Polycythemia vera and essential thrombocythemia: 2012 update on diagnosis, risk stratification, and management

Authors

  • Ayalew Tefferi

    Corresponding author
    1. Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, Minnesota
    • Ayalew Tefferi, Division of Hematology, Department of Medicine, Mayo Clinic, 200 First St. SW, Rochester, MN 55905
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  • Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, Minnesota.

    Conflict of interest: Nothing to report.

Abstract

Disease overview: Polycythemia vera (PV) and essential thrombocythemia (ET) are myeloproliferative neoplasms primarily characterized by erythrocytosis and thrombocytosis, respectively. Other disease features include 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 a JAK2 mutation confirms the diagnosis and its absence, combined with normal or increased serum erythropoietin level, excludes the diagnosis. Differential diagnosis of ET had to include chronic myelogenous leukemia and prefibrotic myelofibrosis. A JAK2 mutation 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 thrombotic complications: high-risk is defined by the presence of age >60 years or presence of thrombosis history; low-risk is defined by the absence of both of these two risk factors. Presence of extreme thrombocytosis (platelet count >1,000 × 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 advanced age, leukocytosis, and history of thrombosis.

Risk-adapted therapy: Survival is near-normal in ET and reasonably long in PV. The 10-year risk of leukemic/fibrotic transformation is <1%/1% in ET and <3%/10% in PV. In contrast, the risk of thrombosis exceeds 20%. The main goal of therapy is therefore to prevent thrombohemorrhagic complications and this is effectively and safely accomplished by the use of low-dose aspirin (PV and ET), phlebotomy (PV) and hydroxyurea (high risk PV and ET). Treatment with busulfan or interferon-α is usually effective in hydroxyurea failures. Screening for clinically significant AvWS is recommended before administrating aspirin in the presence of extreme thrombocytosis. Am. J. Hematol. 87:285–293, 2012. © 2012 Wiley Periodicals, Inc.

Disease Overview

Myeloproliferative neoplasms (MPN) constitute one of five categories of myeloid malignancies, according to the World Health Organization (WHO) classification system for hematopoietic tumors (Table I) [1]. “BCR-ABL1-negative MPN” is an operational sub-category of MPN that includes polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF) [2]. All three disorders are characterized by stem cell-derived clonal myeloproliferation but their disease-causing mutations remain unidentified despite a plethora of mutations described beginning in 2005 [3].

Table I. World Health Organization (WHO) classification of myeloid malignancies
  • a

    Acute myeloid leukemia-related precursor neoplasms include “therapy-related myelodysplastic syndrome” and “myeloid sarcoma.”

  • b

    Either mono- or bi-cytopenia: hemoglobin level <10 g/dL, absolute neutrophil count <1.8 × 109/L, or platelet count <100 × 109/L. However, higher blood counts do not exclude the diagnosis in the presence of unequivocal histological/cytogenetic evidence for myelodysplastic syndrome.

  • c

    Genetic rearrangements involving platelet-derived growth factor receptor α/β (PDGFRA/PDGFRB) or fibroblast growth factor receptor 1 (FGFR1).

1. Acute myeloid leukemia (AML) and related precursor neoplasmsa
2. Myeloproliferative neoplasms (MPN)
 2.1.  Classic MPN
  2.1.1. Chronic myelogenous leukemia, BCR-ABL1 positive (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 (2–4% circulating or 5–9% marrow blasts)
  3.4.2. RAEB-2 (5–19% circulating or 10–19% marrow blasts or Auer rods present)
 3.5. MDS associated with isolated del(5q)
 3.6. MDS, unclassifiable
4. 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,cPDGFRB,c or FGFR1c
 5.1. Myeloid and lymphoid neoplasms with PDGFRA rearrangement
 5.2. Myeloid neoplasms with PDGFRB rearrangement
 5.3. Myeloid and lymphoid neoplasms with FGFR1 abnormalities

Almost all patients with PV harbor a JAK2 (Janus kinase 2; 9p24) mutation; approximately 96 and 3% displaying somatic activating mutations in exon 14 (JAK2V617F) and exon 12 of JAK2, respectively [4, 5]. JAK2V617F also occurs in ET and PMF with respective mutational frequencies of 55 and 65% [3]. JAK2 exon 12 mutations are rare in ET or PMF [6]. MPL (myeloproliferative leukemia virus oncogene; 1p34) mutations occur in approximately 4% of ET patients, 8% of PMF patients, and rarely in PV [7]. MPL mutations cluster in exon 10, the most frequent being MPLW515L/K [8–10]. MPLS505N is both a germline (hereditary thrombocythemia) [11, 12] and somatic (ET) mutation [10]. Both JAK2V617F and MPL mutations also occur infrequently in other myeloid malignancies [3]. Conversely, other mutations such as TET2 or IDH mutations are occasionally seen in PV and ET [10, 13–18].

