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Myeloproliferative Disorders

Myeloproliferative Disorders

Myeloproliferative neoplasms (MPNs), previously called Myeloproliferative diseases, are disorders of the blood, where there is uncontrolled expansion of myeloid type blood cells.

The constituents of blood are created from haemopoietic stem cells that divide asymmetrically to form myeloid and lymphoid progenitors as well as more haemopoietic stem cells. In myeloproliferative disorders, the disorder is with myeloid progenitor cells, whereby they give rise to too many daughter cells. They can be classified into different diseases depending on which cell predominates.

Although myeloproliferative disorders are a collection of neoplastic disorders, they are not malignant but rather pre-malignant, with a significant proportion transforming into acute or chronic leukaemias.

MPNs are classified into 4 different groups:

  1. Chronic myelogenous leukaemia (CML) – characterised by the presence of the Philadelphia chromosome, is discussed in another article so will only be touched on here.
  2. Polycythaemia (Rubra) Vera (PV) – A disorder of erythropoiesis leading to an increase in the absolute red cell mass. Not to be confused with apparent polycythaemia.
  3. Essential Thrombocythaemia (ET) – Persistent elevation of the platelet count.
  4. Primary Myelofibrosis (MF) – Uncontrolled proliferation of haemopoietic stem cells leading to fibrosis of the bone marrow.

 

NB there are other less common MPNs – Mastocytosis, Chronic neutrophilic leukaemia and chronic eosinophilic leukaemia; but they are so rare they are beyond the scope of this article

 

Key Points:

  • Heterogeneous set of disorders characterised by clonal expansion of myeloid progenitors
  • Each have the propensity to evolve into other MPNs, especially PV to MF
  • The presence of JAK2 mutation increases chance of transformation into acute myeloid leukaemia (most likely from MF)
  • MPNs also tend to transform into myelodysplastic syndrome

 

Polycythaemia Vera

PV is the opposite of anaemia. Patients have an increase in total red cell mass, and as a result have elevated Hb on blood tests. They may also have concomitant increase in both WCC and platelet count as a result of increased clonal expansion of myeloid progenitor cells.

Patients are most likely diagnosed incidentally, as PV is asymptomatic in its earlier stages. As the amount of red cell mass increases however, patients start to exhibit symptoms of hyperviscosity:

Pruritus (classically after having a hot bath), night sweats, weight loss, weakness and bone pain.

They may also have signs of extramedullary haemopoiesis, such as splenomegally.

95% of patients have the JAK2 V617F mutation, a mutation that is common to all non-BCR-ABL MPNs. Although the pathogenesis of all MPNs is not fully understood, it is thought that the JAK-STAT signalling pathway is key. This pathway is involved in controlling the proliferation of myeloid progenitors as well as erythropoiesis and lymphopoiesis. An excellent more detailed description of the role of JAK signalling in MPNs can be found here:  http://www.areampn.com/index.jsp

 

Treatment

Patients with PV (just as those with ET) do not have a significantly altered life expectancy, and therefore treatment is based largely upon reducing the risk of thrombosis and managing symptoms.

Venesection (phlebotomy) is still the treatment of choice alongside low dose aspirin (75mg). 

 

Essential Thrombocythaemia

Essential thrombocythaemia is characterised by a sustained increase in platelet count > 450 x 109/L. It is caused by megakaryocyte proliferation leading to overproduction of platelets.

Approximately 50% of patients have a JAK2 mutation.  In those with the mutation, they often have higher Hb and WCC.

Most often ET is an incidental diagnosis where a patient is noticed to have persistent thrombocytosis despite no clear precipitant eg inflammation/infection.  In a small number of cases it is diagnosed following thrombosis.

Diagnosis is made by exclusion:

No pre-existing myeloid malignancy, MPN or myelodysplastic syndrome.

No reactive cause of thrombocytosis such as haemorrhage, chronic iron deficiency, infection, malignancy, connective tissue disease, splenectomy. 

A bone marrow trephine may sometimes be required to confirm the diagnosis.

 



Treatment

  • Patients are prone to thrombosis and haemorrhage, focus is on decreasing this risk.
  • Management of standard cardiovascular risk factors
  • Stratify into high, medium and low risk:

 

Low risk: Low dose aspirin in most cases

High risk: Hydroxycarbamide (aka. hydroxyurea) is most commonly used treatment, but has side effects of causing skin ulceration or pigmentation.

Anagrelide can be used instead of aspirin as a platelet inhibitor in high risk patients. It has potentially more side effects and a possible increased risk of transformation into myelofibrosis.

Prognosis

Often stable for 10-20yrs may transform to myelofibrosis. 5% risk of transforming to acute leukaemia.

Primary Myelofibrosis

Primary myelofibrosis is a condition where the rapid turnover of haemopoietic stem cells leads to the progressive fibrosis of the bone marrow, changing it from a regenerative environment to a baron hypocellular structure. As a result the body adapts and regresses back to using extramedullary organs such as the liver and spleen as sites of secondary haemopoiesis.

Most patients present with:

  • Anaemia
  • Constitutional sx: Fatigue (84%); Night sweats (56%); Pruritus (50%); Bone pain (47%); Weight loss (20%); Fever (18%);
  • Massive splenomegaly
  • (A small portion of patients have related otosclerosis)
  • JAK2 mutation in 56%
  • 1/3 have previous hx of PV or ET.

 

Clinical features

  • Insidious onset
  • Older age group (median age 67) presenting with anaemia and massive splenomegaly
  • Hypermetablic symptoms eg weight loss, anorexia, fever, night sweats

 

    Investigations

    • WCC and Plt initially high, but then become low as disease progresses.
    • Leucoerythroblastic blood film with characteristic tear-drop poikilocytes
    • Trephine biopsy – Fibrotic hypocellular marrow with increased megakaryocytes.
    • High serum urate and LDH levels due to high haemopoietic cell turnover.
    • Transformation to AML in 10-20%

     

    Treatment

    • Palliative/Supportive – Symptom relief from anaemia and massive splenomegaly.
    • Anaemia – Regular blood transfusion and folic acid supplements
    • Hydroxyurea – may help reduce splenomegaly and hypermetabolic symptoms
    • Splenectomy in patients with severe symptoms eg. Abdominal discomfort, indigestion.
    • Splenic radiation is an alternative but usually only provides symptom relief for 3-6 months.
    • Allopurinol required as prophylaxis against gout and urate nephropathy.

     

    Prognosis

    • Prognosis is usually poor, with median survival of only 5.7 years.
    • Prognosis is particularly poor in the patients in which MF transforms to AML.

     

    Acknowledgements and further reading:

    Hoffbrand and Moss. Essential Haematology - 6th edition. 2011. 

    http://www.areampn.com

     

     

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