NCCN Establishes Treatment Guidelines for MPNs

For the first time in history, MPN guidelines have been set by the NCCN.
BY Gina Columbus
PUBLISHED December 15, 2016
The National Comprehensive Cancer Network (NCCN) recently established guidelines for treating myeloproliferative neoplasms (MPNs), emphasizing diagnosis, treatment and supportive care for myelofibrosis. In the future, more guidelines will be established that will focus on other MPNs, such as thrombocythemia (ET), polycythemia vera (PV).

“My focus was really for our colleagues here on the new guidelines for the therapy for MPNs,” said Ruben Mesa, M.D. “This is the first time there have been US-based guidelines through the NCCN for the diagnosis and treatment for MPNs, so we’re trying to get this cutting-edge information across to our colleagues.”

In an interview, Mesa, who is chair of the Division of Hematology and Medical Oncology at Mayo Clinic, provided his expert insight on these guidelines; recent advancements for patients with ET, PV and myelofibrosis; and ongoing clinical trials with the potential to change practice in the management of MPNs.

What do the new guidelines state?

For the first time ever there are guidelines for MPNs, which we hope will have an impact on equality, as well as trying to have care be more homogenous across the United States. We begin with guidelines regarding the diagnosis and prognosis of ET, PV and myelofibrosis, and then it really goes into the treatment guidelines for myelofibrosis for this first iteration. We plan, in the beginning of 2017, to have treatment guidelines for ET and PV.

The fundamental of the guidelines are trying to describe with primarily one FDA-approved therapy of Jakafi (ruxolitinib) and determining the role for Jakafi for patients with myelofibrosis. Both of the on-label indications are in intermediate-2 and high-risk patients, which are now in a clear and mature set of data with Jakafi. However, what are the situations for which we consider it for patients with low- and intermediate-1 risk?

We also try to flesh out where transplantation is to be considered, as well as the factors that impact transplantation. We need to look at both risk, quality of the candidate for transplant in terms of their health, as well as where the new molecular mutations fit into play.

Finally, we highlight the importance of many steps in consideration of clinical trials, but discuss a variety of off-label therapies, as well. Where we consider interferons and other therapies that can be supportive, particularly anemia.

What do we know about the role of Jakafi in myelofibrosis thus far, and what do we still need to determine with it?

It’s been a very impactful drug for myelofibrosis. It’s been approved for about five years, and we clearly see its impact in improving splenomegaly, symptoms and survival. Without question, as someone who focuses on myelofibrosis, my patients are living longer on Jakafi. Our long-term data suggest that there are no long-term, hidden, negative, unexpected side effects, so that’s very reassuring. Despite how beneficial Jakafi is, there is still room for improvement without question.

There are patients who benefit from Jakafi but eventually have progression of disease, or have room for further benefit, whether it is reduction of splenomegaly and symptoms, or improvement in cytopenia such as anemia or thrombocytopenia.

We have a great, unmet need for patients with advanced disease—patients who are moving toward acute leukemia or have transformed to it. We know that our current therapies are largely inadequate. As many investigational approaches are being looked at — new JAK inhibitors such as pacritinib and momelotinib, imetelstat and PRM-151 — that really seek to see where they can be of benefit in patients who have failed benefit from Jakafi, or in situations where we know Jakafi has not been helpful.

What is the next step to take in patients who are progressing with Jakafi?

It’s a good question; there are a couple choices. Transplantation has been held in reserve for patients who are reasonable transplant candidates. That’s clearly a time to be considering that, or even before they’ve lost that response. Some patients may be best off being transplanted during the time of their peak Jakafi response, particularly if they have adverse additional somatic mutations, such as ASXL1 or other high-risk features.

What other ongoing studies in MPNs are potentially practice-changing?

There are four drugs that are really at the forefront for myelofibrosis, ET, and PV. In ET and PV, there is still great interest in trying to finalize a role for interferons. There is a long-acting interferon that is out of Austria and Taiwan that is a proline pegylated interferon-beta-1a. That is currently in a randomized phase 3 trial as upfront therapy for high-risk patients with PV. If that is positive, it could really have a big impact in how we treat frontline PV. There is another trial looking at proline pegylated interferon-alpha-2a.

In myelofibrosis, I would break the drugs into two categories. There are additional JAK2 inhibitors: pacritinib and momelotinib. Both studies have been impactful in improving cytopenia or being safe in people with baseline cytopenias. Pacritinib has maturing data and has been on a clinical hold, but new data may end up resolving that hold and having that as an option for patients.

Momelotinib is in phase 3 studies and we hope to see data soon. We hope it potentially has an improvement in anemia while also improving splenomegaly symptoms.

Another drug in advanced phase 2 trials is the telomerase inhibitor imetelstat. In a study, we saw a very interesting and deep response in about one-third of patients, but those responses were impressive. Therefore, a randomized phase 2 study is ongoing to see the impact of that agent.

The final drug I highlighted is PRM-151 — an anti-fibrosing agent — that is also being looking at in pulmonary fibrosis. In early studies, it showed very favorable improvements in cytopenias, splenomegaly, and symptoms—even improvements in fibrosis. There is a favorable toxicity profile, so with that there is a randomized phase 2 study to determine the optimal dose. However, if similar efficacy is seen from earlier studies, the two may suggest another drug that may be practice changing.

It is an exciting time; there are four to five different agents being specifically developed for MPNs that truly would be very transformational.

Why is the incidence of splenomegaly so high in MPNs?

It’s a good question. The spleen clearly enlarges with MPNs, particularly in those with myelofibrosis or progressive ET or PV. The spleen can become enlarged in any hematologic malignancies, but the mechanism in MPNs may be slightly different. In lymphoid malignancies, it tends to be truly proliferation of the lymphoid malignancy right in the spleen. Lymphocytes are growing whether it is chronic lymphocytic leukemia (CLL), mantle cell lymphoma, marginal zone lymphoma—but it is just a straight tumor.

In the MPNs, it’s probably a bit distinct. There are some thoughts that some of the inflammatory cytokines involved in the disease may lead to hypersplenism. Also, that splenic sequestration of the amateur cells being released from the bone marrow, as part of the fibrosing process, may lead to these cells being sequestered in the spleen. These are cells that normally don’t circulate in the peripheral blood—myelocytes, metamyelocytes, blasts and things of that nature. With the sequestering in the spleen, there is extramedullary hematopoiesis. While it typically is ineffective hematopoiesis, there is a true hematopoietic element. In a patient with myelofibrosis, you see a lot of the extramedullary hematopoiesis. These are the reasons why the JAK inhibitors have really been crucial in reducing splenomegaly.

The mainstay of the therapy at the moment is really around JAK inhibition, and it has been very impactful in PV and myelofibrosis. It likely will soon be beneficial if we see that patients with ET with progressive splenomegaly receive a JAK inhibitor.

What does the future hold for MPN treatment?

There will be multiple new approved medications. We will have many more options to really help flesh out the treatment algorithms that we develop in the guidelines. We will have greater clarity not only around frontline therapy, but also around subsequent lines of therapy.
 
Even in myelofibrosis, we only have one line of therapy. Everything after that is a clinical trial or off-label combinations of a variety of things. That will be very helpful. There will be increasing information for molecular profiling that will help us in terms of selection of agents, but also better refine the timing of transplantation. There is still a lot of uncertainty; it’s a therapy that can have significant morbidities or mortality, and the optimal timing is still unknown. I suspect that we will have better ways to refine that along the way.

Finally, we will better understand why patients progress and likely will have new agents developed that are aimed at avoiding progression, as well as perhaps being able to better monitor our therapies with other surrogates of response.
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