JAK2V617F presence or increased allele burden does not appear to affect survival or leukemic transformation in PV or ET [5, 19, 20]. In ET, the presence of JAK2V617F has been associated with an increased risk of arterial thrombosis and a lower risk of post-ET MF [20, 21]. In PV, a higher JAK2V617F mutant allele burden has been associated with pruritus and fibrotic transformation [19]. In general, JAK2V617F clusters with older age, higher hemoglobin level, leukocytosis, and lower platelet count [5]. JAK2 exon 12 mutation-positive patients usually present with predominantly erythroid myelopoiesis, subnormal serum erythropoietin level, and younger age at diagnosis, but were prognostically similar to JAK2V617F [22]. MPL mutations have been inconsistently [23] associated with older age, female gender, lower hemoglobin level, and higher platelet count [10, 14, 15]; no associations with survival or leukemic transformation have been reported [10, 14].

Diagnosis

Diagnosis of PV and ET is currently according to WHO criteria and based on a composite assessment of clinical and laboratory features (Table II) [24]. Figure 1 provides a practical diagnostic algorithm that begins with peripheral blood mutation screening for JAK2V617F. The laboratory detection of JAK2V617F is highly sensitive (97% sensitivity) and virtually 100% specific for distinguishing PV from other causes of increased hematocrit [25, 26]; the possibility of false positive or false negative mutation test result is effectively addressed by the concomitant measurement of serum erythropoietin (Epo) level, which is expected to be subnormal in more than 85% of patients with PV [27]. A subnormal serum Epo level in the absence of JAK2V617F mandates additional mutational analysis for JAK2 exon 12 mutation to capture some of the approximately 3% of PV patients who are JAK2V617F-negative [4]. Bone marrow examination is not essential for the diagnosis of PV because patients who otherwise fulfill the diagnostic criteria for PV are labeled as having PV even if they display substantial bone marrow fibrosis (Table II) [24].

Figure 1.

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

Table II. World Health Organization (WHO) Diagnostic Criteria for Polycythemia Vera, Essential Thrombocythemia and Primary Myelofibrosis
2008 WHO Diagnostic Criteria
  Polycythemia veraa Essential thrombocythemiaa Primary myelofibrosisa
  • BM, bone marrow; Hgb, hemoglobin; Hct, hematocrit; Epo, erythropoietin; EEC, endogenous erythroid colony; WHO, World Health Organization; CML, chronic myelogenous leukemia; PV, polycythemia vera; PMF, primary myelofibrosis; MDS, myelodysplastic syndromes; LDH, lactate dehydrogenase.

  • a

    PV diagnosis requires meeting either both major criteria and one minor criterion or the first major criterion and two minor criteria. ET diagnosis requires meeting all four major criteria. PMF diagnosis requires meeting all three major criteria and two minor criteria.

  • b

    or Hgb or Hct >99th percentile of reference range for age, sex, or altitude of residence or red cell mass >25% above mean normal predicted or Hgb >17 g/dL (men)/>5 g/dL (women) if associated with a sustained increase of ≥2 g/dL from baseline that cannot be attributed to correction of iron deficiency.

  • c

    Small to large megakaryocytes with aberrant nuclear/cytoplasmic ratio and hyperchromatic and irregularly folded nuclei and dense clustering.

  • d

    or In the absence of reticulin fibrosis, the megakaryocyte changes must be accompanied by increased marrow cellularity, granulocytic proliferation, and often decreased erythropoiesis (i.e., pre-fibrotic PMF).

