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MinnaLehto

Myelofibrosis (Mf)

A chronic myeloproliferative disease with no curative pharmacotherapy available.
The only curative treatment is allogeneic stem cell transplantation from a healthy donor.
Anaemia is a common problem; other possible causes of anaemia should be excluded and treated as far as possible.
Cytostatic chemotherapy may be used to suppress marked leukocytosis and thrombocytosis, as necessary.
JAK inhibitors are used particularly to reduce the size of an enlarged spleen and to relieve severe general symptoms.

MF is a chronic myeloproliferative disease that is caused by pathological proliferation of haematopoietic cells, especially megakaryocytes, and by the associated secondary fibrosis.

About 1 new case / 100 000 / year
Diagnosis is often made at the age of 67-70 years. Around 15-20% of patients are under 50.
Equally common in men and in women

The aetiology remains unknown.
This is either a primary disease or a secondary disease, developing from polycythaemia vera (PV) Polycythaemia Vera (Pv) or essential thrombocythaemia (ET) Thrombocytosis.
The JAK2V617F gene defect can be detected in about 50-60% of patients, the CALR (calreticulin) gene defect in about 20% and the MPL gene defect in a few percent. About 10% of patients are negative for all three mutations (triple-negative), i.e. they do not have any of the aforementioned driver mutations.

Diagnosis is always based on the changes found in the bone marrow biopsy (trepanation sample).
Diseases to be considered in differential diagnosis include, among others
- prefibrotic myelofibrosis
- other myeloproliferative diseases (e.g. essential thrombocythemia Thrombocytosis, chronic myeloid leukaemia Chronic Myelogenous Leukaemia (CML))
- hairy cell leukaemia http://www.orpha.net/en/disease/detail/58017
- bone marrow metastasis of carcinoma.
The WHO 2022 criteria for the diagnosis of myelofibrosis require that all 3 major criteria and at least one minor criterium are met.
- Major criteria
  - Atypia and proliferation of megakaryocytes in the bone marrow sample and fibrosis grade 2-3/3 in the trepanation sample
  - Not compatible with any other hematologic(al) disease (e.g. chronic myeloid leukemia, ET or PV)
  - Identified JAK2, CALR or MPL gene defect
- Minor criteria
  - Anaemia
  - Blood leukocyte count HASH(0x2fe85d0) 11 × 10⁹/l
  - Leukoerythroblastic blood picture
  - Enlarged spleen
  - Increased blood LD concentration

Progression is usually slow at first, and there are few symptoms.
As the disease progresses, common symptoms include fatigue, aquagenic pruritus (increasing itching of the skin after taking a shower), anaemia-associated symptoms, abnormally excessive sweating at night, slight fever in the evenings, and unintentional weight loss.
Growth of the spleen leads to early satiety during meals. Upper abdominal and flank pain is also common.

Blood picture
- Anaemia, usually normocytic
- Leukocyte concentration often increased.
- Leukoerythroblastic blood picture, i.e. a differential leukocyte count shows precursors of the neutrophil series (metamyelocytes/myelocytes) and nucleated precursors of erythrocytes (erythroblasts).
- Varying platelet levels
Other blood test abnormalities
- Plasma LD often elevated, sometimes also urate andALP
JAK2, CALR or MPL gene defect (some triple-negative)
In many patients the enlarged spleen is palpable. Its size is most commonly measured by upper abdominal ultrasound examination and, as considered necessary, with other imaging methods.
If the patient undergoes a CT or MRI scan with other indications, an abnormal bone marrow signal may be an incidental finding.

This is a malignant disease with variable prognosis.
- Various scoring systems can be used in the prognostic assessment, e.g. IPSS (only for scoring at the diagnostic stage), DIPSS, DIPSS-plus, MYSEC-MF (scoring of secondary myelofibrosis), MIPSS70, GIPSS, etc.
- Risk scores are calculated based on, for example, general symptoms, anaemia, increased leukocytosis, blood blasts, as well as chromosomal and genetic abnormalities of poor prognosis.
- In the lower risk group, the remaining life expectancy may exceed 10-15 years, but in the high risk group it is only 1-2 years.
Increasing anaemia, increasing leukocyte count, blasts appearing the circulation, and increasing size of the spleen usually signify progression of the disease.

Thromboembolic events, such as splenic infarction
Bleeding problems (particularly at a late stage of the disease)
Progression to the blast phase, where 20% or more blasts are found in the blood or bone marrow (about 10-20% of patients).
Susceptibility to infections may increase, and a low Hb may predispose the patient to circulatory disturbances.

The only curative treatment is allogeneic stem cell transplantation, the feasibility of which should always be assessed in younger patients with intermediate-risk or higher-risk myelofibrosis.
Early pharmacotherapy of asymptomatic disease has not been shown to be beneficial.
Treatment initiation is planned on the basis of symptoms and blood tests.
Treatment of anaemia is usually started if the Hb is around 100 g/l.
- Erythropoietin is most commonly used. Treatment response is more likely if the serum EPO level is below 500 IU/l and the spleen is not very large.
- Other treatment options for anaemia include danazol,thalidomide and glucocorticoids.
In the treatment of an enlarged spleen, the best response to treatment is obtained with JAK inhibitors, which also subdue the organ system's cytokine storm and reduce possible general symptoms.
Radiotherapy decreases the size of the spleen but subsequently may lead to severe cytopenias as extramedullary blood formation in the spleen ceases. For the same reason, splenectomy is not performed.
Cytostatic chemotherapy (e.g. hydroxyurea) can be considered to lower leukocyte levels, for instance, but haemoglobin levels may also fall. Hydroxyurea can be used to try to prevent spleen enlargement or to reduce the size of the spleen. The results vary greatly.
The overall treatment strategy should be planned by a haematologist or by a specialist in internal medicine with appropriate expertise.

Kr�ger N, Bacigalupo A, Barbui T, et al. Indication and management of allogeneic haematopoietic stem-cell transplantation in myelofibrosis: updated recommendations by the EBMT/ELN International Working Group. Lancet Haematol 2024;11(1):e62-e74.[PubMed]
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Garmezy B, Schaefer JK, Mercer J, et al. A provider's guide to primary myelofibrosis: pathophysiology, diagnosis, and management. Blood Rev 2021;45:100691. [PubMed]
Nordic care program for patients with essential thrombocythemia, polycythemia vera and primary myelofibrosis. 4th version March 2017. Nordic MPN Study Group. http://www.nmpn.org/index.php/guidelines/17-nmpn-care-program-2017/file
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