Primary myelosclerosis

Synonyms: myelofibrosis, agnogenic/idiopathic myeloid metaplasia with myelofibrosis.

Definition

This is one of the chronic myeloproliferative disorders. It is an acquired, malignant clonal disorder, characterised by expansion of pluripotent stem cells. They show deranged production of one or more myeloid lines and have a variable tendency to transform to leukaemia.

Epidemiology

Incidence

Although this condition is seen at any age, it is most often seen over the age of 50 years. Peak incidence is at 60-70 years.

Prevalence

It is very rare. Approximately 1 case per 300,000 per year. Males and females are equally affected.

Pathogenesis

• Marrow fibrosis with either greater or decreased cellularity is a constant feature. The fibrosis is thought to be due to platelet-derived growth factor produced by malignant megakaryocytes. This is a known mitogenic agent for fibroblasts.

• Primary myelosclerotic marrow is hypocellular due to extensive fibrosis replacing the myeloid and erythrocytic element.

• Megakaryocytes, which are not always increased in number, are morphologically abnormal.

• Osteosclerosis is a common finding.

• As marrow fibrosis progresses the amount of extramedullary myeloid metaplasia increases.

• The spleen is the primary site of extramedullary metaplasia. The liver, lymph nodes and kidneys can also become involved.

Aetiology

Genomic aberrations are more common than previously thought. Approximately 50% of cases are known to possess an activating JAK2 V617F mutation on chromosome 9.¹²

Presentation

Symptoms

• Patients may be asymptomatic for some time; 2 years is common. There may be incidental finding with anaemia or splenomegaly.

• Fatigue and weakness (secondary to anaemia) are common presenting complaints.

• It may present as unusual bleeding.

• It may present as early satiety, with accompanying weight loss, and abdominal distension due to splenomegaly. Systemic symptoms are also found: bone pain, night sweats and fever.

Signs

• Massive splenomegaly

• Portal hypertension and hepatomegaly

• Infections

• Hyperuricaemia (may show as kidney stones)/gout

• Cachexia

• Amyloidosis

Differential diagnosis

• Metastatic neoplasia

• Inflammation

• Leukaemias
  

  • Chronic myelogenous leukaemia

  • Hairy cell leukaemia

• Polycythaemia vera

• Essential thrombocytosis

• Tuberculosis

• Histoplasmosis

Investigations

• FBC reveals moderate-to-severe normochromic, normocytic anaemia.

• There is anisocytosis with marked poikilocytosis, characterised by teardrop shapes - dacrocytes.

• Nucleated red blood cells (RBCs) are present.

• Leukocytosis with immature forms is seen. Leukocyte alkaline phosphatase (LAP) score - a histochemical stain used to identify the neutrophil enzyme in myeloid disease - is normal or unusually high.

• There are abnormal platelets and sometimes megakaryocyte nuclei are seen.

Not all these features are there in early disease.

Complications

End-stage disease can be accompanied by haemorrhagic episodes, infection, heart failure, portal hypertension and acute leukaemic transformation.

Management

General measures

Transfusion of packed RBCs and platelets may be helpful.

Drugs

• Glucocorticoids help RBC survival time, which is often reduced.

• Recombinant erythropoetin and hydroxyurea have been used to treat anaemia. Cladribine is particularly useful post-splenectomy with thrombocytopenia and hepatomegaly.³ Thalidomide was thought to give a good response in 20-60%,⁴ but a recent Cochrane review showed that there was no substantial efficacy in anaemic myelosclerotic patients.⁵ The placebo group also showed spontaneous periods of remission of anaemia.

• Testosterone also reduces transfusion requirements, but is poorly tolerated by women.

• Chemotherapy with hydroxyurea or interferon alfa 2b can reduce splenomegaly. Interferon reduces spleen size in 30-50% of patients with myeloproliferative disease.⁶

Surgical

• Painful splenomegaly can be treated with radiation or splenectomy.⁷ Decision to operate must balance potential palliative gain with postoperative mortality rate of 9%,³ and morbidity from infection, thrombosis or bleeding of 30%.

• Allogenic, peripheral bone marrow or stem cell transplant.⁸

Prognosis

Average survival is 5 years, with a range of 1-16 years. The first 2 years are usually asymptomatic. Prognostic factors include:

• Age

• Degree of anaemia

• Degree of leukopenia or leukocytosis

• Number of circulating blasts

• Karyotypic abnormalities present and presence of systemic symptoms

If 2 of these are present, median survival is <3 years.⁹ If only one factor is present, prognosis is much better - up to 15 years.¹⁰ Patients who present at age <45 years have a survival of <3 years when they present with haemoglobin concentration of 10 g/dL and constitutional symptoms.¹⁰