Major criteria1Hgb >18.5 g/dL (men), >16.5 g/dL (women), orb1Platelet count ≥450 × 109/L1Megakaryocyte proliferation and atypiac accompanied by either reticulin and/or collagen fibrosis, ord
2Presence of JAK2V617F or JAK2 exon 12 mutation2Megakaryocyte proliferation with large and mature morphology2Not meeting WHO criteria for CML, PV, MDS, or other myeloid neoplasm
3Not meeting WHO criteria for CML, PV, PMF, MDS, or other myeloid neoplasm3Demonstration of JAK2V617F or other clonal marker or no evidence of reactive marrow fibrosis
4Demonstration of JAK2V617F or other clonal marker or no evidence of reactive thrombocytosis
Minor criteria1BM trilineage myeloproliferation 1Leukoerythroblastosis
2Subnormal serum Epo level2Increased serum LDH level
3EEC growth3Anemia
4Palpable splenomegaly

When evaluating thrombocytosis, the detection of JAK2V617F confirms the presence of an underlying MPN but its absence does not rule out the possibility since up to 40% of patients with ET might be JAK2V617F-negative [28]. It is also important to note that other JAK2V617F-positive MPN (or MDS/MPN) can mimic ET in their presentation; these include prefibrotic PMF [29] and refractory anemia with ring sideroblasts with marked thrombocytosis (RARS-T) [18]. Therefore, bone marrow examination is often necessary to make an accurate morphologic diagnosis of ET and distinguish it from other myeloid neoplasms, especially from prefibrotic PMF; megakaryocytes in ET are large and mature-appearing, whereas those in prefibrotic PMF display abnormal maturation with hyperchromatic and irregularly folded nuclei [30]. A recent large international study confirmed the prognostic relevance of distinguishing ET from pre-fibrotic PMF [20]. In the absence of JAK2V617F, the possibility of CML is readily addressed by BCR-ABL1 mutation screening but it is also to be noted that megakaryocytes in CML (small and hypolobulated) are easily distinguished from those of ET [31]. The diagnosis of post-PV or post-ET MF had to adhere to criteria recently published by the International Working Group for MPN Research and Treatment (IWG-MRT; Table III) [32].

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]
  1. Grade 2–3 according to the European classification: [114] diffuse, often coarse fiber network with no evidence of collagenization (negative trichrome stain) or diffuse, coarse fiber network with areas of collagenization (positive trichrome stain). Grade 3–4 according to the standard classification: [115] diffuse and dense increase in reticulin with extensive intersections, occasionally with only focal bundles of collagen and/or focal osteosclerosis or diffuse and dense increase in reticulin with extensive intersections with coarse bundles of collagen, often associated with significant osteosclerosis.

Criteria for post-polycythemia vera myelofibrosis
Required criteria:
1Documentation of a previous diagnosis of polycythemia vera as defined by the WHO criteria (see Table II)
2Bone marrow fibrosis grade 2–3 (on 0–3 scale) or grade 3–4 (on 0–4 scale) (see footnote for details)
Additional criteria (two are required):
1Anemia or sustained loss of requirement for phlebotomy in the absence of cytoreductive therapy
2A leukoerythroblastic peripheral blood picture
3Increasing 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
4Development of ≥1 of three constitutional symptoms: >10% weight loss in 6 months, night sweats, unexplained fever (>37.5°C)
Criteria for post-essential thrombocythemia myelofibrosis
Required criteria:
1Documentation of a previous diagnosis of essential thrombocythemia as defined by the WHO criteria (see Table II)
2Bone marrow fibrosis grade 2–3 (on 0–3 scale) or grade 3–4 (on 0–4 scale) (see footnote for details)
Additional criteria (two are required):
1Anemia and a ≥2 g/dL decrease from baseline hemoglobin level
2A leukoerythroblastic peripheral blood picture
3Increasing 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
4Increased lactate dehydrogenase
5Development of ≥1 of three constitutional symptoms: >10% weight loss in 6 months, night sweats, unexplained fever (>37.5°C)

Risk Stratification

Current risk stratification in PV and ET is designed to estimate the likelihood of thrombotic complications and not necessarily survival or risk of leukemic/fibrotic transformation (Table IV) [33]. Age ≥60 years and history of thrombosis are the two risk factors used to classify patients with PV or ET into low (0 risk factors) and high (1 or 2 risk factors) risk groups (Table IV) [34–37]. In addition, because of the potential risk for bleeding, low-risk patients with extreme thrombocytosis (platelet count >1,000 × 109/L) are considered separately (Table IV) [38]. The presence of cardiovascular risk factors is currently not taken under consideration during formal risk categorization.

