Polycythemia Vera and Essential Thrombocythemia

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Continuing medical education activityin American Journal of Hematology

CME Editor and Author: Ayalew Tefferi, MD

Article Title: Polycythemia vera and essential thrombo-

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Upon completion of this educational activity, participantswill be better able to:

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ANNUAL CLINICAL UPDATES IN HEMATOLOGICAL MALIGNANCIES: A CONTINUING

MEDICAL EDUCATION SERIES

Polycythemia vera and essential thrombocythemia: 2012 update on

diagnosis, risk stratification, and managementAyalew Tefferi*

Disease overview: Polycythemia vera (PV) and essential thrombocythemia (ET) are myeloproliferative neo-plasms primarily characterized by erythrocytosis and thrombocytosis, respectively. Other disease featuresinclude leukocytosis, splenomegaly, thrombohemorrhagic complications, vasomotor disturbances, pruritus,and a small risk of disease progression into acute myeloid leukemia or myelofibrosis.Diagnosis: Almost all patients with PV harbor a JAK2 mutation. When PV is suspected, the presence of aJAK2mutation confirms the diagnosis and its absence, combined with normal or increased serum erythro-poietin level, excludes the diagnosis. Differential diagnosis of ET had to include chronic myelogenous leu-kemia and prefibrotic myelofibrosis. A JAK2mutation is found in approximately 60% of patients with ET.Risk stratification: Current risk stratification in PV and ET is designed to estimate the likelihood of throm-botic complications: high-risk is defined by the presence of age >60 years or presence of thrombosis his-tory; low-risk is defined by the absence of both of these two risk factors. Presence of extreme thrombocyto-sis (platelet count >1,000 3 109/L) might be associated with acquired von Willebrand syndrome (AvWS)and, therefore, risk of bleeding. Risk factors for shortened survival in both PV and ET include advancedage, leukocytosis, and history of thrombosis.Risk-adapted therapy: Survival is near-normal in ET and reasonably long in PV. The 10-year risk of leuke-mic/fibrotic transformation is


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and virtually 100% specific for distinguishing PV from othercauses of increased hematocrit [25,26]; the possibility offalse positive or false negative mutation test result is effec-tively addressed by the concomitant measurement of serumerythropoietin (Epo) level, which is expected to be subnor-mal in more than 85% of patients with PV [27]. A subnor-mal serum Epo level in the absence of JAK2V617F man-dates additional mutational analysis for JAK2 exon 12mutation to capture some of the approximately 3% of PVpatients who are JAK2V617F-negative [4]. Bone marrowexamination is not essential for the diagnosis of PV

because patients who otherwise fulfill the diagnostic criteriafor PV are labeled as having PV even if they display sub-stantial bone marrow fibrosis (Table II) [24].

When evaluating thrombocytosis, the detection ofJAK2V617F confirms the presence of an underlying MPNbut its absence does not rule out the possibility since up to40% of patients with ET might be JAK2V617F-negative[28]. It is also important to note that other JAK2V617F-posi-tive MPN (or MDS/MPN) can mimic ET in their presenta-tion; these include prefibrotic PMF [29] and refractory ane-mia with ring sideroblasts with marked thrombocytosis(RARS-T) [18]. Therefore, bone marrow examination is of-ten necessary to make an accurate morphologic diagnosisof ET and distinguish it from other myeloid neoplasms,

TABLE I. World Health Organization (WHO) classification of

myeloid malignancies

1. Acute myeloid leukemia (AML) and related precursor neoplasmsa

2. Myeloproliferative neoplasms (MPN)

2.1. Classic MPN

2.1.1. Chronic myelogenous leukemia,BCR-ABL1positive (CML)

2.1.2. Polycythemia vera (PV)

2.1.3. Primary myelofibrosis (PMF)

2.1.4. Essential thrombocythemia (ET)

2.2. Nonclassic MPN

2.2.1. Chronic neutrophilic leukemia (CNL)2.2.2. Chronic eosinophilic leukemia, not otherwise specified (CEL-NOS)

2.2.3. Mastocytosis

2.2.4. Myeloproliferative neoplasm, unclassifiable (MPN-U)

3. Myelodysplastic syndromes (MDS)

3.1. Refractory cytopeniab with unilineage dysplasia (RCUD)

3.1.1. Refractory anemia (ring sideroblasts< 15% of erythroid precursors)

3.1.2. Refractory neutropenia

3.1.3. Refractory thrombocytopenia

3.2. Refractory anemia with ring sideroblasts (RARS; dysplasia limited to

erythroid lineage and ring sideroblasts 15% of bone marrow erythroid

precursors)

