Clinical Review

Polycythemia Vera and Essential Thrombocythemia

Journal of Clinical Outcomes Management. 2018 October;25(8):371-384

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Interferons were studied in ET in parallel with PV. PEG-IFN-alfa-2a proved effective in patients with ET, with responses observed in 80% of patients [103]. PEG-IFN- alfa-2b produced similar results, with responses in 70% to 90% of patients in small studies and discontinuation observed in 20% to 38% of cases [105,106,113]. Because the very long-term leukemogenic potential of hydroxyurea has remained somewhat uncertain, anagrelide or IFN might be preferable choices in younger patients.

The approach to treatment of ET based on thrombotic risk level is illustrated in Figure 2.

Assessing Response to Therapy

For both patients with PV and ET the endpoint of treatment set forth for clinical trials has been the achievement of a clinicohematologic response. However, studies have failed to show a correlation between response and reduction of the thrombohemorrhagic risk [114]. Therefore, proposed clinical trial response criteria were revised to include absence of hemorrhagic or thrombotic events as part of the definition of response (Table 3) [94].

Approach to Patients Refractory to or Intolerant of First-line Therapy

According to the European LeukemiaNet recommendations, an inadequate response to hydroxyurea in patients with PV (or myelofibrosis) is defined as a need for phlebotomy to maintain the hematocrit below < 45%, the platelet count > 400 × 10³/μL, and a WBC count > 10,000/μL, or failure to reduce splenomegaly > 10 cm by > 50% at a dose of ≥ 2 g/day or maximum tolerated dose. Historically, treatment options for patients with PV or ET who failed first-line therapy (most commonly hydroxyurea) have included alkylating agents, such as busulfan, chlorambucil, pipobroman, and phosphorus (P)-32. However, the use of these drugs is limited by the associated risk of LT [93,115,116]. IFN (or anagrelide for ET) is often considered in patients previously treated with hydroxyurea, and vice versa.

Ruxolitinib is a JAK1 and JAK2 inhibitor currently approved for the treatment of PV patients refractory to or intolerant of hydroxyurea [7]. Following promising results of a phase 2 trial [117], ruxolitinib 10 mg twice daily was compared with best available therapy in the pivotal RESPONSE trial (n = 222). Ruxolitinib proved superior in achieving hematocrit control, reduction of spleen volume, and improvement of symptoms. Grade 3-4 hematologic toxicity was infrequent and similar in the 2 arms [118]. In addition, longer follow-up of that study suggested a lower rate of thrombotic events in patients receiving ruxolitinib (1.8 versus 8.2 per 100 patient-years) [119]. In a similarly designed randomized phase 3 study in PV patients without splenomegaly (RESPONSE-2), more patients in the ruxolitinib arm had hematocrit reduction without an increase in toxicity. Based on the results of these studies, ruxolitinib can be considered a standard of care for second-line therapy in this post-hydroxyurea patient population [120]. Ruxolitinib is also being tested in patients with high-risk ET who have become resistant to, or were intolerant of hydroxyurea, but currently has no approved indication in this setting [121,122]. Common side effects of ruxolitinib include cytopenias (especially anemia), increased risk of infections, hyperlipidemia, and increased risk of non-melanoma skin cancer.