Key Facts

Myelofibrosis is characterised by progressive replacement of bone marrow by fibrotic tissue, leading to bone marrow failure and extramedullary haematopoiesis (predominantly in the spleen and liver). It can present de novo (primary MF) or evolve from PV or ET.

Epidemiology

• Incidence: 0.5-1 per 100,000/year in the UK
• Median age at diagnosis: 65-70 years
• Slight male predominance
• Rarest of the classic MPNs

Aetiology

• JAK2 V617F: ~60%
• CALR: ~25% (type 1 has better prognosis than type 2)
• MPL: ~7%
• Triple-negative: ~8% (worst prognosis)
• Additional mutations (ASXL1, EZH2, SRSF2, IDH1/2) modify prognosis

Pathophysiology

• Clonal stem cell disorder with abnormal megakaryocyte proliferation
• Megakaryocytes release fibrogenic cytokines (TGF-β, PDGF, VEGF) → progressive marrow fibrosis
• Marrow failure → cytopenias
• Extramedullary haematopoiesis → massive splenomegaly, hepatomegaly
• Altered stem cell niche → leukoerythroblastic picture in peripheral blood
• Constitutional symptoms driven by pro-inflammatory cytokine excess

Common Presentations

• Massive splenomegaly (often below umbilicus) – most prominent finding
• Constitutional symptoms: fatigue, weight loss, night sweats, fevers (up to 30%)
• Anaemia symptoms: fatigue, dyspnoea
• Abdominal discomfort/early satiety (from splenic enlargement)
• Bone pain (marrow fibrosis)

Complications

• Splenic infarction: acute left upper quadrant pain
• Portal hypertension: ascites, variceal bleeding
• Extramedullary haematopoiesis: pulmonary hypertension, spinal cord compression
• Transformation to AML: 10-20% at 10 years

Red Flags

• Rapidly increasing spleen size → disease progression or blast transformation
• New cytopenias with circulating blasts → leukaemic transformation
• Severe thrombocytopenia (<50 × 10⁹/L) → high bleeding risk

Bedside

• Physical examination: splenomegaly (often massive), hepatomegaly

Bloods

• FBC: anaemia (normocytic, often severe), WCC variable (raised or low), platelets variable
• Blood film: leukoerythroblastic picture – tear-drop poikilocytes (dacrocytes), nucleated RBCs, immature myeloid cells, large platelets
• LDH: elevated (marrow turnover)
• Uric acid: often raised
• JAK2 V617F, CALR, MPL mutations
• Additional molecular profiling: ASXL1, SRSF2, EZH2, IDH1/2 (prognostic)

Imaging

• Abdominal ultrasound/CT: splenomegaly, hepatomegaly, portal hypertension
• MRI: assess extramedullary haematopoiesis if clinically indicated

Special Tests

• Bone marrow biopsy (trephine essential): reticulin/collagen fibrosis (graded MF-0 to MF-3), megakaryocyte atypia, reduced haematopoietic tissue
• Cytogenetics: complex karyotype is adverse
• Dry tap on aspirate is common due to fibrosis

Non-pharmacological

• Risk stratification using DIPSS or DIPSS-Plus before treatment decisions
• Observation if asymptomatic, low-risk disease
• Red cell transfusion support for symptomatic anaemia

Pharmacological

JAK inhibitors (COMFORT-I/II, SIMPLIFY trials):

• Ruxolitinib 15-20mg BD (based on platelet count): reduces spleen size by ≥35% in ~40% and improves constitutional symptoms
• Start at 20mg BD if platelets >200, 15mg BD if 100-200
• Monitor FBC closely (dose-limiting cytopenias)
• Fedratinib 400mg OD: second-line JAK inhibitor (JAKARTA trial)

Anaemia management:

• Erythropoiesis-stimulating agents: if EPO <500 and low transfusion burden
• Danazol 200mg TDS: may improve anaemia
• Thalidomide 50mg OD + prednisolone – can improve anaemia and splenomegaly
• Luspatercept for transfusion-dependent anaemia

Splenomegaly:

• Ruxolitinib (first-line for symptomatic splenomegaly)
• Splenectomy: considered for refractory symptomatic splenomegaly, transfusion-dependent anaemia (high perioperative risk ~9% mortality)
• Splenic irradiation: for non-surgical candidates

Surgical/Interventional

• Allogeneic stem cell transplant: only curative option; consider in intermediate-2/high-risk patients aged <70 with suitable donor
• Transplant-related mortality ~20-30%

Referral Criteria

• All suspected MF → haematology
• Intermediate-2/high-risk → consider transplant referral early

• Median survival varies widely by risk group:
  • DIPSS Low risk: >15 years
  • DIPSS Intermediate-1: 6-7 years
  • DIPSS Intermediate-2: 2.5-4 years
  • DIPSS High risk: 1-2 years
• Overall median survival for primary MF: 3.5-5.5 years
• AML transformation: 10-20% at 10 years (prognosis very poor once transformed)
• Post-PV/ET MF generally has better prognosis than primary MF
• Allogeneic SCT can cure but significant morbidity/mortality

DIPSS Prognostic Scoring

Landmark Trials