The Role of Advanced Practitioners in Optimizing Clinical Management and Support of Patients With Polycythemia Vera.

CASE STUDY Mr. M, a 65-year-old male, presented to his primary care physician with progressive fatigue, difficulty sleeping, and daily headaches for the past 3 weeks. His headaches were not associated with visual disturbances, cognitive deficits, or nausea/vomiting, and he had no history of migraines. He had a history of hypertension and hyperlipidemia, did not smoke, rarely drank alcohol, and had no recent illnesses or hospitalizations. His previous physical examination and laboratory studies 2 years ago were normal. The current physical examination revealed a plethoric yet well-appearing, well-nourished male in no acute distress. His lungs were clear to auscultation bilaterally without wheezes, rales, or rhonchi. He had a regular heart rate and rhythm without murmur. His abdomen was soft, without tenderness, distension, or palpable hepatosplenomegaly. Examination of the extremities was negative for edema. Distal pulses and sensation in the hands and feet were intact and equal bilaterally. Cranial nerves II to XII were deemed intact, and no gross focal deficits were observed. Complete blood count (CBC) revealed a slightly elevated white blood cell (WBC) count (14.6 × 109/L [normal range, 3.9-10.7 × 109/L; Wians, 2015]), erythrocytosis (red blood cell [RBC] count, 6.5 × 1012/L [normal range, 4.2-5.9 × 1012/L; Wians, 2015], hemoglobin, 19 g/dL [normal range, 14-17 g/dL; Wians, 2015], and hematocrit, 54.3% [normal range, 41%-51%; Wians, 2015]), thrombocytosis (platelet count, 500 × 109/L [normal range, 150-350 × 109/L; Wians, 2015]), and microcytosis (mean cell volume [MCV], 75 fL [80-100 fL; Wians, 2015]), which combined were cause for referral to a hematology/oncology clinic. During his hematology/oncology evaluation, Mr. M described "never feeling rested" and being unable to sleep with uncertain snoring habits. He was experiencing itching during hot showers yet did not have rashes and had not recently introduced a new soap. He had no family history of blood disorders and no personal history of blood clots. The second CBC and laboratory tests confirmed erythrocytosis (RBC count, 6.5 × 1012/L; hemoglobin, 18.9 g/dL; hematocrit, 54%) and microcytosis (MCV, 75 fL). Serum iron (22 μg/dL [normal range, 60-160 μg/dL]) and ferritin (5 ng/mL [normal range, 15-200 ng/mL]) were suggestive of iron deficiency, serum erythropoietin was 8 mU/mL (normal range, 4.0-18.5 mU/mL), and a Janus kinase 2 (JAK2) mutation analysis was positive for JAK2V617F. Platelet count remained 500 × 109/L and WBC count was 10.2 × 109/L.

T here are an estimated 100,000 patients with polycythemia vera (PV) in the United States (Mehta, Wang, Iqbal, & Mesa, 2014). Because there is no curative medical treatment option (Vannucchi, 2014), these patients require disease management for the remainder of their lives. Patients with PV have an increased risk of mortality (Hultcrantz et al., 2012), often because of cardiovascular or thromboembolic events (Tefferi et al., 2013), and experience burdensome signs and symptoms (Emanuel et al., 2012;Tefferi et al., 2013). Advanced practitioners (APs), including nurse practitioners, PAs, and pharmacists, play key roles in managing these patients. Knowledge of current diagnostic criteria and management strategies is critical to prolonging survival and improving quality of life (QOL).
Although the WHO guidelines are the standard for diagnosing PV, they may not aid in identifying patients with masked PV, a condition characterized by JAK2 mutations and PV-consistent bone marrow morphology, despite subthreshold hemoglobin levels . Consequently, the 2016 WHO guidelines include lower thresholds for hemoglobin levels and inclusion of bone marrow results in the major criteria (Table 1).

