Treatment of the myeloproliferative neoplasms polycythemia vera (PV) and essential thrombocythemia (ET) generally focuses on reducing the risk of thrombosis and relieving disease symptoms. Patients are categorized based on thrombotic risk and those considered at high risk for vascular complications are prescribed cytoreductive therapy, typically with hydroxyurea, although pegylated interferon (PEG-IFN) is also available for use in the first line. Ruxolitinib is approved for use in the second line for patients with PV.  

A recent review in the Journal of the National Comprehensive Cancer Network (JNCCN) explored whether the current treatment paradigm places cytoreductive therapy at the wrong point in therapy and targets the wrong patients.

Doctor discussing treatment with patient. Source: Getty

A 2017 trial that looked at cytoreduction therapy in ET patients with intermediate risk prompted the re-evaluation. That study compared treatment with hydroxycarbamide plus aspirin to aspirin monotherapy in very-low or low-risk patients. It did not find compelling evidence to support upfront use of hydroxyurea/hydroxycarbamide in patients without high-risk features.

Current NCCN guidelines call for treatment with low dose aspirin for all PV patients and phlebotomy to keep hematocrit below 45%. ET patients with microvascular disturbances or vascular symptoms may also be prescribed low-dose aspirin, but the benefit is less clear. Guidelines recommend cytoreductive therapy in patients who cannot tolerate phlebotomy, have progressive or symptomatic splenomegaly, severe symptoms, progressive leukocytosis or platelet count greater than 1,500 x 109/L.

The review authors noted that the use of hydroxyurea for cytoreductive therapy in PV “is based on consensus recommendations and only a scarce evidence base.” Further, “hydroxyurea has not been previously studied in low-risk patients” with PV. Instead, the therapy’s benefit has been extrapolated from studies of ET patients.

The ANAHYDRET trial challenged hydroxyurea’s primacy in ET, however, showing that anagrelide is  noninferior to hydroxyurea. NCCN now recommended anagrelide, hydroxyurea and interferon all as first-line cytoreductive agents. Recent studies have shown interferon therapy to control myeloproliferation and offer hematologic, histological and molecular responses in newly diagnosed PV and ET patients.

For PV patients, the PROUD-PV trial showed that lower-risk patients receiving the novel mono-peylated IF-alfa, ropeginterferon alfa-2b (ropeg), achieved substantially higher CHR than those on hydroxyurea at 24 months (70.5% vs 49.3%) and were far more likely to have partial molecular response (69.9% vs 28.6%).

“These data show the safety and efficacy of ropeg in not only achieving a durable hematologic response in PV but also significantly reducing JAK2-mutant allele burden,” the authors wrote. “Interestingly, in the first report of PROUD-PV, the likelihood of achieving a molecular response was lower in patients with a longer history of PV prior to study entry and in those previously treated with hydroxyurea,” indicating that early therapy may be particularly beneficial.

The authors concluded that cytoreductive therapy with hydroxyurea did not have strong evidence to support its use outside of high risk ET and ruxolitinib should be used in PV patients who are resistant or intolerant of hydroxyurea. They noted that “long-acting IFNs would be the best candidates if early initiation of therapy is to be considered.” If high-quality trials support indications that IFNs or other new cytoreductive agents alter the natural history of ET or PV without undue risk or excessive, then a “paradigm shift in ET/PV management will be upon us.”