful in differentiating PV from other related diseases that can present very similarly.

How have novel agents impacted the field?

Myelofibrosis is a more difficult challenge. Myelofibrosis is largely diagnosed off the bone marrow biopsy. It can present in any number of ways with thrombocytosis, erythrocytosis, or leukocytosis. It can present with cytopenias and relatively normal blood counts, but a lot of symptoms and splenomegaly. It's different for every patient, and so we normally go based on the bone marrow morphology. Next-generation sequencing has helped us to some degree to identify driver mutations in addition to cooperating mutations that we know occur more often in these diseases.Ruxolitinib has had a huge impact across the MPN field. It's an intelligently designed drug that acts on the JAK-STAT pathway, which we know is hyperactive in all of these conditions. In myelofibrosis, it has probably made the biggest change in how we approach the disease. It’s allowed patients who are incredibly symptomatic to be resolved of their symptoms and go back to feeling normal. This wasn't previously possible. We're still trying to understand how much it's revolutionized the landscape as far as how it's improving transplant outcomes, why we're seeing survival benefits, etc.

Are there ongoing trials with other JAK2 inhibitors?

What about pacritinib?

Does momelotinib have a role in this field?

What changes do you hope to see in the landscape?

In PV, it has really added to the field if not changed the landscape. It's viewed as a great option as a second-line therapy after hydroxyurea intolerance or failure. It's made us more aware of the symptoms that patients have. That's been something that we've pushed to the side in our effort to prevent thrombotic events. Ruxolitinib has really shown us that these patients are symptomatic, and we can help with that. These are the things that make patients appreciate the treatments we give them. They're not as aware as us preventing thrombotic potential, but they know if they feel better on a day-to-day basis.A lot of JAK2 inhibitors have come out and been tested. To my knowledge, there is about 6 that have been tested, at least through phase I trials; 3 have made it through phase III trials. All of them seem to have something that has held them back in some way, shape, or form. I don't know if any of them are truly out of the picture. There's still some life in different phases for them. We're still waiting [to find out] what our next JAK inhibitor is going to be. What do we do for these patients who either don't tolerate ruxolitinib or lose their response?Pacritinib has a complicated history. We were part of the initial work with pacritinib in the phase II studies. It made it to phase III but was put on a clinical hold for some concerns with bleeding and other cardiovascular issues. Part of this may have been due to the fact that it enrolled a pretty high-risk patient population, since it works in a thrombocytopenic population. The clinical hold was since lifted, and it's back in phase II trials. It potentially has a way forward. Certainly, a lot of people in the field see a rational use for it and see a patient population that would benefit, but it's all about getting it there.People were very excited about using this JAK inhibitor in patients with anemia. It [was hoped to have] potential improvements in hemoglobin counts, whereby ruxolitinib typically causes a transient decrease in hemoglobin. Unfortunately, in its pivotal trial, it didn't meet either of its endpoints, so it's unclear what its future is.There's a lot we can improve upon. Myelofibrosis is a disease in which we have 1 FDA-approved therapy. That's pretty poor; we would like to expand upon that. Additionally, we're talking about an FDA-approved therapy that treats a subset of the disease—not all [patients with it]. It treats patients who have symptomatic splenomegaly or significant symptom burden. It doesn't modify the underlying disease that we know of, it doesn't treat patients with cytopenias, and it doesn't do much for the accelerated phase of the disease. There's definitely strides to make, as far as that goes.

In PV, the risk categories we use are a little bit rigid as far as using age and prior thrombotic history as determining high and low risk. We can do better than that. We need to understand interferon a little bit better and see if we can give it in a more tolerable fashion. It's always been limited by its toxicity, but better formulations are coming to the forefront. We'll see where that takes the disease.

Additionally, does decreasing the JAK2-mutant allele burden mean anything? We're not getting rid of it entirely. We're not seeing complete molecular responses like we see in chronic myeloid leukemia, so does it matter? It's certainly encouraging, but I don't know if it actually makes a difference clinically.