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1312 Part X: Malignant Myeloid Diseases Chapter 85: Essential Thrombocythemia 1313

TABLE 85–3. Risk Stratification for Patients with Essential
JAK2 Mitotic
V617F recombination Thrombocythemia
No High-Risk Features
High Risk Low Risk Intermediate Risk
Age >60 years Age <40 years Age 40–60 years
Figure 85–5. Mitotic recombination leads to duplication of the Prior thrombosis
JAK2 V617F mutation, resulting in a V617F-homozygous subclone. Platelets >1500 × 10 /L
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distinguish ET from PMF. Constitutive activation of JAK2 has been agents. Although retrospective studies suggest that thrombotic com-
31
implicated as a driver of clonal progression, as expression of mutant plications in those younger than 60 years of age without additional
JAK2 leads to the accumulation of reactive oxygen species, increased risk factors may be no higher than controls, prospective data are lack-
DNA damage, and aberrant DNA repair. 67–70 ing. Patients with ET are currently stratified on the basis of their risk
of thrombotic complications (Table 85–3), with cytoreductive therapy
Blastic Phase Disease likely to benefit high-risk patients. Patients without high-risk features
For a minority of patients with ET, their disease terminates in AML, can be divided into low risk (age less than 40 years) and intermediate
also referred to as blastic phase. In some patients, the disease phenotype risk (age 40 to 60 years). Cytoreductive therapy is unlikely to offer a sig-
shows a stepwise transition from ET to PMF to AML, thus mimicking nificant protective effect for those with low-risk disease, in whom the a
the triphasic disease pattern of CML observed in the preimatinib era priori risk of thrombosis is small. There is currently little evidence avail-
(Chap. 89). In other cases, AML arises directly following ET. 71 able to guide treatment decisions in the intermediate-risk group. The
The mutational profile of blastic phase disease shares some similar- ongoing PT-1 trials (http://www.haem.cam.ac.uk/primary-thrombocy-
ities with de novo AML. Mutations in transcriptional control pathways thaemia/), comprising a randomized trial of hydroxyurea and aspirin
(including TET2, ASXL1, EZH2, and IDH1) are more common in blastic versus aspirin alone for intermediate-risk patients and an observational
phase than in the early disease phases. In addition, mutations are seen study of low-risk patients treated with aspirin alone, will provide pro-
in DNA repair and cellular differentiation pathways (including TP53, spective data to help clarify therapeutic decisions for these patients.
RUNX1, and IKZF1) which are rarely mutated in early stage MPNs. In Although the degree of thrombocytosis is not a reliable indicator of
contrast to de novo AML, balanced chromosomal translocations are thrombotic risk, many physicians consider cytoreductive therapy in
rare in post-MPN AML. 72–74 Of note, patients with JAK2 V617F -positive patients with a very high platelet count (e.g., greater than 1500 × 10 /L).
9
ET may develop AML that is negative for the JAK2 mutation. 49,71
Once cytoreductive therapy is instituted, dose adjustment is rec-
ommended to keep the platelet and leucocyte counts within the normal
THERAPY range. 35
MODIFICATION OF CARDIOVASCULAR RISK Choice of Cytoreductive Agent (Table 85–4)
FACTORS Choices of first and second line therapies for patients with ET are sum-
Established risk factors for cardiovascular disease, such as hypertension, marized in Table 85–4). Hydroxyurea, a ribonucleotide reductase inhib-
diabetes, smoking, hypercholesterolemia, and obesity, should be iden- itor also known as hydroxycarbamide, is widely regarded as first-line
tified and treated appropriately. The broad efficacy of the cholesterol- therapy for patients requiring treatment, and is the only cytoreductive
lowering statin drugs in the prevention of atherosclerotic disease has agent proven to reduce thrombotic events in a randomized controlled
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raised the possibility that such agents may be useful in ET, although this trial. Major complications of this drug include reversible myelosup-
has yet to be tested in a prospective study. pression and ulceration of the buccal mucosa or lower leg. Although
hydroxyurea appears nonleukemogenic when used to treat sickle cell
ANTIPLATELET THERAPY
A large randomized trial in PV demonstrated a reduction in thrombotic TABLE 85–4. Choice of Cytoreductive Agent in Essential
events in those taking low-dose aspirin (100 mg daily) without a con- Thrombocythemia
comitant increase in the risk of hemorrhage. Although retrospective Age Group First Line Second Line
75
studies have suggested a similar protective effect in ET, prospective
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trials have not been performed. Based on current evidence, aspirin is <40 years old Interferon-α Hydroxyurea
recommended for all ET patients unless contraindicated. Although Anagrelide
there are few data concerning the use of newer antiplatelet agents such 40–60 years Interferon-α Anagrelide
as clopidogrel in ET, their proven track record in preventing compli- Hydroxyurea
cations of atherosclerotic disease suggests they may be appropriate for
patients unable to tolerate aspirin. >60 years Hydroxyurea Anagrelide
Pipobroman*
CYTOREDUCTIVE THERAPY Busulphan*
Indications to Treat Radioactive phosphorus*
A prospective randomized trial demonstrated a clear role for cytore- *These agents increase the frequency of transformation to acute
ductive therapy with hydroxyurea in reducing thrombotic events in leukemia in PV studies and their use is only recommended in patients
high-risk ET patients (age >60 years or history of prior thrombosis), older than 75 years of age after careful consideration on a case-by-
approximately 70 percent of whom were also receiving antiplatelet case basis.

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