myelofibrosis
MYELOFIBROSIS
Treatment Guideline Chart

A clonal myeloproliferative stem cell disorder characterized by reactive bone marrow fibrosis, extramedullary hematopoiesis, and abnormal cytokine expression leading to systemic symptoms.
It belongs to a group of heterogeneous disorders of the hematopoietic system which is collectively known as Philadelphia chromosome-negative myeloproliferative neoplasms (MPN).
May present either as a de novo disorder [primary myelofibrosis (PMF)] or can develop from the transformation of polycythemia vera (PV) and essential thrombocythemia (ET).

Choice of treatment for patients with myelofibrosus is based on the risk score and presence of symptoms

Myelofibrosis Diagnosis

Diagnosis

  • Diagnosis of myelofibrosis is based on World Health Organization (WHO) criteria and requires a combination of clinical, laboratory, cytogenetic, and molecular features

2016 World Health Organization (WHO) Diagnostic Criteria of MF

Prefibrotic/Early PMF 

  • Diagnosis of pre-PMF requires fulfilling all 3 major criteria and ≥1 minor criterion:
    • 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 WHO criteria for BCR-ABL1+ CML, PV, ET, myelodysplastic syndromes, or other myeloid neoplasms
      • Presence of JAK2, CALR, or MPL mutation or in the absence of these mutations, presence of another clonal marker (presence of ASXL1, EZH2, TET2, ISH1/IDH2, SRSF2, SF3B1 mutations), or absence of minor reactive bone marrow reticulin fibrosis (grade 1 reticulin fibrosis secondary to infection, autoimmune disorder or other chronic inflammatory conditions, hairy cell leukemia or other lymphoid neoplasm, metastatic malignancy, or toxic myelopathies)
    • Minor criteria: Presence of ≥1 of the following confirmed in 2 consecutive examinations 
      • Anemia not due to a comorbid condition
      • LDH elevated to above upper limit of normal (ULN) of institutional range
      • White blood cells (WBC) ≥11 x 109/L
      • Palpable splenomegaly

Overt PMF 

  • Diagnosis of overt PMF requires fulfilling all 3 major criteria and ≥1 minor criterion:
    • Major criteria:
      • Presence of megakaryocytic proliferation and atypia, with either reticulin and/or collagen fibrosis grades 2 or 3
      • Not meeting WHO criteria for ET, PV, BCR-ABL1+ CML, myelodysplastic syndromes, or other myeloid neoplasms
      • Presence of JAK2, CALR, or MPL mutation or in the absence of these mutations, 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 neoplasm, metastatic malignancy, or toxic myelopathies) 
    • Minor criteria: Presence of ≥1 of the following confirmed in 2 consecutive examinations
      • Anemia not due to a comorbid condition
      • LDH elevated >ULN of institutional range
      • WBC ≥11 x 109/L
      • Palpable splenomegaly
      • Leukoerythroblastosis

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

  • Required criteria: 
    • Bone marrow fibrosis grade 2-3 on a 0-3 scale or grade 3-4 on a 0-4 scale
    • Documentation of a previous diagnosis of PV as defined by the WHO criteria
  • At least 2 additional criteria must be present:
    • Anemia or sustained loss of requirement of either phlebotomy in the absence of cytoreductive therapy or cytoreductive treatment for erythropoiesis
    • 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) MF 

  • Required criteria: 
    • Bone marrow fibrosis grade 2-3 on a 0-3 scale or grade 3-4 on a 0-4
    • Documentation of a previous diagnosis of ET as defined by the WHO criteria
  • At least 2 additional criteria must be present:
    • 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

History

  • Assess for cardiovascular risk factors 
  • Evaluate for thrombotic or hemorrhagic events 
  • Ask for medication and transfusion history 

Physical Examination

  • Spleen enlargement: Hallmark of PMF
  • Hepatomegaly

Laboratory Tests

Essential Tests

  • Complete blood count, with differential and platelet count: Leukocytosis or leukopenia, thrombocytopenia or thrombocytosis may occur
  • Peripheral smear 
  • Metabolic panel, including lactate dehydrogenase (LDH) and serum uric acid levels 
  • Liver function tests (LFTs) and renal function tests 
  • Serum erythropoietin (EPO) and serum iron tests 
  • Human leukocyte antigen (HLA) typing is recommended for patients with MF when allogeneic hematopoietic stem cell transplant (HSCT) is being considered 

Biopsy

Bone Marrow Aspirate with Iron Stain and Biopsy

  • Necessary for the demonstration of fibrosis which is required for the diagnosis of MF 
  • Reticulin stain is used to demonstrate bone marrow fibrosis and trichrome stain is used to distinguish between myelofibrosis grades

