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| Myelofibrosis |
| Classification and external resources |
| ICD-10 |
C94.5, D47.1 |
| ICD-9 |
289.83 |
| ICD-O: |
9932, M9961/3 |
| OMIM |
254450 |
| DiseasesDB |
8616 |
| MeSH |
D055728 |
Myelofibrosis, also known as myeloid metaplasia, chronic idiopathic myelofibrosis, osteomyelofibrosis and primary myelofibrosis is a disorder of the bone marrow. It is currently classified as a myeloproliferative disease in which the proliferation of an abnormal type of bone marrow stem cell results in fibrosis, or the replacement of the marrow with collagenous connective tissue fibers.[1]
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Contents
- 1 History and terminology
- 2 Signs and symptoms
- 3 Clinical Course
- 4 Morphology
- 5 Pathophysiology
- 6 Treatment
- 7 Epidemiology
- 8 References
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History and terminology
Myelofibrosis was first described in 1879 by Gustav Heuck.[2][3]
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,[4] who published a description under the term "osteosclerosis" in 1907.[5]
It was characterised as a myeloproliferative condition in 1951 by Dameshek.[6][7]
Signs and symptoms
- Abdominal fullness related to an enlarged spleen (splenomegaly).
- Bone pain
- Bruising and easy bleeding due to inadequate numbers of platelets
- Fatigue
- Increased susceptibility to infection, such as pneumonia or diarrhea
- Pallor and shortness of breath while doing physical work due to anemia
- Because of a high rate of cell turnover, hyperuricemia and gout may also complicate the picture
Clinical Course
- Primary myelofibrosis can begin with a blood picture suggestive of Polycythemia Vera or CML
- Most patients have moderate to severe anemia
- Eventually patient develops thrombocytopenia
- The peripheral smear appears markedly abnormal
- Red cell abnormality includes bizarre shapes
- Nucleated erythroid precursors are seen in the peripheral blood
- Immature white cells are also seen and basophils are increased
Morphology
The principal site of extramedullary hematopoiesis in myeloid metaplasia with primary myelofibrosis is the spleen which is usually markedly enlarged, sometimes weighing as much as 4000 g. As is always true when splenomegaly is massive, multiple subcapsular infarcts are often present. Histologically the spleen contains normoblast, granulocyte precursor and megakaryocytes, which are often prominent in terms of their numbers and bizarre morphology. Sometimes disproportional activity of any one of the three major cell lines 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.
The bone marrow in a typical case is hypocellular and diffusely fibrotic. Both early and late in disease, megakaryocytes are often prominent and are usually dysplastic.
Pathophysiology
The bone marrow is replaced by collagen fibrosis, impairing the patient's ability to generate new blood cells resulting in a progressive pancytopenia. It is usually reactive following other myeloproliferative disorders, such as polycythemia rubra vera or essential thrombocytosis. Extramedullary haematopoeisis occurs as the haemopoetic cells migrate away from the bone marrow, to the liver and spleen. Patients often have hepatosplenomegaly and poikilocytosis.
In primary myelofibrosis, a progressive scarring (fibrosis) of the bone marrow occurs. As a result, blood forms in sites other than the bone marrow, such as the liver and spleen. This causes an enlargement of these organs. The cause and risk factors are unknown. It commonly occurs in the spent phase of Polycythemia rubra vera, possibly in response to the medication hydroxyurea poisoning the marrow and blood.
