Polycythaemia vera (PV), essential thrombocythaemia (ET) and idiopathic myelofibrosis (IMF), known collectively as the classic myeloproliferative disorders (MPDs), are clonal disorders originating from a neoplastic haemopoietic stem cell. They are most common in middle or older age, and share several features, including a potential to transform into acute leukaemia and into each other. Treatment of PV and ET can greatly influence prognosis, hence the importance
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| Figure 4.1 Diagrammatic representation of the JAK2 tyrosine kinase. The domain structure of the protein is outlined. The V617F (Val617Phe) substitution found in the majority of MPDs (arrow) disrupts the inhibitory pseudokinase domain (JH2) and leads to constitutive activation of the kinase. |
of differentiating them from other conditions associated with polycythaemia or a raised platelet count (thrombocytosis), the prognosis and treatment of which are different. Myelofibrosis may arise de novo (IMF) or result from progression of PV or ET. Recently, acquired activating mutations in the gene for the tyrosine kinase JAK2, leading to a valine to phenylalanine substitution at amino acid 617 (V617F), were identified in nearly all cases of PV and approximately half the cases of ET and IMF (Fig. 4.1). The abnormally active mutant JAK2 is thought to amplify signalling downstream of cytokine receptors and thus to have a central role in the pathogenesis of MPDs.
Polycythaemia
An elevation in packed cell volume (PCV) defines polycythaemia (Fig. 4.2). A raised PCV (> 0.51 in men, > 0.48 in women) needs to be confirmed on a specimen taken without prolonged venous stasis (tourniquet), and patients with a persistently raised PCV may
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Figure 4.2 Raised pack cell volume (PCV) in a patient
with polycythaemia vera
(left) compared to a blood sample from a person
with a normal PCV (right). |
have to be investigated to exclude or confirm a diagnosis of PV (Fig. 4.1).
Estimation of total red cell mass or volume has been a key inves- tigation in determining the cause of a raised PCV. Red cell mass is best expressed as the percentage difference between the measured value and that predicted for the patient’s height and weight (derived from published tables). Red cell mass measurements > 25% above the predicted value constitute true polycythaemia, which can be subclassified into aetiological categories (Box 4.1). When the PCV is raised but the red cell mass is not, the condition is known as ap- parent polycythaemia, and is secondary to a reduction in plasma volume. The role of red cell mass estimation is changing with the advent of molecular testing for JAK2 mutations.
Polycythaemia vera
Presentation can be incidental but is classically associated with a history of occlusive vascular lesions (stroke, transient ischaemic attack, ischaemic digits, venous thrombosis), headache, mental clouding, facial redness, itching, abnormal bleeding or gout.
Investigations
A raised white cell count (> 10 × 109/L neutrophils) or a raised platelet count (>400 × 109/L) suggest primary polycythaemia, especially if both are raised in the absence of an obvious cause, such as infection or carcinoma. Serum ferritin concentration should be determined as iron deficiency may mask a raised PCV, resulting in a missed di- agnosis of PV. If the spleen is not palpable, splenic size should be determined by ultrasonography. Red cell mass should be measured to confirm true polycythaemia, unless a very high PCV (> 0.60 in men or > 0.56 in women) is present, as this invariably predicts a raised value (Box 4.2). Secondary polycythaemia should be excluded by confirming the absence of hypoxia and of a high serum erythropoietin concentration. Bone marrow cytogenetic analysis should be performed to identify acquired chromosomal abnormalities (Fig. 4.3). In addition, erythroid colony growth from blood in the absence of added erythropoietin culture from peripheral blood would support the diagnosis. However, this is a specialist test and not widely available. Finally, molecular testing for the JAK2 V617F mutation has rapidly become a key investigation, as it is present in most cases of PV. A proposed set of diagnostic criteria based on these investigations is outlined in Box 4.3. As the JAK2 mutation is present in the vast majority of cases, the diagnosis of PV is usually made on the basis of diagnostic criteria A1 + A2 + A4 (Box 4.3).
Treatment
Repeated venesection to maintain the PCV at < 0.45 has been shown to reduce the risk of thrombotic episodes in PV, as has the administration of low-dose aspirin (Box 4.4). Venesection has to be frequent at first, but is eventually needed only every 6–10 weeks in most patients. If thrombocytosis is present, concurrent therapy to maintain )the platelet count to < 400 × 109/L is necessary. Hydroxyurea (0.5–
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| Figure 4.3 Deletion within the long arm of chromosome 20 in polycythaemia vera demonstrated by fluorescence in situ hybridization. ■, Probe for centromere of chromosome 20; ■, probe for part of long arm of chromosome 20. |
1.5 g daily) is recommended for this purpose and is not thought to have a pronounced leukaemogenic potential. Some physicians use interferon-α in preference to hydroxyurea in younger patients, as this drug is theoretically even less likely to carry a leukaemogenic risk. Anagrelide can specifically reduce the platelet count but should be used with caution (see under Essential thrombocythaemia). Treatment with radioactive phosphorus (32P) has been superseded because of the additional risk of inducing malignancies, including acute leukaemia, in later life, although oral busulfan may be a con- venient drug in elderly patients.
