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Chapter 69 Essential Thrombocythemia 1123

Personal Approach to Therapy of Essential Thrombocythemia
The optimal therapy for all patients with essential thrombocythemia (ET) considered; it is less clear to us if patients who achieve better platelet
remains uncertain. Therapy is geared toward interventions to reduce the control with cytoreductive therapy should also be so treated. However,
potential for developing thrombotic episodes. Patients with the greatest in studies from Europe addressing this question in polycythemia vera,
risk of developing a thrombus have a number of characteristics, including the approach of combining aspirin with cytoreduction therapy appears to
age 60 years or older, history of a thrombotic event, leukocytosis (platelet minimize thrombotic complications. The use of anagrelide and aspirin in
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count ≥11,000 × 10 /L), and cardiovascular risk factors (hypertension, combination should be avoided because of the high risk of a hemorrhage.
hypercholesterolemia, diabetes mellitus, obesity). Patients with ET or In patients with thrombotic episodes, especially episodes involving the
a prefibrotic form of MF can frequently present with elevated platelet microcirculation or large vessels, we administer low-dose aspirin (81 mg/
counts and are treated in a similar fashion by us. No known therapy is day). This dose of aspirin does increase the number of bleeding episodes
commercially available that is capable of reversing the bone marrow (BM) to a modest degree but is effective in the treatment of thrombotic events.
fibrosis in such patients or delaying or eliminating evolution to myelofi- This low-dose aspirin therapy is given in addition to an agent, which
brosis (MF). Certain concepts, however, apply to all patients. All patients reduces platelet numbers.
with ET should stop smoking to minimize the risk factors associated with Hydroxyurea can be started at a dose of 1 g/day and then adjusted
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atherosclerotic disease. Indiscriminant use of high doses of nonsteroidal to achieve the target platelet count (≤600 × 10 /L) without developing
antiinflammatory drugs should be avoided because this practice can lead leukopenia. Anagrelide is initiated at 0.5 mg twice daily and increased
to an increased risk of hemorrhage. Use of such agents is particularly by 0.5 mg/day every 5–7 days if platelet counts do not begin to drop.
frequent in elderly patients in whom ET is common. In patients with The usual dose to achieve platelet number control is 2.0–2.5 mg/day.
a life-threatening thrombotic or hemorrhagic episode, plateletpheresis Alternatively, combination therapy with anagrelide and hydroxyurea may
should be initiated in addition to starting them on hydroxyurea therapy. be considered. Some patients do not tolerate either hydroxyurea or
In high-risk patients, cytoreductive therapy has been shown to lessen anagrelide. In this patient group, IFN-α therapy is initiated at 3 million
the chance of developing additional thrombotic events with the reduction units three times per week subcutaneously, or consideration to therapy
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of extreme thrombocytosis to platelet counts below 600,000 × 10 /L. with a pegylated form of interferon (peg-IFNα-2a) should be given.
High-risk patients include patients older than 60 years of age and patients Busulfan at 4 mg/day for 2-week courses every time the platelet count
with a history of a previous thrombotic episode, including erythromelalgia, rises above the normal range is another therapeutic option. Busulfan
transient ischemic attacks, or large-vessel thrombosis. Even though this therapy is typically reserved for patients older than 70 years.
treatment philosophy has been considered common practice, the recom- Complications even in young, otherwise healthy patients with platelet
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mendation to treat patients older than the age of 60 years who have not counts greater than 2000 × 10 /L are unusual. However, these marked
experienced a thrombotic episode with cytoreductive therapy is not based elevations of platelet numbers can be anxiety-provoking situations for the
on robust data from multiple randomized trials. Asymptomatic high-risk patient and the clinician.
patients without cardiovascular risk factors may not necessarily benefit In certain situations, in young, low-risk patients, treatment should be
from this treatment, and the decision on how to treat them should be instituted. Surgery can increase the risk of thrombosis, and the use of
based on individual assessment. antiinflammatory agents can increase the risk of bleeding postoperatively.
