ET is one of the classic Philadelphia chromosome-negative myeloproliferative neoplasms, characterized by near normal survival and low rates of progression to post-ET myelofibrosis and, rarely, to acute myeloid leukemia. As such, therapy for patients with ET focuses on the prevention of thrombohemorrhagic complications, a leading cause of morbidity and mortality in this neoplasm.
Several thrombosis risk assessment tools — such as the revised International Prognostic Score for ET (IPSET), endorsed by National Comprehensive Cancer Network — help identify patients with ET in need of cytoreductive therapy to control platelet numbers and decrease risk for thrombosis.
In the United States, hydroxyurea is typically a cytoreductive agent of choice. Anagrelide or interferon usually are chosen as second-line therapy for patients who fail hydroxyurea, although either agent also may be used upfront.
Normalization of the platelet count is the goal of cytoreductive therapy for high-risk patients with ET; however, for patients with elevated white blood cell count, normalization of white blood cell count also may lead to a reduction in thrombotic risk. Such a possibility is suggested from observations that elevated white blood cell count might be a risk factor for thrombosis.
For example, in one study of 891 patients with WHO-defined ET, a baseline leukocytosis greater than 11 x 109/L predicted arterial thrombosis but not venous thrombosis. In another study of 776 patients with ET, leukocytosis during follow-up correlated with occurrence of both thrombosis and major bleeding.
A separate issue with treatments for patients with ET is underappreciation of a need for better ET-related symptom control. For example, a formal definition of resistance/intolerance to hydroxyurea among patients with ET exists, but it does not address the frequently encountered issue of persistent symptoms despite adequate control of hematologic parameters. In one large internet-based survey of 304 patients with ET, 72% reported fatigue, and 40% or more reported itching, night sweats and bone pain.
Ruxolitinib, a JAK1 and JAK2 inhibitor, is approved for the treatment of patients with intermediate- or high-risk myelofibrosis, as well as for patients with hydroxyurea-resistant or -intolerant polycythemia vera. Its possible role as therapy for patients with ET is being evaluated in several clinical studies. Long-term follow-up from a phase 2 study of 39 patients with ET refractory to or intolerant of hydroxyurea showed its ability to reduce platelets and leukocytes among many patients, and control their ET-related symptoms. The MAJIC trial is the first study to report a comparison between ruxolitinib and best available therapy among patients with ET resistant to or intolerant of hydroxyurea. Results showed no significant difference between the two groups with regard to complete hematologic response, or with regard to rates of thrombosis, hemorrhage, transformation or treatment discontinuation. On the other hand, patients who received ruxolitinib experienced greater symptom improvement than those who received best available therapy.
The RUXO-BEAT trial (NCT02577926) in Germany is comparing ruxolitinib to best available therapy for both treatment-naive and previously treated patients with ET as long as at least one high-risk feature (eg, age older than 60 years, platelets greater than 1500 x 109/L, previous thrombosis or severe hemorrhage related to ET) is present. RUXBETA (NCT02962388) — a study in France for patients with high-risk ET and hydroxyurea resistance or intolerance — is designed to compare ruxolitinib with physician’s choice of anagrelide or interferon.
All of these randomized trials have been initiated and performed by physicians in academic medical centers, clearly identifying a need for new therapies in ET. Along this line of thought, an ongoing pivotal, randomized, double-blind clinical study (NCT03123588) in the United States is underway to compare ruxolitinib with anagrelide for patients with ET resistant to or intolerant of hydroxyurea who have elevated platelets and leukocytes. The study goal is to compare control of both parameters, as well as ET-related symptoms.
This is an exciting time in our attempts to develop new therapies for selected patients with ET who need better control of their ET-related symptoms and signs.
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HemOnc Today Editorial Board Member
The University of Texas MD Anderson Cancer Center