Myelofibrosis

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Myelofibrosis
Classification and external resources
Specialty Hematology and oncology
ICD-10 C94.4, D47.4
ICD-9-CM 289.83
ICD-O 9932, M9961/3
OMIM 254450
DiseasesDB 8616
MedlinePlus 000531
Patient UK Myelofibrosis
MeSH D055728

Myelofibrosis, also known as osteomyelofibrosis, is a rare bone marrow cancer.[1] It is currently classified as a myeloproliferative neoplasm, in which the proliferation of an abnormal clone of hematopoietic stem cells in the bone marrow and other sites results in fibrosis, or the replacement of the marrow with scar tissue.[2][3]

The term myelofibrosis alone usually refers to primary myelofibrosis (PMF), also known as chronic idiopathic myelofibrosis (cIMF); the terms idiopathic and primary mean that in these cases the disease is of unknown or spontaneous origin. This is in contrast with myelofibrosis that develops secondary to polycythemia vera or essential thrombocythaemia. Myelofibrosis is a form of myeloid metaplasia, which refers to a change in cell type in the blood-forming tissue of the bone marrow, and often the two terms are used synonymously. The terms Agnogenic myeloid metaplasia and myelofibrosis with myeloid metaplasia (MMM) are also used to refer to myelofibrosis.

Signs and symptoms[edit]

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

Causes[edit]

There is an association between mutations to the JAK2, CALR, or MPL gene and myelofibrosis.[5] Approximately 90% of those with myelofibrosis have one of these mutations and 10% carry none of these mutations. These mutations are not specific to myelofibrosis, and are linked to other myeloproliferative disorders, specifically essential thrombocythemia.[3]

The V617F mutation to the JAK2 protein is found in approximately half of individuals with primary myelofibrosis.[6] The V617F mutation is a change of valine to phenylalanine at the 617 position. Janus kinases (JAKs) are non-receptor tyrosine kinases essential for the activation of signaling that is mediated by cytokine receptors lacking catalytic activity. These include receptors for erythropoietin, thrombopoietin, most interleukins and interferon.[6] JAK2 mutations are significant because JAK2 plays a role in controlling production of blood cells from hematopoietic stem cells. The V617F mutation appears to make hematopoietic cells more sensitive to growth factors that need JAK2 for signal transduction, which include erythropoietin and thrombopoietin.[7]

The MPL gene codes for a protein that acts as a receptor for thrombopoietin. A mutation in that gene, known as a W515 mutation, leads to the production of an abnormal thrombopoietin receptor protein, which results in the overproduction of abnormal megakaryocytes. The abnormal megakaryocytes stimulate other cells to produce collagen in the bone marrow.[8]

Mechanism[edit]

Myelofibrosis is a clonal neoplastic disorder of hematopoiesis, the formation of blood cellular components. It is one of the myleoproliferative disorders, diseases of the bone marrow in which excess cells are produced. Production of cytokines such as fibroblast growth factor by the abnormal hematopoietic cell clone (particularly by megakaryocytes)[9] 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.

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

Myelofibrosis can be a late complication of other myeloproliferative disorders, such as polycythemia vera, and less commonly, essential thrombocythaemia. 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.[10]

The cause and risk factors for primary myelofibrosis are unknown.

Sites of hematopoesis[edit]

The principal site of extramedullary hematopoiesis in myelofibrosis is the spleen, which is usually markedly enlarged, sometimes weighing as much as 4000 g. As a result of massive enlargement of the spleen, multiple subcapsular infarcts often occur in the spleen, meaning that oxygen supply to the spleen is interrupted, leading to partial or complete tissue death. On the cellular level, the spleen contains red blood cell precursors, granulocyte precursors and megakaryocytes, with the megokarycytes 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 "Pathophysiology" 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.

There are also reports of hematopoiesis taking place in the lungs. These cases are associated with hypertension in the pulmonary arteries.[11]

The bone marrow in a typical case is hypercellular and diffusely fibrotic. Both early and late in disease, megakaryocytes are often prominent and are usually dysplastic.

Diagnosis[edit]

Epidemiologically, the disorder usually develops slowly and is mainly observed in people over the age of 50.[12] It may also develop as a side-effect of treatment with some drugs that target hematological disorders, such as polycythemia vera or chronic myelogenous leukemia. Diagnosis of myelofibrosis is made on the basis of bone marrow biopsy.[3] A physical exam of the abdomen may reveal enlargement of the spleen, the liver, or both.[3]

Blood tests are also used in diagnosis. Primary myelofibrosis can begin with a blood picture similar to that found in polycythemia vera or chronic myelogenous leukemia. Most people with myelofibrosis have moderate to severe anemia. Eventually thrombocytopenia, a decrease of blood platelets develops. When viewed through a microscope, a blood smear will appears markedly abnormal, with presentation of pancytopenia, which is a reduction in the number of all blood cell types: red blood cells, white blood cells, and platelets. Red blood cells may show abnormalities including bizarre shapes, such as teardrop-shaped cells, and nucleated red blood cell precursors may appear in the blood smear. Normally, mature red blood cells in adults do not have a cell nucleus, and the presence of nucleated red blood cells suggests that immature cells are being released into the bloodstream in response to a very high demand for the bone marrow to produce new red blood cells. Immature white cells are also seen in blood samples, and basophil counts are increased.

