myelofibrosis

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Key Terms: Anemia, Benzene, Biopsy, Fibrosis, Glucocorticoid therapy, Leukemia, Portal hypertension.

Definition

Myelofibrosis is a rare disease of the bone marrow in which collagen builds up fibrous scar tissue inside the marrow cavity. This is caused by the uncontrolled growth of a blood cell precursor, which results in the accumulation of scar tissue in bone marrow. Myelofibrosis goes by many names including idiopathic myelofibrosis, agnogenic myeloid metaplasia, chronic myelosclerosis, aleukemic megakaryocytic myelosis, and leukoerythroblastosis.

Description

Myelofibrosis can be associated with many other conditions including breast cancer, prostate cancer, Hodgkin's disease, non-Hodgkin's lymphomas, acute myelocytic leukemia, acute lymphocytic leukemia, hairy cell leukemia, multiple myeloma, myeloproliferative diseases, tuberculosis, Gaucher's disease, and Paget's disease of bone. Myelofibrosis typically becomes progressively worse and can cause death.

In myelofibrosis, abnormal cells (hematopoietic stem cells) grow out of control and begin to produce both immature blood cells and excess scar (fibrous) tissue. The fibrous tissue builds up (fibrosis) primarily in the bone marrow, the place where blood cells are produced. The fibrous tissue interferes with the production of normal blood cells. The outcome of this is that the blood made by the bone marrow is of poor quality. To compensate for this, blood cell production occurs in other parts of the body (extramedullary hematopoiesis), but most notably in the spleen and liver. This causes enlargement of the spleen (splenomegaly) and the liver (hepatomegaly). Extramedullary hematopoiesis is not effective and, combined with the reduced production of blood cells by the bone marrow, a condition called anemia results.

The abnormal stem cells can spread throughout the body, settle in other organs, and form tumors that produce more abnormal blood cells and fibrous tissue. These tumors are most commonly found in the adrenals, kidneys, lymph nodes, breast, lungs, skin, bowel, thymus, thyroid, prostate, and urinary tract.

Demographics

Most patients with myelofibrosis are over 50 years old; the average age at diagnosis is 65 years. However, myelofibrosis can occur at any age. Myelofibrosis occurs with equal frequency in women and men, but in children it affects girls twice as often as it does boys.

Causes and Symptoms

Myelofibrosis is caused by an abnormality in a single stem cell, which causes it to grow out of control. Myelofibrosis tumors that have originated from a single cell are called monoclonal. The cause of the stem cell abnormality is unknown. Persons who were exposed to benzene or high doses of radiation have developed myelofibrosis. There may be an association between myelofibrosis and autoimmune diseases, such as systemic lupus erythematosus and scleroderma, in which the immune system treats certain molecules of the body as foreign invaders.

Symptoms usually appear slowly over a long period of time. About one quarter of all patients with myelofibrosis have no symptoms (asymptomatic). An enlarged spleen discovered at an annual medical examination may be the first clue. Symptoms of myelofibrosis include:

• fatigue
• weight loss
• paleness
• fever
• sweating
• weakness
• heart palpitations
• shortness of breath
• itching
• feeling full after eating a small amount of food
• stomach pain or discomfort
• pain in the left shoulder or upper left portion of the body
• unexpected bleeding
• bone pain, especially in the legs

Diagnosis

Because symptoms are similar to other diseases (mostly leukemias), myelofibrosis is not easy to diagnose. The doctor would use his or her hands to feel (palpate) for enlargement of the spleen and liver. Blood tests and urine tests would be performed. Bone marrow aspiration and biopsy can help make a diagnosis, but they often fail because of the fibrosis. X-ray imaging and magnetic resonance imaging (MRI) may be performed.

Treatment

Many asymptomatic patients, if stable, do not require treatment. There is no cure for myelofibrosis, although bone marrow transplantation is curative in some cases. Treatment is aimed at reducing symptoms and improving quality of life.

Medications

Male hormones (androgens) can be used to treat anemia but, in women, these drugs can cause the development of male characteristics (e.g., hair growth on the face and body). Glucocorticoid therapy is also an effective treatment of anemia and can improve myelofibrosis in children. Nutrients that stimulate blood formation (hematinics), such as iron, folic acid, and vitamin B₁₂, may reduce anemia. Cancer chemotherapy (usually hydroxyurea) can decrease splenomegaly and hepatomegaly, reduce symptoms of myelofibrosis, lessen anemia, and sometimes reduce bone marrow fibrosis. The bone marrow of myelofibrosis patients is often not strong enough to withstand the harsh chemotherapy drugs, so this treatment is not always an option. Interferon-alpha has been shown to reduce spleen size, reduce bone pain, and, in some cases, increase the number of blood platelets (structures involved in blood clotting).

