NCCN May Already Be Updating MPN Guidelines

After publishing them in October 2016,the National Comprehensive Cancer Network (NCCN) is already seeking to update and expand their guidelines for diagnosing and treating patients with myeloproliferative neoplasms (MPNs).

The guidelines focused initially on diagnosing each of the MPNs and treatment options for patients with myelofibrosis, as that was the disease type with the greatest unmet need, Ruben A. Mesa, M.D., explained in an interview with CURE following his presentation at the 2017 NCCN Annual Conference.

“The myeloproliferative neoplasms were probably one of the most significant of the hematologic malignancies that did not yet have NCCN guidelines,” said Mesa, a professor of medicine and chair of hematology at Mayo Clinic in Phoenix, and chair of the panel for the NCCN guidelines on MPNs. “The guidelines are very helpful in terms of improving quality of care by providing more homogeneity of care in the US, trying to bring in current evidence regarding treatment that can be utilized, as well as clarifying the role of a variety of things, ranging from transplantation to therapies.”

The guidelines look to explain the criteria for diagnosing each of the MPNs, including the World Health Organization’s (WHO) recent update to the classification of MPNs, and risk assessment. Yet currently treatment options are only included for patients with myelofibrosis in this edition of the guidelines. Treatment guidelines for patients with polycythemia vera (PV) or essential thrombocythemia (ET) are expected in the update, which Mesa remarked are expected in the summer of this year.

The myelofibrosis guidelines incorporate scoring systems for risk stratification, including the International Prognostic Scoring System (IPSS), the Dynamic IPSS (DIPSS) and the DIPSS-Plus. Mesa also noted that the guidelines endorse the 2013 International Working Group for Myelofibrosis Research and Treatment and European LeukemiaNet consensus response criteria, as well as the scoring system for total symptom burden.

“In myelofibrosis there are clinical improvement criteria that can stand alone. You can have reduction in splenomegaly that counts as a response. What that leads to for the clinical decision making is more subtle, and like all of these guidelines, they are married to clinical experience and expertise in terms of the character of response, and how that balances against any negatives that come with the treatment in terms of side effects or toxicities, as well as expense,” he said.

The guidelines also describe the prognostic significance of a number of common mutations in patients with primary myelofibrosis. Patients with an MPL W515L/K mutation, for example, have a higher risk of thrombosis compared with patients who have a CALR mutation, and they usually have an intermediate prognosis. Those who do not have JAK2, MPL or CALR mutations have an interior prognosis compared to patients with these driver mutations, with lower leukemia-free and overall survival rates. Patients with TP53 mutations are associated with a greater risk for transformation to acute myeloid leukemia.

For patients with low-risk asymptomatic myelofibrosis, the guidelines recommend either observation for signs and symptoms of disease progression or a clinical trial. For symptomatic patients who are low-risk, the guidelines suggest interferons, a clinical trial, or Jakafi (ruxolitinib)—the only FDA-approved targeted agent for patients with myelofibrosis. Jakafi, a JAK1/2 inhibitor, is also recommended for patients with intermediate-1 and -2 disease, especially for those with intermediate-2 disease who are not candidates for transplant and have a high platelet count.

“Ruxolitinib is the only FDA-approved therapy, so obviously, it leaves you somewhat challenged when you fail that therapy,” Mesa said. “That’s the greatest unmet need and certainly many of the current clinical trials are aimed at trying to assist patients that have ‘failed ruxolitinib.’”

Although the guidelines do consider some options for when a patient is Jakafi -intolerant or resistant, including agents such as fludarabine and busulfan, they strongly encourage clinical trials. However, Mesa noted that in the expected updates to the MPN guidelines, they will delve further into more options for patients following progression on Jakafi.

Mesa also addressed in his presentation several promising second-line agents currently in development, including pacritinib, momelotinib, imetelstat and PRM-151. “We’ve seen data recently that certainly was encouraging. Although neither agent is approved yet, both pacritinib and momelotinib had beneficial data in that second-line setting. Data from two clinical trials are eagerly anticipated for PRM-151, the anti-fibrosing agent, as well as imetelstat. Those are two second-lines studies that are of great interest,” Mesa said.

“We desperately need other agents approved because we really only have one approved drug: ruxolitinib…. If a second drug becomes approved we will undoubtedly work to revise the guidelines in a very rapid fashion to provide clarity and situational use,” Mesa continued.

He remarked that the guidelines are a starting point for oncologists who are less familiar with diagnosing and treating patients with these diseases, yet the experience of oncologists more familiar with MPNs could outweigh the recommendations in the guidelines.

“We’re hopeful that [the guidelines] will be a good resource for community oncologists in clarifying a range of issues with these diseases,” Mesa concluded. “How one walks that path, there’s a lot of individual factors and clinical experience that are highly relevant.”