Myeloproliferative neoplasms (MPNs) are chronic haematological disorders characterised by elevated blood counts. MPNs arise from uncontrolled proliferation of haematopoietic stem cells in the bone marrow.

There are 3 main MPN subtypes: essential thrombocythaemia (ET), polycythaemia vera (PV) and myelofibrosis. ET is characterised by an elevated platelet count and PV by a high haemoglobin and haematocrit. Myelofibrosis classically demonstrates marrow fibrosis, splenomegaly, a leukoerythroblastic blood picture and varying degrees of elevated blood counts and cytopaenias. Myelofibrosis can occur as primary myelofibrosis, or can develop from the progression of ET and PV to secondary myelofibrosis.

EPIDEMIOLOGY

Based on data from the USA and Europe, the incidence of ET, PV and myelofibrosis is 1.9-2.8 per 100,000, 1.5-2.5 per 100,000 and 0.4-1.5 per 100,000 respectively. The corresponding prevalence of ET, PV and myelofibrosis is 24-40 per 100,000, 22-30 per 100,000 and 0.5-2.7 per 100,000.

Using this data, it is estimated that there are approximately 2,600 to 4,000 people in Singapore with an MPN. It is likely that a doctor in primary care would encounter a patient with an MPN either at presentation or for the treatment of other conditions at least once in their career.

The median age of diagnosis is in the sixth to seventh decade of life but up to 20% are below the age of 40 at presentation. There is a slight male predominance in PV and myelofibrosis, while ET is more often seen in females. The cause of MPNs is unknown.

PRESENTATION AND SYMPTOMS

Up to a quarter of patients may be asymptomatic and the diagnosis made incidentally such as during a health screening.

Often the General Practitioner (GP) is the person who first detects the elevated blood counts and is the initial point of contact to ensure that patients with elevated blood counts are appropriately referred for further evaluation.

Symptoms in MPN are often non-specific and can be categorised into:

• Symptoms related to elevated blood counts. These include giddiness, headache and transient visual disturbances.
• Constitutional symptoms. Often such symptoms are cytokine-related. The most prevalent constitutional symptom in MPNs is fatigue but may also include bone pain, fever, night sweats, and unexplained weight loss.
• Symptoms related to hepatosplenomegaly. Common symptoms relate to mass effect and include early satiety, abdominal distension and a sensation of fullness or pain at the left hypochondrium.

ET patients may have erythromelalgia, a condition where there is redness, warmth and a burning pain in the hands and feet. PV patients classically have itch, especially after a shower or bath but in the local context, this is not frequent.

PROGNOSIS AND COMPLICATIONS

Compared to many other haematological malignancies, the survival in MPNs is relatively good. In myelofibrosis, the median survival is 7 years but can vary from 1 to 2 years to more than 10 years. Survival in ET can measure decades while in PV, survival can be 20 to 30 years. Untreated however, the median survival in PV is between 6 to 18 months.

The overriding risk in MPNs is thrombosis. Thrombosis is more commonly arterial but can also be venous. In patients with ET and extreme thrombocytosis (platelet count ≥1000 x 109/L), the risk of haemorrhage is also increased. This is due to abnormalities in platelet function and increased consumption of von Willebrand factor.

All MPNs can undergo disease transformation to acute leukaemia while ET and PV can progress to secondary myelofibrosis. There is no current treatment that can alter the natural history or prevent disease progression.

The long-term risk of progression to acute leukaemia is approximately 5% for ET, 10% for PV and 10-20% for myelofibrosis. Rates of progression to myelofibrosis are 5-10% for ET and 10- 20% for PV.

DIAGNOSIS

There are several mutations that are seen in MPNs and are used in the diagnostic work-up. These include:

• JAK2 V617F mutation
• Calreticulin (CALR) mutation
• MPL mutation
• JAK2 exon 12 mutation

The JAK2 V617F mutation is seen in 95% of PV patients and the JAK2 exon 12 mutation in 1-3% of PV cases. If patients with elevated haemoglobin are negative for these two JAK2 mutations, it is unlikely that the elevated haemoglobin is due to polycythaemia vera and secondary causes of polycythaemia have to be considered. The CALR and MPL mutations are not seen in PV.

In ET and myelofibrosis, the JAK2 V617F mutation is seen in 50-60% of patients, CALR in 15-25% and MPL in 5-10%. The presence of one of these mutations demonstrates that the patient has an MPN but a bone marrow is required to ascertain if this is ET or myelofibrosis.

