Primary myelofibrosis

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Myelofibrosis
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"Myelofibrosis" redirects here. It is not to be confused with fibromyalgia.

Primary myelofibrosis
Other namesPMF, Overt PMF, Myelofibrosis
SpecialtyOncology and Hematology

Primary myelofibrosis (PMF) is a rare

erythrocytes (red cells), granulocytes and megakaryocytes, the latter cells responsible for the production of platelets
.

Signs and symptoms include fever, night sweats, bone pain, fatigue, and abdominal pain. Increased infections, bleeding and an enlarged spleen (splenomegaly) are also hallmarks of the disease. Patients with myelofibrosis have an increased risk of acute meyloid leukemia and frank bone marrow failure.

In 2016, prefibrotic primary myelofibrosis was formally classified as a distinct condition that progresses to overt PMF in many patients, the primary diagnostic difference being the grade of fibrosis.[2]

Signs and symptoms

The primary feature of primary myelofibrosis is bone marrow fibrosis,[3] but it is often accompanied by:

  • Abdominal fullness related to an enlarged spleen (splenomegaly).
  • Enlargement of both the liver and spleen
    • Splenomegaly due to extramedullary hematopoiesis (hematopoiesis occurring outside of the bone marrow)
  • Bone pain
  • Bruising and easy bleeding due to inadequate numbers of platelets
  • Increased risk of thrombosis
  • Cachexia (loss of appetite, weight loss, and fatigue)
  • Fatigue
  • Fevers
  • Chills
  • Weight loss
  • Gout and high uric acid levels
  • Increased susceptibility to infection, such as pneumonia
  • Pallor and shortness of breath due to anemia
  • Leukoerythroblastic smear (tear-drop RBCs, nucleated RBCs, and immature granulocytes)
  • In rarer cases, a raised red blood cell volume
  • Cutaneous myelofibrosis is a rare skin condition characterized by dermal and subcutaneous nodules.[4]: 746 

Causes

The underlying cause of PMF is almost always related to an acquired mutation in JAK2, CALR or MPL in a hematopoietic stem/progenitor cell in the bone marrow.

JAK2, CALR, or MPL genes and myelofibrosis.[6] Approximately 90% of those with myelofibrosis have one of these mutations; 10% do not have mutations in these three genes. These mutations are not specific to myelofibrosis, but are observed in other myeloproliferative neoplasms, specifically polycythemia vera and essential thrombocythemia.[3]

The JAK2 protein is mutated giving risk to a variant protein with an amino acid substistution commonly referred to as V617F; the mutation causing this variant is found in approximately half of individuals with primary myelofibrosis.

hematopoietic cells more sensitive to growth factors that use JAK2 for signal transduction, which include erythropoietin and thrombopoietin.[8]

The

TGF-β1.[10]

Mechanism

Myelofibrosis is a

hematopoiesis, the formation of blood cellular components. It is one of the myeloproliferative disorders, diseases of the bone marrow in which excess cells are produced at some stage. Production of cytokines such as fibroblast growth factor by the abnormal hematopoietic cell clone (particularly by megakaryocytes)[11] leads to replacement of the hematopoietic tissue of the bone marrow by connective tissue via collagen fibrosis. The decrease in hematopoietic tissue impairs the patient's ability to generate new blood cells, resulting in progressive pancytopenia, a shortage of all blood cell types. However, the proliferation of fibroblasts and deposition of collagen is a secondary phenomenon, and the fibroblasts themselves are not part of the abnormal cell clone.[citation needed
]

In primary myelofibrosis, progressive scarring, or fibrosis, of the bone marrow occurs, for the reasons outlined above. The result is extramedullary hematopoiesis, i.e. blood cell formation occurring in sites other than the bone marrow, as the hemopoietic cells are forced to migrate to other areas, particularly the liver and spleen. This causes an enlargement of these organs. In the liver, the abnormal size is called hepatomegaly. Enlargement of the spleen is called splenomegaly, which also contributes to causing pancytopenia, particularly thrombocytopenia and anemia. Another complication of extramedullary hematopoiesis is poikilocytosis, or the presence of abnormally shaped red blood cells.[citation needed]