NATURAL HISTORY AND DISEASE BURDEN
Mr. M presented with fatigue, headaches, pruritus, and difficulty sleeping. Patients with PV may also present with a thromboembolic event or other disease-related signs, including a palpable spleen (Tefferi et al., 2013). However, many patients are diagnosed asymptomatically based on routine blood work (Passamonti, 2012). Iron deficiency may result from the expanding erythrocyte population with a lower-than-normal erythropoietin level, and may mask the diagnosis of PV (Kambali & Taj, 2016). As the disease progresses, patients are at risk for cardiovascular, thromboembolic, and hemorrhagic events and may develop solid malignancies Tefferi et al., 2013). Polycythemia vera may also transform to myelofibrosis (MF), which is diagnosed by 2008 International Working Group for Myelofibrosis Research and Treatment (IWG-MRT) criteria (Table 2; Barosi et al., 2008), and/or transform to acute myeloid leukemia (AML), which is identifiable by ≥ 20% blasts in the peripheral blood or bone marrow as well as by extramedullary tumoral blast proliferation (myeloid sarcoma) per 2008 WHO criteria (Vardiman et al., 2009). Cardiovascular or thromboembolic events, solid malignancies, and disease transformation to MF or AML are the leading contributors to an increased mortality risk for patients with PV compared with the age-and sex-matched general population (Hultcrantz et al., 2012;Marchioli et al., 2005;Tefferi KURTIN Table 1 2. Bone marrow fibrosis grade 2-3 (on 0-3 scale) a or grade 3-4 (on 0-4 scale) b Additional criteria (2 are required) 1. Anemia c or sustained loss of requirement of either phlebotomy (in the absence of cytoreductive therapy) or cytoreductive treatment for erythrocytosis 2. A leukoerythroblastic peripheral blood picture 3. Increasing splenomegaly defined as either an increase in palpable splenomegaly of ≥ 5 cm (distance of the tip of the spleen from the left costal margin) or the appearance of a newly palpable splenomegaly 4. Development of ≥ 1 of 3 constitutional symptoms: > 10% weight loss in 6 months, night sweats, unexplained fever (> 37.5°C) Note. PV = polycythemia vera; WHO = World Health Organization. Adapted with permission from Barosi et al. (2008). a According to the European classification: diffuse, often coarse fiber network with no evidence of collagenization (negative trichrome stain) or diffuse, coarse fiber network with areas of collagenization (positive trichrome stain; Thiele et al., 2005). b According to the standard classification: diffuse and dense increase in reticulin with extensive intersections, occasionally with only focal bundles of collagen and/or focal osteosclerosis or diffuse and dense increase in reticulin with extensive intersections with coarse bundles of collagen, often associated with significant osteosclerosis (Manoharan, Horsley, & Pitney, 1979 , 2013). Splenomegaly-associated symptoms, including early satiety, and abdominal discomfort are not uncommon in patients with PV (Emanuel et al., 2012). Based on patient-reported experiences, PV-related symptoms reduce QOL and may hinder activities of daily living and work productivity (Mesa et al., 2016a).

MANAGEMENT Treatment Goals
The treatment goals for PV are to reduce thromboembolic and hemorrhagic risk, to manage disease-related symptoms, and to minimize the risk of fibrotic or leukemic transformation . Patients with a history of thromboembolic events and those aged ≥ 60 years have increased thrombotic risk Vannucchi, 2014). In addition, the Cytoreductive Therapy in PV (CYTOPV) trial demonstrated the importance of controlling hematocrit and possibly WBC count. Maintaining a hematocrit < 45% was associated with a fourfold reduced risk of death from cardiovascular or thrombotic events compared with hematocrit maintenance between 45% and 55% (Marchioli et al., 2013). Similarly, WBC count < 7 × 10 9 /L was associated with a fourfold reduced risk of major thrombosis compared with ≥ 11 × 10 9 /L ( Barbui et al., 2015). In our case, the patient presented at 65 years of age with a hematocrit of 54%, indicating high risk for thromboembolic events. It is important that APs develop an evidencebased treatment plan ( Figure 1). Patients should be monitored routinely for changes in hematocrit and blood count , with the frequency dictated by the patient's disease severity and risk of complications and/or progression. Those with stable blood count may require follow-up every 3 months, whereas some patients, including those with a recent diagnosis or change in treatment, may require weekly monitoring to achieve hematocrit control and appropriate dosing of cytoreductive therapy. Symptom burden should be regularly assessed with an objective instrument such as the MPN Symptom Assessment Form (Figure 2; Barbui et al., 2011;Scherber et al., 2011). Finally, it is important to address comorbidities and history of cardiovascular, thromboembolic, and hemorrhagic events. An emphasis should be placed on achieving optimal control of conventional cardiovascular risk factors (i.e., elevated cholesterol, current smoking status, diabetes mellitus, and high systolic blood pressure; Goff et al., 2014) and monitoring for signs of disease transformation to MF (Table 2) (Barosi et al., 2008) or AML (Vardiman et al., 2009).

Case Study Continued
Following diagnosis, Mr. M received weekly phlebotomies until hematocrit was < 45% and started low-dose aspirin (81 mg/d), as is recommended for patients with PV (Landolfi et al., 2004;Marchioli et al., 2013) unless specific contraindications to low-dose aspirin exist, such as extreme thrombocytosis (platelet count > 1,000 × 10 9 /L), at which point acquired von Willebrand syndrome should be ruled out due to risk of bleeding (Tefferi & Barbui, 2015). Because his age was > 60 years, the patient was considered high risk for thrombosis, and therefore started cytoreductive therapy with hydroxyurea.

