What’s new ?
• A randomized trial has demonstrated the benefit of aspirin in polycythaemia vera
Claire N Harrison
• A mutation in the von Hippel–Lindau gene has been reported as a common cause of familial polycythaemia • Use of low-dose thalidomide in combination with prednisolone may be beneficial in myelofibrosis
The myeloproliferative disorders (MPDs) are an interlinked group of diseases. The main entities are polycythaemia vera (PV), essential thrombocythaemia (ET), idiopathic myelofibrosis (IMF, also termed ‘agnogenic myeloid metaplasia’) and chronic myeloid leukaemia (CML). Other, rarer conditions include chronic neutrophilic and eosinophilic leukaemia. CML is a distinct disorder with characteristic biological features and is discussed on page 70.
venesection or cytoreductive therapy (particularly in patients with an elevated platelet count). The target PCV is 0.45 (some use 0.42 in females) and platelets 400 x 109/litre. Antiplatelet drugs (traditionally aspirin and now clopidogrel, and others) also have a role. In earlier PVSG studies, larger doses of aspirin (900 mg) were associated with increased haemorrhage. Aspirin is contraindicated in those with known aspirin intolerance, asthma, active or previous peptic ulcer disease, prominent bleeding symptoms or a very high platelet count (> 1500), because of the increased risk of paradoxical bleeding). Hydroxyurea is the standard cytoreductive drug used to treat PV and other MPDs. It is generally well tolerated, but there is concern that it might increase the risk of leukaemia. Phosphorus32 and busulfan were used in the past, but their usefulness is restricted because of their well-defined leukaemogenic potential. Emerging therapies include interferon-α and anagrelide. These have the advantages of preserving fertility and being nonleukaemogenic, but long-term follow-up of patients taking these drugs is lacking. Treated patients have a median survival of at least 8–15 years and are at risk of transformation to myelofibrosis (spent phase). This phase of the disease is characterized by progressive spleno-
Polycythaemia vera PV is characterized by erythrocytosis and sometimes thrombocytosis. The median age at presentation is 55–60 years. Clinical features – vascular thromboses (particularly arterial) and, more rarely, bleeding are the major clinical events. In the longer term (10–15 years), myelofibrosis or ‘spent phase’ occurs in 10–15% of patients and acute myeloid leukaemia (AML) (partially treatment related) in 5% (Figure 1). Aquagenic pruritus, gout and splenomegaly are classical clinical features, but occur in only a few patients. Investigations – an erythrocytosis is defined as a PCV of more than 0.51 in men and more than 0.48 in women. An RBC mass study is performed to determine whether this is absolute erythrocytosis (increased RBC mass) or apparent erythrocytosis (normal RBC mass, reduced plasma volume). If the erythrocytosis is absolute, further investigations are required to determine whether the patient has PV or secondary erythrocytosis, or whether there is no clear cause (idiopathic erythrocytosis). The next stage is to exclude possible causes of secondary erythrocytosis (Figure 2). Hypoxaemia can be screened for using pulse oximetry (92% is the arbitrary cut-off point) and renal conditions by abdominal ultrasonography. Serum erythropoietin, p50 estimation (to demonstrate high-affinity haemoglobin) and sleep studies are useful specialist investigations. To confirm the diagnosis of PV, specific criteria are applied. The most commonly used are those of the Polycythaemia Vera Study Group (PVSG) (Figure 3). The WHO has recently proposed new, broadly similar criteria. Management and prognosis – thrombosis is the major cause of death in untreated patients, in whom median survival is only 18 months. Control of the elevated PCV is achieved by repeated
Relationship between the myeloproliferative disorders and acute leukaemia Myelofibrosis 10% at 10 years
1–2% at 10 years
5% at 10 years Acute leukaemia1 25% variable Idiopathic myelofibrosis
Claire N Harrison is Consultant Haematologist at Guy’s and St Thomas’ Hospital, London, UK. She qualified from the University of Oxford, and trained in haematology at University College London. Her research interests include myeloproliferative disorders and platelet/megakaryocyte biology.
