Pediatric Polycythemia Vera Treatment & Management

Treatment of polycythemia vera (PV) depends on whether the disease is in the plethoric phase or the spent phase.

In the plethoric phase, the goal of treatment is controlling thrombotic episodes by restraining monoclonal proliferation rather than restoring polyclonal growth and maturation of cells. Interferon alfa is an exception; a few case reports have reported restoration of polyclonality.

In the plethoric phase, polycythemia vera is treated first by performing phlebotomy until the hematocrit is under reasonable control. Most patients can tolerate removal of 450-500 mL of blood every 2-4 days. As more blood is removed and the patient becomes iron deficient, the hematocrit becomes easier to control, and the phlebotomy schedule should be adjusted accordingly. Although phlebotomy is effective for controlling erythrocytosis, it does not affect the variable leukocytosis, thrombocytosis, or thromboembolic events found in polycythemia vera.

For many years, the mainstay of therapy of polycythemia vera has been phlebotomy with a goal hematocrit level of less than 45% in men and less than 42% in women. This recommendation is based on retrospective data that are now almost 30 years old and, the authors believe, potentially inaccurate. Recently, DiNisio and colleagues published data in patients with polycythemia vera that suggested that differences in hematocrit in the range of 40-55% were not associated with the risk of thrombosis nor with mortality.^[15]

Landolfi et al performed an extensive retrospective review of 1638 PV patients studied as part of the European collaboration study on low-dose aspirin in polycythemia (ECLAP).^[16] In this trial, no correlation was observed between hematocrit and risk of thrombosis.

Limitations of this study include its retrospective nature and relatively short follow-up (2.8 y median). Therefore, the authors of this eMedicine article believe that the true hematocrit goal in polycythemia vera is not clear (if it is present at all). This issue remains to be sorted out in prospective fashion. Although phlebotomy is still recommended by many experts, it is clearly a controversial issue.

In most patients, low-dose aspirin is started to reduce the risk of thromboembolic events, and phlebotomy is continued as necessary to control the hematocrit. This recommendation is based on results of the ECLAP study, in which patients with polycythemia vera and no clear indications for aspirin were randomly assigned to receive aspirin 100 mg/d or no aspirin.^[16]

The study showed a minor but statistically significant decreased risk of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, pulmonary embolism, and major venous thrombosis with aspirin therapy. Also, low-dose aspirin did not significantly increase rates of hemorrhage.

The retrospective review of the ECLAP data confirmed older age and previous thrombosis as risk factors for thrombotic events.

Although no correlation was demonstrated between thrombosis risk and hematocrit, what was shown was that a WBC count of more than 15,000/μL, when compared with a WBC < 10,000/μL, was an independent risk factor for major thrombosis, primary manifested as an increased risk of myocardial infarction.

Risk stratification is important in deciding whether or not chemotherapeutic cytoreductive therapy is indicated.

Most agree that high risk for thrombosis is present when the patient is older than 70 years and/or has a previous history of thrombosis. Note that the age is different than in risk stratification of essential thrombocythemia.

A platelet count of more than 1.5 million/μL is a risk factor for bleeding and is frequently considered a high risk indication favoring chemotherapeutic cytoreduction. Uncontrolled traditional cardiac risk factors, especially smoking, are considered by most to place a patient in a high-risk category. However, when these factors are well controlled, therapy for high risk may not be justified. Whether an additional agent should be given depends on the patient's thrombotic risk. The decision is a tradeoff between a reduction in thrombotic events and an increased incidence of malignancy. The initial Polycythemia Vera Study Group (PVSG) investigators compared phlebotomy, phlebotomy with³² P, and phlebotomy with chlorambucil. Median survival was 13 years, 11 years, and 9 years, respectively. The incidence of thrombosis was 23% in the phlebotomy-only group versus 16% in the³² P-and-phlebotomy group.

The rate of acute myeloid leukemia was 1.5%, 10%, and 13% for phlebotomy, phlebotomy with³² P, and phlebotomy with chlorambucil, respectively. Because of the increased rate of acute myeloid leukemia in polycythemia vera treated with chlorambucil, this drug is no longer used for myelosuppression. Rates of GI and skin cancers also increased 4%, 9%, and 12% when patients were treated with phlebotomy, phlebotomy with³² P, and phlebotomy with chlorambucil, respectively. Clearly, myelosuppression reduces the incidence of thrombotic events but increases the risk of malignancy.

Because of these results, a phase II efficacy trial was performed by using hydroxyurea instead of chlorambucil or³² P to see if a less leukemogenic agent could control thrombosis. In that trial, 51 patients with polycythemia vera were given hydroxyurea 30 mg/kg/day for 1 week then 15 mg/kg/day with the goal to maintain a platelet count of < 600,000/cm³ and a hematocrit of < 50% with minimal phlebotomy. The incidence of thrombosis in the first 2 years of treatment (when most thromboses occur) was 9%, significantly lower than the historical control of 23% for phlebotomy alone in the PVSG trial. At a median follow up of 8.6 years, the incidence for acute myeloid leukemia was 6% for hydroxyurea compared with 1.5% for phlebotomy only. At the time of analysis, this difference was not statistically significant but the later addition of 2 cases of myelodysplasia in the hydroxyurea arm increased the incidence to a significant 8%.