Traditional Treatment Options
Best practices should be used for phlebotomy, including temporary cessation of the phlebotomy or administration of intravenous fluids for hypotension or other phlebotomy-related symptoms (e.g., acute illness, dizziness, dehydration; Parker, Deel, & Arner, 2004). Patients who are high risk (≥ 60 years or with a history of thromboembolic events) should be started on cytoreductive therapy. Additionally, patients with poor disease control with aspirin and phlebotomy alone (continually elevated blood count and/or persistent signs or symptoms) may benefit from the addition of cytoreductive treatment  with hydroxyurea (Fruchtman et al., 1997;Kiladjian, Chevret, Dosquet, Chomienne, & Rain, 2011) or interferon-α (Hasselbalch, 2011).
Hydroxyurea is often recommended for firstline cytoreductive therapy (Vannucchi, 2014); however, approximately 1 in 4 patients become resistant or intolerant (Alvarez-Lárran et al., 2012) per European LeukemiaNet (ELN) criteria (Table 3). Hydroxyurea resistance is associated with a 5.6-fold increased risk of death compared with hydroxyurea responders (Alvarez-Lárran et al., 2012). Approaches to the treatment of PV-includ-KURTIN and LYLE GRAND ROUNDS ing indications, common adverse events, and clinical implications-are provided in Table 4.

Case Study Continued
Mr. M's disease was successfully managed for a few years. In regular follow-up, the WBC count increased over the course of a year to 20 × 10 9 /L, and the patient developed progressive fatigue, pruritus, and night sweats, despite administering hydroxyurea at the maximum tolerated dose, indicating hydroxyurea resistance.  (EMA, 2015). Although interferon-α is an effective treatment option for some patients, it is not indicated by the FDA or EMA for patients with PV. Long-term treatment with interferon-α may be challenging for some patients because of its inconvenience as an injectable medication and treatment-related adverse events, which may include chills, depression, diarrhea, fatigue, fever, headache, musculoskeletal pain, myalgia, nausea, and weight loss (Hasselbalch, 2011). For these reasons, we did not consider interferon-α for Mr. M.
Regulatory approval of the oral JAK1/JAK2 inhibitor ruxolitinib (Quintás-Cardama et al., 2010) was based on the randomized, open-label, multicenter phase III RESPONSE trial, which evaluated ruxolitinib vs. best available therapy (BAT; i.e., hydroxyurea, interferon-α, anagrelide, immunomodulators, pipobroman, and observation alone) in patients with PV who required phlebotomy to control hematocrit, had splenomegaly, and were resistant to or intolerant of hydroxyurea . Ruxolitinib was superior to BAT for hematocrit control without phlebotomy, reduction in enlarged spleen size, and normalization of blood count . In addition, treatment with ruxolitinib may reduce the severity of PV-related symptoms and improve

Initial treatment for all patients
Low-dose aspirin a and Phlebotomy to maintain hematocrit < 45% b

History of thromboembolic events c or
Age ≥ 60 years c or Phlebotomy intolderance/resistance or frequent phlebotomies to maintain hematocrit < 45% b or

Elevated blood counts d or
Persistent PV-related symptoms

Cytoreductive therapy No additional treatment
Hydroxyurea e or Ruxolitinib g Continue hydroxyurea or interferon-α

Brief Fatigue Inventory ©
Instructions: Please fill out all questions as best able, reflecting how these symptoms affected you over the LAST WEEK unless directed otherwise. Complete forms until STOP instruction toward the end of the packet.
Adverse events with ruxolitinib were primarily grade 1 or 2, with a lower grade 3 or 4 adverse event rate (28.8 per 100 patient-years of exposure) compared with BAT (44.0 per 100 patient-years of exposure; Vannucchi et al., 2015). Among patients treated with ruxolitinib, MF and AML transformation rates were consistent with published rates for high-risk patients with PV Passamonti et al., 2004;Vannucchi et al., 2015). Herpes zoster infections were all grade 1 or 2 and only occurred with ruxolitinib (6.4%); no patients discontinued ruxolitinib because of herpes zoster . Nonmelanoma skin cancer occurred in more patients in the ruxolitinib arm (3.6%) compared with the BAT arm (1.8%); however, all patients in the ruxolitinib arm had a history of nonmelanoma skin cancer or precancerous lesions . No patients died while receiving randomized treatment; two patients died for reasons that were considered unrelated to ruxolitinib treatment after crossing over to ruxolitinib from BAT.

