What is myelofibrosis?

What is Myelofibrosis

Myelofibrosis (MF) is a BCR-ABL1-negative chronic myeloproliferative neoplasm characterized by clonal stem cell proliferation with megakaryocyte proliferation and atypia, bone marrow fibrosis, splenomegaly from extramedullary hematopoiesis, constitutional symptoms, and shortened survival. 1, 2

Disease Classification and Pathophysiology

Myelofibrosis encompasses three distinct entities 2:

• Primary myelofibrosis (PMF) - arising de novo
• Post-polycythemia vera myelofibrosis - transformation from PV
• Post-essential thrombocythemia myelofibrosis - transformation from ET

The disease is driven by dysregulated JAK-STAT signaling, which underlies myeloproliferation, bone marrow fibrosis, constitutional symptoms, and cachexia 1. Clonal markers are present in the majority of cases: JAK2 V617F mutations occur in approximately 50% of patients, with CALR and MPL mutations accounting for additional cases 3, 2.

Diagnostic Criteria

According to WHO criteria, diagnosis requires meeting all 3 major criteria plus 2 of 4 minor criteria 3:

Major Criteria 3

1. Megakaryocyte proliferation and atypia (small to large megakaryocytes with aberrant nuclear/cytoplasmic ratio, hyperchromatic, bulbous, or irregularly folded nuclei with dense clustering), usually with reticulin/collagen fibrosis OR in absence of fibrosis, increased bone marrow cellularity with granulocytic proliferation and decreased erythropoiesis (prefibrotic cellular-phase disease)
2. Exclusion of other myeloid neoplasms - not meeting WHO criteria for PV, BCR-ABL1-positive CML, MDS, or other myeloid disorders
3. Clonal marker demonstration - JAK2 V617F, MPL W515K/L, or other clonal marker; OR in absence of clonal markers, no evidence of secondary bone marrow fibrosis from infection, autoimmune disorder, chronic inflammation, lymphoid neoplasm, metastatic malignancy, or toxic myelopathies

Minor Criteria 3

1. Leukoerythroblastosis
2. Elevated serum lactate dehydrogenase
3. Anemia
4. Palpable splenomegaly

Clinical Manifestations

The disease presents with a constellation of findings 1, 2:

• Splenomegaly - resulting from extramedullary hematopoiesis
• Cytopenias - particularly anemia, though thrombocytosis or thrombocytopenia may occur
• Constitutional symptoms - fatigue, weight loss, night sweats, fever
• Bone marrow fibrosis - progressive scarring on biopsy
• Some patients remain asymptomatic at diagnosis 2

Disease Phases

Myelofibrosis can present in two distinct phases 3:

Prefibrotic (Cellular) Phase 3

• Minimal or absent reticulin fibrosis
• Bone marrow hypercellularity
• Neutrophilic proliferation
• Megakaryocytic proliferation with atypia
• Mild or no splenomegaly
• Mild anemia, leukocytosis, thrombocytosis
• Minimal leukoerythroblastosis

Fibrotic Phase 3

• Prominent reticulin and/or collagen fibrosis
• Progressive splenomegaly
• Worsening cytopenias
• Marked leukoerythroblastosis
• Dacryocytes (teardrop cells) on peripheral smear

Critical Distinguishing Features

Megakaryocyte morphology is the cardinal diagnostic feature 3:

• PMF shows megakaryocytes in sizable loose to tight clusters, ranging from small to large with aberrant nuclear/cytoplasmic ratio, hyperchromatic, bulbous, or irregularly folded nuclei
• Bare megakaryocytic nuclei are common
• This contrasts with MDS (small megakaryocytes with monolobated nuclei, not clustered) and ET (giant mature megakaryocytes with deeply lobulated nuclei) 3

The presence of JAK2 V617F, MPL, or CALR mutations indicates clonal (primary) disease rather than reactive bone marrow fibrosis 4, 2.

Life-Threatening Complications

Fatal complications include 1:

• Transformation to acute leukemia - occurs in a subset of patients
• Thrombohemorrhagic events - both thrombosis and bleeding
• Organ failure - from extramedullary hematopoiesis or disease progression
• Infections - from cytopenias and immune dysfunction
• Portal hypertension and variceal bleeding - from hepatosplenomegaly
• Spinal cord compression, intracranial hypertension, pulmonary hypertension - from extramedullary hematopoiesis in various organs

Prognosis and Treatment Context

Primary myelofibrosis is the least common myeloproliferative neoplasm but carries the worst prognosis with shortened survival and risk of leukemic transformation 2. Allogeneic stem cell transplantation remains the only potentially curative therapy, though it is suitable for few patients 1, 5. JAK inhibitors like ruxolitinib improve splenomegaly and symptoms but do not eliminate the underlying clone 2, 5.