The National Comprehensive Cancer Network published its first set of guidelines for myeloproliferative neoplasms in October 2016 and is already looking to update and expand these guidelines.
Ruben A. Mesa, MD
The National Comprehensive Cancer Network (NCCN) published its first set of guidelines for myeloproliferative neoplasms1 (MPNs) in October 2016 and is already looking to update and expand these guidelines to match the need for direction in diagnosing and treating patients with MPNs.
The guidelines initially focused 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, MD, explained in an interview with OncologyLive® 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, Arizona, 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 United States, 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 recent update to the classification of MPNs, and risk assessment. Yet the current edition of the guidelines only included current treatment options for patients with myelofibrosis. Treatment guidelines for patients with polycythemia vera or essential thrombocythemia are expected in the update, which Mesa remarked is 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 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 several 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 inferior 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 (Table).
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 ruxolitinib (Jakafi), the only FDA-approved targeted agent for patients with myelofibrosis. Ruxolitinib, 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.
In a retrospective analysis of patients with myelofibrosis treated with ruxolitinib, patients with low-risk disease experienced a substantial improvement in symptoms.2 The proportion of patients with moderate to severe splenomegaly reduced from 64% to 16% with treatment and the rate for patients with moderate to severe fatigue decreased from 90% to 37%. Similar findings were noted in patients with intermediate-1—risk with a reduction in splenomegaly proportion from 53% to 10% and in the proportion of fatigue from 76% to 42%.
A pooled analysis from the COMFORT-I and COMFORT-II studies demonstrated that patients with intermediate-2- or high-risk myelofibrosis had an improved overall survival rate from treatment with ruxolitinib.3
“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 ruxolitinib-intolerant or -resistant, including agents such as fludarabine and busulfan, they strongly encourage clinical trials. However, he noted that the expected updates to the MPN guidelines will delve further into more options for patients following progression on ruxolitinib.
In his presentation, Mesa also addressed 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 2 clinical trials are eagerly anticipated for PRM-151, the antifibrosing agent, as well as imetelstat. Those are 2 second-lines studies that are of great interest. We desperately need other agents approved because we only have 1 approved drug, [and that is] 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. However, 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.”