Expert Discusses Guidelines, Next Steps With MPNs

Brady L. Stein, MD

Updates to the NCCN guidelines on myeloproliferative neoplasms (MPNs) will drastically change how these diseases are managed, according to Brady L. Stein, MD.

“They were the only [malignancy] that had lacked representation from the NCCN, so we're really pleased that MPNs finally have guidelines,” said Stein. “That is the first and foremost important thing, is that we have practical management tips and these are, perhaps, largely based on consensus more so than evidence. [However], an evidence basis is starting to emerge for the management of these conditions.”

OncLive: Can you share insight on the updates to the NCCN guidelines that include MPNs?

In an interview during the 2017 OncLive^® State of the Science Summit^TM on Hematologic Malignancies, Stein, an associate professor of medicine at Feinberg School of Medicine at Northwestern University, discussed the differences between the types of MPNs, the NCCN guideline changes, and the important role of JAK inhibitors.Stein: What is most important is that these somewhat rare entities finally have guidelines. They finally have some guidance for decision making in the setting of a relatively rare illness that had been previously unrepresented. I focused on the 3 classical MPNs: essential thrombocythemia (ET), polycythemia vera (PV), and myelofibrosis.

In ET, there are a couple of important themes. First, with establishing a proper diagnosis, the differential diagnosis might include early myelofibrosis. We may not change management initially, but the long-term prognosis is very different between those 2 entities. It matters when we see young patients and we certainly see young patients who present with high platelet counts. [It] matters that we properly establish a diagnosis because this is meaningful in terms of the long-term expectations and prognosis.

The second part is learning how to use mutations in ET to guide management. There are 3 major mutations a patient with ET might have. The mutations certainly influence practical management; if a patient lacks a JAK2 mutation, they might not necessarily need aspirin. They might fit into a lower-risk category in terms of thrombosis risks, so they don’t always need cytoreductive therapies, such as hydroxyurea. There is a practical management that can come from knowing the mutation that your patient with ET has. In terms of novel therapies for ET, the clinical trial landscape is certainly more scarce compared with some of the other entities. We see less development in this area. There are certainly patients who need a second- or third-line therapy, but we don’t have many clinical trials yet to satisfy that patient population. There is certainly work to be done there.

The next is PV. What is different in the 2016 and 2017 range are the changing diagnostic criteria. The hemoglobin threshold has been lowered, so that we're not missing cases of PV. It’s important to make a proper diagnosis because there's a natural therapeutic [pattern] that will follow if we confirm the diagnosis of PV. Here we have guideline representation to help outline about the hematocrit target with phlebotomy, the use of aspirin, and which patients might be candidates for cytoreduction. It is so important. In terms of therapies for PV, hydroxyurea is widely used. It’s not necessarily used based on evidence; its use is based on experience and a lack of other good options.

There are other options that are currently being studied. One, of course, is pegylated interferon. There are important, randomized, phase III, high-quality studies comparing this class of medications to hydroxyurea. Having evidence to decide on first-line therapy is important for PV. Second-line therapies are well defined. With ruxolitinib (Jakafi)—there are data to use this as a second-line therapy in the small number of patients in whom hydroxyurea is inadequate. In terms of other agents, there are more agents in development for PV than there are certainly in ET and not as many in myelofibrosis. However, we are slowly changing to new developments and, hopefully, we will have approved drugs for the frontline setting. We already have an approved drug for the second-line setting.

Myelofibrosis…is the most challenging to manage because it is the rarest of the 3 [MPNs]. It’s 10 times less common than ET or PV in terms of its prevalence. It’s very hard to follow some of the nuanced management tactics. With treatment, we also have some guidance from NCCN. We have guidelines; they are in their second iteration and evolving. That is important.

We treat largely based on risk and symptoms. Lower-risk patients who are asymptomatic might be observed. Patients with symptoms need to be treated. We treat based on the type of symptoms they have, whether its anemia, the consequence of a large spleen, or constitutional symptoms. We fit a distinct treatment paradigm for those patients. Here, clinical trials are certainly much more developed. There are an unprecedented number of clinical trials for this very, very rare illness.

What take-home message do you have for community physicians regarding the MPN guidelines?

One of our own clinical trials is an investigator-initiated study. We are working closely with Mayo Clinic and the University of Miami Health System. This is based on preclinical data from one of my lab colleagues, Dr John D. Crispino. He has fully characterized the preclinical spectrum and identified a novel target and a novel drug. I hope that we can translate this into clinical practice.Community physicians need to know that the guidelines exist, because they are brand new. The first thing to know is that they’re available and they should know the basic themes of the guidelines. The basic themes—whether a patient has ET, PV, or myelofibrosis—are two-fold. Treatment is largely based on risk classification and symptom profiles. In ET and PV, the risk classification is largely looking for patients who are at high risk for thrombosis and treating them appropriately.

Please expand on the mutational targets in this field.

The other important theme is that there may be patients with MPNs who are not necessarily high-risk patients, but they still can have robust symptoms. They may be thought to have a more indolent course, but they can certainly be symptomatic. The point here is don’t observe symptomatic patients. Observation or watchful waiting is useful for asymptomatic patients as long as it’s consistent with their preferences.The major target is JAK-STAT activation. That’s really the major target for patients with MPNs. Also, [it is important to know] whether a patient has a JAK2 mutation or lacks one. This is most relevant for myelofibrosis and ET, even if the mutations differ in their names; the downstream consequences are pretty similar. They all activate the JAK-STAT pathway, so it’s really a central pathway to disease pathogenesis.

What are some next steps with ruxolitinib?

That’s why there were many JAK inhibitors in development, and there are less now. The pipeline has reduced in size in terms of the development of JAK inhibitors, but there is still a need to develop better ones. That is still a foundation of therapy because it’s the unique signature that is universal in MPNs, so it’s an important signal and an important target. However, targeting alone with what we have is currently insufficient, so we’ve got to look for combination partners. It is the foundation for many combination studies; it’s the building block. There are many clinical trials that have been previously conducted with various partners to ruxolitinib. It’s considered the standard or the foundation, so there have been many of those trials. I’d have to say that so far, most of those combinations are disappointing. The idea is to try to either find synergy, build upon a response, or find something to satisfy a need that ruxolitinib can’t.

JAK inhibitors, as a class, are helpful at shrinking the spleen and addressing symptoms. What they don’t do yet is affect bone marrow fibrosis in a meaningful way. They don’t improve blood counts. In fact, one of the side effects will be anemia for many patients. We're very far from having patients enter complete remission. [These drugs] don’t put patients into complete remission, so it’s really an important first step. You can’t undermine the usefulness. There were no approved drugs for myelofibrosis 5 years ago and much of what was being used was really no different than a placebo. We have to at least acknowledge that we have a drug that can be prescribed that can help quality of life for many patients. The next step is to try to build upon that.