Table IV. Risk Stratification in Polycythemia Vera and Essential Thrombocythemia and Risk-Adopted Therapy
Risk categoriesEssential thrombocythemiaPolycythemia veraManagement during pregnancy
Low-risk without extreme thrombocytosis (age <60 years and no thrombosis history)Low-dose aspirinLow-dose aspirin + phlebotomyLow-dose aspirin + phlebotomy if PV
Low-risk with extreme thrombocytosis (platelets >1,000 × 109/L)Low-dose aspirin provided ristocetin cofactor activity >30%Low-dose aspirin provided ristocetin cofactor activity >30% + phlebotomyLow-dose aspirin provided ristocetin cofactor activity >30% + phlebotomy if PV
High-risk (age ≥60 years and/or presence of thrombosis history)Low-dose aspirin + hydroxyureaLow-dose aspirin + phlebotomy + hydroxyureaLow-dose aspirin + phlebotomy if PV + interferon-α
High-risk disease that is refractory or intolerant to hydroxyureaLow-dose aspirin + interferon-α (age <65 years) or busulfan (age ≥65 years)Low-dose aspirin + phlebotomy + interferon-α (age <65 years) or busulfan (age ≥65 years)Low-dose aspirin + phlebotomy if PV + interferon-α

Risk factors for shortened survival in both PV and ET include history of thrombosis, leukocytosis, and advanced age [34–36, 39]. During a recent international study of over 1,000 patients with ET, the prognostically detrimental effect (on survival, leukemic transformation, and fibrotic progression) of prefibrotic morphology was demonstrated and the study also identified age >60 years, leukocyte count >11 × 109/L, anemia, and thrombosis history as additional independent risk factors for survival [20]. The study also identified older age, anemia, and absence of JAK2V617F as risk factors for fibrotic progression and history of thrombosis and extreme thrombocytosis as risk factors for leukemic transformation. Using age ≥60 years, hemoglobin below normal value and leukocyte count >15 × 109/L, one study demonstrated a median survival of >20 years in the absence of all three risk factors and ∼9 years in the presence of two of the three risk factors [39]. A similar strategy in PV revealed median survivals of ∼23 and 9 years in the absence of advanced age and leukocytosis or presence of both risk factors, respectively [36]. Leukocytosis has also been associated with leukemic [36] and JAK2V617F allele burden with fibrotic [19] transformation in PV [19]. The relationship between thrombosis and leukocytosis [40, 41], thrombosis, and JAK2V617F [5] or pregnancy-associated complications and JAK2V617F [42–44] have been examined by different groups of investigators with findings that were conflicting and inconclusive.

Risk-Adapted therapy

Because survival in strictly WHO-defined ET is near-normal (15-year survival of ∼80%) and the 10-year risk of AML or MF less than 1% [20], it would be inappropriate to suggest that any current treatment modifies the natural history of the disease. Similarly, in WHO-defined PV, the 10-year projected rates for survival, leukemic transformation, and fibrotic progression were >75, <5, and <10%, respectively [45]. In contrast, the risk of thrombosis, in both PV and ET, exceeds 20% and a substantial proportion of patients experience vasomotor disturbances (e.g., headaches, lightheadedness, acral paresthesias, erythromelalgia, atypical chest pain) [46], and in case of PV, pruritus [47]. In addition, in both PV and ET, some patients may develop acquired von Willebrand syndrome (AvWS), especially in the presence of extreme thrombocytosis (platelets >1,000 × 109/L), and be at risk for aspirin-associated bleeding [48]. Accordingly, the goal of current therapy in PV and ET is primarily to prevent thrombohemorrhagic complications, without increasing bleeding risk, and secondarily to control the aforementioned symptoms. In this regard, treatment is tailored to individual patients according to their risk for thrombosis or bleeding (Table IV).