Myelofibrosis can be a late complication of other myeloproliferative disorders, such as polycythemia vera, and less commonly, essential thrombocythemia. In these cases, myelofibrosis occurs as a result of somatic evolution of the abnormal hematopoietic stem cell clone that caused the original disorder. In some cases, the development of myelofibrosis following these disorders may be accelerated by the oral chemotherapy drug hydroxyurea.[12]

Sites of hematopoiesis

The principal site of

On the cellular level, the spleen contains red blood cell precursors, granulocyte precursors and megakaryocytes, with the megakaryocytes prominent in their number and in their bizarre shapes. Megakaryocytes are believed to be involved in causing the secondary fibrosis seen in this condition, as discussed under "Mechanism" above. Sometimes unusual activity of the red blood cells, white blood cells, or platelets is seen. The liver is often moderately enlarged, with foci of extramedullary hematopoiesis. Microscopically, lymph nodes also contain foci of hematopoiesis, but these are insufficient to cause enlargement.[citation needed
]

There are also reports of hematopoiesis taking place in the

hypertension in the pulmonary arteries.[13]

The

dysplastic.[citation needed
]

Diagnosis

Epidemiologically, the disorder usually develops slowly and is mainly observed in people over the age of 50.[14]

Diagnosis is made on the basis of

bone marrow biopsy. Fibrosis grade 2 or 3 defines overt PMF whereas grade 0 or 1 defines prefibrotic primary myelofibrosis.[citation needed
]

A physical exam of the abdomen may reveal enlargement of the spleen, the liver, or both.[3]Fibrosis with scattered linear reticulin in the early stages. In this patient, the symptoms and findings are consistent with primary myelofibrosis (PMF). PMF is a clonal myeloproliferative disorder that is often associated with a JAK2 mutation. One of the key features of PMF is the development of fibrosis in the bone marrow. In the early stages of the disease, the fibrosis is characterized by scattered linear reticulin fibers. This can be observed on a bone marrow biopsy. The other answer options are not consistent with the findings seen in PMF. Essential thrombocytopenia,would show hypercellularity with numerous abnormal megakaryocytes on bone marrow biopsy. Polycythemia vera ,would show hypercellularity with fibrosis in later stages. Myelodysplastic syndromes,

would show ringed sideroblasts and less than 20% myeloblasts. Aplastic anemia , would show a hypocellular bone marrow.

Treatment

The one known curative treatment is allogeneic

stem cell transplantation, but this approach involves significant risks.[15]
Other treatment options are largely supportive, and do not alter the course of the disorder (with the possible exception of
folic acid,[17] allopurinol[18] or blood transfusions.[19] Dexamethasone, alpha-interferon and hydroxyurea (also known as hydroxycarbamide) may play a role.[20][21][22]

Lenalidomide and thalidomide may be used in its treatment, though peripheral neuropathy is a common troublesome side-effect.[22]

hypersplenism, particularly if they have a heavy requirement for blood transfusions. However, splenectomy in the presence of massive splenomegaly is a high-risk procedure, with a mortality risk as high as 3% in some studies.[23]

In November 2011, the US Food and Drug Administration (FDA) approved ruxolitinib (Jakafi) as a treatment for intermediate or high-risk myelofibrosis.[24][25] Ruxolitinib serves as an inhibitor of JAK 1 and 2. Data from two phase III studies of ruxolitinib showed that the treatment significantly reduced spleen volume, improved symptoms of myelofibrosis, and was associated with much improved overall survival rates compared to placebo.[26][27] However, the beneficial effect of ruxolitinib on survival has been recently questioned.[28]

In August 2019, the FDA approved fedratinib (Inrebic) as a treatment for adults with intermediate-2 or high-risk primary or secondary (post-polycythemia vera or post-essential thrombocythemia) myelofibrosis (MF).[29]

