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 and comorbid conditions, to evaluate for thrombotic or hemorrhagic events, and to ask for medication and transfusion history. It is also important to inquire about recurrent or severe infections, nutritional deficiencies, kidney or thyroid dysfunction, autoimmune disorders, and other conditions that may cause cytopenias.

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 2024 World Health Organization (WHO) and International Consensus Classification (ICC) diagnostic criteria and requires a combination of clinical, laboratory, cytogenetic, and molecular features.  

ICC and 2024 WHO Diagnostic Criteria of Primary Myelofibrosis

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 (confirmed in 2 consecutive examinations):

• Major criteria: 
  • Megakaryocytic proliferation and atypia, without reticulin fibrosis grade >1, accompanied by increased age-adjusted bone marrow cellularity, granulocytic proliferation, and often decreased erythropoiesis
  • Not meeting diagnostic criteria for BCR::ABL1-positive chronic myeloid leukemia (CML), polycythemia vera, essential thrombocythemia, 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
  • Elevated lactate dehydrogenase (LDH)
  • White blood cells (WBC) ≥11 x 10⁹/L
  • Palpable splenomegaly or detected by imaging

Overt Primary Myelofibrosis

The diagnosis of overt primary myelofibrosis requires fulfilling all three major criteria and ≥1 minor criterion which are as follows (confirmed in 2 consecutive examinations): 

• Major criteria:
  • Presence of megakaryocytic proliferation and atypia, with reticulin and/or collagen fibrosis grades 2 or 3 
  • o   Not meeting diagnostic criteria for essential thrombocythemia, polycythemia vera, 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
  • Elevated LDH
  • WBC ≥11 x 10⁹/L
  • Palpable splenomegaly or detected by imaging
  • Leukoerythroblastosis 

Myelofibrosis Grading

ICC and 2024 WHO Diagnostic Criteria of Essential Thrombocythemia and Post-Essential Thrombocythemia Myelofibrosis  

Essential Thrombocythemia  

The diagnosis of essential thrombocythemia requires fulfilling all major criteria or the first 3 major criteria plus 1 minor criteria:

• Major criteria:
  • Platelet count ≥450 x 10⁹/L
  • Bone marrow biopsy showing proliferation mainly of megakaryocytic lineage, with increased numbers of enlarged, mature megakaryocytes with hyperlobulated nuclei, no significant increase or left shift in neutrophil granulopoiesis or erythropoiesis; very rarely a minor (grade 1) increase in reticulin fibers
  • WHO criteria for BCR::ABL1-positive CML, polycythemia vera, essential thrombocythemia, primary myelofibrosis, and other myeloid neoplasms are not met
  • AK2, CALR or MPL mutation
• Minor criteria:
  • Presence of a clonal marker or
  • Exclusion of reactive thrombocytosis

Post-Essential Thrombocythemia Myelofibrosis  

The diagnosis of post-essential thrombocythemia required fulfilling both required and ≥2 minor criteria:  

• Required criteria:
  • Bone marrow fibrosis grade 2 to 3 on a scale of 0 to 3
  • Documentation of a previous diagnosis of essential thrombocythemia as defined by the WHO criteria
• Additional criteria
  • Anemia (below the reference range given age, sex, and altitude considerations) and >2 g/dL drop from baseline hemoglobin level
  • Leukoerythroblastosis
  • Increasing splenomegaly, defined as either an increase in palpable splenomegaly or >50 mm from baseline (distance from the left costal margin, or on imaging) or newly palpable splenomegaly
  • Elevated LDH
  • Development of ≥2 of the following constitutional symptoms: >10% weight loss in 6 months, night sweats, unexplained fever (>37.5⁰C)

Diagnosis of post-essential thrombocythemia requires fulfilling both required and ≥2 minor criteria:

• Required criteria:
  • Bone marrow fibrosis grade 2 to 3 on a scale of 0 to 3
• Additional criteria
  • Anemia (below the reference range given age, sex, and altitude considerations) and >2 g/dL drop from baseline hemoglobin level
  • Leukoerythroblastosis
  • Increasing splenomegaly, defined as either an increase in palpable splenomegaly or >50 mm from baseline (distance from the left costal margin, or on imaging) or newly palpable splenomegaly
  • Elevated LDH
  • Development of ≥2 of the following constitutional symptoms: >10% weight loss in 6 months, night sweats, unexplained fever (>37.5⁰C)

ICC and 2024 WHO Diagnostic Criteria of Polycythemia Vera and Post-Polycythemia Vera Myelofibrosis  

Polycythemia Vera  

The diagnosis of polycythemia vera requires fulfilling all major criteria or the first 2 major criteria plus the minor criteria. In patients with sustained absolute erythrocytosis (hemoglobin concentrations of >18.5 g/dL in men or >16.5 g/dL in women, or hematocrit values of >55.5% in men or >49.5% in women), the second major criterion may not be required if the third major and minor criteria is met.

• Major criteria:
  • Elevated hemoglobin concentration (>16.5 g/dL in men, >16.0 g/dL in women) or elevated hematocrit (>49% in men, >48% in women); in the absence of a JAK2 mutation, a higher hematocrit target (eg 52%) could be considered in men before further investigation is required
  • Bone marrow biopsy showing age-adjusted hypercellularity with trilineage proliferation (panmyelosis), including prominent erythroid, granulocytic, and megakaryocytic proliferation with pleomorphic, mature megakaryocytes (differences in size)
  • Presence of JAK2 p.V617F exon 12 mutation
• Minor criterion:
  • Decreased serum erythropoietin level

Post-Polycythemia Vera  

The diagnosis of post-polycythemia vera requires fulfilling all required criteria and ≥2 additional criteria.

• Required criteria:
  • Documentation of a previous diagnosis of polycythemia vera as defined by the WHO criteria
  • Bone marrow fibrosis of grade 2 to 3 on a scale of o to 3
• Additional criteria:
  • Anemia (below the reference range given age, sex, and altitude considerations) or sustained loss of requirement of either phlebotomy (in the absence of cytoreductive therapy) or cytoreductive treatment for erythrocytosis
  • Leukoerythroblastosis
  • Increasing splenomegaly, defined as either an increase in palpable splenomegaly or >50 mm from baseline (distance from the left costal margin, or on imaging) or newly palpable splenomegaly
  • Development of ≥2 of the following constitutional symptoms: >10% weight loss in 6 months, night sweats, unexplained fever (>37.5⁰C)