Polycythemia Vera Treatment & Management

The goals of treatment of polycythemia vera (PV) are as follows:

• Reduce the risk of thrombosis
• Prevent bleeding events
• Minimize the risk of transformation to post–polycythemia vera myelofibrosis and acute myeloid leukemia
• Ameliorate the symptom burden

The optimal management remains elusive despite the findings of the Polycythemia Vera Study Group (PVSG). ^[4] However, general principles in the management of PV include the following:

• Tailor therapy to suit the clinical needs of the patient; consider the status of the formed elements of the blood, bone marrow, and organomegaly.

• Normalize red blood cell mass with phlebotomy as rapidly as clinically possible (250-500 mL every other day); patients who are elderly or have cardiovascular compromise should be phlebotomized cautiously, and smaller amounts should be removed.

• Suppress myeloproliferative activity with chemotherapy (hydroxyurea) in all patients older than 50 years.

• A recent advance in the treatment of PV is the development of JAK inhibitors. ^[19] The JAK1/2 inhibitor ruxolitinib is approved for treatment of PV in patients who have had an inadequate response to or are intolerant of hydroxyurea. ^[20] The JAK inhibitor fedratinib is approved treatment of adults with intermediate-2 or high-risk primary or secondary (post-PV or post–essential thrombocythemia) myelofibrosis.

• Ropeginterferon alfa-2b-njft (Besremi) is approved by the US Food and Drug Administration (FDA) for treatment of adults with PV. It is the first FDA-approved medication for PV that patients can take regardless of their treatment history, and the first interferon therapy specifically approved for PV. ^[21]

• In general, phosphorus-32 (³² P) therapy should be reserved for patients older than 80 years or patients with comorbid conditions in whom life expectancy is less than 5-10 years and the convenience of ³²P dosing outweighs the substantial risks of developing acute leukemia 5-15 years after ³²P administration.

• Patients with thrombotic tendencies or those who develop thrombocytosis after phlebotomy should be treated with marrow suppression; consider anagrelide in younger patients (aged 50-70 y).

• Maintain blood values at reference range levels by regular examination and treatment.

• Avoid overtreatment and toxicity by careful and judicious use of chemotherapy and radiation; supplemental phlebotomy is preferred over excess marrow suppression.

• Postpone elective surgery until long-term control of the disease is established.

• Women of childbearing age should be treated with phlebotomy only.

• In young males, myelosuppressive therapy can lead to aspermia; thus, evaluate treatment carefully before using any chemotherapy or radiotherapy.

• The PVSG no longer recommends the use of alkylating agents because of the associated increased incidence of leukemia and certain types of cancer.

• Treat hyperuricemia with allopurinol (100-300 mg/d) until remission has been attained; for acute gouty attacks, colchicine or other anti-inflammatory agents are indicated (see Gout and Pseudogout)

The long-term risks of polycythemia vera (PV) include leukemic and fibrotic transformation, which occur in fewer than 5% and 10% of patients, respectively, at 10 years. Current treatment modalities do not change these outcomes. Instead, treatment for PV is intended to decrease the risk of arterial and venous thrombotic events, which could be approximately 20%.

Patients can be risk-stratified for their risk of thrombosis according to their age and history of thrombosis. Patients older than 60 years or with a previous history of thrombosis are considered to be high risk. Patients younger than 60 years and with no prior history of thrombosis are considered low risk.

All patients with PV should undergo phlebotomy to keep their hematocrit below 45%. Lower hematocrit targets have been proposed for women with PV, but no empiric evidence supports that recommendation. ^[1]

All patients with PV should take aspirin, 81 mg daily, unless contraindicated by major bleeding or gastric intolerance. ^[1] A systematic review concluded that in patients with PV, use of low-dose aspirin is associated with a reduction in the risk of fatal thrombotic events and all-cause mortality; however, the reduction was statistically nonsignificant (P = 0.07). The review found no increased risk of major bleeding with low-dose aspirin therapy in PV. ^[22]  The initial Polycythemia Vera Study Group (PVSG) study of antiplatelet drugs, which used aspirin at 300 mg 3 times a day plus dipyridamole at 75 mg 3 times a day, showed an increase in the incidence of hemorrhage.