Patients who do not carry any of these mutations are referred to as ‘triple negative’. For triple negative patients with an elevated platelet or white cell count and do not have secondary causes to account for the elevated counts, a bone marrow will be required to confirm the diagnosis and subtype of MPN. Sometimes additional investigations are required to confirm the diagnosis and exclude reactive causes.

TREATMENT

In ET and PV, the major goal of treatment is to reduce the risk of thrombosis.

Secondary aims of treatment are to decrease symptoms related to elevated blood counts and in patients with extreme thrombocytosis (platelet count >1000 x 109/L), to lessen the risk of haemorrhagic events. Based on the risk of thrombosis, a risk-stratified approach is used.

Using the risk factors of age ≥60 years and a history of thrombosis, a low-risk patient has zero risk factors, while a high-risk patient has one or both risk factors.

Low-risk ET patients with a platelet count <1500 x 109/L should receive low-dose aspirin but there is no indication for cytoreduction. For low-risk ET patients with a platelet count >1500 x 109/L or high-risk ET patients, cytoreduction is administered. Options for cytoreduction include hydroxyurea, anagrelide and pegylated interferon.

For high-risk ET patients, hydroxyurea would be the agent of choice in lowering the platelet count. One of the concerns with hydroxyurea is whether it could potentially contribute to the risk of acute leukaemia. From available literature however, hydroxyurea has not been demonstrated to increase the risk of leukaemic progression.

All PV patients should receive lowdose aspirin. The haematocrit should be maintained at less than 45%. This can be achieved with regular venesection or cytoreductive therapy using either hydroxyurea or pegylated interferon. Low-risk PV patients can be managed with venesection while high-risk patients should receive cytoreduction to optimise the haematocrit.

The management of myelofibrosis is often challenging. Patients may face a range of concerns including thrombotic risk, elevated blood counts, constitutional symptoms, splenomegaly, anaemia, thrombocytopaenia and leukopaenia.

There is no effective treatment to improve thrombocytopaenia and leukopaenia. Treatment has to be individualised depending on the myelofibrosis- related issues, age, comorbidities, patient’s fitness and wishes and aims of treatment.

There is no curative treatment apart from allogeneic stem transplant. However transplant can only be considered for fit younger patients who have high risk/advanced myelofibrosis. The risk of transplant for myelofibrosis is quite substantial and up to 50% may have transplant related complications or even death.

Depending on the issues that patients have, treatment is tailored to address these issues. Patients with anaemia may require regular blood transfusions. Agents such as erythropoietin, thalidomide (with or without prednisolone) or danazol can be tried but often patients may not have an improvement in the haemoglobin level, or only a transient response.

In patients with an elevated white cell or platelet count, cytoreduction may be required while patients who have constitutional symptoms or symptoms related to splenomegaly may benefit from ruxolitinib, a JAK inhibitor. For patients who are asymptomatic, management can be expectant.

CONCLUSION

Although GPs are unlikely to be directly managing the MPN, GPs play a vital role in ensuring that patients with elevated blood counts are referred for further evaluation and working with patients’ haematologists to provide comprehensive and holistic care to patients with MPNs.

WHEN TO REFER

Refer patient urgently to A&E if the patient has symptoms suggestive of hyperviscosity or a thrombotic event regardless of blood counts.

For pregnant patients with elevated blood counts who do not fulfill the criteria for urgent referral, please contact the haematologist on call for advice and early appointment.

Platelet count

• Urgent referral to A&E if platelet count >1000 x 109/L
OR if platelet count less than 1000 but patient has current/recent bleeding or thrombosis or neurological symptoms
• Non-urgent referral if the platelet count is persistently elevated (at least 2 platelet readings above the upper limit of normal over a 4-6 week period)

Haemoglobin

• Urgent referral to A&E if Hb >20 g/dL or Haematocrit ≥60%
• Non-urgent referral if Hb is persistently elevated for at least 2 readings 4-6 weeks apart: women Hb >16.0 g/dL, men Hb >16.5 g/dL

White cell count

• Urgent referral to A&E if blasts or a leukoerythroblastic picture is noted OR if WBC >50 x 109/L
• Non-urgent referral if WBC persistently elevated (>20 x 109/L) for at least 2 readings 4-6weeks apart

By: Dr Grace Kam, Senior Consultant, Department of Haematology, Singapore General Hospital; SingHealth Duke-NUS Blood Cancer Centre  

Dr Grace Kam is a Senior Consultant with the Department of Haematology, Singapore General Hospital. She received her MBBS with Honours from the University of Melbourne, Australia and is a Member of the Royal College of Physicians, UK. In addition, she is also a Clinical Tutor with the Yong Loo Lin School of Medicine at the National University of Singapore.