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January 2007: Acquired mutation the key to MPDs

What is the risk of transformation to leukaemia?

How do you distinguish MPDs from other conditions that present with an abnormal FBC?

How is genetic screening carried out?

What is the risk of transformation to leukaemia?

How do you distinguish MPDs from other conditions that present with an abnormal FBC?

How is genetic screening carried out?

Recently there have been significant breakthroughs in the understanding of the basic pathophysiology of myeloproliferative disorders (MPDs).

A specific, acquired, point mutation in the tyrosine kinase JAK2, present in the blood cells of patients with MPDs has been discovered. This has provided a new positive diagnostic test for MPDs and creates the potential for specifically targeted drug therapy in the future.

The MPDs are a group of diseases that are incurable at present, but can be managed with simple treatments which, when applied meticulously, can support normal life expectancy.

MPDs are haematological diseases that result from an acquired clonal change in a haemopoietic stem cell. This change causes abnormalities in the number and function of one or more myeloid blood cell types.

The term MPD generally refers to polycythaemia vera (PV), essential thrombocythaemia (ET) and idiopathic myelofibrosis (IM). Other, more rare conditions classed as MPDs include hypereosinophilic syndrome and systemic mastocytosis. Chronic myeloid leukaemia (CML) is usually considered as a separate entity.

Prevalence

True primary myeloproliferative disease is uncommon, with an annual incidence of one to three cases per 100,000. The prevalence of MPDs is significantly greater than the incidence, as with good management the median survival time is more than 10 years. Most patients present over the age of 60 years but up to 20 per cent of patients may present before the age of 40.

There is considerable overlap between the disease groups; ET may transform to PV, and both conditions may transform to IM in up to five per cent of cases.

The most feared, but rare, complication of these diseases is a transformation to acute leukaemia, which occurs in around 0.3 per cent of patients per year. Leukaemic transformation does not occur in patients under 60 years of age.

The risk of leukaemia is significantly increased by the previous use of alkylating agents such as busulfan or the use of radioactive phosphorus 32P.

Leukaemic transformation tends to be sudden and the response to treatment is generally extremely poor.

Presentation

The MPDs can present in a variety of ways. They are most commonly detected by an abnormal full blood count (FBC). Patients with PV will have an elevated haematocrit level (HCT), and can also have raised white cell (WBC) and platelet (PLT) counts. Patients with ET have elevated PLT counts, but may also have high WBC counts. Patients with IM are mostly cytopenic, although they can have elevated counts.

One of the greatest difficulties for clinicians is differentiating true MPDs from other medical problems that present with an abnormal FBC. As a general rule it is always worth checking an isolated abnormal finding in a basically well person (where HCT <0.58, PLT <1,000) with a repeat count six to eight weeks later. It is important to advise the patient to maintain good oral hydration in the interim.

Conversely, some patients with MPDs may have a broadly normal FBC (Hb, total WBC and PLT within normal range) and still have symptomatic MPD. Close examination of the red cell parameters and/or a blood film will almost invariably detect abnormalities.

The classic pitfall is an elderly patient with PV, but with a normal Hb because of concomitant iron deficiency; in this case a low mean cell volume should be considered a diagnostic indicator of PV. If there is diagnostic uncertainty, specialist advice should be sought.

The spectrum of clinical symptoms and signs that can be associated with MPDs is broad. The most common problems are caused by arterial or venous thromboembolism, with occurrence rates of up to 20 per cent per annum in patients with prior episodes and poor disease control.

Vascular events associated with MPDs include TIA, MI, ischaemic CVA, DVT, PE, digital ischaemia, superficial thrombophlebitis and other rare but characteristic complications, including Budd-Chiari syndrome, portal vein thrombosis and superior sagittal venous thrombosis. In women the risk of antenatal complications may be increased.

There may be an increased risk of haemorrhagic complications because of primary platelet dysfunction (acquired von Willebrand's disease is well recognised with PLT >1,000), or as a consequence of antiplatelet or anticoagulant therapy. Less specific symptoms include headache and other neurological symptoms, fatigue, erythromelalgia and pruritus. Patients with IM are more likely to experience constitutional symptoms or complications relating to low counts, such as an infection or haemorrhage.

Diagnosis

Clinical examination is often normal, but non-specific findings may include a flushed face, evidence of vascular insufficiency, purpura or bruising, splenomegaly and hepatomegaly.

Beyond FBC and blood film, some basic investigations that are often used as circumstantial evidence to support or refute a diagnosis of an MPD include ESR (if this is high it suggests a reactive cause for thrombocytosis), renal and liver function tests (abnormal function is probably a secondary problem), urate (which could be abnormal with an MPD), B12 (often high in PV), folate, iron status and peripheral oxygen saturation ( hypoxia suggests secondary problems).

More specific tests to aid diagnosis include serum erythropoietin (which may be paradoxically low in PV), abdominal ultrasound (to detect splenomegaly and exclude secondary causes for an abnormal FBC), red cell mass/plasma volume studies and bone marrow tests including aspirate, trephine and cytogenetics.

Historically, clinicians have relied on diagnostic guidelines to establish a diagnosis of MPD. The diagnostic criteria have been based on confirmation of an abnormal blood count and exclusion of a secondary cause for this abnormality, together with positive contributory, though not specific, clinical data, such as splenomegaly. The need for these criteria originally arose because, unlike CML, which can be positively diagnosed by the presence of the BCR-ABL translocation, there was not a single diagnostic test for PV, ET and IM. This has undoubtedly resulted in inaccurate diagnosis and treatment in some patients.