If a patient is at high risk for thrombosis, cytoreductive therapy is added to the management plan. Hydroxyurea at a starting dose of 500 mg twice daily is the most commonly used cytoreductive agent. It can be titrated on the basis of blood counts. In patients whose PV is refractory to hydroxyurea or who cannot tolerate the drug, interferon alpha can be used as an alternative. Busulfan is also an option for patients older than 65 years. ^[23]

Alvarez-Larran et al reported resistance or intolerance to hydroxyurea in 137 of 890 (15.4%) patients with PV. With a median survival of 19 years, resistance or intolerance had no impact on survival, but patients who developed cytopenia had increased risk of death (hazard ratio [HR] 3.5, P = 0.003) and of myelofibrotic transformation  (HR 5.1, P = 0.001). Cytopenia at the lowest dose required to achieve a response was also an independent risk factor for transformation to acute leukemia (HR 20.3,  P < 0.001). ^[24]

Leukocytosis may be a risk factor for thrombosis. In a subanalysis of the Cytoreductive Therapy in Polycythemia Vera (CYTO-PV) trial, risk of thrombosis was increased in patients whose WBC exceeded 7000/µL, and reached statistical significance at levels of 11,000/µL and above (HR 3.90, P = 0.02). An association between elevated WBC counts and thrombosis has also been found in studies of patients with essential thrombocythemia. These authors recommend including the WBC count when evaluating response to cytoreductive therapy. ^[25]

Interferon

Pegylated interferon is considered an alternative to hydroxyurea for certain patients, including the following ^[2] :

• Young women of reproductive age
• Patients with intolerance of or resistance to hydroxyurea therapy
• Patients requiring treatment to reduce their phlebotomy requirement rather than to prevent thrombosis

However, research also supports a role for interferon alpha as a first-line treatment. Although toxicity can be problematic, a systematic review and meta-analysis concluded that interferon alpha can be a safe and effective long-term treatment for PV, with an annualized rate of thromboembolic complications of 0.5% and that of treatment discontinuation due to adverse events of 6.5%. ^[26]

Unlike aspirin and hydroxyurea, which are purely symptomatic treatments, interferon therapy can reduce the allele burden of driver mutations and so may have a disease-modifying effect. ^[26] In a single-center retrospective study of 470 PV patients, longer duration of interferon alpha therapy was associated with a lower risk of myelofibrosis (HR 0.91) and lower mortality (HR 0.94) compared with hydroxyurea or phlebotomy-only treatment. ^[27]

In the phase III PROUD-PV trial and its extension study, CONTINUATION-PV, in patients with early PV, ropeginterferon alfa-2b (a long-acting pegylated interferon alfa-2b) did not show non-inferiority to hydroxyurea with respect to hematologic response and normal spleen size at 12 months. However, response to ropeginterferon alfa-2b increased over time, and by 36 months, responses were superior to those seen with hydroxyurea. ^[28] The European Medicine Agency has approved ropeginterferon alfa-2b for monotherapy in adults with PV without symptomatic splenomegaly. ^[29] In November 2021, the US Food and Drug Administration approved ropeginterferon alfa-2b for treatment of adults with PV, regardless of their treatment history. ^[21]

Phlebotomy (bloodletting) has long been the mainstay of therapy for polycythemia vera (PV). The object is to remove excess cellular elements, mainly red blood cells, to improve the circulation of blood by lowering the blood viscosity. Because phlebotomy is the most efficient method of lowering the hemoglobin and hematocrit levels to the reference range, all newly diagnosed patients are initially phlebotomized to decrease the risk of complications.

Patients can be phlebotomized once or twice a week to reduce the hematocrit to less than 45%. A randomized trial demonstrated a significant difference in the rate of thrombotic events and cardiovascular deaths (2.7% vs 9.8%) when the hematocrit goal was 45% versus 50%. ^[30] Patients with severe plethora who have altered mentation or associated vascular compromise can be bled more vigorously, with daily removal of 500 mL of whole blood.

Elderly patients with some cardiovascular compromise or cerebral vascular complications should have the volume replaced with saline solution after each procedure to avoid postural hypotension. The presence of elevated platelet counts, which may be exacerbated by phlebotomy, is an indication to use myelosuppressive agents to avoid thrombotic or hemorrhagic complications.

