Myelofibrosis

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Myelofibrosis
Classification and external resources
ICD-10 C94.4, D47.1
ICD-9 289.83
ICD-O: 9932, M9961/3
OMIM 254450
DiseasesDB 8616
MedlinePlus 000531
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 clone of hematopoietic progenitor cells in the bone marrow and other sites results in fibrosis, or the replacement of the marrow with collagenous connective tissue fibers.[1]

Signs and symptoms[edit]

  • 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
  • In rarer cases, a raised Mean corpuscular volume above normal ranges (I.e. 100fl+)
  • Cutaneous myelofibrosis is a rare skin condition characterized by dermal and subcutaneous nodules.[2]:746

Pathophysiology[edit]

Myelofibrosis is a clonal neoplastic disorder of hematopoiesis, and is one of the myeloproliferative disorders. Production of cytokines such as fibroblast growth factor by the abnormal hematopoietic cell clone (particularly by megakaryocytes)[3] leads to replacement of the hematopoietic tissue of the bone marrow by collagen fibrosis, impairing the patient's ability to generate new blood cells and resulting in a progressive pancytopenia. However, the proliferation of fibroblasts and deposition of collagen is a secondary phenomenon, and the fibroblasts are not themselves part of the abnormal cell clone. Enlargement of the spleen commonly results in hypersplenism, which also contributes to causing pancytopenia, particularly thrombocytopenia and anemia. Myelofibrosis can result as a late complication of other myeloproliferative disorders, such as polycythemia vera or essential thrombocytosis. Extramedullary haematopoeisis occurs as the haemopoetic cells migrate away from the bone marrow, to the liver and spleen, and patients often have hepatomegaly, massive splenomegaly and poikilocytosis.

In primary myelofibrosis, progressive scarring (fibrosis) of the bone marrow occurs, for the reasons discussed above. As a result, extramedullary hematopoeisis (blood cell formation occurring in sites other than the bone marrow) ensues, particularly in the liver and spleen. This causes an enlargement of these organs. The cause and risk factors for primary myelofibrosis are unknown. Myelofibrosis also commonly occurs as a late complication of Polycythemia rubra vera, and less commonly as a late complication of essential thrombocytosis, by means of somatic evolution (clonal evolution) of the underlying abnormal hematopoietic progenitor cell clone, and possibly accelerated by the oral chemotherapy drug hydroxyurea in some cases.[4]

Sites of hematopoesis[edit]

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 red blood cell precursors, granulocyte precursors and megakaryocytes, with the latter usually being prominent in terms of their numbers and bizarre morphology. Sometimes disproportional activity of any one of the three major cell lines is seen. Megakaryocytes are believed to be involved in causing the secondary fibrosis seen in this condition, as discussed under "Pathophysiology" above.

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 extramedullary hematopoiesis taking place in the lungs. These cases are associated with pulmonary arterial hypertension.[5]

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]

  • Primary myelofibrosis can begin with a blood picture suggestive of Polycythemia Vera or CML
  • Most patients have moderate to severe anemia
  • Eventually the patient develops thrombocytopenia
  • The peripheral smear appears markedly abnormal
  • Red cell abnormality includes bizarre shapes (teardrop-shaped RBCs on a peripheral smear).
  • Nucleated erythroid precursors are seen in the peripheral blood
  • Immature white cells are also seen and basophils are increased

Dry tap on bone marrow aspiration +Reticulin or collagen fibrosis in bone marrow biosy

Treatment[edit]

The one known curative treatment is allogeneic stem cell transplantation, but this approach involves significant risks.[6] Other treatment options are largely supportive, and do not alter the course of the disorder (with the possible exception of ruxolitinib, as discussed below).[7] These options may include regular folic acid,[8] allopurinol[9] or blood transfusions.[10] Dexamethasone, alpha-interferon and hydroxyurea (also known as hydroxycarbamide) may play a role.[11][12][13]

Lenalidomide and thalidomide may be used in its treatment, though peripheral neuropathy is a common troublesome side-effect.[13]

Frequent blood transfusions may also be required.[10] 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.[14]

In November 2011, the FDA approved ruxolitinib (Jakafi) as a treatment for myelofibrosis.[15][16] 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.[17][18]

Epidemiology[edit]

The disorder usually develops slowly and is mainly observed in people over the age of 50.[19] It may also develop as a side-effect of treatment with some drugs that target hematological disorders.