Molecular and Genetic Analysis

  • Molecular testing for JAK2, CALR and MPL mutations is recommended for the diagnosis of PMF 
    • Molecular testing for JAK2 V617F mutation is recommended in the initial workup and if negative, molecular testing for MPL & CALR mutations is recommended 
    • Multigene next-generation sequencing (NGS) may be used to test for JAK2, CALR and MPL mutations 
  • Other clonal markers include ASXL1, EZH2, TET2, IDH1, IDH2, SRSF2 and SF3B1 gene mutations 

Multiplex Reverse Transcriptase Polymerase Chain Reaction (RT-PCR)

  • Preferred method to detect BCR-ABL1 transcripts and rule out CML

Fluorescence in situ Hybridization (FISH) 

  • Performed on peripheral blood to detect BCR-ABL1 transcripts and rule out CML

Other Tests

Coagulation Tests 

  • Performed in patients who will undergo high-risk surgery or those with elevated platelet counts and/or splenomegaly or unexplained bleeding, to evaluate for acquired von Willebrand disease and/or other coagulopathies 
    • Prothrombin time (PT), partial thromboplastin time (PTT), fibrinogen
      • Plasma von Willebrand Factor Antigen (VWFA) measurement and Von Willebrand Ristocetin Cofactor (VWF:RCo) activity may be used if initial screening tests (eg PT, PTT) are prolonged and cannot be corrected 

Prognostic Markers

  • Presence of triple-negative mutation status (absence of JAK2, CALR or MPL mutations) is associated with worse prognosis in patients with PMF 
  • Presence of ASXL1, EZH2, SRSF2, TP53, IDH1, or IDH2 mutations are high-molecular risk mutation and are associated with shorter overall survival and leukemia-free survival in patients with PMF 
    • ASXL1, EZH2 and SRSF2 mutations are predictive of overall survival 
    • ASXL1, SRSF2 and IDH1 or IDH2 mutations are predictive of leukemic transformation 
  • Presence of TET2 or TP53 mutations is associated with worse overall prognosis and increased rate of leukemic transformation 
  • Presence of U2AF1 mutations is associated with poorer survival in patients with PMF 

Staging

MF Grading

MF-0 Scattered linear reticulin without intersections corresponding to normal bone marrow
MF-1 Loose network of reticulin with many intersections, especially in perivascular areas
MF-2
Diffuse and dense increase in reticulin with extensive intersections, occasionally with focal bundles of thick fibers mostly consistent with collagen, and/or focal osteosclerosis
MF-3 Diffuse and dense increase in reticulin with extensive intersections and course bundles of thick fibers consistent with collagen, usually associated with osteosclerosis

Risk Stratification

  • All patients should be categorized at baseline according to risks associated with MF 
  • Necessary for deciding on treatment options 
  • International Prognostic Scoring System (IPSS), Dynamic International Prognostic Scoring System (DIPSS), and DIPSS-Plus are the most common prognostic scoring systems used for the risk stratification of patients with MF
    • IPSS is the recommended tool for risk stratification at the time of diagnosis and stratifies patients into low-risk, intermediate-1-risk, intermediate-2-risk and high-risk 
      • Estimates survival based on 5 independent risk factors: >65 years of age, hemoglobin <10 g/dL, leukocyte count >25 x 109/L, circulating blasts ≥1% and presence of constitutional symptoms 
    • DIPSS-Plus is the recommended tool for risk stratification during the course of treatment 
    • DIPSS is an option if karyotyping is not available 
  • Mutation-enhanced international prognostic scoring system for patients aged ≤70 years (MIPSS-70) or mutation- and karyotype-enhanced IPSS (MIPSS-70+ Version 2.0) are the preferred prognostic scoring systems for patients with PMF 
  • Myelofibrosis secondary to PV and ET prognostic model (MYSEC-PM) is the method used for patients diagnosed with post-PV MF or post-ET MF 

Prognostic Scoring Systems for Patients with PMF 

Mutation-enhanced International Prognostic Scoring System (MIPSS-70) for Patients with PMF Aged ≤70 Years 

  • Stratifies patients into low-risk, intermediate-risk and high-risk with corresponding median overall survival of 28 years, 7 years and 2 years respectively and 5-year overall survival rates of 95%, 70% and 29% respectively  

Mutation and Karyotype-enhanced IPSS (MIPSS-70+ Version 2.0) 

  • Stratifies patients into low-risk, intermediate-risk, high-risk and very high-risk with corresponding 5-year overall survival rates of 91%, 66%, 42% and 7% respectively 

