Myelofibrosis
Summary
Myelofibrosis (MF) is the most aggressive of the Philadelphia-negative Myeloproliferative Neoplasms (MPNs). It is characterised by clonal stem cell proliferation, reactive bone marrow fibrosis, anaemia, and massive splenomegaly due to Extramedullary Haematopoiesis (EMH).
- Primary Myelofibrosis (PMF): De novo.
- Secondary Myelofibrosis: Transformation from Polycythaemia Vera (Post-PV MF) or Essential Thrombocythaemia (Post-ET MF). The median survival (5-6 years) is significantly worse than PV/ET. [1,2]
Clinical Pearls
The Dry Tap: A classic exam feature. Because the marrow is full of collagen scar tissue, a liquid aspiration yields nothing ("Dry Tap"). A Trephine Biopsy (core sample) is essential for diagnosis, showing Reticulin fibrosis (Silver stain).
Tear Drop Cells (Dacrocytes): Pathognomonic on the blood film. As red cells squeeze through the fibrotic marrow meshwork to enter the sinusoids, they are mechanically distorted into a distinct tear-drop shape.
Constitutional Symptoms: MF patients suffer profoundly from "drenching" night sweats, fevers, and cachexia. This is driven by a "cytokine storm" (TNF-alpha, IL-6) released by the clonal cells.
Demographics
- Incidence: 0.5-1.5 per 100,000.
- Age: Disease of the elderly (Median 67 years).
- Gender: M > F.
Genetics (Driver Mutations)
- JAK2 V617F (50-60%): The most common.
- CALR (Calreticulin) (25-30%): Better prognosis.
- MPL (5-10%).
- Triple Negative (10%): High risk of leukaemic progression.
The Cytokine Hypothesis
- Clonal Proliferation: Of Megakaryocytes and Granulocytes (driven by JAK2 pathway).
- Dysplastic Megakaryocytes: They release profibrotic cytokines: TGF-beta, PDGF, bFGF.
- Fibroblast Activation: The marrow fibroblasts are NOT malignant. They are simply reacting to the chemical signals by laying down collagen and reticulin.
- Fibrosis & Osteosclerosis: Marrow space is obliterated.
- Extramedullary Haematopoiesis: Stem cells migrate to the Spleen and Liver to establish new niches, causing hepatosplenomegaly.
Symptoms
Signs
- Abdomen: Measure spleen size below costal margin (cm). Check for ascites (portal hypertension from high splenic inflow).
- Skin: Look for leukaemia cutis or Sweet's syndrome (neutrophilic dermatosis).
Bloods
- FBC:
- Anaemia: Normocytic/Normochromic.
- WCC/Platelets: Can be High (early cellular phase) or Low (late fibrotic phase).
- Blood Film: Leucoerythroblastic Picture (Precursors: Myelocytes + Nucleated RBCs). Dacrocytes (Teardrops).
- Biochemistry: High LDH (turnover). High Urate.
Bone Marrow
- Aspirate: Usually dry.
- Trephine: Fibrosis (Reticulin stain Grade MF-1 to MF-3). Osteosclerosis. Impaired haematopoiesis.
Genetics
- PCR for JAK2, CALR, MPL.
- NGS (Next Gen Sequencing) for high risk mutations (ASXL1, EZH2) - "High Molecular Risk" profile.
Stratification (DIPSS Plus)
Decisions depend on risk score (Age, Constitutional symptoms, Hb less than 100, Blasts >1%, WCC >25).
Management Algorithm
MYELOFIBROSIS DIAGNOSED
(Assess Risk: DIPSS)
↓
ASYMPTOMATIC (Low Risk)
↓
WATCH & WAIT
(Monitor bloods q3-6mo)
│
└─> SYMPTOMATIC / INTERMEDIATE-2 / HIGH RISK
│
v
IS PATIENT TRANSPLANT CANDIDATE?
