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1314 Part X: Malignant Myeloid Diseases Chapter 85: Essential Thrombocythemia 1315

disease, controversy remains about potential leukemogenicity in the TABLE 85–5. ANAHYDRET and PT-1 Randomized
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MPNs. Some studies suggest an increased risk of acute leukemia in
hydroxyurea-treated ET patients, 77,78 but others have failed to observe Controlled Trials of Anagrelide versus Hydroxyurea for the
this association. 79,80 Problems with these studies include small patient Treatment of Essential Thrombocythemia
numbers, inclusion of patients who have received multiple cytotoxic ANAHYDRET
agents, lack of proper controls, retrospective data collection, and rela- Trial 83 PT-1 Trial 30
tively short followup. Of note, analysis of blood cells from sickle cell and Diagnosis WHO criteria PVSG criteria
MPN patients receiving hydroxyurea showed equivalent rates of DNA (2001)
mutations to normal controls, suggesting that the mutagenic potential Central review of Diagnosis by
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of hydroxyurea is low. At present it is not clear whether hydroxyurea histology* treating physician
used as a single agent is associated with an increased risk of acute leu-
kemia; however, any increased risk is likely to be small and should be Patients High risk High risk
balanced against the reduction in thrombotic complications. Treatment naïve Treated or untreated
Anagrelide, a quinazoline derivative, reduces the platelet count by Median age: AN/HU 58/56 61/62
inhibition of megakaryocyte differentiation. Although the white cell Patient number:
count is unaffected, anemia is common and often progressive. Up to a AN/HU 122/131 405/404
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third of patients cannot tolerate anagrelide because of side effects, many
of which result from its vasodilatory and positive inotropic actions Followup 730 patient-years 2653 patient-years
including palpitations and arrhythmias, fluid retention, heart failure Total events:
and headaches. Use of this drug requires particular caution in elderly Arterial thrombosis 15 54
patients or those with preexisting cardiac disease. Although anagrelide
is not cytotoxic, and therefore unlikely to be leukemogenic, the PT-1 Venous thrombosis 8 17
randomized trial demonstrated that anagrelide plus aspirin was infe- Hemorrhage 7 30
rior to hydroxyurea plus aspirin in high-risk ET patients. In this study, Transformation to MF 3 21
anagrelide- treated patients experienced reduced event-free survival
(p = 0.03) with higher rates of arterial thrombosis (p = 0.004), major AN, anagrelide; HU, hydroxyurea; MF, myelofibrosis; WHO, World
hemorrhage (p = 0.008) and progression to myelofibrosis (p = 0.01), Health Organization.
despite equivalent control of the platelet count, although rates of venous *82.2 percent of patients met WHO 2001 diagnostic criteria for ET.
thrombosis were decreased (p = 0.006). In contrast to hydroxyurea,
30
anagrelide therapy was also associated with an increase in marrow
reticulin over time. Comparison of patients in the PT-1 (compar- the platelet count in ET, although there is little direct evidence for effi-
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ison of hydroxyurea versus anagrelide) and Italian (comparison of cacy in thrombosis prevention. However, studies of patients with PV
hydroxyurea versus no cytoreductive therapy) prospective studies sug- have indicated that long-term use of this agent is associated with an
gests that anagrelide does provide partial protection from thrombo- increased risk of developing leukemia. 80,86
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sis, and therefore may be suitable as second-line therapy for patients The identification of mutations in JAK2 and studies highlighting
in whom hydroxyurea therapy is inadequate or not tolerated. It has a central role for increased JAK2 activity in the pathogenesis of the
been suggested that the results of the ANAHYDRET trial (compar- MPNs have driven the rapid development of targeted JAK2 inhibitors
ing hydroxyurea to anagrelide) show that anagrelide is not inferior to (e.g., ruxolitinib). Randomized trials indicate a role for these agents in
hydroxyurea in the treatment of ET. However, the number of patients relieving symptoms and possibly prolonging survival in patients with
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enrolled, duration of followup, and primary end points recorded were PMF. 87,88 Although early phase clinical trials have demonstrated efficacy
relatively small (Table 85–5) and as such this trial was not powered to in reducing the platelet count in patients with ET, their place in routine
see the differences observed in the PT-1 study. In addition, the ethical management has yet to be defined.
basis for performing noninferiority trials may be questioned. 84
Recombinant interferon-α is effective at controlling the platelet
count in ET, although there is little direct evidence of efficacy in pre- SPECIAL CONSIDERATIONS
vention of thrombosis. Treatment is often associated with significant Conception and Pregnancy
side effects, including flu-like symptoms and psychiatric disturbance First trimester fetal loss complicates up to 50 percent of pregnancies
that may mandate cessation of therapy. As this agent is free from leuke- in ET patients, with other complications such as intrauterine growth
mogenic or teratogenic effects, interferon-α is often used for younger retardation, stillbirth, and preeclampsia also occurring more frequently.
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patients or during conception and pregnancy. The adverse side-effect Such complications occur irrespective of the platelet count prior to con-
profile, however, means that it is generally avoided in older patients. ception but may be more prominent in those with JAK2 V617F -positive
Pegylated interferon-α, for which less-frequent administration is disease. Whether the use of aspirin or cytoreductive agents can improve
required, may be more convenient but the side-effect profile appears pregnancy outcome is uncertain, with studies reporting contradictory
similar to the native compound. results. However, a large meta-analysis of preeclampsia patients with-
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Radioactive phosphorus and alkylating agents such as busulphan out ET suggested that aspirin use in pregnancy is safe for both mother
are effective at controlling the platelet count, but are associated with an and fetus, and it therefore seems reasonable to consider its use for all
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increased risk of progression to acute leukemia, particularly when used pregnant ET patients. Although hydroxyurea has been used during
sequentially with hydroxyurea, and thus should be avoided in younger pregnancy, usually without adverse effects for mother or fetus, it is ter-
patients. Both radioactive phosphorus and busulphan can be given atogenic in various non-human mammals and should be avoided if
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intermittently with long intervals between doses, and may be useful in possible. Anagrelide can cross the placenta with unknown effects on
treating older patients who are unable to attend the clinic on a regu- fetal development and should also be avoided. Interferon-α is nonter-
lar basis. Pipobroman, a piperazine derivative, is effective at reducing atogenic and is the agent of choice for patients with high-risk disease
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