Dynamic International Prognostic Scoring Systems (DIPSS) 

  • May be used at any time during the course of disease 
    Prognostic Variable
    Points
    0 1 2
    Age
    White blood cell count
    Hemoglobin
    Peripheral blood blast
    Constitutional symptoms
    ≤65 years
    ≤25 x 109/L
    ≥10 g/dL
    <1%
    None
    >65 years
    >25 x 109/L
    -
    ≥1%
    Present
    -
    -
    <10 g/dL
    -
    -

    Risk Group Points
    Low
    Intermediate-1 (INT-1)
    Intermediate-2 (INT-2)
    High
    0
    1 or 2
    3 or 4
    5 or 6
DIPSS-Plus 
  • A refined prognostic scoring system for PMF which incorporates prognostic information from karyotype, platelet count and transfusion status and is an alternative if molecular testing is not available 
  • Stratifies patients into low-risk, intermediate-1-risk, intermediate-2-risk and high-risk with corresponding median overall survival rates of 15.4 years, 6.5 years, 2.9 years and 1.3 years respectively  
    Prognostic Variable Points
    DIPSS low-risk
    DIPSS intermediate-risk 1 (INT-1)
    DIPSS intermediate-risk 1 (INT-2)
    DIPSS high-risk
    Platelets <100 x 109/L
    Transfusion need
    Unfavorable karyotype1
    0
    1
    2
    3
    1
    1
    1

    Risk Group Points
    Low
    Intermediate-1 (INT-1)
    Intermediate-2 (INT-2)
    High
    0
    1
    2 or 3
    4 to 6

1Includes complex karyotype or sole or 2 abnormalities which include trisomy 8, 7/7q-, i(17q), 5/5q-, 12p-, inv(3), or 11q23 rearrangement

Risk Stratification

Lower Risk 

  • MIPSS-70: ≤3 
  • MIPSS-70+ Version 2.0: ≤3 
  • DIPSS-Plus: ≤1 
  • DIPSS: ≤2 
  • MYSEC-PM: <14 

Higher Risk 

  • MIPSS-70: ≥4 
  • MIPSS-70+ Version 2.0: ≥4 
  • DIPSS-Plus: >1 
  • DIPSS: >2 
  • MYSEC-PM: ≥14 

Prognostic Scoring Systems for Patients with Post-PV and Post-ET MF 

Myelofibrosis Secondary to PV and ET-Prognostic Model (MYSEC-PM) 

  • Stratifies patients into low-risk, intermediate-1-risk, intermediate-2-risk and high-risk

  • Prognostic Variable Points
    Age at diagnosis
    Hemoglobin <11 g/dL
    Circulating blasts ≥3%
    Absence of CALR-1 type mutation
    Platelets <150 x 109/L
    Constitutional symptoms
    0.15 per patient’s year of age
    2
    2
    2
    1
    1

Assessment of Symptom Burden

  • Recommended for all patients at baseline and during the course of treatment 
  • Myelofibrosis Symptom Assessment Form (MS-SAF) is a 20-item questionnaire used to assess MF-associated symptoms including fatigue, constitutional symptoms such as night sweats, bone pain, fever, itching and weight loss, symptoms associated with splenomegaly which include abdominal pain or discomfort, early satiety, inactivity and cough, and quality of life 

Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score (MPN-SAF TSS) 

  • Recommended assessment tool for symptoms at baseline and for monitoring symptom status during the course of treatment 
  • Assessment is done by the patients themselves and scoring is from 0 (absent) to 10 (worst) on the following symptoms: 
    • Fatigue (tiredness or weariness) during the past 24 hours 
    • Early satiety 
    • Abdominal discomfort 
    • Inactivity 
    • Problems with concentration compared to before onset of disease 
    • Night sweats 
    • Itching or pruritus 
    • Bone pain not associated with joint pain or arthritis 
    • Fever 
    • Unintentional weight loss in the last 6 months 
  • Represents the sum of all individual scores which can range from 0-100

Differential Diagnosis

  • Acute myelofibrosis 
    • Rare form of acute myeloid leukemia (AML) 
    • Characterized by non-palpable spleen with rapid onset of severe bone marrow fibrosis with fever and pancytopenia, teardrop-shaped RBCs and leukoerythroblastic blood features 
  • Chronic myeloid leukemia (CML) 
  • Essential thrombocythemia (ET) 
  • Polycythemia vera (PV) 
  • Myelodysplastic syndrome 
  • Hairy cell leukemia 
  • Multiple myeloma
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