(Usually less than 70, functional fit)
┌─────────┴─────────┐
YES NO
↓ ↓
ALLOGENEIC SYMPTOM CONTROL
STEM CELL (Palliative intent)
TRANSPLANT │
(Curative) ├─ CONSTITUTIONAL / SPLEEN PROB?
│ -> **Ruxolitinib** (JAK Inhibitor)
│
├─ ANAEMIA PROB?
│ -> Transfusion / EPO
│ -> Danazol / Thalidomide
│
└─ HIGH COUNTS PROB?
-> Hydroxycarbamide
Specific Therapies
- JAK Inhibitors (Ruxolitinib / Fedratinib):
- Inhibits the JAK-STAT pathway (regardless of JAK2 mutation status!).
- Drastically reduces spleen size and B-symptoms.
- Does NOT reverse fibrosis or cure disease (though may prolong survival).
- Side Effect: Can cause anaemia/thrombocytopenia.
- Allogeneic HSCT:
- The biological cure.
- High TRM (Transplant Related Mortality) risk in this older/frail demographic (20-30%).
- Blast Transformation: 15-20% transform to AML. Highly resistant to chemo. Median survival less than 6 months.
- Portal Hypertension: Variceal bleeding forms due to massive splenic inflow.
- Thrombosis: Similar vascular risk to other MPNs.
- Highly variable.
- Low Risk: Survival >15 years.
- High Risk: Survival less than 2 years.
Key Guidelines
| Guideline | Organisation | Key Recommendations |
|---|---|---|
| Myelofibrosis | BSH (2014) | Criteria for diagnosis and transplant eligibility. |
| MPN Management | ELN (European LeukemiaNet) | Algorithm for JAK inhibitor use. |
Landmark Evidence
1. COMFORT-I and -II Trials (NEJM 2012)
- Pivotal trials proving Ruxolitinib superior to placebo/best available therapy for spleen reduction and symptom control. Led to global approval.
What is Myelofibrosis?
It is a condition where the bone marrow (the blood factory inside your bones) gets severely scarred. "Myelo" = Marrow, "Fibrosis" = Scar. Because the factory is scarred shut, your body tries to act smart and sets up "pop-up factories" in the Spleen and Liver.
Why is my spleen so big?
The spleen swells up massively because it is doing the work of the bone marrow. This makes your tummy feel full and uncomfortable.
Is it cancer?
It is a type of chronic blood cancer. Unlike acute leukaemia which strikes suddenly, this usually progresses slowly over years. However, it affects your quality of life significantly (fatigue, sweats).
What is the new drug?
Ruxolitinib is a tablet that blocks the faulty signal causing the scarring and inflammation. It makes the spleen shrink and stops the night sweats, making you feel much better, though it isn't a total cure.
Primary Sources
- Reilly JT, et al. Guideline for the diagnosis and management of myelofibrosis. Br J Haematol. 2012. (BSH).
- Verstovsek S, et al. A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis (COMFORT-I). N Engl J Med. 2012.
- Cervantes F, et al. New prognostic scoring system for primary myelofibrosis (DIPSS). Blood. 2010.
Common Exam Questions
- Diagnosis: "Dry Tap + Tear Drop cells?"
- Answer: Myelofibrosis.
- Pathology: "Stain for fibrosis?"
- Answer: Reticulin (Silver) stain.
- Genetics: "Commonest mutation?"
- Answer: JAK2 V617F.
- Pharmacology: "Drug for splenomegaly?"
- Answer: Ruxolitinib.
Viva Points
- Massive Splenomegaly Differentials: Myelofibrosis, CML, Malaria, Leishmaniasis, Gaucher's Disease.
- Leucoerythroblastic: This term refers to the presence of immature cells (nucleated red cells and myelocytes) in the blood. It implies marrow infiltration (by fibrosis or cancer).
Medical Disclaimer: MedVellum content is for educational purposes and clinical reference. Clinical decisions should account for individual patient circumstances. Always consult appropriate specialists.