Management of low-risk PV or ET, in the absence of extreme thrombocytosis

Controlled studies have confirmed the anti-thrombotic value of low-dose aspirin in PV, among all risk categories [49]. In a retrospective study, aspirin use has also been reported to be beneficial in JAK2V617F-positive low-risk ET, in preventing venous thrombosis, and also in patients with cardiovascular risk factors, in preventing arterial thrombosis [50]. There is also uncontrolled evidence that supports phlebotomy for all patients with PV [51] and two recent studies suggested a hematocrit target of either <55% [37] or <48% [45] as being acceptable in patients receiving aspirin therapy.

Low-dose aspirin therapy has also been shown to be effective in alleviating vasomotor (microvascular) disturbances associated with ET or PV [52]. Vasomotor symptoms in ET constitute headaches, lightheadedness, transient neurologic or ocular disturbances, tinnitus, atypical chest discomfort, paresthesias, and erythromelalgia (painful and burning sensation of the feet or hands associated with erythema and warmth). These symptoms are believed to stem from small vessel-based abnormal platelet-endothelial interactions [53]. Histopathological studies in erythromelalgia have revealed platelet-rich arteriolar microthrombi with endothelial inflammation and intimal proliferation accompanied by increased platelet consumption that is coupled with abundant VW factor deposition [53–55].

Aspirin therapy is also considered to be adequate, and potentially useful in preventing complications during pregnancy, especially in JAK2V617F-positive cases [43, 44, 56]. First-trimester spontaneous miscarriage rate in ET or PV (>30%) [57–59] is significantly higher than the 15% rate expected in the control population and does not appear to be influenced by specific treatment [60]. Late obstetric complications as well as maternal thrombohemorrhagic events are relatively infrequent and platelet count usually decreases substantially during the second and third trimesters [61]. Neither platelet count nor cytoreductive therapy appears to affect either maternal morbidity or pregnancy outcome. Therefore, cytoreductive treatment is currently not recommended for low-risk women with ET that are either pregnant or wish to be pregnant.

Pruritus occurs in the majority of patients with PV (and a substantial number with PMF) [62] and is often exacerbated by hot bath [47]. In the low-risk disease setting, management had to start with simple nondrug measures, such as avoidance of precipitating conditions, dry skin, and temperature control of one's environment and water used for bathing. Etiology of PV-associated pruritus remains to be determined and treatment responses to antihistamines have been both unpredictable and variable [47]. In contrast, recent studies have suggested a greater than 50% response rate in PV-associated pruritus treated with paroxetine (20 mg/day), which is a selective serotonin reuptake inhibitor [63]. Other treatment modalities that have been reported to be useful in PV-associated pruritus include JAK inhibitors [64], IFN-α [65] and narrow-band ultraviolet B phototherapy [66].

Recommendations: I recommend the use low-dose aspirin (81 mg/day; range 40–100 mg/day) in all patients with low-risk PV or ET, provided there are no major contraindications. In PV patients, I prefer a hematocrit target of 45% but do not object to a higher target of as high as 50%, in aspirin-treated patients. I manage, pregnant patients or women of child-bearing potential, in the same general manner and I do not use platelet-lowering agents or heparin therapy in the setting of low-risk disease. In the presence of aspirin-resistant symptoms, it is reasonable to utilize alternative anti-platelet agents such as clopidogrel (75 mg/day) alone or in combination with aspirin [67], as long as patients are monitored closely for drug-side effects. One might also consider platelet-lowering agents (e.g., hydroxyurea) in such aspirin-refractory cases, but the target platelet count in this instance should be the level at which relief of symptoms is observed, and not necessarily 400 × 109/L. I no longer use anagrelide for the treatment of PV or ET because of its reported association with increased risk of arterial thrombosis, major bleeding and fibrotic progression [68]. Based on preliminary data from ongoing anti-JAK2 clinical trials, I suspect that JAK inhibitors might become the most effective agents for the treatment of MPN-associated pruritus [64, 69].

Management of low-risk PV or ET patients with extreme thrombocytosis or abnormal bleeding diathesis

Bleeding diathesis in ET or PV is currently believed to be multi-factorial in etiology. Laboratory evidence of AvWS occurs in the majority of patients with ET or PV and is characterized by the loss of large von Willebrand factor multimers, linked to their increased proteolysis by the ADAMTS13 cleaving protease, in a platelet count-dependent fashion [38, 70–73]. This results in a functionally more relevant defect that may not be apparent when measuring VWF:Ag and FVIII levels alone [38, 74] and requires the use of assays that assess VWF function (e.g., ristocetin cofactor activity; VWF:RCoA) [75–77]. Other causes of platelet dysfunction in ET or PV include acquired storage pool deficiency, increased platelet activation, decreased adrenergic receptor expression, impaired response to epinephrine, and decreased platelet membrane glycoprotein receptor expression [78–86].

