Polycythemia vera (PV) is a progressive, chronic myeloproliferative neoplasm characterized by a primary, clonally-driven abnormal increase in red cell mass and elevations in platelet and white blood cell (WBC) counts [1]. The 2008 World Health Organization major diagnostic criteria for PV require erythrocytosis (i.e., elevated hemoglobin, hematocrit, red cell mass levels) or an activating mutation in JAK2; minor diagnostic criteria include bone marrow trilineage myeloproliferation, subnormal serum erythropoietin level, and endogenous erythroid colony growth [2]. A confirmed diagnosis per these criteria requires a patient to meet either (1) both major criteria and 1 minor criterion or (2) the first major criterion (i.e., erythrocytosis) and 2 minor criteria. There are over 100,000 patients with PV in the United States [3]. The condition is associated with an elevated risk of thrombosis (both arterial and venous), which is one of the most common causes of death in patients with PV [4]. As the disease progresses, a number of other hematologic complications may evolve, including secondary acute myeloid leukemia, myelodysplastic syndrome, and post-PV myelofibrosis [4, 5]. Although presentation is most common at 60 years of age or older [4, 6], one-third of PV cases occur in patients younger than age 50 [4].

Treatment of PV is aimed at the prevention of thrombotic events [1], and typical frontline management includes a combination of low-dose aspirin and phlebotomy (PBT) to decrease hematocrit (Hct) to <45 % [7, 8]. Management of WBC counts and platelet levels are also important treatment goals [9]. Underscoring the importance of careful management of PV, a study by Marchioli et al. found that treating to a higher Hct target range of 45–50 % versus stringently maintaining a Hct of <45 % was associated with a fourfold increase in death from cardiovascular causes or major thrombosis after a median follow-up of 31 months [7].

Some patients with PV require cytoreductive therapy to achieve target Hct levels [10] and to normalize WBC and platelet counts per European LeukemiaNet (ELN) response criteria [11]. Ruxolitinib is the only agent with regulatory approval for use in the PV setting, indicated by the US Food and Drug Administration for patients with PV who have had an inadequate response to or are intolerant of hydroxyurea (HU; also known as hydroxycarbamide) [12] and by the European Medicines Agency for the treatment of adult patients with PV who are resistant to or intolerant of HU [13]. Interferon-α is used to treat some patients with PV [10] and additional options are currently in development (e.g., other JAK2 inhibitors [14, 15], histone deacetylase inhibitors [16, 17]). Although not approved by regulatory agencies for the treatment of PV, HU is the most commonly used cytoreductive agent in the PV setting [1]. HU can be clinically efficacious; however, some patients may not receive adequate benefit or may not tolerate long-term therapy [18]. Indeed, a study by Alvarez-Larrán et al. found that 12 and 13 % of patients with PV had resistance and intolerance to HU, respectively, with the former significantly associated with an increased risk of death [18]. Thus, about one in four patients with PV who receive treatment with HU fall short of treatment goals. In real-world clinical practice, HU resistance is often secondary (i.e., develops over time). Indeed, the treatment patterns for high-risk patients with PV or those whose disease advances over time can sometimes evolve toward the combined use of HU and PBT. In the latter case, patients whose disease had been adequately controlled by HU end up needing more aggressive management, thus forcing the treating clinician to reintroduce PBT to the ongoing cytoreductive therapy to achieve control of blood cell counts and/or control of disease-related symptom burden [1, 19].

Although several studies have examined PV and its treatment in European populations [7, 18], none to our knowledge have studied the effectiveness and limitations of HU in clinical practice in the United States. Using a retrospective chart review method, this study investigated patterns of HU use and the impact of HU on the signs, symptoms, and complications of PV in a real-world US population.

Patients with PV experience a significant disease burden that can interfere with their quality of life and ability to engage in daily activities [20, 21]. Patients are also at significant increased risk for morbidity and mortality, including the risk for thromboembolic events [4, 22]. Despite the established importance of maintaining Hct levels <45 % using traditional treatment approaches such as HU cytoreduction to avoid these adverse outcomes, more than one-fourth of patients do not achieve this Hct target [7, 8]. The current report examines real-world treatment patterns among a large, representative sample of patients with PV currently or previously treated with HU across multiple treatment centers in the US.

