Primary myelofibrosis (PMF)
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):
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).
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*
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
* 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
of patients with PMF have a JAK2 V617F mutation (Onkopedia Guideline PMF)
Diagnostics of primary myelofibrosis
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
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
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
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.
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).