Based on the above, the use of aspirin in both PV and ET requires caution, especially in the presence of extreme thrombocytosis (platelet count >1,000 × 109/L), which promotes the development of AvWS. However, clinically relevant AvWS can occur even when the platelet count is well below 1,000 × 109/L, and that laboratory evaluation of AvWS must be performed in the presence of abnormal bleeding, regardless of platelet count [87].

Recommendations: In patients with PV or ET and extreme thrombocytosis, the use of aspirin can lead to bleeding complications because of AvWS; therefore, in the presence of platelets >1,000 × 109/L, screening for ristocetin cofactor activity is advised and consideration be given to withhold aspirin therapy if the result shows <30% activity. On the other hand, extreme thrombocytosis neither defines high-risk disease nor warrants the use of cytoreductive therapy.

Management of high-risk PV or ET

Summary of randomized studies in PV.

In the first controlled study in PV, the PV study group (PVSG) randomized 431 patients, between 1967 and 1974, for treatment with either phlebotomy alone or phlebotomy with either oral chlorambucil or intravenous radioactive phosphorus (P32) [88]. The results significantly favored treatment with phlebotomy alone with a median survival of 12.6 years when compared with 10.9 and 9.1 years for treatment with radiophosphorus and chlorambucil, respectively. The difference in survival was attributed to an increased incidence of AMLin patients treated with chlorambucil or radiophosphorus when compared with those treated with phlebotomy alone (13.2% vs. 9.6% vs. 1.5% over a period of 13–19 years) [89]. Furthermore, 3.5% of the patients treated with chlorambucil developed large cell lymphoma and theincidence of gastrointestinal and skin cancer was increased inthose patients treated with either chlorambucil or radiophosphorus.

The European Organization for Research on Treatment of Cancer (EORTC) randomized 293 patients between 1967 and 1978 for treatment with either radiophosphorus or oral busulfan [90]. The results favored busulfan in terms of both first remission duration (median, 4 years vs. 2 years) and overall survival (10-year survival rates of 70% vs. 55%). At a median follow-up period of 8 years, there was no significant difference in the risk of leukemic transformation (2% vs. 1.4%), nonhematologic malignancy (2.8% vs. 5%), vascular complications (27% vs. 37%), or transformation into post-PV MF (4.8% vs. 4.1%) between the two arms.

Other randomized studies in PV have compared hydroxyurea against pipobroman (the first report showed a significant difference favoring pipobroman in the incidence of transformation into post-PV MF but no difference in survival, incidence of thrombosis, or the rate of leukemic conversion; however, a longer-term follow-up revealed a shorter survival, an increased risk of leukemic transformation, and a lower risk of post-PV MF, associated with pipobroman therapy) [91, 92] radiophosphorus alone or with HU (no difference in survival, incidence of thrombosis, or risk of transformation into post-PV MF but radiophosphorus alone was associated with significantly less incidences of both acute leukemia and other cancers) [93], and radiophosphorus plus phlebotomy against phlebotomy plus high-dose aspirin (900 mg/day) in combination with dipyridamole (225 mg/day) (the addition of antiplatelet agents provided no benefit in terms of thrombosis prevention but increased the risk of gastrointestinal bleeding) [94].

The lack of anti-thrombotic value from anti-platelet agents in the above-mentioned PVSG-aspirin study may have been influenced by the fact that 27% of the patients randomized to the phlebotomy–aspirin–dipyridamole arm had a prior history of thrombosis when compared with 13% in the other arm. This contention was confirmed by the most recent study from the European collaboration study on low-dose aspirin in polycythemia (ECLAP) [49]. The study enrolled 518 patients with PV in a double-blind randomized trial to low-dose aspirin (100 mg daily) or placebo. Treatment with aspirin did not increase the incidence of major bleeding and instead reduced the risk of combined endpoints for “nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes” and “nonfatal myocardial infarction, nonfatal stroke, pulmonary embolism, major venous thrombosis, or death from cardiovascular causes” [95].

