Polycythemia vera (PV) is characterized by erythropoiesis and JAK2-activating mutations, with increased risks of morbidity and mortality. Most patients with PV are iron deficient, and treatment often includes hematocrit control with phlebotomy, which may exacerbate iron deficiency-associated complications. The phase 3 RESPONSE trial evaluated the JAK1/JAK2 inhibitor ruxolitinib (n = 110) versus best available therapy (BAT; n = 112) in patients with PV who were hydroxyurea-resistant/intolerant. Ruxolitinib was superior to BAT for hematocrit control, reduction in splenomegaly, and blood count normalization. This exploratory analysis, the first to evaluate iron status in a prospective study of patients with PV, investigated ruxolitinib effects on 7 serum iron markers and iron deficiency-related patient-reported outcomes (PRO). Among patients with evidence of baseline iron deficiency, ruxolitinib was associated with normalization of iron marker levels, compared with lesser improvement with BAT. Iron levels remained stable in ruxolitinib patients with normal iron levels at baseline. Regardless of baseline iron status, treatment with ruxolitinib was associated with improvements in concentration problems, cognitive function, dizziness, fatigue, headaches, and inactivity, although improvements were generally greater among patients with baseline iron deficiency. The improvements in iron deficiency markers and PROs observed with ruxolitinib are suggestive of clinical benefits that warrant further exploration.

Introduction

Polycythemia vera (PV) is a clonal hematologic malignancy that is distinguished from other myeloproliferative neoplasms by ery throcytosis and activating mutations in Janus kinase 2 (JAK2) [1]. Risks of morbidity [2] and mortality [3] are increased in patients with PV, at least in part from cardiovascular/thromboembolic events and iron deficiency. Most patients with PV have depleted bone marrow iron levels [4,5], and constitutive activation of JAK2 may further promote iron deficiency by dysregulating hepcidin, a hormone that controls the iron exporter ferroportin in a JAK2- dependent fashion [6]. Iron deficiency is associated with fatigue [7], cognitive impairment [7,8], headaches [9,10], and restless leg syndrome [11], and may be associated with increased risk of cardiovascular/thromboembolic events [12–۱۵]. Unless contraindicated, patients with PV are often treated with aspirin [16] and phlebotomy to reduce the risk of cardiovascular-related morbidity or mortality [17], as supported by prospective, randomized clinical trial evidence and the European LeukemiaNet treatment guidelines [18]. However, frequent phlebotomies to control hematocrit may worsen iron deficiency [19]. Analyses exploring the impact of contemporary treatment options for PV on iron deficiency markers are lacking from the biomedical literature. Ruxolitinib is a potent JAK1/JAK2 inhibitor approved by the US Food and Drug Administration for patients with PV who have had an inadequate response to or are intolerant of hydroxyurea [20] and by the European Medicines Agency for adult patients with PV who are resistant to or intolerant of hydroxyurea [21]. The phase 3 RESPONSE trial evaluated ruxolitinib versus best available therapy in patients with PV who were resistant to or intolerant of hydroxyurea. Best available therapy, chosen per investigator judgment, was hydroxyurea for 58.9% of patients, which reflected real-world clinical practice and underscored an unmet treatment need in this setting.