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Ruben Mesa, MD
© ASCO/Zach Boyden-Holmes

NEW YORK—The 11th NCCN Congress: Hematologic Malignancies coincided with the release of the inaugural edition of the NCCN treatment guideline on myeloproliferative neoplasms (MPNs), and Ruben A. Mesa, MD, took the opportunity to discuss the framework of the document and the evolving management of MPNs.

Dr Mesa, of the Mayo Clinic Cancer Center in Arizona, is the chair of the MPN guideline committee.

This initial version of the guideline focuses on the workup and diagnosis of primary myelofibrosis (MF), post-polycythemia vera MF, and post-essential thrombocythemia MF, and treatment guidelines for MF. 

The committee decided to first tackle the treatment guidelines in MF because, as Dr Mesa explained, MF is “the most severe of the MPNs with the most unmet needs in terms of guidance.”

Treatment guidelines for polycythemia vera (PV) and essential thrombocythemia (ET) will be forthcoming in 2017, he said, as well as diagnosis and treatment of atypical MPNs, such as hypereosinophilic syndrome and systemic mast cell disease.

Workup of an MPN

The guideline committee focused on information regarding diagnosis—the time and place to consider bone marrow biopsies, when to use cytogenetics, and when to perform next-generation sequencing. 

They stressed the importance of quantifying disease burden and utilizing the now-validated symptom assessment tools, particularly in MF.

“Finally, we leveraged the many prognostic scoring systems that have been developed for these diseases, particularly IPSS for myelofibrosis at diagnosis or the DIPSS and DIPSS-plus at subsequent time points,” Dr Mesa said. 

In addition to clinical-based prognostic scoring systems, information regarding molecular features and their impact is evolving, he said. 

The guideline provides a table of mutations with prognostic significance.  JAK2, MPL, or CALR mutations are “brighter mutations,” he said, while adverse prognostic markers include ASXL1, EZH2, IDH1/2, SRSF2, and TP53. 

“All of these have some significant prognostic implications in primary myelofibrosis, specifically,” he said.

Assessing MPN burden

“When treating these patients, it’s important to be mindful of the overall burden of the disease,” Dr Mesa said.

He called this emphasis on disease burden “an evolution from the past, where therapy was either supportive or primarily focused on prevention of thrombosis with ET or PV.” 

Practitioners need to be additionally mindful of the risk of vascular events, progression, the impact of cytopenias, splenomegaly, the burden of symptoms, and the baseline degree of comorbidities.

“[W]e encourage the use of validated symptom tools that have been used now in the majority of clinical trials in this setting,” Dr Mesa added.  

The MPN-10 assessment tool, included in the guideline, evaluates 10 symptoms—early satiety, abdominal discomfort, inactivity, problems concentrating, numbness/tingling, night sweats, itching, bone pain, fever, and unintentional weight loss—on a scale of 0 to 10. 

Patients with MF are the most symptomatic, Dr Mesa commented, although “it is notable how frequent symptoms are present in patients with PV and ET.”

Response criteria

For a complete response, individuals must have marked improvement to near normalization in both bone marrow and peripheral blood in addition to resolution of their disease symptoms. 

Partial response is basically “just shy” of the complete response level, Dr Mesa said, with bone marrow resolution not being required. 

The guideline also outlines response criteria for progressive, stable, and relapsed disease, clinical improvement, and anemia, spleen, and symptom response. 

“But I’ll highlight that the majority of the responses that are received currently with medical therapy are in the area of clinical improvement,” Dr Mesa said.

Treatment guidance

Specific treatment guidelines for low-risk, intermediate-1 risk, intermediate-2- or high-risk MF from the new guideline have been described in an earlier article and will not be discussed here. 

Of note, however, Dr Mesa explained that ruxolitinib is a very important part of the treatment guideline because it is the only therapy approved by the US Food and Drug Administration (FDA) to treat MF.

“Over time, it’s been shown that there is an improvement in survival [with ruxolitinib],” Dr Mesa said, perhaps because of a decrease with treatment in the morbidity and the debilitation of patients. 

Investigators presented the 5-year update of this information at ASCO 2016 and reported that patients maintained reduction in splenomegaly up through 5 years, both in those randomized to ruxolitinib and those crossing over from placebo. 

“Long-term, we clearly looked to see whether there was a signal of new onset or late onset toxicities,” Dr Mesa said, which largely was not the case. “Toxicities have been well described in earlier studies, primarily around anemia, thrombocytopenia, and mild constitutional symptoms.” 

However, long-term therapy increases the rate of development of shingles and non-melanoma skin cancer. Rates of transformation to acute myeloid leukemia were consistent with those published for similar patient populations with MF.

“If I see a patient stable on ruxolitinib who has a marked drop in their counts later on in the course of their disease,” Dr Mesa added, “I’m certainly suspicious of progression.”

He also works them up for other causes of anemia if it evolves out of the blue. 

Support in MF-related anemia

“With anemia, we’re mindful of iron stores, EPO level, and being certain there’s not the presence of hemolysis or other contributors,” Dr Mesa said. 

The guideline recommends stratifying patients based on serum EPO levels—those with less than 500 mU/mL and those with 500 mU/mL and higher. 

“If we lower the EPO level, the greater the likelihood of response,” Dr Mesa said. “In my experience, the lower the transfusion burden, the greater the likelihood of response.”

Other than erythropoiesis-stimulating agents for individuals with lower serum levels, androgens and immunomodulatory drugs for those with higher levels have some benefit.

But “they all have their limitations,” Dr Mesa said, and “they tend to range in benefit from 20% to 30%.”

The future 

Dr Mesa discussed a few agents in the pipeline that “might impact these guidelines,” such as the JAK2/FLT3 inhibitor pacritinib and the JAK1/JAK2 inhibitor momelotinib.

Pacritinib had a positive phase 3 study, but the mortality rate was higher than expected, and it was put on an FDA hold. 

Data from a second phase 3 study (PERSIST-1) will be reviewed in the aggregate to evaluate the benefit of pacritinib and whether the mortality rate was associated with drug-related side effects or adverse patient selection, “which we suspect might be the case,” Dr Mesa said. 

“This agent may come off hold, depending upon the data of that second phase 3 study,” he added.

Momelotinib is also in an advanced phase 3 program with 2 trials underway. Both trials have completed accrual. 

One is an upfront study of momelotinib versus ruxolitinib (NCT01969838). The goal is to reduce anemia without inferiority of splenomegaly and MPN symptoms.

The other phase 3 momelotinib trial is a second-line study versus best alternative therapy, including ruxoltinib (NCT02101268).

Combination studies are ongoing with a ruxolitinib base and a variety of secondary agents, including danazol, pomalidomide, PEG IFN α2a, 5-AZA, panobinostat, BKM-120, and LDE-225. All agents appear to achieve improvement in splenomegaly and symptoms. 

But  “incremental benefit over ruxolitinib alone is not yet clear,” Dr Mesa said. “I would say there’s not yet a recommended off-label combination which is widely being used.”

Dr Mesa also highlighted PRM-151, an antifibrosing drug that had a favorable early stage study with several doses, and the telomerase inhibitor imetelstat, which had a deep set of molecular responses in about a third of patients with MF. Imetelstat is currently being evaluated in the second-line setting (NCT02426086). 

Regarding the possible positioning of new therapies, Dr Mesa believes “momelotinib and pacritinib may play a role in front-line, depending on the final data from those studies.” 

“In second-line for MF—this is where most of the activity is in the trials,” he said. “Momelotinib, pacritinib, PRM-151, and imetelstat have possibilities.” end hematology article

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