In March 2022, the FDA approved

indication to treat adults who have intermediate or high-risk primary or secondary myelofibrosis and who have platelet (blood clotting cells) levels below 50,000/µL.[30]

Momelotinib (Ojjaara) was approved for medical use in the United States in September 2023.[31] It is indicated for the treatment of intermediate or high-risk myelofibrosis, including primary myelofibrosis or secondary myelofibrosis [post-polycythemia vera and post-essential thrombocythemia], in adults with anemia.[31][32]

History

Myelofibrosis was first described in 1879 by Gustav Heuck.[33][34] Eponyms for the disease are Heuck-Assmann disease or Assmann's Disease, for Herbert Assmann,[35] who published a description under the term "osteosclerosis" in 1907.[36]

It was characterised as a myeloproliferative condition in 1951 by William Dameshek.[37][38]

The disease was also known as myelofibrosis with myeloid metaplasia and agnogenic myeloid metaplasia[39] The World Health Organization utilized the name chronic idiopathic myelofibrosis until 2008, when it adopted the name of primary myelofibrosis.

In 2016, the WHO revised their classification of myeloproliferative neoplasms to define Prefibrotic primary myelofibrosis as a distinct clinical entity from overt PMF.[2]

References

  1. ^ "Myelofibrosis Facts" (PDF). The Leukemia and Lymphoma Society. Retrieved 5 October 2014.
  2. ^
    PMID 30405096
    .
  3. ^
    S2CID 26059182
    .
  4. ISBN 978-0-7216-2921-6
    .
  5. ^ "Primary Myelofibrosis". NORD (National Organization for Rare Disorders). Retrieved 20 July 2020.
  6. S2CID 52852665
    .
  7. ^
    PMID 24058768
    .
  8. S2CID 31976721
    .
  9. PMID 20428194
    .
  10. S2CID 10085331
    .
  11. PMID 12648509
    .
  12. PMID 9345019
    .
  13. PMID 21138888
    .
  14. ^ Primary Myelofibrosis, Merck.
  15. S2CID 32940012
    .
  16. PMID 18185525
    .
  17. PMID 20655352
    .
  18. PMID 21134837. Archived from the original
    on 5 October 2011. Retrieved 5 April 2011.
  19. PMID 20029953
    .
  20. ISBN 978-1-60761-265-0
    .
  21. S2CID 22568536
    .
  22. ^
    S2CID 7011964
    .
  23. PMID 21224796
    .
  24. ^ "FDA Approves Incyte's Jakafi (ruxolitinib) for Patients with Myelofibrosis" (Press release). Incyte. Archived from the original on 24 June 2017. Retrieved 2 January 2012.
  25. ^ McCallister E, Usdin S (5 December 2011). "A Professional Trial". BioCentury. 5: 12.
  26. PMID 22375970
    .
  27. PMID 22375971
    .
  28. PMID 28031182
    .
  29. ^ "FDA approves fedratinib for myelofibrosis". U.S. Food and Drug Administration (FDA). 16 August 2019.
  30. ^ "FDA approves drug for adults with rare form of bone marrow disorder". U.S. Food and Drug Administration (FDA). 1 March 2022. Retrieved 3 March 2022. Public Domain This article incorporates text from this source, which is in the public domain.
  31. ^ a b "FDA Roundup: September 19, 2023". U.S. Food and Drug Administration (FDA) (Press release). 19 September 2023. Retrieved 20 September 2023. Public Domain This article incorporates text from this source, which is in the public domain.
  32. ^ "Novel Drug Approvals for 2023". U.S. Food and Drug Administration (FDA). 15 September 2023. Retrieved 20 September 2023. Public Domain This article incorporates text from this source, which is in the public domain.
  33. S2CID 20399830
    .
  34. S2CID 32911188
    .
  35. Who Named It?
    ,
  36. ISBN 978-0-387-73744-7
    .
  37. ISBN 978-1-58829-621-4
    . Retrieved 13 November 2010.
  38. PMID 14820991
    .
  39. S2CID 33814200
    .

External links

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