Once the patient's hemoglobin and hematocrit values are reduced to within the reference range, implement a maintenance program either by inducing iron deficiency by continuous phlebotomies (the frequency of the procedure depends on the rate of reaccumulation of the red blood cells) or by using a myelosuppressive agent. The choice depends on the risks of secondary leukemias and the rate of thrombosis or bleeding. Patients must be cautioned to not take iron supplements.

The risks for secondary leukemia depend on the type of therapy (eg, phlebotomy, chlorambucil) or the type of myelosuppressive agents (eg, hydroxyurea [HU], anagrelide, interferon alfa) and duration of therapy.

The Polycythemia Vera Study Group (PVSG) demonstrated a decreased survival rate and increased mortality rate from acute leukemia in the first 5 years, and a total of 17% of patients had leukemia after 15 years with chlorambucil and with phosphorus-32. ^[31] Increased risk of leukemia was also found with use of phosphorus-32; production of this radionuclide has been discontinued and it is no longer available in the United States or elsewhere.

An increased incidence of thrombotic complications occurred in the phlebotomy arm. This indicates that phlebotomy is not ideal for patients with elevated platelet counts and previous thrombosis, as are observed in patients who are older. In this situation, using HU has decreased these complications.

Hydroxyurea has been the mainstay therapy for PV since the PVSG results indicated it is an effective agent for myelosuppression; however, concerns have been raised regarding long-term risks for leukemic transformation. ^[32] In the PVSG trial, HU therapy reduced the risk of thrombosis compared with phlebotomy alone; the PVSG recommended that HU should be the drug of choice for patients older than 40 years. ^[33]

The role of HU in leukemic transformation is not clear. Several nonrandomized studies have supported or refuted a significant rise in leukemic conversion with the long-term use of HU in patients with essential thrombocythemia (from 0% to 5.5%) and in patients with PV (from 2.1% to 10%).

The PVSG closed the chlorambucil arm because of increased rates of acute leukemia after 7 years. However, in the 15-year follow-up of the HU arm compared with the phlebotomy-alone arm, the trend for leukemic transformation was greater in the HU arm but the differences did not meet statistical significance. Followup for a median of 8.6 years and a maximum of 795 weeks showed that 5.4% of patients developed leukemia in the HU arm compared with 1.5% of patients treated with phlebotomy alone.

Other case series have reported secondary leukemia in 3-4% of patients, which is relatively low compared with the benefits of preventing thrombotic complications.

In an open-label study by Huang and colleagues that included 136 patients with JAK2V617F mutation–positive PV, treatment with interferon alfa 2b (IFN α-2b) did not produce a superior overall hematologic response, compared with HU. However, IFN α-2b provided better 5-year progression-free survival (66.3% versus 46.7%, P< 0.01) and clinical improvement (in vasomotor symptoms, distal paresthesias, and erythromelalgia). No severe hematological adverse events were observed in patients receiving IFN α-2b. ^[34]

Do not administer alkylating agents to younger patients (< 40 y) who need long-term treatment. Alternative nonleukemogenic agents are needed for these patients

Low-dose aspirin suppresses thromboxane biosynthesis by platelets, which is increased in PV and essential thrombocythemia. The European Collaboration on Low-dose Aspirin in Polycythemia Vera (ECLAP) found that low doses of aspirin (40 mg/d) were effective for preventing thrombosis and controlling microvascular painful symptoms (erythromelalgia), which result from spontaneous platelet aggregation, in patients with PV and essential thrombocythemia, without creating a bleeding diathesis. ^[35]

Ruxolitinib (Jakafi), a Janus-associated kinase (JAK1/JAK2) inhibitor, was approved by the FDA in 2014 for the treatment of patients with polycythemia vera who have had an inadequate response to or are intolerant of hydroxyurea. Approval was based on data from the phase III RESPONSE trial. In this trial, patients treated with ruxolitinib demonstrated superior hematocrit control and reductions in spleen volume compared with best available therapy. A greater proportion of patients on the ruxolitinib treatment arm achieved complete hematologic remission (ie, hematocrit control and lowered platelet count and WBC). Hematologic adverse reactions are prevalent with ruxolitinib (incidence > 20%) and include thrombocytopenia and anemia. ^[36]

Ruxolitinib had initially been approved in the United States in 2011 for patients with intermediate- or high-risk myelofibrosis, including primary myelofibrosis, post–polycythemia vera myelofibrosis, and post–essential thrombocythemia myelofibrosis.