Prognosis
Adequately treated patients with PV have a long median survival (> 10 years) but there is also a 20% incidence of transformation to myelofibrosis and 5% to acute leukaemia. The incidence of leukaemia is fur- ther increased in those who have transformed to myelofibrosis and in those treated with 32P radiotherapy or multiple cytotoxic agents.
Secondary polycythaemia
Many causes of secondary polycythaemia have been identified, the commonest being chronic hypoxaemia and renal diseases, the kidneys being the site of erythropoietin production (Box 4.1). In recent years, the misuse of drugs such as erythropoietin and anabolic steroids has become a factor that also needs to be considered. Investigations aim to determine the underlying disorder to which the polycythaemia is secondary.
Treatment
Treatment is aimed at removing the underlying cause when practi- cable. In most cases of secondary polycythaemia, the risk of vascular occlusion is much less pronounced than in PV, and venesection is usually undertaken only in patients with a very high PCV. At this level, the harmful effects of increased viscosity outweigh the oxygen-carrying benefits of polycythaemia, and reduction to a PCV of 0.50–0.52 may result in an improved cardiopulmonary function. In practice, the symptoms experienced by individual patients often dictate the target PCV. In polycythaemia associated with renal le- sions or other tumours, the PCV should generally be reduced to < 0.45.
Apparent polycythaemia
In apparent or relative polycythaemia, red cell mass is not increased and the raised PCV is secondary to a decrease in plasma volume. An association exists with smoking, alcohol excess, obesity, diuretics and hypertension.
Treatment
The need for treatment is uncertain. Lowering the PCV by venesec- tion is undertaken only in patients who have a significantly increased risk of vascular complications for other reasons. On follow-up, up to one-third of patients spontaneously revert to a normal PCV.
Thrombocytosis
A raised platelet count (thrombocytosis) most commonly represents a reactive response to one or more of a diverse group of stimuli such as iron deficiency, inflammation or infection. Additionally, thrombocytosis can be due to one of several clonal blood disorders (Box 4.5).
Essential thrombocythaemia
A persisting platelet count > 600 × 109/L is the central diagnostic fea- ture, but other reactive and clonal causes of a raised platelet count need to be excluded before a diagnosis of ET can be made. The diagnosis should not be missed, however, as, unlike reactive thrombocytosis, where the risk is small, ET carries a high risk of occlusive vascular events.
Laboratory investigations
The JAK2 V617F mutation is found in about half of cases with this disorder. In such cases, if PV and IMF can be ruled out, a diagnosis of ET can confidently be made. In the absence of JAK2 V617F, investigations will aim to exclude other causes of a raised platelet count. Apart from a full blood count and blood film, these investigations should include the erythrocyte sedimentation rate, serum C reac-
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| Bone marrow trephine biopsy from a patient with essential thrombocythaemia |
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| Figure 4.4 Bone marrow trephine biopsy from a patient with essential thrombocythaemia showing clustering of megakaryocytes (arrows) |
tive protein, serum ferritin and bone marrow aspirate, trephine and cytogenetic analysis (Fig. 4.4). Trephine histology can often reveal features such as clusters of large megakaryocytes that are suggestive of ET, and although cytogenetics are generally normal in ET, certain abnormalities may favour a diagnosis of myelodysplasia or help to exclude a diagnosis of chronic myeloid leukaemia.
Presentation and prognosis
Between 30% and 50% of patients with ET have microvascular occlusive events, such as burning pain in the extremities (erythromelalgia) or digital ischaemia (Fig. 4.5), major vascular occlusive events, or haemorrhage at presentation. These are most pronounced in the elderly, in whom the risk of stroke, myocardial infarction or other vascular occlusion is high if left untreated. Patients with pre-existing vascular disease will also be at higher risk of such complications. The risk in young patients is lower, although major life-threaten-
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| Figure 4.5 Toe ischaemia in a patient with essential thrombocythaemia. |
ing events can still occur. In a minority of patients, transformation to myelofibrosis or acute leukaemia can occur, usually after many years.
