23rd July 2024

Primary myelofibrosis (PMF)

Background of PMF

PMF is an MPN characterised by bone marrow fibrosis, extramedullary haematopoiesis (causing splenomegaly) and leucoerythroblastic blood films. It primarily causes proliferation of cells of megakaryocyte and granulocyte lineage. PMF refers to only de novo myelofibrosis. Myelofibrosis from another cause is called secondary or reactive myelofibrosis. Myelofibrosis occurring from PV or ET are termed post-PV and post-ET myelofibrosis respectively.

PMF is the least common MPN. Median age of diagnosis is ~65 years with a slight male predominance.

Precise aetiology is unknown. The JAK2 V617F mutation is found in up to 58% of patients. Mutually exclusive JAK2, CALR or MPL mutations are found in ~90% of PMF.

Presentation and diagnosis of PMF

Fatigue is the most common presenting complaint. Weight loss, fevers and night sweats are also common and are due to an overexpression of inflammatory cytokines, resulting in a hypercatabolic state.

Marked splenomegaly is a hallmark of PMF. It is present in almost all patients, and they may present with symptoms from this such as left upper quadrant discomfort and early satiety.

A significant minority are asymptomatic at diagnosis, incidentally being identified with abnormal bloods or splenomegaly.

Diagnosis is multimodal:

• Bloods: usually show anaemia; platelets and white cells may be low, normal or high (thrombocytosis>thrombocytopenia)
• Blood film: teardrop-shaped red blood cells and a leucoerythroblastic picture (nucleated red cells, immature white cells) are disease hallmarks
• Bone marrow aspirate: usually unsuccessful, ‘dry tap’
• Bone marrow biopsy: extensive fibrosis, may be hypercellular

Further immunophenotyping and mutation analysis are required to ensure secondary causes of myelofibrosis are ruled out.

Management and prognosis of PMF

If eligible, patients should undergo allogeneic SCT. This can prolong survival and has curative potential.

If ineligible for transplant, treatment is for symptomatic relief. Ruxolitinib and fedratinib (JAK2 inhibitors) are effective at improving symptoms (reducing organomegaly and improving blood counts). Hydroxycarbamide can be used if JAK2 inhibitors are ineffective but it is less efficacious. Splenectomy and red cell transfusion are also used to manage symptoms. Symptomatic treatments do not affect prognosis.

Median survival is ~6 years, ranging from <1 to >30 years.

Death is usually from leukaemic transformation or from bone marrow failure complications (infection, haemorrhage).