Myelofibrosis

Summary

Myelofibrosis (MF) is a chronic myeloproliferative neoplasm (MPN) in which clonal megakaryocytes drive fibrosis of the bone marrow, forcing blood production to shift to the spleen and liver (extramedullary hematopoiesis).

• Key mutation: JAK2 V617F (~50–60%), CALR, or MPL.
• Classic patient: elderly adult with massive splenomegaly, fatigue, weight loss, and night sweats.
• Blood smear: teardrop cells (dacrocytes) + leukoerythroblastic picture (nucleated RBCs, immature WBCs).
• Bone marrow: "dry tap" on aspiration; biopsy shows fibrosis (reticulin/collagen).
• Treatment: supportive care, JAK2 inhibitor (ruxolitinib), and allogeneic stem cell transplant (only cure).

Definition

Primary myelofibrosis (PMF) is a BCR-ABL negative chronic myeloproliferative neoplasm characterized by:

• Clonal proliferation of an abnormal hematopoietic stem cell (mainly the megakaryocyte line).
• Progressive replacement of the bone marrow by fibrous tissue (reticulin and collagen).
• Compensatory extramedullary hematopoiesis in the spleen and liver → massive splenomegaly.

MF can be primary (de novo) or secondary — arising from polycythemia vera (post-PV MF) or essential thrombocythemia (post-ET MF).

Epidemiology

• Age: typically > 60 years (median ~65).
• Sex: slight male predominance.
• Incidence: the rarest of the classical MPNs (~1 per 100,000/year).
• Risk factors: prior radiation or benzene exposure; preceding PV or ET.

Etiology and Genetics

Myelofibrosis is driven by mutations that constitutively activate the JAK-STAT signaling pathway, causing uncontrolled myeloid proliferation.

• JAK2 V617F — most common (~50–60%).
• CALR (calreticulin) — ~25%; better prognosis.
• MPL (thrombopoietin receptor) — ~5–10%.
• "Triple-negative" (~10%) — worst prognosis.

Important: MF is BCR-ABL negative — this distinguishes it from CML, which is defined by the Philadelphia chromosome t(9;22).

Pathophysiology

The disease begins as a clonal stem cell disorder, but the fibrosis itself is not clonal — it is a reactive response driven by abnormal megakaryocytes.

1. Clonal megakaryocyte proliferation in the marrow (driven by JAK-STAT mutations).
2. Megakaryocytes secrete cytokines: PDGF, TGF-β, bFGF, VEGF.
3. TGF-β stimulates marrow fibroblasts → deposit reticulin and collagen.
4. Fibrotic marrow can no longer support hematopoiesis → pancytopenia.
5. Hematopoiesis shifts to the spleen and liver → massive splenomegaly + hepatomegaly.
6. RBCs are mechanically deformed squeezing through the fibrotic marrow and enlarged spleen → teardrop cells (dacrocytes).

Clinical Features

Onset is usually insidious. Up to 30% of patients are asymptomatic at diagnosis and discovered incidentally with splenomegaly or abnormal CBC.

Constitutional symptoms (from high cytokines):

• Fatigue, weight loss, low-grade fever, night sweats, pruritus.

Splenomegaly (extramedullary hematopoiesis) — the hallmark:

• Massive splenomegaly (often crosses the midline).
• Early satiety, left upper quadrant pain, splenic infarcts.

Cytopenias (from marrow failure):

• Anemia → pallor, dyspnea on exertion.
• Thrombocytopenia → bleeding (later disease).
• WBC count may be high, normal, or low.

Other findings: hepatomegaly, gout (high cell turnover → hyperuricemia), bone pain.

Diagnosis

Diagnosis combines blood smear, bone marrow biopsy, and molecular testing.

1. CBC and Peripheral Blood Smear

• Anemia (usually normocytic).
• WBC and platelets variable (often initially high, then low).
• Leukoerythroblastic smear = immature WBCs + nucleated RBCs.
• Teardrop cells (dacrocytes) — classic.

Click to view: peripheral blood smear with dacrocytes and nucleated RBCs

2. Bone Marrow

• Aspirate → "dry tap" (cannot aspirate due to fibrosis).
• Biopsy (the diagnostic step): hypercellular early, then fibrotic marrow with reticulin/collagen deposition and atypical megakaryocyte clusters.

Click to view: bone marrow biopsy showing marrow fibrosis

3. Molecular and Lab Workup

• JAK2, CALR, MPL mutation testing.
• BCR-ABL testing → must be negative to exclude CML.
• ↑ LDH, ↑ uric acid, ↑ ALP.

Differential Diagnosis

The key task is to distinguish PMF from other myeloproliferative neoplasms and from secondary causes of marrow fibrosis.

• Other MPNs (CML, PV, ET) — see comparison below.
• Secondary myelofibrosis: metastatic cancer to marrow, lymphoma, infections (TB), autoimmune disease (SLE), vitamin D deficiency, hairy cell leukemia.
• Acute leukemias — especially when blast count rises.
• Aplastic anemia — pancytopenia but marrow is hypocellular without fibrosis.

Reference table: diagnostic features and mutations across the four chronic myeloproliferative disorders

Management

There is no cure except allogeneic stem cell transplant. Most management is symptomatic and based on the patient's risk score (DIPSS / IPSS).

Low-risk / asymptomatic

• Observation ("watch and wait").

Symptomatic / intermediate–high risk

• Ruxolitinib — oral JAK1/JAK2 inhibitor; reduces splenomegaly and constitutional symptoms. First-line drug.
• Hydroxyurea — for high WBC/platelet counts or symptomatic splenomegaly.
• Anemia management: transfusions, erythropoietin, danazol, or thalidomide/lenalidomide.
• Splenectomy — only for refractory painful splenomegaly or transfusion-dependent anemia.
• Splenic irradiation — for poor surgical candidates.

Curative

• Allogeneic hematopoietic stem cell transplant (HSCT) — the only curative option; reserved for younger, fit, high-risk patients.

Complications and Prognosis

• Transformation to AML — in ~10–20%; carries a very poor prognosis.
• Severe anemia and transfusion dependence.
• Infections (from neutropenia).
• Bleeding (from thrombocytopenia or platelet dysfunction).
• Thrombosis (Budd-Chiari, portal vein thrombosis).
• Portal hypertension from extramedullary hematopoiesis in the liver.
• Gout / urate nephropathy from high cell turnover.

Median survival: ~5 years overall, but ranges from <2 years (high-risk) to >10 years (low-risk).

Mnemonics