When an attempt is made to take a sample of bone marrow by aspiration it will result in a dry tap, meaning that where the needle can normally suck out a sample of semi-liquid bone marrow, it produces no sample because the marrow has been replaced with collagen fibers. A bone marrow biopsy will reveal collagen fibrosis, rather than the marrow that should occupy the space.

Treatment[edit]

The one known curative treatment is allogeneic stem cell transplantation, but this approach involves significant risks.[13] Other treatment options are largely supportive, and do not alter the course of the disorder (with the possible exception of ruxolitinib, as discussed below).[14] These options may include regular folic acid,[15] allopurinol[16] or blood transfusions.[17] Dexamethasone, alpha-interferon and hydroxyurea (also known as hydroxycarbamide) may play a role.[18][19][20]

Lenalidomide and thalidomide may be used in its treatment, though peripheral neuropathy is a common troublesome side-effect.[20]

Frequent blood transfusions may also be required.[17] If the patient is diabetic and is taking sulfonylureas medication this should be stopped periodically to rule out drug-induced thrombocytopenia.[citation needed]

Splenectomy is sometimes considered as a treatment option for patients with myelofibrosis in whom massive splenomegaly is contributing to anaemia because of 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.[21]

In November 2011, the FDA approved ruxolitinib (Jakafi) as a treatment for intermediate or high-risk myelofibrosis.[22][23] Ruxolitinib serves as an inhibitor of JAK 1 and 2. The New England Journal of Medicine (NEJM) published results from two Phase III studies of ruxolitinib. These data showed that the treatment significantly reduced spleen volume, improved symptoms of myelofibrosis, and was associated with improved overall survival compared to placebo.[24][25]

History[edit]

Myelofibrosis was first described in 1879 by Gustav Heuck.[26][27]

Older terms include "myelofibrosis with myeloid metaplasia" and "agnogenic myeloid metaplasia". The World Health Organization utilizes the name "chronic idiopathic myelofibrosis", while the International Working Group on Myelofibrosis Research and Treatment calls the disease "primary myelofibrosis". Eponyms for the disease are Heuck-Assmann disease or Assmann's Disease, for Herbert Assmann,[28] who published a description under the term "osteosclerosis" in 1907.[29]

It was characterised as a myeloproliferative condition in 1951 by Dameshek.[30][31] The Leukemia and Lymphoma Society describes myelofibrosis as a rare type of blood cancer, manifesting as a type of chronic leukemia.[32]

References[edit]