Treatment and survival
All patients should receive daily low-dose aspirin, unless contraindi- cated because of allergy, bleeding or peptic ulceration. This reduces the risk of vascular occlusion but may increase the risk of haemorrhage, particularly at very high platelet counts.
Reduction of the platelet count with cytoreductive agents (daily hydroxyurea, or intermittent low-dose busulfan in elderly people) reduces the incidence of vascular complications and appreciably improves survival in older patients (from a median of about 3 years in untreated patients to 10 years or more in treated patients). Anagrelide is a platelet-specific agent, but as it appears to be less effective in reducing venous thromboses and to marginally increase the risk of transformation to myelofibrosis, it should be used as a second line agent. Interferon-α has also been used and is particularly useful in pregnancy.
Idiopathic myelofibrosis
The main features are bone marrow fibrosis, extramedullary hae- mopoiesis (production of blood cells in organs other than the bone marrow), splenomegaly and a leucoerythroblastic blood picture (im- mature red and white cells in the blood) (Fig. 4.6). Good evidence exists that the fibroblast proliferation is secondary and not part of the clonal process. In some patients, the fibrosis is accompanied by new bone formation (osteomyelosclerosis). IMF needs to be distinguished from causes of secondary myelofibrosis (see below).
Presentation
IMF can have a long pre-clinical period and, in some cases, patients may have had undiagnosed PV or ET. Although the diagnosis may be made in asymptomatic patients, the absence of a palpable spleen at presentation is rare. Usual presenting features are abdominal full-
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| Figure 4.6 Bone marrow trephine biopsy from a patient with advanced idiopathic myelofibrosis. Note the marked linear reticulin staining (arrow). |
ness or discomfort (splenomegaly), anaemia, fatigue and a bleeding diathesis. Fevers, night sweats and weight loss (hypermetabolic state) may be present and are associated with more advanced disease.
Laboratory investigations
Significant bone marrow fibrosis is the sine qua non of IMF. A leu- coerythroblastic blood picture is characteristic but not diagnostic of IMF as it can occur in cases of marrow infiltration (e.g. by malig- nancy, amyloidosis, tuberculosis, osteopetrosis), severe sepsis, severe haemolysis and other circumstances (Box 4.6). The blood count in IMF is variable. In the initial ‘proliferative phase’, red cell produc- tion may be normal or even increased, and about half of presenting patients may have a raised white cell or platelet count (absence of the Philadelphia chromosome will distinguish from chronic myeloid leukaemia) (Fig. 4.7). However, as the bone marrow becomes more fibrotic, the more familiar ‘cytopenic phase’ supervenes. The JAK2 V617F mutation is found in about half of cases of IMF and can help to confirm the diagnosis.
Progression and management
The quoted median survival of 3 years may be much longer in pa- tients who are asymptomatic at presentation. More recently, it has been shown that the presence of anaemia, a very high or low white cell count, the presence of bone marrow chromosomal abnormali- ties and advanced patient age are all associated with a worse prog- nosis, as is the presence of the JAK2 V617F mutation (Box 4.7).
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| Figure 4.7 Leucoerythroblastic blood film in a patient with idiopathic myelofibrosis. Note the nucleated red blood cell (arrowhead) and the myelocyte (arrow). |
Bone marrow transplantation from a matched sibling or unrelat- ed donor should be offered to young patients with poor prognostic features. This is the only curative treatment modality for myelofibro- sis, but, in view of its toxicity, it cannot be performed in the majority of patients with this disorder, who are > 50 years old at diagnosis.
Supportive blood transfusion may be needed for anaemic patients. Cytotoxic agents may be useful in the proliferative phase, particularly if the platelet count is raised. More recently, antifibrotic and antiangiogenic agents, such as thalidomide, have been used to inhibit progression of fibrosis, but success has been limited. Androgenic steroids, such as danazol and oxymethalone, can improve haemoglobin in a proportion of anaemic patients. There is also considerable interest in the possibility that it may be feasible to design specific inhibi- tors of activated (mutant) JAK2.
Splenectomy may improve the quality of life (although not the prognosis) by reducing the need for transfusions or the pain sometimes associated with a very enlarged spleen. Operative morbidity and mortality can be high, and are usually secondary to thrombosis or haemorrhage, making preoperative correction of coagulation abnormalities imperative. Low-dose irradiation of the spleen may be helpful in frail patients.
Death can be due to haemorrhage, infection or transformation to acute leukaemia. Portal hypertension with varices, iron overload from blood transfusion and compression of vital structures by ex- tramedullary haemopoietic masses may also contribute to morbid- ity and mortality.
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