History[edit]

Myelofibrosis was first described in 1879 by Gustav Heuck.[20][21]

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,[22] who published a description under the term "osteosclerosis" in 1907.[23]

It was characterised as a myeloproliferative condition in 1951 by Dameshek.[24][25] The Leukemia and Lymphoma Society describes myelofibrosis as a rare type of blood cancer, manifesting as a type of chronic leukemia.[26]

References[edit]

  1. ^ "myelofibrosis" at Dorland's Medical Dictionary
  2. ^ James, William D.; Berger, Timothy G.; et al. (2006). Andrews' Diseases of the Skin: clinical Dermatology. Saunders Elsevier. ISBN 0-7216-2921-0. 
  3. ^ 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. doi:10.1016/S0145-2126(02)00268-0. PMID 12648509. 
  4. ^ 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. PMID 9345019. 
  5. ^ Trow, TK; et all (2010). "A 71-Year-Old Woman With Myelofibrosis, Hypoxemia, and Pulmonary Hypertension". Chest 136 (6): 1506. doi:10.1378/chest.10-0973. PMID 21138888. 
  6. ^ 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. 
  7. ^ 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. 
  8. ^ 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.
  9. ^ Narasimhaiah Srinivasaiah, Mohammad K Zia and Vummiti Muralikrishnan, Peritonitis in myelofibrosis: a cautionary tale, Hepatobiliary & Pancreatic Diseases International 2010; 9: 651-653.
  10. ^ 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.
  11. ^ 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.
  12. ^ 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.
  13. ^ 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.
  14. ^ Barugola G et al (2010). "The role of splenectomy in myelofibrosis with myeloid metaplasia". Minerva Chirurgica 65 (6): 619. 
  15. ^ "FDA Approves Incyte's Jakafi(TM) (ruxolitinib) for Patients with Myelofibrosis" (Press release). Incyte. Retrieved 2012-01-02. 
  16. ^ McCallister E, Usdin S. "A PROfessional Trial". BioCentury, December 5th 2011. 
  17. ^ 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. 
  18. ^ Verstovsek, Srdan; Mesa, Ruben A.; Gotlib, Jason; Levy, Richard S.; Gupta, Vikas; DiPersio, John F.; Catalano, John V.; Deininger, Michael; Miller, Carole; Silver, Richard T.; Talpaz, Moshe; Winton, Elliott F.; Harvey, Jimmie H.; Arcasoy, Murat O.; Hexner, Elizabeth; Lyons, Roger M.; Paquette, Ronald; Raza, Azra; Vaddi, Kris; Erickson-Viitanen, Susan; Koumenis, Iphigenia L.; Sun, William; Sandor, Victor; Kantarjian, Hagop M. (March 2012). "A Double-Blind, Placebo-Controlled Trial of Ruxolitinib for Myelofibrosis". New England Journal of Medicine 366 (9): 799–807. doi:10.1056/NEJMoa1110557. 
  19. ^ Primary Myelofibrosis, Merck.
  20. ^ 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. 
  21. ^ Heuck G. Zwei Fälle von Leukämie mit eigenthümlichem Blut-resp Knochenmarksbefund. Virchows Arch (Pathol Anat) 78; 475: 1879.
  22. ^ synd/2799 at Who Named It?,
  23. ^ Ansell, Stephen M. (1 January 2008). Rare Hematological Malignancies. Springer Science+Business Media, LLC. pp. 28–. ISBN 978-0-387-73744-7. 
  24. ^ Judith E. Karp (2007). Acute myelogenous leukemia. Humana Press. pp. 385–. ISBN 978-1-58829-621-4. Retrieved 13 November 2010. 
  25. ^ Dameshek W (April 1951). "Some speculations on the myeloproliferative syndromes". Blood 6 (4): 372–5. PMID 14820991. 
  26. ^ "Myelofibrosis Facts". Leukemia and Lymphoma Society. Retrieved 20 December 2012. 

External links[edit]