A breakthrough in the understanding of MPDs occurred in 2005, with the identification of a specific point mutation in the tyrosine kinase JAK2 associated with the MPDs, in particular PV.1-5 The gene encoding for JAK2 lies at the tip of the short arm of chromosome 9 (9p), and the mutation results in a single amino acid substitution of phenylalanine for valine at position 617 of the protein (V617F).

Approximately one third of patients with PV have acquired uniparental expression of 9p,6 and one third of PV patients have homozygous expression of V617F JAK2.

Up to 97 per cent of patients with PV and around 50 per cent of those with ET or IM will express V617F JAK2. This mutation is occasionally seen in patients with other haematological diseases, but is not seen in non-haematological disease or in normal individuals.

The mutation is acquired, not inherited, and is confined to haemopoietic cells. It is also restricted to blood cells known to be affected in MPD; it does not, for example, involve T-lymphocytes.

JAK2 is critical to intracellular signalling pathways and it is believed that the V617F mutation contributes to the pathophysiology of the MPDs by a reduction in the auto-inhibitory activity of the enzyme. Affected cells have preferentially ‘switched on' JAK2 activity that may result in increased cell proliferation and resistance to apoptosis.

Screening for the V617F JAK2 mutation involves fairly simple, but quite time-consuming, PCR-based techniques on DNA derived from affected cells in fresh anticoagulated peripheral blood.

The test is currently available in some research centres and is likely to become more widely available as the presence of the mutation is incorporated into the diagnostic criteria.7 It should be stressed that while this test may enhance positive diagnostic accuracy, the result may be negative in some patients with MPDs. A negative result does not obviate the need for other investigations.

Treatment

The MPDs are incurable, except in a small minority of younger patients for whom risk/benefit analysis makes haemopoietic stem cell transplantation a reasonable treatment option.

With careful long-term follow-up and therapy the vast majority of MPD patients can lead normal lives. However, the psychological burden of living with a chronic disease with the potential for premature death should not be underestimated.

It is vital that patients are well informed and engaged in their own management from the outset, so that their haematological disease control is optimal and other cardiovascular risk factors are minimised. A specialist unit with a dedicated nurse practitioner can provide invaluable support to patients.

Observational research by the ECLAP group8 has shown that low-dose aspirin significantly reduces cardiovascular morbidity and mortality in patients with PV.

The recently published evidence-based British Committee for Standards in Haematology guidelines for polycythaemia recommend venesection to maintain a HCT of <0.45 in patients with PV.

Cytoreductive therapy should be considered for patients who are intolerant of venesection, have progressive splenomegaly, constitutional symptoms, or additional thrombocytosis.9

Cytoreductive therapy options include interferon-?, hydroxycarbamide, anagrelide, 32P and busulfan.

Interferon-? does not have leukaemogenic potential, and is the agent of choice in pregnancy as it is not teratogenic. Interferon-? is not generally used in older patients, as it must be self-administered by injection and has a significant side-effect profile. Hydroxycarbamide has pancytoreductive effects, is generally well tolerated and is probably not leukaemogenic when used on its own. Anagrelide is useful for specific platelet control and is not leukaemogenic.

Busulfan and 32P are pancytoreductive and have the advantage of single intermittent dosage, however both agents are leukaemogenic in the long term and should only be considered for use in the elderly.

The high-risk arm of the randomised, controlled PT1 trial recently closed and has provided evidence for the management of ET in this group. Patients were defined as high risk according to their cardiovascular risk factors, age over 60 years and PLT >1,000.

The study recommends first-line treatment with hydroxycarbamide, with low-dose aspirin added in when PLT <1,000. Anagrelide was shown to be a valuable second-line therapy.10

The low- and intermediate-risk arms of this study are still running and the best treatment options for these patients are still unclear. Either observation alone, low-dose aspirin alone or low-dose aspirin in combination with cytoreductive therapy may be recommended, according to the individual risk profile and the wishes of the patient.

The standard management of IM is less clear, as the problem is generally a symptomatic reduction (not elevation) of blood counts. Supportive therapy, including intermittent blood transfusion and recombinant human erythropoietin, may be useful for symptomatic anaemia. Antibiotics are required for infections, and platelet transfusions may help with episodes of bleeding.

Cytoreductive agents can reduce constitutional symptoms, and a number of other drugs, including danazol, may improve counts in some patients. Splenectomy may also be considered. Referral for stem cell transplantation should be considered in younger high-risk patients.

Imatinib does have some disease modifying effect in PV, but is not generally used because of the additional risk factors when compared with alternative therapies. Imatinib is not indicated in ET or IM.

The discovery of the JAK2 mutation in PV, ET and IM has sparked great interest in the therapeutic potential of JAK2 inhibitors. Unfortunately, current inhibitors are fairly non-specific, with considerable off-target activity. Another significant problem is that JAK2 expression is not limited to haemopoietic cells, and inhibitors of JAK2 would be likely to block both mutant and wild type JAK2 in various cell types. This is, however, a rapidly evolving field with great potential in the medium term.

Key points Author

Dr Tamara Everington
MB BS MRCP
consultant haematologist, Salisbury Health Care NHS Trust

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