Treatment
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This section requires expansion. |
The one known treatment is allogeneic stem cell transplantation, but this approach involves significant risks.[8] Other treatment options are largely supportive, and do not alter the course.[9] These options may include regular folic acid,[10] allopurinol[11] or blood transfusions.[12] Dexamethasone, alpha-interferon and hydroxycarbamide may play a role.[13][14][15]
Lenalidomide and thalidomide may be used in its treatment, though they can cause gout and leave the patient susceptible to diseases such as pneumonia.[15]
Frequent blood transfusions may also be required.[12] If the patient is diabetic and is taking sulfonylureas medication this should be stopped periodically to rule out drug-induced thrombocytopenia.[citation needed]
In November 2011, the FDA approved ruxolitinib (Jakafi) as a treatment for myelofibrosis[16][17]. Ruxolitinib is a twice daily drug which serves as an inhibitor of JAK 1 and 2. The New England Journal of Medicine (NEJM) published results from two Phase III studies of Jakafi™ (ruxolitinib), a JAK1 and JAK2 inhibitor recently approved by the Food and Drug Administration (FDA) for the treatment of intermediate or high-risk myelofibrosis (MF). These data, which were included in the New Drug Application for Jakafi, showed that the treatment significantly reduced spleen volume and improved symptoms of MF. Additionally, in an updated analysis, treatment with Jakafi was associated with improved overall survival compared to placebo.[18][19]
Epidemiology
The disorder usually develops slowly and is mainly observed in people over the age of 50.[20] It may also develop as a side-effect of treatment with some drugs that target hematological disorders. .
References
- ^ "myelofibrosis" at Dorland's Medical Dictionary
- ^ 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.
- ^ Heuck G. Zwei Fälle von Leukämie mit eigenthümlichem Blut-resp Knochenmarksbefund. Virchows Arch (Pathol Anat) 78; 475: 1879.
- ^ synd/2799 at Who Named It?,
- ^ Stephen M. Ansell (2008). Rare Hematological Malignancies. シュプリンガー・ジャパン株式会社. pp. 28–. ISBN 9780387737430. http://books.google.com/books?id=cR_kOJoN7sYC&pg=PA28. Retrieved 13 November 2010.
- ^ Judith E. Karp (2007). Acute myelogenous leukemia. Humana Press. pp. 385–. ISBN 9781588296214. http://books.google.com/books?id=l0XWHNYyxBYC&pg=PA385. Retrieved 13 November 2010.
- ^ Dameshek W (April 1951). "Some speculations on the myeloproliferative syndromes". Blood 6 (4): 372–5. PMID 14820991. http://www.bloodjournal.org/cgi/pmidlookup?view=long&pmid=14820991.
- ^ Cervantes F (March 2005). "Modern management of myelofibrosis". Br. J. Haematol. 128 (5): 583–92. doi:10.1111/j.1365-2141.2004.05301.x. PMID 15725078.
- ^ Kröger N, Mesa RA (March 2008). "Choosing between stem cell therapy and drugs in myelofibrosis". Leukemia 22 (3): 474–86. doi:10.1038/sj.leu.2405080. PMID 18185525.
- ^ Vener Claudia, Novembrino Cristina, et al, Oxidative stress is increased in primary and post−polycythemia vera myelofibrosis (abstract), Experimental Hematology, 1 Nov 2010, Vol 38 Iss 11, 1058-1065, doi:10.1016/j.exphem.2010.07.005.
- ^ Narasimhaiah Srinivasaiah, Mohammad K Zia and Vummiti Muralikrishnan, Peritonitis in myelofibrosis: a cautionary tale, Hepatobiliary & Pancreatic Diseases International 2010; 9: 651-653.
- ^ a b Tefferi, A., Siragusa, S., et al, 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): 14–17 (2010). doi:10.1002/ajh.21574.
- ^ 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.
- ^ Spivak, Jerry L1; Hasselbalch, Hans, Hydroxycarbamide: a user's guide for chronic myeloproliferative disorders, Expert Review of Anticancer Therapy, Vol. 11(3), Mar. 2011, pp. 403-414.
- ^ a b Lacy, M. and Tefferi, A., Pomalidomide therapy for multiple myeloma and myelofibrosis: an update, Leukemia & Lymphoma, April 2011, 52(4), pp. 560-566, doi:10.3109/10428194.2011.552139.
- ^ "FDA Approves Incyte's Jakafi(TM) (ruxolitinib) for Patients with Myelofibrosis" (Press release). Incyte. http://investor.incyte.com/phoenix.zhtml?c=69764&p=irol-newsArticle&ID=1631201&highlight=. Retrieved 2012-01-02.
- ^ McCallister E, Usdin S. "A PROfessional Trial". BioCentury, December 5th 2011.