Case Study Continued
Because of hydroxyurea resistance, Mr. M was evaluated for treatment with ruxolitinib. Hepatic, renal, and platelet function were noted to be within normal limits. Review of the medication profile did not reveal any potential drug-drug interactions. Therefore, he was started on ruxolitinib 10 mg twice daily. After 3 months of treatment, Mr. M maintained hematocrit control and had improvements in symptoms and leukocytosis.
Ruxolitinib exposure may be affected by hepatic and renal impairment (Chen et al., 2013), as well as concomitant treatment with a cytochrome P450 3A4 inhibitor (Shi et al., 2012), and dosing should be modified as appropriate (Incyte Corporation, 2016). Mr. M was informed about the risks for herpes zoster infections and nonmelanoma skin cancer and continues to be monitored accordingly.

ASPECTS OF INDIVIDUALIZED PATIENT MANAGEMENT
Advanced practitioners play a critical role in managing patients with PV. Regular patient contact enables the AP to closely monitor laboratory values to optimize medical management and to educate patients about potential disease symptoms, adverse events related to current and/or alternative treatment options, and lifestyle or treatment modifications to achieve improvements (Raedler, 2014). When dispensing medication, pharmacists are provided an opportunity to inform patients about the specifics of treatment delivery and dosing as well as potential drug-drug interactions for those patients receiving concomitant medications. Finally, APs can facilitate improved patient compliance and adherence by placing reminder phone calls to patients, offering direct-to-patient deliveries, and coordinating with health plans and patient assistance programs to facilitate payment.

Table 3. European LeukemiaNet Criteria for Resistance to or Intolerance of Hydroxyurea in Patients
With Polycythemia Vera 1. Need for phlebotomy to keep hematocrit < 45% after 3 mo of ≥ 2 g/day of hydroxyurea or 2. Uncontrolled myeloproliferation (i.e., platelet count > 400 × 10 9 /L and white blood cell count > 10 × 10 9 /L) after 3 mo of ≥ 2 g/day of hydroxyurea or 3. Failure to reduce massive a splenomegaly by > 50% as measured by palpation or failure to completely relieve symptoms related to splenomegaly after 3 mo of ≥ 2 g/day of hydroxyurea or 4. Absolute neutrophil count < 1.0 × 10 9 /L or platelet count < 100 × 10 9 /L or hemoglobin < 100 g/L at the lowest dose of hydroxyurea required to achieve a complete or partial clinicohematologic response b or 5. Presence of leg ulcers or other unacceptable hydroxyurea-related nonhematologic toxicities, such as mucocutaneous manifestations, gastrointestinal symptoms, pneumonitis, or fever at any dose of hydroxyurea Note. Reproduced with permission from Barosi et al. (2010) a Organ extending by more than 10 cm from the costal margin. b Complete response was defined as: hematocrit < 45% without phlebotomy, platelet count ≤ 400 × 10 9 /L, white blood cell count ≤ 10 × 10 9 /L, and no disease-related symptoms. Partial response was defined as: hematocrit < 45% without phlebotomy or response in ≥ 3 of the other criteria (Barosi et al., 2009).

DISCUSSION
Patients with PV require long-term management to prolong survival and improve QOL. Familiarity with the 2008 WHO diagnostic criteria (Tefferi & Vardiman, 2008), as well as possible exceptions for masked PV , will allow the AP to quickly and accurately identify patients with PV. Although nearly all patients should initially receive treatment with aspirin (Landolfi et al., 2004) and phlebotomy to achieve a target hematocrit < 45% Marchioli et al., 2013), management should evolve with the natural course of the disease . Management decisions should be informed by current evidence, based on both objective measures (e.g., CBC, bone marrow biopsy, manual spleen palpation) and subjective measures (e.g., patient-reported symptoms with comprehensive instruments such as the Myeloproliferative Neoplasm Symptom Assessment Form) to identify patients who will benefit from the ad-dition of cytoreductive treatment such as hydroxyurea Scherber et al., 2011). Knowledge of the ELN criteria for hydroxyurea resistance and intolerance (Barosi et al., 2010) will allow the AP in hematology/oncology to identify high-risk patients who may benefit from a change in therapy, including consideration of ruxolitinib . Advanced practitioners may also identify high-risk patients in need of an alternate disease management strategy based on the IWG-MRT criteria for fibrotic transformation (Barosi et al., 2008) and the WHO criteria for leukemic transformation (Vardiman et al., 2009). Early diagnosis and evidence-based patient management by APs will promote improved outcomes and better QOL. l

Acknowledgment
Editorial assistance was provided by Cory Pfeiffenberger, PhD (Complete Healthcare Communi-  KURTIN and LYLE GRAND ROUNDS cations, LLC, an ICON plc company), whose work was funded by Incyte Corporation.

Disclosure
Ms. Kurtin received a consulting fee or honorarium from Incyte Corporation and served as a board member for The MDS Foundation without compensation. Ms. Lyle received a consulting fee or honorarium from and previously served on a speakers bureau for Incyte Corporation.