Myelofibrosis

Question 1

Myelofibrosis is a clonal haematopoietic stem cell disorder (myeloproliferative neoplasm).

It is characterised by:
1. Ineffective haematopoiesis -> pancytopenia
2. Progressive bone marrow fibrosis/scarring
3. Extramedullary haematopoiesis of spleen and liver with organomegaly
4. Constitutional symptoms - fatigue, weight loss, fever, night sweats

It can arise:
1. De novo (primary myelofibrosis)
2. Pre-existing myeloproliferative neoplasm - PRV, essential thrombocytopenia

Question 2

Pathophysiology of myelofibrosis

Answer 2

1. Clonal haematopoiesis of abnormal myeloid cells (especially megakaryocytes)
2. Mutation drivers: JAK2, CALR, MPL
3. Clonal cells release cytokines and growth factors (TGF-B, PDGF, FGF) stimulating fibroblasts and endothelial cells in bone marrow - excessive deposition of ECM proteins and leading to fibrosis (reactive process, not malignant clone)
4. Extramedullary haematopoiesis due to fibrotic bone marrow. Migration of stem cells to mainly spleen and liver (hepatosplenomegaly)
   - Others: lymph nodes, lungs, pleural, peritoneum
5. Constitutional symptoms and cachexia from overproduction of cytokines (IL-1, IL-6, TNF-a)

Question 3

Epidemiology of myelofibrosis

Answer 3

Rare: 1-1.5 per 100,000
Elderly 65-70 years old

Question 4

Clinical presentation of myelofibrosis

Answer 4

1. Constitutional symptoms - fever, weight loss, night sweat, fatigue
2. Anaemia - weakness, dyspnoea, pallor, fatigue
3. Thrombocytopenia - bleeding, bruising
4. Neutropenia - frequent infection
5. Splenomegaly compression - early satiety, abdominal discomfort, LUQ fullness
6. Hepatomegaly and portal hypertension
7. Arterial or venous thrombosis
8. Transformation to AML

Question 5

Stage and progression of myelofibrosis

Answer 5

A. Pre-fibrotic (early)
- Clonal marker, atypical megakaryocytes) with no/minimal reticulin fibrosis
- Mild anaemia, leukocytosis, LDH, splenomegaly
- May remain stable for many years

B. Overt
- Reticulin and collagen fibrosis of bone marrow
- Profound cytopenia and splenomegaly
- Constitutional symptoms
- Leukoerythroblastosis

C. Transformation to AML

Question 6

Investigations for myelofibrosis

Answer 6

1. FBC - varying cytopenias
2. PBF - teardrop cells (dacrocytes), leukoerythroblastosis, large bizarre platelets
3. BMAT - dry tap
   If successful: variable cellularity (early hypercellular; late hypocellular), megakaryocytes clustering/large, granulocytic hyperplasia, reticulin/collagen fibrosis
4. Molecular test - JAK2, CALR, MPL
   (Next gen sequencing for high risk mutations: ASXL1, EZH2, SRSF2, IDH1/2, U2AF1)
5. Cytogenetics for karyotyping

Question 7

Management of myelofibrosis

Answer 7

1. Mostly watch and wait for asymptomatic
2. JAK inhibitors
   - Ruxolitinib (JAK1/2 - first in class)
   - Fedratinib (JAK2)
   - Pacritinib (JAK2-IRAK1)
   - Memelotinib (JAK1/2-ACVR1)
3. Management of anaemia
   - Transfusion
   - Erythropoietin
   - Danazol
   - Immunomodulators: thalidomide, lenalidomide, prednisolone
   - Luspatercept (used in MDS)
   - Momelotinib
4. Management of thrombosis, bleeding, portal hypertension
5. Cytoreduction for thrombocytosis/leukocytosis (early stage)
   - Hydroxyurea, pegylated interferon alpha
6. Splenectomy or splenic irradiation
7. Allogenic stem cell transplant (allo-SCT)
   - Transplant eligible with intermediate to high risk disease