Myelofibrosis Initial Assessment

Clinical Presentation

Approximately 30% of patients are asymptomatic; however, some patients may present with constitutional symptoms, the most common being fatigue, other symptoms include an enlarged spleen, weight loss, low-grade fever, night sweats, and bone pain. Patients may also present with pruritus and should also be assessed for signs and symptoms of severe anemia, splenic infarct, thrombosis, bleeding, and cachexia. 

History

During history-taking, it is important to assess for cardiovascular risk factors, evaluate for thrombotic or hemorrhagic events, and ask for medication and transfusion history.

Physical Examination

During physical examination, it is important to look for signs of spleen enlargement since it is the hallmark of primary myelofibrosis. Other patients may also present with hepatomegaly.  

Diagnosis or Diagnostic Criteria

Diagnosis of myelofibrosis is based on 2022 World Health Organization (WHO) and International Consensus Classification (ICC) diagnostic criteria and requires a combination of clinical, laboratory, cytogenetic, and molecular features.  

ICC and 2022 WHO Diagnostic Criteria of Primary Myelofibrosis (PMF)

Prefibrotic or Early Primary Myelofibrosis 

The diagnosis of pre-primary myelofibrosis requires fulfilling all three major criteria and ≥1 minor criterion which are as follows:

• Major criteria: 
  • Megakaryocytic proliferation and atypia, bone marrow fibrosis grade <2 accompanied by increased age-adjusted bone marrow cellularity, granulocytic proliferation, and often decreased erythropoiesis
  • Not meeting diagnostic criteria for BCR::ABL1-positive CML, PV, ET, myelodysplastic syndromes, or other myeloid neoplasms 
  • Presence of JAK2, CALR, or MPL mutation or presence of another clonal marker (presence of ASXL1, EZH2, TET2, ISH1/IDH2, SRSF2, SF3B1 mutations), or absence of reactive bone marrow reticulin fibrosis (grade 1 reticulin fibrosis secondary to an infection, autoimmune disorder or other chronic inflammatory conditions, hairy cell leukemia or other lymphoid neoplasms, metastatic malignancy, or toxic myelopathies)
• Minor criteria: Presence of ≥1 of the following confirmed in two consecutive examinations
  • Anemia not due to a comorbid condition
  • Lactate dehydrogenase (LDH) above reference range 
  • White blood cells (WBC) ≥11 x 10⁹/L
  • Palpable splenomegaly 

Overt Primary Myelofibrosis

The diagnosis of overt primary myelofibrosis requires fulfilling all three major criteria and ≥1 minor criterion which are as follows: 

• Major criteria:
  • Presence of megakaryocytic proliferation and atypia, with reticulin and/or collagen fibrosis grades 2 or 3 
  • Not meeting diagnostic criteria for ET, PV, BCR::ABL1-positive CML, myelodysplastic syndromes, or other myeloid neoplasms 
  • Presence of JAK2, CALR, or MPL mutation or presence of another clonal marker (presence of ASXL1, EZH2, TET2, ISH1/IDH2, SRSF2, SF3B1 mutations), or absence of reactive myelofibrosis (bone marrow fibrosis due to infection, autoimmune disorder or other chronic inflammatory conditions, hairy cell leukemia or other lymphoid neoplasms, metastatic malignancy, or toxic myelopathies) 
• Minor criteria: Presence of ≥1 of the following confirmed in two consecutive examinations
  • Anemia not due to a comorbid condition
  • LDH above reference range
  • WBC ≥11 x 10⁹/L
  • Palpable splenomegaly
  • Leukoerythroblastosis 

Myelofibrosis Grading

International Working Group for Myelofibrosis Research and Treatment (IWG-MRT) Diagnostic Criteria Post-Polycythemia Vera (Post-PV) Myelofibrosis

For post-PV myelofibrosis, the required criteria are bone marrow fibrosis grade 2-3 on a 0-3 scale or grade 3-4 on a 0-4 scale and documentation of a previous diagnosis of PV as defined by the WHO criteria. 

In addition to the required criteria, at least two additional criteria must be present among the following:

• Anemia or sustained loss of requirement of either phlebotomy in the absence of cytoreductive therapy or cytoreductive treatment for erythrocytosis
• Leukoerythroblastic peripheral blood picture
• Increasing splenomegaly defined as an increase in palpable splenomegaly of ≥5 cm or the appearance of a newly palpable splenomegaly
• Appearance of ≥1 of 3 constitutional symptoms: >10% weight loss in 6 months, night sweats, unexplained fever 

Post-Essential Thrombocythemia (Post-ET) Myelofibrosis  

For post-ET, the required criteria are bone marrow fibrosis grade 2-3 on a 0-3 scale or grade 3-4 on a 0-4 scale and documentation of a previous diagnosis of ET as defined by the WHO criteria.

In addition to the required criteria, at least two additional criteria must be present among the following:

• Anemia and ≥2 g/dL drop from baseline hemoglobin level
• Leukoerythroblastic peripheral blood picture
• Increasing splenomegaly defined as an increase in palpable splenomegaly of ≥5 cm or the appearance of a newly palpable splenomegaly
• Elevated LDH
• Appearance of ≥1 of 3 constitutional symptoms: >10% weight loss in 6 months, night sweats, unexplained fever (>37.5°C) 

Post-Essential Thrombocythemia (Post-ET) Myelofibrosis  

For post-ET, the required criteria are bone marrow fibrosis grade 2-3 on a 0-3 scale or grade 3-4 on a 0-4 scale and documentation of a previous diagnosis of ET as defined by the WHO criteria.  

In addition to the required criteria, at least two additional criteria must be present among the following:

• Anemia and ≥2 g/dL drop from baseline hemoglobin level
• Leukoerythroblastic peripheral blood picture
• Increasing splenomegaly defined as an increase in palpable splenomegaly of ≥5 cm or the appearance of a newly palpable splenomegaly
• Elevated LDH
• Appearance of ≥1 of 3 constitutional symptoms: >10% weight loss in 6 months, night sweats, unexplained fever (>37.5°C)