At present, no therapy is indicated in asymptomatic patients younger Under these circumstances, the platelet count should be lowered to the
than 60 years of age. If a patient has a platelet count greater than or equal normal range. In pregnant patients with ET, low-dose aspirin therapy is
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to 1500 × 10 /L and acquired von Willebrand syndrome with bleeding the first treatment option. If the patient develops symptoms as a result of
symptoms, platelet-reduction therapy is indicated to avoid the high risk of thrombosis, platelet reduction therapy is necessary, and IFN-α therapy
hemorrhage. In totally asymptomatic patients with platelet counts greater is the treatment of choice.
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than 1500 × 10 /L, we frequently observe the patients and do not feel In a patient with ET and a serious acute hemorrhagic event, the site
compelled to treat them. Patients with acquired von Willebrand syndrome of bleeding should be determined immediately, and any antiplatelet-
should clearly avoid the use of aspirin. aggregating agents should be stopped. Although the platelet count may
In patients requiring platelet reduction therapy, the choice among the be high, these platelets should be considered to be qualitatively abnor-
use of anagrelide, interferon (IFN)-α, pegylated IFN, or hydroxyurea mal, leading to defective hemostasis. The patient may have acquired
therapy is based on patient age, ease of administration, and drug-related von Willebrand syndrome. In patients with acquired von Willebrand
toxicity. Randomized trials comparing these treatments in high-risk syndrome, desmopressin (DDAVP) or factor VIII concentrates containing
patients are ongoing. Until the results are available, we use the following von Willebrand factor can be used immediately at the same time chemo-
strategy. In patients older than 50 years, hydroxyurea therapy is the therapy is being administered. If acquired von Willebrand syndrome is not
treatment of choice, but in younger patients, we prefer to initiate therapy present, the transfusion of normal platelets is suggested. In patients with
with IFN-α. IFN therapy should be avoided in patients with a history of persistent hemorrhage, immediate reduction of the platelet count can be
depression, autoimmune disorders, or retinitis. If the patient cannot toler- achieved by platelet pheresis. If this approach fails, some consideration
ate IFN-α or it is not available, we feel comfortable treating symptomatic to the use of activated factor VIIa should be given. Hydroxyurea at 2–4 g/
patients younger than 50 years of age with anagrelide or hydroxyurea. day for 3–5 days should be administered immediately and then reduced
Although we remain concerned about the leukemogenic potential of to 1 g/day. All patients receiving hydroxyurea should be monitored for
hydroxyurea, the risk appears to be low if not associated with the prior use the onset of granulocytopenia or thrombocytopenia. Reduction of platelet
of an alkylating agent. The development of malleolar ulcers is a frequent counts is usually observed within 3–5 days of hydroxyurea treatment.
complication of hydroxyurea treatment and is a signal for the elimination In contrast, patients with acute arterial thrombosis require immediate
of hydroxyurea as a therapeutic agent for that particular patient. institution of platelet antiaggregating agents. Aspirin at a dose of 81 mg/
Patients who initially receive hydroxyurea and no longer respond to day is suggested. Patients with erythromelalgia or transient ischemic
this agent or experience toxicity and require another agent should not attacks will have a rapid cessation of symptoms after the use of low-dose
receive an alkylating agent. This sequence of administration is associated aspirin. In a patient with a life-threatening arterial thrombosis, the platelet
with an extremely high risk of leukemic transformation. Patients who count should be lowered with either a combination of apheresis and
have had a trial of hydroxyurea and require further treatment should hydroxyurea or with hydroxyurea alone, depending on the severity of
receive either anagrelide, IFN-α, or pegylated IFN. Doses of each of these the event. If the arterial thrombosis involves the microcirculation and
agents required for disease control will, of course, be dependent on the is not life threatening (transient ischemic attacks or erythromelalgia),
target platelet level that one hopes to achieve. Strict control to a platelet immediate low-dose aspirin therapy is indicated, and platelet-reduction
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count of lower than 600 × 10 /L does not appear to be necessary. In therapy (hydroxyurea, anagrelide, or IFN-α) can be initiated using a
these patients, the addition of low-dose aspirin (81 mg/day) should be standard dose and schedule.