Summary of randomized studies in ET.

Unlike the case with PV, the PVSG did not carry out large scale randomized studies in ET. In one of the very few controlled studies in ET, Cortelazzo et al. [96] randomized 114 mostly high-risk patients to hydroxyurea (n = 56) or not (n = 58). After 27 months of follow-up, the incidences of thrombotic complications were 3.6% for hydroxyurea and 24% for no hydroxyurea, although the “thrombotic” episodes in two patients in the nonhydroxyurea arm constituted superficial thrombophlebitis. This is the only study, to-date, which randomized patients with ET to a drug vs. no drug.

More recently, two studies randomized ET patients to hydroxyurea or anagrelide. In the earlier study [68], 809 high-risk patients were given low-dose aspirin plus either anagrelide or hydroxyurea. Hydroxyurea was better in terms of reducing the risk of arterial thrombosis, major bleeding, and fibrotic progression. Anagrelide performed better in preventing venous thrombosis. In addition, adverse drop out rate was significantly higher in the anagrelide arm. In the second study [97], which was designed as a noninferiority trial, 258 previously untreated high-risk patients were randomized to either anagrelide (n = 122) or hydroxyurea (n = 136). After a mean observation time of 2.1 years, 75.4% patients on anagrelide and 81.7% on hydroxyurea normalized their platelet count. There were not significant differences in ET-related events between the two arms. Adverse drug reactions or poor response led to discontinuation of the study drug in 19 patients treated with anagrelide and 10 patients treated with hydroxyurea. Transformations to myelofibrosis were not reported during the whole-study period.

Overview of single arm alkylating therapy in PV and ET.

In a nonrandomized study by the PVSG, treatment with hydroxyurea was associated with a lower incidence of early thrombosis when compared with a historical cohort treated with 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 either chlorambucil or radiophosphorus, was significantly lower (5.9% vs. 10.6% vs. 8.3%, respectively, in the first 11 years of treatment) [98]. Other studies have confirmed the low incidence of AML in PV patients treated with hydroxyurea (1–5.6%) [99–101].

Many studies have reported on the use of pipobroman as a single agent in PV [102, 103]. In one of these studies involving 163 patients, the drug was effective in more than 90% of the patients and median survival exceeded 17 years [102]. In the first 10 years, the incidences of thrombotic events, acute leukemia, post-PV MF, and other malignancies were 16, 5, 4, and 8%, respectively. A similar retrospective study in 164 patients with ET treated with pipobroman as first-line therapy (starting dose 1 mg/kg/day) and followed for a median of 100 months, AML occurred in 5.5% of the cases [104]. In another study of 33 young patients (<50 years of age) with ET treated with pipobroman only and followed for a median of almost 16 years, the complete remission rate was 94% and only one patient (3%) developed AML, whereas no patient experienced thrombotic complications [105].

Favorable outcome has also been reported in single arm studies using oral busulfan [106, 107]. In 65 busulfan-treated patients with PV followed between 1962 and 1983, median survival was 19 years in patients whose disease was diagnosed before age 60 years [106]. Only two patients (3.5%) treated with busulfan alone developed acute leukemia. A similar percentage (3%) developed the complication in another study involving ET patients [108]. These figures were well within the baseline risk that is intrinsic to the diseases and no different than those seen with hydroxyurea [108]. The safety and efficacy of busulfan treatment in ET was recently underlined by a long-term study of 36 patients above age 60 years of age [109]; no instances of AML or other malignancies were documented after a median follow-up of 72 months.

Interferon therapy.

It is now well established that IFN-α can control erythrocytosis or thrombocytosis in the majority patients with PV or ET (usual dose is 3 million units SC thrice a week) [110]. A similar degree of benefit is appreciated in terms of reduction in spleen size or relief from pruritus. Two recent studies of pegylated INF-α (∼90 μg SC weekly) in PV and ET reported hematologic remissions of ∼80% accompanied by decreases in JAK2V617F allele burden (complete molecular remission rate of 5–10%) [111, 112]. In one of the two studies [111], 77 cases were evaluable after a median follow up of 21 months and 76 and 70% of patients with ET or PV, respectively, achieved a complete hematologic remission, mostly in the first 3 months; side effects were recorded in 96% of the patients and 22% had discontinued treatment.