15–20% at 10 years
Usually acute myeloid leukaemia
© 2004 The Medicine Publishing Company Ltd
Causes of absolute erythrocytosis
Essential thrombocythaemia Clinical features – ET is characterized by a persistent thrombocytosis; more than 600 x 109/litre is the generally accepted threshold for diagnosis. Short-term complications of ET include thrombosis and, less commonly, haemorrhage. Long-term problems include myelofibrosis and acute leukaemia, though these are less common than in PV. Thrombotic events affect arteries, veins, the microvasculature and the placental circulation. Microvascular events tend to predominate in ET, typically causing erythromelalgia (painful, reddened digits), gangrene or transient ischaemic attacks. About 30–50% of patients are symptomatic at presentation. Investigations – there is no diagnostic hallmark for ET. The diagnosis is made by excluding other MPDs and reactive, or secondary, thrombocytosis. Causes of reactive thrombocytosis include iron-deficiency anaemia, chronic inflammation (e.g. rheumatoid arthritis, inflammatory bowel disease), splenectomy, acute haemorrhage and malignant disease. In an otherwise well patient, diagnosis is generally straightforward. Diagnosis may be more difficult in those with coexisting conditions that may cause reactive thrombocytosis (e.g. connective tissue disorders). Recent WHO diagnostic criteria for ET place greater emphasis on bone marrow histology, particularly megakaryocyte morphology, but this has not gained wide acceptance. Myelodysplasia must also be excluded when diagnosing ET. This is usually associated with a low rather than high platelet count and is characterized by dysplastic features morphologically and particular chromosomal abnormalities. Management and prognosis – patients with ET are predisposed to thrombosis, which is a major cause of morbidity and mortality. Haemorrhage occurs less commonly and is particularly associated with platelet counts of more than 1500 x 109/litre and acquired von Willebrand’s disease. Initial management should be to address life-style issues associated with vascular events (e.g. smoking, diabetes, hypercholesterolaemia). Most patients benefit from aspirin or other antiplatelet drugs; the exceptions are those with active haemorrhage, aspirin intolerance, asthma, active or previous peptic ulcer disease, or a very high platelet count (> 1500). The risk of thrombosis and haemorrhage is significantly reduced by therapy to control the platelet count to a target of 400 x 109/litre. The current gold-standard cytoreductive drug is hydroxyurea. Alternatives include 32P and busulfan.
Primary (abnormality within RBCs) Congenital • Truncated erythropoietin receptor Acquired • Polycythaemia vera • Other myeloproliferative disease (essential thrombocythaemia) Secondary (abnormality outside RBCs) Congenital • Inherited high erythropoietin levels • Abnormal haemoglobin with increased oxygen affinity • Reduced 2,3-diphosphoglycerate • Mutation in von Hippel–Lindau gene Acquired (increased erythropoietin) • Conditions causing low oxygen levels – high altitude, chronic lung disease, some congenital heart diseases • Renal disease – tumours (hypernephroma), cysts (usually benign), hydronephrosis, following kidney transplantation • Liver disease – hepatoma, cirrhosis, hepatitis • Tumours – bronchial cancer, fibroids in the uterus, cerebellar haemangiomata • Endocrine abnormalities – Cushing’s syndrome, phaeochromocytoma Idiopathic (undefined primary or secondary) Apparent erythrocytosis • Normal variant • Early absolute erythrocytosis • Obesity, fluid loss, diuretics, smoking, hypertension, alcohol, renal disease, psychological stress
megaly and pancytopenia and is generally treated supportively. Bone marrow transplantation is an option in a minority of patients. AML as a terminal feature of PV, as in any MPD, is often refractory.
Criteria for diagnosis of polycythaemia vera Major criteria • A1 Raised RBC mass • A2 Absence of cause of secondary erythrocytosis • A3 Palpable splenomegaly • A4 Clonality marker (acquired abnormal marrow karyotype)
Minor criteria • B1 Thrombocytosis (platelet count > 400 x 109/litre) • B2 Neutrophil leucocytosis (neutrophil count > 10 x 109/litre, > 12 x 109/litre in smokers) • B3 Splenomegaly demonstrated on isotope scanning/ ultrasonography (splenomegaly detected by ultrasonography only is less significant) • B4 Characteristic growth of burst-forming units, erythroid, or reduced serum erythropoietin
Polycythaemia vera is established by the presence of A1 and A2, plus A3 or A4 or any two B 3
© 2004 The Medicine Publishing Company Ltd
Interferon-α controls platelet count in most patients but is poorly tolerated; up to 30% are unable to continue this treatment long term. Interferon and anagrelide (the newest drug for the treatment of ET) are non-leukaemogenic and preserve fertility. A direct comparison between hydroxyurea and anagrelide in patients with ET is under way in the MRC-PT1 study. Because survival in ET is long and cytoreductive agents have a poor side-effect profile, current practice is to use these agents only in patients at high risk of thrombosis. This group includes the over-60s, and those with prior thrombosis or extreme thrombocytosis (> 1000 x 109/litre). Aspirin alone is probably sufficient in young patients (< 40 years), with none of these risk factors. The management strategy is unclear in patients aged 40–60 years without other risk factors; best practice is to randomize them into MRC-PT1, where they will receive aspirin alone or in combination with hydroxyurea.
unsuccessful in patients from whom stem cells were harvested in the advanced phase. The role of autologous stem cells harvested early in the disease remains unclear. Median survival is less than 2 years in patients with anaemia (< 10 g/dl), in the elderly (> 70 years), and in those with an abnormal karyotype and WBC count than less 3 x 109/litre or more than 30 x 109/litre or constitutional symptoms. In patients without these features, median survival is 6–10 years. Occasionally, patients survive for more than 20 years.
