Myelofibrosis

The cause of primary myelofibrosis (PMF) is unknown, and a specific clonal marker has not been identified. Environmental and genetic factors may be involved in the development of PMF. However, there are no specific common risk factors identified in most patients with PMF.

Environmental factors

A high incidence of PMF has been reported in patients exposed to thorium dioxide-based radiographic contrast medium (used in x-ray diagnostics in the 1930s to 1950s), and in survivors of the Hiroshima atomic bomb.[7][8] PMF was observed at 15 to 20 times the expected incidence rate in Hiroshima survivors (on average 6 years after the incident).[8]

Benzene, toluene, and many other aromatic solvents have been associated with haematological malignancies, including PMF.[9]

Genetics factors

Chromosomal abnormalities with prognostic significance are present in 35% to 50% of patients with PMF.[10] These include cytogenetic abnormalities involving chromosomes 13 (del.13q), 20 (del.20q), +8 (trisomy 8), 1, 5 (-5/del5q), 7 (-7/del7q), +9 (trisomy 9), 12 (del12p), and 17.[10] Sole +9, del.13q, del.20q, and normal cytogenetics have the most favourable prognosis; sole +8, 5, 7, 12, 17, and complex mutations have a distinctly poorer prognosis.[10][11][12][13]

Somatic driver mutations in the Janus kinase 2 (JAK2), myeloproliferative leukaemia virus oncogene (MPL), or calreticulin (CALR) genes are commonly present in patients with PMF and other myeloproliferative neoplasms (MPNs, e.g., polycythaemia vera, essential thrombocythaemia).[14][15] MPN driver mutation expression is not mutually exclusive, but patients typically only have one driver mutation that is clonally dominant. There may be a familial or germline predilection for acquiring MPN driver mutations, but this is subject to investigation.[16][17]

The V617F mutation in the JAK2 gene (located on chromosome 9p) has been identified in approximately 58% of patients with PMF.[14][15] The JAK2 V617F mutation causes an increase in production of normal leukocytes and platelets in many patients with PMF, but in some patients haematopoiesis is depressed.

Mutations in the MPL gene (on chromosome 1p) have been identified in approximately 8% of patients with PMF.[14][15] The W515L/K/A mutations are the most frequently reported MPL mutations in PMF.[10][18] MPL mutations can cause abnormal blood cells to grow and proliferate uncontrollably.

Patients with PMF with an MPL mutation have lower haemoglobin levels, higher platelet counts, and reduced bone marrow cellularity compared with their JAK2 V617F-positive counterparts. However, survival does not differ considerably between those with MPL mutations and those with JAK2 mutations.

Mutations in the CALR gene (on chromosome 19) have been identified in approximately 25% of patients with PMF.[15] Mutations in CALR are associated with improved overall survival compared with JAK2 V617F or MPL W515 mutations.[19] Type 1 CALR mutations (52-bp deletion) are more common, and have a more favourable impact on prognosis, than type 2 CALR mutations (5-bp insertion) in PMF.[20][21]

The CALR gene encodes a multi-functional protein involved in protein folding and calcium homeostasis.[15][22] Mutated CALR serves as a chaperone to the thrombopoietin receptor MPL, causing its activation.[23] CALR mutations (insertions or deletions) occur in exon 9 and cause a one base pair frameshift.

Approximately 10% of patients with PMF are negative for JAK2, CALR, and MPL mutations (i.e., triple negative); therefore, absence of these MPN driver mutations does not exclude the diagnosis.[24] Some triple-negative patients may have uncommon MPL mutations.[25] Triple-negative mutation status is associated with a worse prognosis in patients with PMF.[19][26]

Other potentially disease-modifying non-driver gene mutations are found in patients with PMF, including ASXL1, EZH2, SRSF2, TP53, IDH1, IDH2, and U2AF1. These are considered high-molecular-risk mutations, associated with shorter overall and leukaemia-free survival.[26][27]

Primary myelofibrosis (PMF) is a clonal haematopoietic stem cell disorder with its origin in a multipotent haematopoietic progenitor cell.[28] PMF is characterised by hyperplasia of morphologically abnormal megakaryocytes in the bone marrow in association with bone marrow fibrosis, osteosclerosis, marrow angiogenesis, extramedullary haematopoiesis, splenomegaly, and leukoerythroblastosis.

Bone marrow fibrosis in PMF is considered to be a secondary, reactive process.[29] The malignant clone stimulates marrow fibroblasts to proliferate and deposit reticulin and collagen fibres in the bone marrow.[28][29][30] Condensation of interstitial reticulin fibres results in the formation of thick, continuous, and wavy bundles of reticulin fibres in the bone marrow. Sinusoidal basement membrane collagen fibres become continuous, leading to sinusoidal dilation and obliteration with an associated capillary neovascularisation.

Megakaryocytic hyperplasia, dysplasia, and clustering are characteristic features of PMF. These cells release fibrogenic cytokines (e.g., platelet-derived growth factor and transforming growth factors) that promote marrow fibroblast proliferation and inhibit collagenase.[29] Transforming growth factors (e.g., TGF-beta) promote the synthesis of osteoprotegerin, which impairs osteoclast proliferation and promotes osteosclerosis. Increased levels of thrombopoietin in PMF also play a role in promoting bone marrow fibrosis.[31][32]

Although bone marrow fibrosis is a key diagnostic feature of PMF, it is the malignant haematopoietic stem cell clone that impairs haematopoiesis and subsequently causes anaemia, extramedullary haematopoiesis, and splenomegaly. Splenomegaly also contributes to anaemia due to red cell sequestration and haemodilution. Folate deficiency (due to increased folate consumption from chronic myeloproliferation) may contribute to anaemia.

Increased marrow angiogenesis is seen frequently in PMF. This is caused by abnormal angiogenic cytokine production (from dysfunctional megakaryocytes), marrow sinusoidal dilation, and intravascular haematopoiesis.[28] Increased angiogenesis appears to be an early feature of PMF and correlates better with increased marrow cellularity than with marrow fibrosis.[33]

The 5th edition of the World Health Organization (WHO) classification of haematolymphoid tumours and International Consensus Classification (ICC) of primary myelofibrosis[2][3]

Primary myelofibrosis (PMF) is divided into the following two sub-classifications (under the main classification of myeloproliferative neoplasms):

Prefibrotic/early stage PMF (pre-PMF)
Overt fibrotic stage PMF

Aetiology

Pathophysiology

Classification