Definition
Primary myelofibrosis is a MPNMyeloproliferative neoplasm characterised by progressive bone marrow fibrosis, resulting in:
- Ineffective haematopoiesis
- Extramedullary haematopoiesis
MPNsMyeloproliferative neoplasms are a group of clonal haematopoietic stem cell disorders characterised by overproduction of mature myeloid lineage cells. The 4 classical myeloproliferative neoplasms are:
- Primary myelofibrosis
- Polycythaemia vera
- Essential thrombocythaemia
- Chronic myeloid leukaemia
MPNsMyeloproliferative neoplasms share several features:
- Mutations affecting the JAK-STAT signalling pathway (most commonly JAK2, but also CALR or MPL mutations)
- CML is distinct, driven by the Philadelphia chromosome (BCR-ABL fusion gene)
- Bone marrow hypercellularity
- ↑ Risk of thrombosis (particularly in polycythaemia vera and essential thrombocythaemia)
- Risk of transformation to AMLAcute myeloid leukaemia
Aetiology
Causes are categorised based on whether the condition arises de novo (primary) or develops from a pre-existing disorder (secondary).
Although various causes of primary and secondary myelofibrosis exist, for exam purposes, it is most important to recognise the association between the JAK2 mutation and primary myelofibrosis.
Primary Myelofibrosis Causes
Most cases are caused by mutations in 3 specific genes:
- JAK2 (present in ~50-60% cases)
- CALR (present in 15-35% caes)
- MPL (present in 6-9% cases)
Secondary Myelofibrosis Causes
In haematology, secondary myelofibrosis refers to the progression of other MPNsMyeloproliferative neoplasms into myelofibrosis, seen in:
- Polycythaemia vera (post-polycythaemia vera myelofibrosis)
- Essential thrombocythaemia (post-essential thrombocythaemia myelofibrosis)
A range of non-MPN conditions can cause reactive bone marrow fibrosis, which should be excluded during evaluation. These include:
- Infection (e.g. HIVHuman immunodeficiency virus, TBTuberculosis, EBVEpstein-Barr virus, visceral leishmaniasis)
- Autoimmune disorders (e.g. SLESystemic lupus erythematosus, Sjogren syndrome, JIAJuvenile idiopathic arthritis)
- Other haematological disorders (e.g. MDSMyelodysplastic syndromes, CMLChronic myeloid leukaemia, Hodgkin lymphoma)
- Metastatic malignancy
Pathophysiology
Primary myelofibrosis is driven by clonal proliferation of abnormal megakaryocytes
- Abnormal megakaryocytes release pro-fibrotic cytokines (e.g. TGF-beta) → bone marrow fibrosis
- Bone marrow fibrosis → ineffective haematopoiesis →
- Early disease is proliferative, often causing leucocytosis and thrombocytosis
- Advanced disease → bone marrow failure → pancytopaenia
- Due to ineffective haematopoiesis → extramedullary haematopoiesis → splenomegaly
Clinical Features
Typically affects older adults, with equal sex incidence.
| Constitutional symptoms |
|
| Features of extramedullary haematopoiesis | Classically causes progressive massive splenomegaly
|
| Bone marrow features |
|
Investigation and Diagnosis
| FBC | Classic early (proliferative) disease findings:
In advanced disease, bone marrow failure can cause pancytopenia (anaemia, leucopaenia, thrombocytopaenia) |
| Blood film |
|
| Molecular testing |
|
| Bone marrow biopsy – gold standard |
|
Management
Key management principles:
| Risk / disease stage | Management |
|---|---|
| Low risk / asymptomatic disease | Active observation |
| Symptomatic / proliferative disease | Symptom-directed therapy:
|
| High risk | Consider allogenic haematopoietic stem cell transplantation
|
Disclaimer:
Management of myelofibrosis typically requires a multidisciplinary team approach. Patients usually undergo prognostic assessment using validated scoring systems, which guides risk-stratified treatment, and may be considered for clinical trials where available.
Detailed prognostic scoring and specialist management pathways are beyond the scope of the UKMLA and junior doctors. The summary above therefore focuses on the key management principles relevant to exams and non-specialist training.
References
BSH Diagnosis and evaluation of prognosis of myelofibrosis
BSH The management of myelofibrosis: A British Society for Haematology Guideline