FUTURE READING Cortelazzo S, Finazzi G, Ruggeri M et al. Hydroxyurea for patients with essential thrombocythemia and a high risk of thrombosis. N Engl J Med 1995; 322: 1132–6. Fialkow P J, Faguet G P, Jacobson R J et al. Evidence that essential thrombocythaemia is a clonal disorder with origin in a multipotent stem cell. Blood 1981; 58: 916–19. Hessling J, Kroger N, Werner M et al. Dose-reduced conditioning regimen followed by allogeneic stem-cell transplantation in patients with myelofibrosis with myelometaplasia. Br J Haematol 2002; 119: 769–72. MRC Working Party on Leukaemia in Adults. Primary Thrombocythaemia Trial, 1997. Mesa R A, Steensma D P, Pardanani A et al. A phase 2 trial of combination low-dose thalidomide and prednisolone for the treatment of myelofibrosis with myeloid metaplasia. Blood 2003; 101: 2534–41. Pearson T C, Lewis S M. Non-leukaemia myeloproliferative disorders. In: Hoffbrand A V, Lewis S M, eds. Postgraduate haematology. Oxford: Butterworth-Heinemann, 1999. Pearson T C, Messinezy M. The diagnostic criteria of polycythaemia rubra vera. Leuk Lymph 1996; 22: (Suppl. 1): 87–93. Reilly J T. Idiopathic myelofibrosis: pathogenesis, natural history and management. Blood Rev 1997; 11: 233–42. Tefferi A, Mesa R A, Gray L A et al. Phase 2 trial of imatinib mesylate in myelofibrosis with myeloid metaplasia. Blood 2002; 99: 3854–6. Wasserman L R, Berk P D, Berlin N I, eds. Polycythaemia vera and the myeloproliferative disorders. Philadelphia: Saunders, 1995.
Chronic idiopathic myelofibrosis IMF may arise de novo or as a late phase of ET or, particularly, PV. Fibrosis is thought to arise from an interaction between diseased megakaryocytes, which release mitogens such as platelet-derived growth factor and transforming growth factor β that directly increase fibroblast proliferation. Clinical features and diagnosis – the median age at presentation is 50–60 years. Symptoms relate to bone marrow failure (anaemia, infection, bleeding) or progressive splenomegaly (pain, weight loss, sweating). Progression to acute leukaemia occurs in up to 25% of patients and may be associated with extramedullary collections of myeloid progenitors (chloromas). It is necessary to exclude other MPDs (PV, ET, CML) and disorders in which marrow fibrosis can develop as a secondary feature (e.g. metastatic carcinoma, lymphoma, irradiation, tuberculosis, leishmaniasis). The following features are generally necessary to confirm the diagnosis of IMF: • splenomegaly • increased bone marrow fibrosis (coarse reticulin fibres arranged in parallel in trephine biopsy); in later stages, new osteoid is formed (osteomyelofibrosis) • leuco-erythroblastic blood film (immature RBCs and myeloid precursors with teardrop-shaped RBCs) • absence of other MPDs • exclude secondary causes of myelofibrosis (see above). Management and prognosis – supportive therapy with RBC transfusions and treatment of infection is the mainstay of management. Androgens or erythropoietin therapy are used in some patients. Chemotherapy, particularly with hydroxyurea, may be useful initially to reduce splenomegaly and slow/reduce fibrosis, though this may not affect prognosis. Thalidomide is of interest, but is toxic and not beneficial in most patients; it may be best used in low doses with corticosteroids. Studies of STI-571 (a ‘designer drug’ for the treatment of CML) appear to be disappointing. Splenectomy is an option in advanced disease, but is often complicated. Splenic irradiation may be useful. Allogeneic bone marrow transplantation may achieve a cure in a few patients, but because of high procedure-related mortality has been performed only in young patients with a poor prognosis. Low-intensity allogeneic transplantation has recently been useful, with reduced procedure-related mortality. Autologous transplantation has been
Practice points • MPDs are rare and include essential thrombocythaemia, polycythaemia vera, chronic myeloid leukaemia and idiopathic myelofibrosis • Common manifestations include thrombosis and haemorrhage • Consider an underlying MPD when thrombosis occurs in an unusual site • MPDs can evolve into acute leukaemia or myelofibrosis • Thrombocytosis or elevated PCV (> 0.51 in men, > 0.48 in women) merits further investigation
© 2004 The Medicine Publishing Company Ltd