3.3. Refractory cytopenia with multi-lineage dysplasia (RCMD; ring sideroblast

count does not matter)

3.4. Refractory anemia with excess blasts (RAEB)

3.4.1. RAEB-1 (24% circulatingor59% marrow blasts)

3.4.2. RAEB-2 (519% circulating or1019% marrow blasts orAuer rods

present)

3.5. MDS associated with isolated del(5q)

3.6. MDS, unclassifiable4. MDS/MPN

4.1. Chronic myelomonocytic leukemia (CMML)

4.2. Atypical chronic myeloid leukemia,BCR-ABL1 negative

4.3. Juvenile myelomonocytic leukemia (JMML)

4.4. MDS/MPN, unclassifiable

4.4.1. Provisional entity: refractory anemia with ring sideroblasts associated

with marked thrombocytosis (RARS-T)

5. Myeloid and lymphoid neoplasms with eosinophilia and abnormalities of

PDGFRA,c PDGFRB,c or FGFR1c

5.1. Myeloid and lymphoid neoplasms with PDGFRA rearrangement

5.2. Myeloid neoplasms withPDGFRB rearrangement

5.3. Myeloid and lymphoid neoplasms with FGFR1abnormalities

aAcute myeloid leukemia-related precursor neoplasms include therapy-related

myelodysplastic syndrome and myeloid sarcoma.b

Either mono- or bi-cytopenia: hemoglobin level 99thpercentileofreferencera

ngeforage,sex,oraltitudeofresidenceorredcell

mass>25%

abovemeannormalpredictedorHgb>

17g/dL(men)/>5g/dL(women)ifassociatedwitha

sustainedincreaseof2g/dL

frombaselinethatcannotbeattributedtocorrectionofirondeficiency.

cSmalltolargemegakaryocyteswithaberrantn

uclear/cytoplasmicratioandhyperchromaticandirregularlyfoldednucleianddenseclustering.

dorIntheabsenceofreticulinfibrosis,themegakaryocytechangesmustbeaccompaniedbyincreas

edmarrowcellularity,granulocyticproliferation,ando

ftendecreasederythropoiesis(i.e.,pre-fibroticPMF).

286 American Journal of Hematology

annual clinical updates in hematological malignancies: a continuing medical education series


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especially from prefibrotic PMF; megakaryocytes in ET arelarge and mature-appearing, whereas those in prefibroticPMF display abnormal maturation with hyperchromatic andirregularly folded nuclei [30]. A recent large internationalstudy confirmed the prognostic relevance of distinguishingET from pre-fibrotic PMF [20]. In the absence ofJAK2V617F, the possibility of CML is readily addressed byBCR-ABL1 mutation screening but it is also to be notedthat megakaryocytes in CML (small and hypolobulated) are

easily distinguished from those of ET [31]. The diagnosis ofpost-PV or post-ET MF had to adhere to criteria recentlypublished by the International Working Group for MPNResearch and Treatment (IWG-MRT; Table III) [32].

Risk StratificationCurrent risk stratification in PV and ET is designed to

estimate the likelihood of thrombotic complications and notnecessarily survival or risk of leukemic/fibrotic transforma-tion (Table IV) [33]. Age 60 years and history of thrombo-sis are the two risk factors used to classify patients with PVor ET into low (0 risk factors) and high (1 or 2 risk factors)risk groups (Table IV) [3437]. In addition, because of thepotential risk for bleeding, low-risk patients with extremethrombocytosis (platelet count >1,0003 109/L) are consid-ered separately (Table IV) [38]. The presence of cardiovas-

cular risk factors is currently not taken under considerationduring formal risk categorization.

Risk factors for shortened survival in both PV and ETinclude history of thrombosis, leukocytosis, and advancedage [3436,39]. During a recent international study of over1,000 patients with ET, the prognostically detrimental effect(on survival, leukemic transformation, and fibrotic progres-sion) of prefibrotic morphology was demonstrated and thestudy also identified age >60 years, leukocyte count >113 109/L, anemia, and thrombosis history as additional inde-pendent risk factors for survival [20]. The study also identi-fied older age, anemia, and absence of JAK2V617F as riskfactors for fibrotic progression and history of thrombosisand extreme thrombocytosis as risk factors for leukemic

TABLE III. International Working Group for Myeloproliferative

Neoplasms Research and Treatment (IWG-MRT) Recommended

Criteria for Post-Polycythemia Vera and Post-Essential

Thrombocythemia Myelofibrosis [32]

Criteria for post-polycythemia vera myelofibrosis

Required criteria:

1 Documentation of a previous diagnosis of polycythemia vera as defined by theWHO criteria (see Table II)

2 Bone marrow fibrosis grade 23 (on 03 scale) or grade 34 (on 04 scale)

(see footnote for details)

Additional criteria (two are required):

1 Anemia or sustained loss of requirement for phlebotomy in the absence of

cytoreductive therapy

2 A leukoerythroblastic peripheral blood picture

3 Increasing splenomegaly defined as either an increase in palpable splenomegaly

of 5 cm (distance of the tip of the spleen from the left costal margin) or the

appearance of a newly palpable splenomegaly

4 Development of 1 of three constitutional symptoms: >10% weight loss in 6

months, night sweats, unexplained fever (>37.58C)

Criteria for post-essential thrombocythemia myelofibrosis

Required criteria:

1 Documentation of a previous diagnosis of essential thrombocythemia as defined

by the WHO criteria (see Table II)

2 Bone marrow fibrosis grade 23 (on 03 scale) or grade 34 (on 04 scale)

(see footnote for details)

Additional criteria (two are required):1 Anemia and a 2 g/dL decrease from baseline hemoglobin level

2 A leukoerythroblastic peripheral blood picture

3 Increasing splenomegaly defined as either an increase in palpable splenomegaly

of 5 cm (distance of the tip of the spleen from the left costal margin) or the

appearance of a newly palpable splenomegaly

4 Increased lactate dehydrogenase

5 Development of 1 of three constitutional symptoms: >10% weight loss in 6

months, night sweats, unexplained fever (>37.58C)

Grade 23 according to the European classification: [114] diffuse, often coarse

fiber network with no evidence of collagenization (negative trichrome stain) or dif-

fuse, coarse fiber network with areas of collagenization (positive trichrome stain).

Grade 34 according to the standard classification: [115] diffuse and dense

increase in reticulin with extensive intersections, occasionally with only focal bun-

dles of collagen and/or focal osteosclerosis or diffuse and dense increase in reticu-

lin with extensive intersections with coarse bundles of collagen, often associated

with significant osteosclerosis.

Figure 1. Diagnostic algorithm for myeloproliferative neoplasms. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]

American Journal of Hematology 287



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transformation. Using age 60 years, hemoglobin belownormal value and leukocyte count >15 3 109/L, one studydemonstrated a median survival of >20 years in the ab-sence of all three risk factors and 9 years in the presenceof two of the three risk factors [39]. A similar strategy in PVrevealed median survivals of 23 and 9 years in the ab-sence of advanced age and leukocytosis or presence ofboth risk factors, respectively [36]. Leukocytosis has alsobeen associated with leukemic [36] and JAK2V617F allele

burden with fibrotic [19] transformation in PV [19]. The rela-tionship between thrombosis and leukocytosis [40,41],thrombosis, and JAK2V617F [5] or pregnancy-associatedcomplications and JAK2V617F [4244] have been exam-ined by different groups of investigators with findings thatwere conflicting and inconclusive.

Risk-Adapted therapyBecause survival in strictly WHO-defined ET is near-nor-

mal (15-year survival of 80%) and the 10-year risk ofAML or MF less than 1% [20], it would be inappropriate tosuggest that any current treatment modifies the natural his-tory of the disease. Similarly, in WHO-defined PV, the 10-year projected rates for survival, leukemic transformation,and fibrotic progression were >75, 30%

1

phlebotomy

Low-doseaspirin

providedristocetincofactor

activity>3

0%

1

phlebotomyifPV

High-risk(age60yearsand/orpresenceofth

rombosishistory)

Low-doseaspirin1

hydroxyurea

Low-doseaspirin1

phleb

otomy1

hydroxyurea

Low-doseaspirin1

phlebotomyifPV1

interferon-a

High-riskdiseasethatisrefractoryorintolerant

tohydroxyurea

Low-doseaspirin1

interferon-a(age1,000 3 109/L), which pro-motes the development of AvWS. However, clinically rele-vant AvWS can occur even when the platelet count is wellbelow 1,000 3 109/L, and that laboratory evaluation of

AvWS must be performed in the presence of abnormalbleeding, regardless of platelet count [87].

Recommendations: In patients with PV or ET andextreme thrombocytosis, the use of aspirin can lead tobleeding complications because of AvWS; therefore, in thepresence of platelets >1,0003 109/L, screening for risto-cetin cofactor activity is advised and consideration be givento withhold aspirin therapy if the result shows


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benefit in terms of thrombosis prevention but increased therisk of gastrointestinal bleeding) [94].