There is no hard data that implicates hydroxyurea or busulfan as being leukemogenic in PV or ET.

There are, to date, no controlled studies that implicate either hydroxyurea or busulfan as being leukemogenic in either ET or PV. Similarly, the two largest noncontrolled studies in ET [39] and PV [101] do not support the concern that leukemia might arise from the use of hydroxyurea and there is additional evidence to that effect from long-term studies of patients receiving hydroxyurea for sickle cell disease [113]. The evidence for busulfan leukemogenicity in the context of treatment for PV or ET is equally weak and inappropriately extrapolated from older patients with advanced phase disease and exposed to multiple cytoreductive drugs. The recurrent flaw in data interpretation, when it comes to examining the relationship between leukemic drugs and leukemic transformation, is best illustrated by the largest prospective/retrospective study, to date, in PV (n = 1,638) [101]. At a median follow-up of 8.4 years from diagnosis, only 1.3% of the patients developed AML. When the authors compared the patients who transformed to those who did not, the former were older and more likely to have leukocytosis (known risk factor for leukemic transformation) at time of diagnosis or registration to the central database. They also had significantly longer disease duration and were more likely to have been treated with multiple drugs. In other words, exposure to alkylating agents other than hydroxyurea probably selects patients who are at a higher risk of leukemic transformation because of older age, longer disease duration and intrinsic aggressive disease biology. This, in my opinion, is the reason for the apparent association in some studies between leukemic transformation and drug therapy in PV or ET.

Recommendations: In addition to low-dose aspirin and phlebotomy in case of PV, high-risk patients with PV or ET had to receive hydroxyurea to minimize their risk of thrombosis (starting dose 500 mg BID). The dose of hydroxyurea is titrated to keep platelet count in the normal range and leukocyte count >2 × 109/L. However, it is to be noted that the recommended platelet target is not based on controlled evidence. PV or ET patients who are either intolerant or resistant to hydroxyurea are effectively managed by INF-α (pegylated preparations preferred) or busulfan. Among these two second-line drugs, I prefer the use of INF-α for patients younger than age 65 years and busulfan in the older age group, although there is no controlled evidence to support or refute such a strategy. Busulfan is started at 4 mg/day, withheld in the presence of platelets <100 × 109/L or WBC <3 × 109/L, and the dose is reduced to 2 mg/day if the corresponding levels are <150 × 109/L and <5 × 109/L. I usually start pegylated IFN-α at 50 mcg once a week and titrate up to 180 mcg once a week if tolerated.

Concluding Remarks

In strictly WHO-defined ET, a recent study has revealed that prognosis is even better than previously assumed [20]. This has been attributed to the possibility that earlier studies unknowingly included patients with prefibrotic MF. Furthermore, disease complications in ET are effectively and safely managed by treatment with low-dose aspirin and, in case of high-risk disease, hydroxyurea. The overall scenario is similar in PV and concerns about drug leukemogenicity involving hydroxyurea or busulfan are largely based on rumors rather facts. Therefore, the following two things are required to justify the risk of unknown long-term health effects of nonconventional drug therapy such as with IFN-α or JAK inhibitors: (i) experimental or in vivo demonstration of disease-modifying activity and (ii) controlled studies to show added value.

I would also argue that hydroxyurea-refractory PV or ET is often adequately managed by treatment with busulfan or IFN-α. Therefore, there is currently no compelling evidence to support the need for JAK inhibitor therapy in the majority of patients with PV or ET, regardless of whether or not they are hydroxyurea-refractory. However, there are occasional patients who are likely to benefit from JAK inhibitor, as opposed to conventional drug, therapy, including those with intractable pruritus, severe constitutional symptoms, or marked splenomegaly [64]. In this regard, it makes more sense to pursue a more specific JAK2 inhibitor, such as SAR302503 [69], rather than a less specific JAK1/2 inhibitor, such as ruxolitinib or CYT387 [64]. Even then, it is important to remember that leukemic transformation in PV or ET usually arises from JAK2V617F-negative progenitors and that the presence of JAK2V617F might actually be protective against fibrotic progression [20]. Therefore, drug-induced reduction in JAK2V617F allele burden might not necessarily translate into long-term benefit in ET or PV.

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