Because of the theoretically possible leukemogenic risk of hydroxyurea, anagrelide has been used to control increased platelet counts with the aim to reduce thrombotic events. In the PT1 trial in the United Kingdom, patients with essential thrombocythemia were randomly assigned to receive hydroxyurea or anagrelide. The study demonstrated an increased risk of thrombosis with anagrelide. The implication for polycythemia vera is unclear, but a reduction in platelet count does not affect rate of thrombosis in essential thrombocytopenia; a similar result is expected in polycythemia vera.

Interferon has been used for myeloproliferative diseases with efficacy in the past, but toxicity/tolerance has always limited its use in patients. However, in a recent phase II study by Kiladjian et al, pegylated interferon alfa-2a (Pegasys) was administered to 40 patients with polycythemia vera (median follow-up, 31.4 mo).^[17] A completed hematologic response was achieved in 94.6%, with 7 patients achieving complete molecular response of the JAK2V617F that was durable. Most patients tolerated interferon well, and no vascular events were recorded. The acceptable tolerability, efficacy and extremely low leukemogenic risk may make interferon alfa first line therapy in the future.

Based on the above data, in the authors' clinical practice, chemotherapeutic cytoreductive therapy is used in all patients who are high risk. Generally, the drug of choice is hydroxyurea. The authors attempt to titrate the drug to achieve normalization of the WBC count. This is based on the data stated above. The authors are honest with patients that this treatment is based on retrospective data that still need to be prospectively proven. The authors also monitor the hematocrit level, and although phlebotomy is performed for symptoms or very high values, the authors do not feel that fully achieving a goal of 45% in men and 42% in women is required.

Patients who are low risk generally do not require chemotherapeutic cytoreductive therapy. However, the concern of increased risk of thrombosis (primarily myocardial infarction) due to leukocytosis brings into question whether or not low-risk patients with a WBC count of more than 15,000/uL should receive cytoreductive therapy. This question remains to be addressed in a prospective fashion; currently, cytoreductive therapy in this situation cannot be firmly recommended.

As stated above, the authors believe that current recommendations to phlebotomize to a goal hematocrit of 45% in men and 42% in women may be inaccurate. Clearly, patients with symptomatic hyperviscosity should receive phlebotomy sufficient to relieve their symptoms. The authors also consider phlebotomy in patients with a very high hematocrit (>55%), but do not feel bound by current guidelines, based on the above data.

All patients receive low dose aspirin, usually 81 mg, unless a contraindication is noted.

As more clinical data is collected on pegylated interferon alfa-2a (Pegasys), some recommend its use as a potential first-line agent for cytoreduction; however, a planned randomized prospective study of Pegasys versus Hydrea should resolve the issue of optimal first-line polycythemia vera therapy.

Occasionally special treatment situations arise.

P32 is a reasonable option in the patient who is unreliable or who has a limited lifespan because of the convenience of one injection resulting in long term control. The principle drawback is the increased risk of malignancy.

In pregnant women, interferon can be used to treat polycythemia vera. The mechanism is unclear, the side effects are moderate and often severe, and the drug is expensive. However, it is not teratogenic, it can reasonably control symptoms, and there are rare case reports of restoration of polyclonality. Interferon is also a reasonable consideration in a young patient because of possible concerns of leukemogenicity of hydroxyurea. Recent data suggest that pegylated interferon-alpha-2a (Pegasys) is likely to be equally (and possibly more) effective. It is dosed once weekly which likely improves compliance. Some suggest that it may also be better tolerated than standard interferon.

Erythromelalgia responds to low dose aspirin or reduction of the platelet count to normal with low dose myelosuppressive agents.

Pruritus can be disabling and life altering in polycythemia vera. High water temperatures vigorous skin rubbing are factors in inciting itching. Taking cooler baths and patting the skin dry can provide some symptomatic relief. Also, starch baths (half a box of Linet starch in a tub of water) can be effective. Pharmacologic treatment options include antihistamines (eg, cyproheptadine at 4 mg orally 3 times daily), histamine 2 (H2) receptor blockers (eg, cimetidine at 300 mg orally 4 times daily), photochemistry, danazol, and interferon alpha. Serotonin reuptake inhibitors (eg, paroxetine at 20 mg orally daily or fluoxetine at 10 mg orally daily) can also be used. In severe refractory cases, myelosuppression may be required.

Patients with symptomatic hyperuricemia (gout, urate kidney stones) receive allopurinol. The authors also obtain uric acid levels and treat asymptomatic hyperuricemia if the level is significantly elevated.

Polycythemia vera is not treated surgically, except in the spent phase when splenectomy may be performed to relieve symptoms related to mass effect and pancytopenia.

Patients undergoing surgery have a very high risk of postoperative thrombosis.

All patients suspected of having polycythemia vera should be referred to a hematologist.

Beer with cobalt foam stabilizers should be eschewed. Otherwise, a normal healthy diet is recommended.

Patients with polycythemia vera can have a normal active life.