- ^ Claire Harrison, D.M., Jean-Jacques Kiladjian, M.D., Ph.D., Haifa Kathrin Al-Ali, M.D., Heinz Gisslinger, M.D., Roger Waltzman, M.D., M.B.A., Viktoriya Stalbovskaya, Ph.D., Mari McQuitty, R.N., M.P.H., Deborah S. Hunter, Ph.D., Richard Levy, M.D., Laurent Knoops, M.D., Ph.D., Francisco Cervantes, M.D., Ph.D., Alessandro M. Vannucchi, M.D., Tiziano Barbui, M.D., and Giovanni Barosi, M.D. N Engl J Med 2012; 366:787-798March 1, 2012
- ^ Srdan Verstovsek, M.D., Ph.D., Ruben A. Mesa, M.D., Jason Gotlib, M.D., Richard S. Levy, M.D., Vikas Gupta, M.D., John F. DiPersio, M.D., Ph.D., John V. Catalano, M.D., Michael Deininger, M.D., Ph.D., Carole Miller, M.D., Richard T. Silver, M.D., Moshe Talpaz, M.D., Elliott F. Winton, M.D., Jimmie H. Harvey, Jr., M.D., Murat O. Arcasoy, M.D., Elizabeth Hexner, M.D., Roger M. Lyons, M.D., Ronald Paquette, M.D., Azra Raza, M.D., Kris Vaddi, Ph.D., Susan Erickson-Viitanen, Ph.D., Iphigenia L. Koumenis, M.S., William Sun, Ph.D., Victor Sandor, M.D., and Hagop M. Kantarjian, M.D. N Engl J Med 2012; 366:799-807March 1, 2012
- ^ Primary Myelofibrosis, Merck.
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Myeloid hematological malignancy/leukemia histology (ICD-O 9590–9989, C81–C96, 200–208)
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CFU-GM/
and other granulocytes |
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CFU-GM
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Myelocyte
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AML: Acute myeloblastic leukemia (M0, M1, M2), APL/M3
MP (Chronic neutrophilic leukemia)
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Monocyte
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AML (AMoL/M5, Myeloid dendritic cell leukemia)
CML (Philadelphia chromosome, Accelerated phase chronic myelogenous leukemia)
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Myelomonocyte
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AML (M4)
MD-MP (Juvenile myelomonocytic leukemia, Chronic myelomonocytic leukemia)
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Other
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Histiocytosis
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CFU-Baso
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AML (Acute basophilic)
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CFU-Eos
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AML (Acute eosinophilic)
MP (Chronic eosinophilic leukemia/Hypereosinophilic syndrome)
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| MEP |
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CFU-Meg
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AML (AMKL/M7)
MP (Essential thrombocytosis)
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CFU-E
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AML (Erythroleukemia/M6)
MP (Polycythemia vera)
MD (Refractory anemia, Refractory anemia with excess of blasts, Chromosome 5q deletion syndrome, Sideroblastic anemia, Paroxysmal nocturnal hemoglobinuria, Refractory cytopenia with multilineage dysplasia)
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| CFU-Mast |
Mastocytoma (Mast cell leukemia, Mast cell sarcoma, Systemic mastocytosis)
Mastocytosis: Diffuse cutaneous mastocytosis · Erythrodermic mastocytosis · Generalized eruption of cutaneous mastocytosis (adult type) · Generalized eruption of cutaneous mastocytosis (childhood type) · Mast cell sarcoma · Solitary mastocytoma · Systemic mastocytosis · Xanthelasmoidal mastocytosis
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| Multiple/unknown |
AML (Acute panmyelosis with myelofibrosis, Myeloid sarcoma) · MP (Myelofibrosis) · Acute biphenotypic leukaemia
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cell/phys (coag, heme, immu, gran), csfs
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rbmg/mogr/tumr/hist, sysi/epon, btst
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drug (B1/2/3+5+6), btst, trns
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クローン性の造血幹細胞の疾患で、骨髄の線維化、髄外造血、脾腫をきたし、病因は不明である。慢性特発性骨髄線維症は最も一般ではないCMPDの一つであり、特定のクローンのマーカーが無い場合、診断は困難である。これは骨髄の線維化や脾腫は多血症や慢性骨髄性白血病でもみられるためである。また骨髄の線維化は様々な疾患でみられるためである(骨髄線維症#病因)。 (HIM.674)