Primary myelofibrosis (PMF)

  • Method:
  • Anticoagulant:
  • Recommendation:
  • Method:
    Cytomorphology
  • Anticoagulant:
    EDTA
  • Recommendation:
    obligatory
  • Method:
    Immunophenotyping
  • Anticoagulant:
    EDTA or Heparin
  • Recommendation:
    facultative
  • Method:
    Chromosome analysis
  • Anticoagulant:
    Heparin
  • Recommendation:
    obligatory
  • Method:
    FISH
  • Anticoagulant:
    EDTA or Heparin
  • Recommendation:
    facultative
  • Method:
    Molecular genetics
  • Anticoagulant:
    EDTA or Heparin
  • Recommendation:
    obligatory

Primary myelofibrosis (PMF) is a myeloproliferative, BCR-ABL1-negative neoplasm. It is characterized by a dominant proliferation of megakaryocytes and granulocytes in the bone marrow and shows increasing reticulin and/or collagen fibrosis in advanced stages. The incidence of primary myelofibrosis is 0.5-1.5 / 100,000 per year and occurs predominantly at the age of 60-70 years.

Primäre Myelofibrose - Klassifikation

According to the WHO classification 2017, primary myelofibrosis is classified as myeloproliferative neoplasm (MPN) and is divided into a prefibrotic/early stage and a fibrotic stage.


Primary myelofibrosis - WHO Classification 2017

Myeloproliferative Neoplasm (MPN)

Primary myelofibrosis (PMF):

  • Prefibrotic/early stage

  • Fibrotic stage


Diagnostic criteria for primary myelofibrosis

According to the WHO classification, all 3 major criteria and at least 1 minor criterion of the diagnostic criteria must be met in order to make a diagnosis of primary myelofibrosis (overt fibrotic stage).

Major criteria

  • Megakaryocyte proliferation and atypia, accompanied by reticulin and/or collagen fibrosis grades 2 or 3 according to WHO

  • WHO criteria for ET, PV, BCR-ABL1-positive CML, MDS or other myeloid neoplasm are not met

  • JAK2, CALR or MPL mutation, or in the absence of these mutations, detection of another clonal marker, or absence of minor reactive bone marrow reticulin fibrosis*

Minor criteria

At least 1 of the following criteria are met in 2 consecutive determinations

  • anaemia not attributed to a comorbid condition
  • Leukocytosis ≥ 11 x 109/l
  • Palpable splenomegaly
  • LDH level above the upper limit of normal (ULN) of the institutional reference range
  • Leukoerythroblastosis

* e.g. ASXL1, EZH2, TET2, IDH1/IDH2, SRSF2, SF3B1
** bone marrow fibrosis due to secondary infection, autoimmune disease or other chronic inflammatory diseases, hairy cell leukemia or other lymphoid neoplasm, metastatic tumor disease or toxic (chronic) myelopathy

60%

of patients with PMF have a JAK2 V617F mutation (Onkopedia Guideline PMF)

Diagnostics of primary myelofibrosis

Prognosis

Among the BCR-ABL1-negative myeloproliferative neoplasms, primary myelofibrosis has the most unfavourable course. There is both a risk of progression of the disease into the fibrotic stage and a risk of leukemic transformation. While the median overall survival is about 6 years (Tefferi et al. (4) 2014), the individual clinical courses are very heterogeneous. The prognosis is influenced by a variety of factors, which can be divided into clinical, cytogenetic and molecular genetic factors. Especially for genetic changes, the description of prognostically relevant factors is still a subject of research. With increasing knowledge, various prognostic scoring systems (~PSS) have been successively established or further developed. Table 2 gives an overview of the published risk stratification systems and the prognostic factors considered therein.

Table 2: Prognostic scoring systems for primary myelofibrosis and its risk factors

Score

 

IPSS

DIPSS

DIPSS Plus

GPSS

MIPSS

GIPSS

MIPSS70

MIPSS70+

MIPSS70+ Version 2.0

International Prognostic Scoring System

 

Dynamic International Prognostic Scoring System

 

Dynamic International Prognostic Scoring System Plus

 

Genetics-based Prognostic Scoring System

Mutation-enhanced International Prognostic Scoring System

Genetically Inspired Prognostic Scoring System

Mutation - Enhanced International Prognostic Scoring System for Transplantation-age Patients

Karyotype enhanced MIPSS70

Mutation and Karyotype-enhanced International Prognostic Scoring System, Version 2.0

Publication

Cervantes et al. 2009

Passamonti et al. 2010

Gangat et al. 2011

Tefferi et al. (5) 2014

Vannucchi et al. 2014

Tefferi et al. (3) 2018

Guglielmelli et al. 2018

Guglielmelli et al. 2018

Tefferi et al. (2) 2018

Considered prognositc factors

clinic

clinic

clinic


clinic

 

clinic

clinic

clinic

 

 

Karyotype

Karyotype

 

Karyotype

 

Karyotype

Karyotype

 

 

 

Mutations

Mutations

Mutations

Mutations

Mutations

Mutations

Calculation for primary myelofibrosis (PMF)

The calculation of the clinical scoring systems IPSS or DIPSS is recommended for the selection of the therapy algorithm according to the DGHO guideline (Onkopedia guideline PMF 2018). Here you can access the forecast calculation of the DIPSS score.

Consideration of cytogenetic and molecular genetic factors would lead to re-classification into a higher risk category for an estimated 25% of patients assigned to the low or intermediate group according to IPSS/DIPSS classification (Onkopedia Guideline PMF 2018). The determination of genetic risk factors can therefore be useful for weighing up for or against a stem cell transplantation (Kröger et al. 2015, Tefferi 2018).

Here you can access the calculation of the DIPSS plus score, which takes a two-step cytogenetic risk model into account. A refined three-level cytogenetic risk model as well as molecular genetic risk factors are integrated in the scoring systems of GIPSS and MIPSS70+ Version 2.0.

Recommendation

In addition to the collection of clinical and laboratory chemical parameters, histological and cytomorphological examination of the bone marrow and blood, cytogenetic analysis and molecular genetic examinations (JAK2 V617F mutation, if negative, CALR, if negative MPL) are recommended. According to the WHO 2017 classification, additional molecular genetic analyses should be added for primary myelofibrosis (ASXL1, EZH2, TET2, IDH1/IDH2, SRSF2, SF3B1).

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