The lack of anti-thrombotic value from anti-platelet agentsin the above-mentioned PVSG-aspirin study may havebeen influenced by the fact that 27% of the patientsrandomized to the phlebotomyaspirindipyridamole armhad a prior history of thrombosis when compared with 13%in the other arm. This contention was confirmed by themost recent study from the European collaboration study

on low-dose aspirin in polycythemia (ECLAP) [49]. Thestudy enrolled 518 patients with PV in a double-blindrandomized trial to low-dose aspirin (100 mg daily) or pla-cebo. Treatment with aspirin did not increase the incidenceof major bleeding and instead reduced the risk of combinedendpoints for nonfatal myocardial infarction, nonfatalstroke, or death from cardiovascular causes and nonfatalmyocardial infarction, nonfatal stroke, pulmonary embolism,major venous thrombosis, or death from cardiovascularcauses [95].

Summary of randomized studies in ET. Unlike thecase with PV, the PVSG did not carry out large scalerandomized studies in ET. In one of the very few controlledstudies in ET, Cortelazzo et al. [96] randomized 114 mostlyhigh-risk patients to hydroxyurea (n5 56) or not (n5 58).

After 27 months of follow-up, the incidences of thromboticcomplications were 3.6% for hydroxyurea and 24% for nohydroxyurea, although the thrombotic episodes in twopatients in the nonhydroxyurea arm constituted superficialthrombophlebitis. This is the only study, to-date, whichrandomized patients with ET to a drug vs. no drug.

More recently, two studies randomized ET patients tohydroxyurea or anagrelide. In the earlier study [68], 809high-risk patients were given low-dose aspirin plus eitheranagrelide or hydroxyurea. Hydroxyurea was better interms of reducing the risk of arterial thrombosis, majorbleeding, and fibrotic progression. Anagrelide performedbetter in preventing venous thrombosis. In addition, adversedrop out rate was significantly higher in the anagrelide arm.In the second study [97], which was designed as a nonin-feriority trial, 258 previously untreated high-risk patientswere randomized to either anagrelide (n5 122) or hydrox-yurea (n 5 136). After a mean observation time of 2.1years, 75.4% patients on anagrelide and 81.7% on hydrox-yurea normalized their platelet count. There were not signif-icant differences in ET-related events between the twoarms. Adverse drug reactions or poor response led to dis-continuation of the study drug in 19 patients treated withanagrelide and 10 patients treated with hydroxyurea. Trans-formations to myelofibrosis were not reported during thewhole-study period.

Overview of single arm alkylating therapy in PV andET.In a nonrandomized study by the PVSG, treatment withhydroxyurea was associated with a lower incidence of earlythrombosis when compared with a historical cohort treatedwith phlebotomy alone (6.6% vs. 14% at 2 years). Similarly,

the incidence of AML in patients treated with hydroxyurea,when compared with a historical control treated with eitherchlorambucil or radiophosphorus, was significantly lower(5.9% vs. 10.6% vs. 8.3%, respectively, in the first 11 yearsof treatment) [98]. Other studies have confirmed the lowincidence of AML in PV patients treated with hydroxyurea(15.6%) [99101].

Many studies have reported on the use of pipobroman asa single agent in PV [102,103]. In one of these studiesinvolving 163 patients, the drug was effective in more than90% of the patients and median survival exceeded 17years [102]. In the first 10 years, the incidences of throm-botic events, acute leukemia, post-PV MF, and other malig-nancies were 16, 5, 4, and 8%, respectively. A similar retro-

spective study in 164 patients with ET treated with pipobro-man as first-line therapy (starting dose 1 mg/kg/day) andfollowed for a median of 100 months, AML occurred in5.5% of the cases [104]. In another study of 33 youngpatients (


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association in some studies between leukemic transforma-tion and drug therapy in PV or ET.

Recommendations: In addition to low-dose aspirin andphlebotomy in case of PV, high-risk patients with PV or EThad to receive hydroxyurea to minimize their risk of throm-bosis (starting dose 500 mg BID). The dose of hydroxyureais titrated to keep platelet count in the normal range andleukocyte count>23 109/L. However, it is to be noted thatthe recommended platelet target is not based on controlled

evidence. PV or ET patients who are either intolerant or re-sistant to hydroxyurea are effectively managed by INF-a(pegylated preparations preferred) or busulfan. Amongthese two second-line drugs, I prefer the use of INF-a forpatients younger than age 65 years and busulfan in theolder age group, although there is no controlled evidence tosupport or refute such a strategy. Busulfan is started at 4mg/day, withheld in the presence of platelets


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Polycythemia Vera and Essential Thrombocythemia