  1. ^ "Myelofibrosis Facts" (PDF). The Leukemia and Lymphoma Society. Retrieved 5 October 2014. 
  2. ^ "myelofibrosis" at Dorland's Medical Dictionary
  3. ^ a b c d e Tefferi, Ayalew (2014). "Primary myelofibrosis: 2014 update on diagnosis, risk-stratification, and management". American Journal of Hematology 89 (9): 915–925. doi:10.1002/ajh.23703. ISSN 0361-8609. 
  4. ^ James, William D.; Berger, Timothy G. et al. (2006). Andrews' Diseases of the Skin: clinical Dermatology. Saunders Elsevier. ISBN 0-7216-2921-0. 
  5. ^ Tefferi, A; Lasho, T L; Finke, C M; Knudson, R A; Ketterling, R; Hanson, C H; Maffioli, M; Caramazza, D; Passamonti, F; Pardanani, A (2014). "CALR vs JAK2 vs MPL-mutated or triple-negative myelofibrosis: clinical, cytogenetic and molecular comparisons". Leukemia 28 (7): 1472–1477. doi:10.1038/leu.2014.3. ISSN 0887-6924. 
  6. ^ a b Staerk, Judith; Constantinescu, Stefan N. (2014). "The JAK-STAT pathway and hematopoietic stem cells from the JAK2 V617F perspective". JAK-STAT 1 (3): 184–190. doi:10.4161/jkst.22071. ISSN 2162-3996. 
  7. ^ Them, Nicole C. C.; Kralovics, Robert (2013). "Genetic Basis of MPN: Beyond JAK2-V617F". Current Hematologic Malignancy Reports 8 (4): 299–306. doi:10.1007/s11899-013-0184-z. ISSN 1558-8211. 
  8. ^ Tefferi, A (2010). "Novel mutations and their functional and clinical relevance in myeloproliferative neoplasms: JAK2, MPL, TET2, ASXL1, CBL, IDH and IKZF1". Leukemia 24 (6): 1128–1138. doi:10.1038/leu.2010.69. ISSN 0887-6924. 
  9. ^ Chou JM et al. (2003). "Bone marrow immunohistochemical studies of angiogenic cytokines and their receptors in myelofibrosis with myeloid metaplasia". Leukemia Research 27 (6): 499–504. doi:10.1016/S0145-2126(02)00268-0. PMID 12648509. 
  10. ^ Najean Y & Rain J-D (1997). "Treatment of polycythemia vera: the use of hydroxyurea and piprobroman in 292 patients under the age of 65 years". Blood 90 (9): 3370–7. PMID 9345019. 
  11. ^ Trow, TK; et all (2010). "A 71-Year-Old Woman With Myelofibrosis, Hypoxemia, and Pulmonary Hypertension". Chest 136 (6): 1506–10. doi:10.1378/chest.10-0973. PMID 21138888. 
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  15. ^ Vener, C; Novembrino, C; Catena, FB; Fracchiolla, NS; Gianelli, U; Savi, F; Radaelli, F; Fermo, E; Cortelezzi, A; Lonati, S; Menegatti, M; Deliliers, GL (Nov 2010). "Oxidative stress is increased in primary and post-polycythemia vera myelofibrosis.". Experimental hematology 38 (11): 1058–65. doi:10.1016/j.exphem.2010.07.005. PMID 20655352. 
  16. ^ Srinivasaiah, N; Zia, MK; Muralikrishnan, V (Dec 2010). "Peritonitis in myelofibrosis: a cautionary tale.". Hepatobiliary & pancreatic diseases international : HBPD INT 9 (6): 651–3. PMID 21134837. 
  17. ^ a b Tefferi, A; Siragusa, S; Hussein, K; Schwager, SM; Hanson, CA; Pardanani, A; Cervantes, F; Passamonti, F (Jan 2010). "Transfusion-dependency at presentation and its acquisition in the first year of diagnosis are both equally detrimental for survival in primary myelofibrosis--prognostic relevance is independent of IPSS or karyotype.". American journal of hematology 85 (1): 14–7. doi:10.1002/ajh.21574. PMID 20029953. 
  18. ^ Barosi, Giovanni, Conventional and Investigational Therapy for Primary Myelofibrosis, in Myeloproliferative Neoplasms, Contemporary Hematology series, 2011 Humana Press, p. 117-138. ISBN 978-1-60761-266-7.
  19. ^ Spivak, JL; Hasselbalch, H (Mar 2011). "Hydroxycarbamide: a user's guide for chronic myeloproliferative disorders.". Expert review of anticancer therapy 11 (3): 403–14. doi:10.1586/era.11.10. PMID 21417854. 
  20. ^ a b Lacy, MQ; Tefferi, A (Apr 2011). "Pomalidomide therapy for multiple myeloma and myelofibrosis: an update.". Leukemia & lymphoma 52 (4): 560–6. doi:10.3109/10428194.2011.552139. PMID 21338284. 
  21. ^ Barugola G et al. (2010). "The role of splenectomy in myelofibrosis with myeloid metaplasia". Minerva Chirurgica 65 (6): 619. 
  22. ^ "FDA Approves Incyte's Jakafi(TM) (ruxolitinib) for Patients with Myelofibrosis" (Press release). Incyte. Retrieved 2012-01-02. 
  23. ^ McCallister E, Usdin S. "A PROfessional Trial". BioCentury, December 5th 2011. 
  24. ^ Harrison, C; Kiladjian, JJ; Al-Ali, HK; Gisslinger, H; Waltzman, R; Stalbovskaya, V; McQuitty, M; Hunter, DS; Levy, R; Knoops, L; Cervantes, F; Vannucchi, AM; Barbui, T; Barosi, G (Mar 1, 2012). "JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis.". The New England Journal of Medicine 366 (9): 787–98. doi:10.1056/NEJMoa1110556. PMID 22375970. 
  25. ^ Verstovsek, S; Mesa, RA; Gotlib, J et al. (Mar 1, 2012). "A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis.". The New England Journal of Medicine 366 (9): 799–807. doi:10.1056/NEJMoa1110557. PMID 22375971. 
  26. ^ Lichtman MA (July 2005). "Is it chronic idiopathic myelofibrosis, myelofibrosis with myeloid metaplasia, chronic megakaryocytic-granulocytic myelosis, or chronic megakaryocytic leukemia? Further thoughts on the nosology of the clonal myeloid disorders". Leukemia 19 (7): 1139–41. doi:10.1038/sj.leu.2403804. PMID 15902283. 
  27. ^ Heuck, G. "Zwei Fälle von Leukämie mit eigenthümlichem Blut- resp. Knochenmarksbefund". Archiv für pathologische Anatomie und Physiologie und für klinische Medicin 78 (3): 475–496. doi:10.1007/BF01878089. 
  28. ^ synd/2799 at Who Named It?,
  29. ^ Ansell, Stephen M. (1 January 2008). Rare Hematological Malignancies. Springer Science+Business Media, LLC. pp. 28–. ISBN 978-0-387-73744-7. 
  30. ^ Judith E. Karp (2007). Acute myelogenous leukemia. Humana Press. pp. 385–. ISBN 978-1-58829-621-4. Retrieved 13 November 2010. 
  31. ^ Dameshek W (April 1951). "Some speculations on the myeloproliferative syndromes". Blood 6 (4): 372–5. PMID 14820991. 
  32. ^ "Myelofibrosis Facts" (PDF). Leukemia and Lymphoma Society. Retrieved 20 December 2012. 

External links[edit]