Another JAK inhibitor, fedratinib (Inrebic), was approved in 2019 for adults with intermediate-2 or high-risk primary or secondary (post-polycythemia vera or post-essential thrombocythemia) myelofibrosis (MF). Efficacy of fedratinib was investigated in JAKARTA (NCT01437787), a double-blind, randomized, placebo-controlled trial in 289 patients with intermediate-2 or high-risk MF, post-polycythemia vera MF, or post-essential thrombocythemia MF with splenomegaly. Patients were randomized to receive either fedratinib 500 mg (N=97), 400 mg (n=96), or placebo (n=96) once daily for at least 6 cycles.

The primary efficacy outcome was the proportion of patients achieving a reduction of 35% or greater from baseline in spleen volume at the end of cycle 6 measured by MRI or CT with a follow-up scan 4 weeks later. Of the 96 patients treated with the recommended dose (400 mg) of fedratinib, 35 (37%) achieved a 35% or greater reduction in spleen volume, compared with 1 of 96 patients who received placebo (p< 0.0001). The median duration of spleen response was 18.2 months for the fedratinib 400 mg group. In addition, 40% of patients who received 400 mg experienced a 50% or greater reduction in myelofibrosis-related symptoms, whereas only 9% of patients receiving placebo experienced a decline in these symptoms. ^[37]

Pemigatinib

Pemigatinib is an orally bioavailable inhibitor of the fibroblast growth factor receptor (FGFR) types 1, 2, and 3 (FGFR1/2/3). It inhibits FGFR 1/2/3 phosphorylation and signaling, and decreases cell viability in cancer cell lines with activating FGFR amplifications and fusions. It is indicated for relapsed or refractory myeloid-lymphoid neoplasms with FGFR1 rearrangement in adults. 

Approval was based on the phase 2 FIGHT-203 clinical trial. Study participants included patients with documented MLNs with an 8p11 translocation on conventional cytogenetics and/or an FGFR1 rearrangement on break-apart FISH testing. 

In patients with chronic phase in the marrow with or without extramedullary disease (EMD) (N = 18), the complete response (CR) rate was 78%. The median time to response of CR was 104 days (range, 44 to 435 days). The median duration of CR was not reached. In patients with blast phase in the marrow with or without EMD (N = 4), 2 patients achieved a CR. For all patients (N = 28 including 3 patients without evidence of morphologic disease) the complete cytogenetic response rate was 79% (22/28; 95% CI: 59, 92). ^[44]  

Consider splenectomy in patients with painful splenomegaly or repeated episodes of thrombosis causing splenic infarction.

Budd-Chiari syndrome occurs in patients with myeloproliferative disease (MPD) and most frequently in young women. Surgical approaches to the management of Budd-Chiari syndrome are, therefore, relevant to patients with polycythemia vera. ^[38]

Budd-Chiari syndrome is a liver-related condition associated with large-vessel thromboses and outflow obstruction with inferior vena cava or portal vein thrombosis. This is associated with the development of ascites, hepatosplenomegaly, abdominal pain, and gastrointestinal bleeding, but 20% of patients are asymptomatic.

The diagnosis is made by using ultrasonography to identify portal vein patency. In addition to the standard computed tomography (CT) scan and magnetic resonance imaging (MRI), patients with Budd-Chiari syndrome may need invasive angiographic imaging to determine the hemodynamics of the liver and the intrahepatic and vena caval gradients to determine the best surgical procedure. The histology of the liver helps determine the acuteness of the problem, the presence of chronic changes, and the degree of cirrhosis. This determines whether a patient requires a shunt or a liver transplant.

The following procedures have been used in patients with Budd-Chiari syndrome:

• Transjugular intrahepatic portosystemic shunt (TIPS)
• Side-to-side portocaval shunt or mesocaval shunt, portocaval/cavoatrial shunt, or mesoatrial shunt

These procedures have been reported to be successful in 38-100% of patients, with follow-up ranging from 9-98 months.

Consultation with a hematologist is recommended in cases of polycythemia vera (PV). Long-term follow-up care of these patients and managing complications of the disease and its treatment can be difficult. ^[20]