Nearly one-fifth of patients in this study discontinued HU therapy, mostly because of a lack of response or safety/tolerability. Using our definition of response (based on applying published ELN criteria to the data collected in this study [9]), approximately 80 % of patients achieved either a CR or PR while on HU treatment. These results suggest that while many patients derive benefit with HU, there is a substantial subset of patients (including patients on HU who had no response and patients who discontinued HU), whose disease remains suboptimally controlled with HU in every-day clinical practice. This is important because the need for HU therapy itself arises when PBT alone becomes inadequate to manage blood cell counts. Indeed, in our cohort, in which all patients were treated with HU for ≥2 months, a large proportion of patients experienced Hct levels above the recommended threshold of 45 %. It is highly likely that such patients required combined therapy with PBT and continued HU. Moreover, the majority of HU users had elevated WBC or platelet counts; the latter, of course, are typically not influenced by the addition of PBT to HU treatment, which further exemplifies the pragmatic management challenges associated with this setting. Evidence suggests that patients with elevated Hct or elevated WBC count are at a significantly higher risk for cardiovascular morbidity and mortality [4, 7]. Patients treated to a higher Hct target range of 45–50 % had 4 times the rate of death from cardiovascular causes or major thrombosis versus patients who were strictly treated to a Hct target of <45 % [7]. Previously, Tefferi et al. identified a significant association between WBC count and subsequent survival [4]. More recently, analysis of data from the prospective Cytoreductive Therapy in Polycythemia Vera (CYTO-PV) trial demonstrated that risk of major thrombosis was approximately four times greater in patients with WBC counts ≥11 × 10⁹/L versus <7×10⁹/L (P = 0.02) [23], further highlighting the importance of proper disease control in patients with PV.

In this study, clinicohematologic response (CHR) rates did not correlate with HU dose, suggesting that at least some patients may be intrinsically resistant to HU. Further, more than 30 % of patients had received ≥2000 mg per day of HU as their highest dose, and more than 10 % of patients were being administered ≥2000 mg per day as their current dose, suggesting that even at these very high doses of HU patients do not achieve their treatment goals.

More than half of patients with PV experienced PV-related signs and symptoms after diagnosis, particularly fatigue and splenomegaly. Although the time frame and the method of assessment (physician-reported data from available chart information vs prospective validated patient-reported symptom assessments) were different in our study compared with past studies, the most frequent symptoms were similar (e.g., fatigue, splenomegaly, pruritus, headache, and abdominal pain) [21, 24, 25]. Additionally, Vannucchi et al. reported that the use of standard therapy (HU for the majority of patients) had little effect on reducing symptom scores in patients with PV; in fact, several symptom scores actually increased over a 32-week period in patients with PV treated with traditional therapies [24]. These findings reinforce the important unmet need of symptom control among many patients with PV.

Our study has various limitations consistent with the nature of a retrospective chart review. Patient charts were occasionally incomplete, leading to missing documentation of possible responses (e.g., unknown laboratory values) and potential post hoc interpretation by physicians (e.g., the presence of fatigue), which could have introduced error. In addition, HU dosing was captured at designated time frames, which may not reflect the complete, detailed evolution of a dosing regimen over time for a given patient. Also, although the sample source was demographically representative of the hematologist-oncologist population based on American Medical Association statistics, the patient charts selected may have differed from the overall population of patients across the US with respect to disease severity or the nature, duration, or intensity of applied treatments. Despite these limitations, this analysis provides a contemporary real-world assessment of the patterns of HU use and the corresponding impact on disease control in a large population of patients with PV from multiple academic and community practices across the US.

Consistent with other reports, this study demonstrates that HU has an important place and role in the treatment of PV in the US. However, a significant subset of patients continue to experience suboptimal control of their PV, as evidenced by persistent elevations in their blood cell counts and the continued presence of burdensome and unremitting disease-related symptoms. Based on our results, it is estimated that for up to a third of patients, PV may be or become suboptimally controlled by HU over the next 5 years. At the time of this study, physicians had few treatment alternatives to consider for PV that was inadequately controlled with HU, even with the concomitant addition of PBT. Therefore, these data further illustrate a significant medical need for a sizeable proportion of patients with PV either currently or previously treated with HU.