29th May 2023

Myeloproliferative disorders

Myeloproliferative disorders are characterised by excessive proliferation of one or more cells originating from the myeloid lineage – RBC, platelets, or monocytes/neutrophils. They are clonal proliferations, often with characteristic genetic mutations and as such are classified as malignancies. They tend to be very slow growing conditions, but all carry a risk of progression to AML. There are three major forms of myeloproliferative disorders:

• Polycythaemia vera (PV)
• Essential thrombocytosis (ET)
• Myelofibrosis (MF)

CML is also sometimes considered a type of myeloproliferative disorder.

It can be helpful to consider these disorders by looking at changes in blood counts, however, it is worth remembering that in reality the situation is more complex than this and there is considerable overlap between these conditions.

Polycythaemia

Polycythaemia is defined as Hb >185 in males and >165 in women. In practice, haematocrit (HCT) is a more reliable indicator of polycythaemia (HCT >0.52 in males, >0.48 in females)

Primary polycythaemia

This includes rare congenital forms but is mostly synonymous with an acquired malignant condition known as polycythaemia vera. This is due to a somatic mutation in a hematopoietic stem cell. In over 95% of cases, this is a mutation in the JAK2 gene.

Because it is the stem cell that is mutated, there can be an increase in all three myeloid cell lines (RBC, platelets, and granulocytes). The erythropoietin (EPO) level will be low due to negative feedback.

The incidence is 2 cases per 100,000 people per year. The median age at presentation is 65-75 years.

Features:

• Splenomegaly
• Arterial and venous thrombosis including Budd-Chiari syndrome
• Pruritus, particularly after a bath or shower
• Erythromelalgia – itching or burning in extremities (see image)
• Haemorrhage
• Gout
• Constitutional symptoms

Photo showing characteristic changes during an episode of erythromelalgia.

Image Source: Wikimedia Commons (2017). Erythromelalgia in left hand, Licensed under a creative commons licence. Available for free at: https://commons.wikimedia.org/wiki/File:Erythromelalgia_in_left_hand.jpg (Accessed on: 10 January 2023).

Confirmation of the diagnosis requires JAK2 positive mutation with a persistently elevated haematocrit >0.52 in males and >0.48 in females.

Without treatment, life expectancy is around 18 months – death is most commonly due to stroke or MI. Median survival is 14 years with treatment. There is a 5-15% risk of transformation to myelofibrosis over 10 years and the risk of progression to AML is ~2% at 10 years and 8% at 20 years.

Management:

1. Reduce cardiovascular risk factors
2. Low dose aspirin for all patients
3. Venesection to reduce the HCT to below 0.45 target
4. Cytoreductive therapy (usually hydroxycarbamide or interferon first line) for high-risk patients (>65 years or history of thrombosis)

Secondary polycythaemia

Secondary polycythaemia is a much more common cause of a raised haematocrit than polycythaemia vera. These conditions will show a raised EPO level. They are summarised in the table below:

Management is generally aimed at identifying and treating the underlying cause.

Relative polycythaemia

This is caused by decreased plasma volume causing a proportional increase in HCT but without an increase in absolute red cell mass. It corrects on normalisation of intravascular plasma volume.

Thrombocytosis

As with polycythaemia, thrombocytosis can be split into primary and secondary causes. Primary thrombocytosis can be associated with a number of haematological disorders, mostly myeloproliferative diseases. This includes PV, MF, CML, CMML and most commonly ET.

Essential thrombocytosis (ET)

This is the most common form of myeloproliferative neoplasm (MPN). Unlike PV, only platelet count is increased. Most patients present between 50-60 years.

It is associated with the following common mutations:

• JAK2 ~50%
• CALR ~30%
• MPL ~10%

The remainder of cases are classed as triple negative. If one of the above mutations is present, along with a platelet count over 450 x 10⁹/L, this is sufficient to establish a diagnosis, providing there is no evidence of another MPN. Without one of the above three mutations, bone marrow investigation is usually necessary to confirm the diagnosis.

Features:

• Increased risk of venous and arterial thrombosis
• Increased risk of haemorrhage
• Constitutional symptoms
• Hepatosplenomegaly may be present
• Headache and dizziness
• Erythromelalgia
• Pregnancy complications

Prognosis

This is generally better than PV. Life expectancy is not affected for the first 10 years but is difficult to quantify afterwards. There is a risk of progression to MF and AML, but this is lower than in PV.

Treatment is similar to PV:

1. Manage CV risk factors
2. Aspirin for all patients
3. Cytoreductive patients only for high-risk patients (age >60, plt >1500, thrombotic or haemorrhagic complication)

Reactive thrombocytosis

There are a multitude of causes for this.

• Infection or inflammation/tissue damage
• Iron deficiency
• Hyposplenism
• Haemorrhage
• Drugs e.g. steroids
• Other malignancy e.g. sarcoma

Myelofibrosis

This is a condition characterised by progressive fibrosis of the marrow secondary to a clonal population of megakaryocytes; these cells interact with the surrounding bone marrow stroma and release pro-inflammatory and fibrotic cytokines. This causes progressive bone marrow failure, plus splenomegaly and constitutional symptoms. Pulmonary hypertension may also develop over time. The blood film may show a leukoerythroblastic picture. It can arise de novo or as a result of progression from PV or ET. Mutations in JAK2, CALR and MPL can be seen (as with ET), plus other somatic mutations are also seen in AML.

In order to make the diagnosis, a bone marrow is performed. This must show significant fibrosis and megakaryocyte proliferation without another causative explanation. A combination of this plus at least one other feature such as anaemia or splenomegaly is usually adequate. The presence of typical mutations (JAK2, CALR or MPL) is supportive.

The prognosis is variable but generally poor. Compared with PV and ET, there is a significantly higher risk of transformation to AML.

A very small minority of patients may be cured with allogeneic stem cell transplant. Many patients are either not fit enough for this or else their disease is mild, and the risk of such intensive treatment outweighs the benefit. Other treatment options include supportive care, cytoreductive therapy or newer drugs such as ruxolitinib (JAK 2 inhibitor).