Other Treatments

In certain cases, the enlarged spleen may be removed (splenectomy). Conditions that warrant splenectomy include spleen pain, the need for frequent blood transfusion, very low levels of platelets (thrombocytopenia), and extreme pressure in the blood vessels of the liver (portal hypertension).

Radiation therapy is used to treat splenomegaly, spleen pain, bone pain, tumors in certain places such as next to the spinal cord, and fluid accumulation inside the abdomen (ascites). Patients who are not strong enough to undergo splenectomy are often treated with radiation therapy.

Bone marrow transplantation may be used to treat some patients with myelofibrosis. This procedure may be performed on patients who are less than 50 years old, have a poor life expectancy, and have a brother or sister with blood-type similarities.

Patients with severe anemia may require blood transfusions.

Prognosis

Similar to leukemias, myelofibrosis is progressive and often requires therapy to control the disease. Myelofibrosis can progress to acute lymphocytic leukemia or lymphoma. Although a number of factors to predict the survival time have been proposed, advanced age or severe anemia are consistently associated with a poor prognosis. The average survival rate of patients diagnosed with myelofibrosis is five years. Death is usually caused by infection, bleeding, complications of splenectomy, heart failure, or progression to leukemia. Spontaneous remission is rare.

Prevention

Persons who have been exposed to radiation, benzene, or radioactive thorium dioxide (a chemical used during certain diagnostic radiological procedures) are at risk for myelofibrosis.

Resources

Books

Lichtman, Marshall. "Idiopathic Myelofibrosis (Agnogenic Myeloid Metaplasia)." In Williams Hematology, edited by Ernest Beutler, et al. New York: McGraw Hill, 2001, pp.1125-36.

Mavroudis, Dimitrios, and John Barrett. "Myelofibrosis (Agnogenic Myeloid Metaplasia)." In Bone Marrow Failure Syndromes, edited by Neal Young. Philadelphia: W.B. Saunders Company, 2000, pp.122-34.

Peterson, Powers. "Myelofibrosis." In Practical Diagnosis of Hematologic Disorders, edited by Carl Kjeldsberg. Chicago: ASCP Press, 2000, pp.477-9.

—Belinda Rowland, Ph.D.; J. Ricker Polsdorfer, M.D.

Fibrosis of the bone marrow associated with myeloid metaplasia, leukoerythroblastosis, and thrombocytopenia. Also called myelosclerosis.

Replacement of bone marrow by fibrous tissue, e.g. in the end-stage of myeloid metaplasia and myelofibrosis.

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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]

Contents 1 History and terminology 2 Signs and symptoms 3 Clinical Course 4 Morphology 5 Pathophysiology 6 Treatment 7 Epidemiology 8 References

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 vera, chronic myeloid leukemia 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

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

1. ^ "myelofibrosis" at Dorland's Medical Dictionary
2. ^ 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. 
3. ^ Heuck G. Zwei Fälle von Leukämie mit eigenthümlichem Blut-resp Knochenmarksbefund. Virchows Arch (Pathol Anat) 78; 475: 1879.
4. ^ synd/2799 at Who Named It?,
5. ^ 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 978-0-387-73743-0. http://books.google.com/books?id=cR_kOJoN7sYC&pg=PA28. Retrieved 13 November 2010. 
6. ^ Judith E. Karp (2007). Acute myelogenous leukemia. Humana Press. pp. 385–. ISBN 978-1-58829-621-4. http://books.google.com/books?id=l0XWHNYyxBYC&pg=PA385. Retrieved 13 November 2010. 
7. ^ 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. 
8. ^ 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. 
9. ^ 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. 
10. ^ 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.
11. ^ Narasimhaiah Srinivasaiah, Mohammad K Zia and Vummiti Muralikrishnan, Peritonitis in myelofibrosis: a cautionary tale, Hepatobiliary & Pancreatic Diseases International 2010; 9: 651-653.
12. ^ ^{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.
13. ^ 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.
14. ^ 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.
15. ^ ^{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.
16. ^ "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. 
17. ^ McCallister E, Usdin S. "A PROfessional Trial". BioCentury, December 5th 2011. 
18. ^ 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
19. ^ 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
20. ^ Primary Myelofibrosis, Merck.

v t e Myeloid hematological malignancy/leukemia histology (ICD-O 9590–9989, C81–C96, 200–208) CFU-GM/ and other granulocytes CFU-GM Myelocyte AML: Acute myeloblastic leukemia (M0, M1, M2), APL/M3 MP (Chronic neutrophilic leukemia) Monocyte AML (AMoL/M5, Myeloid dendritic cell leukemia) CML (Philadelphia chromosome, Accelerated phase chronic myelogenous leukemia) Myelomonocyte AML (M4) MD-MP (Juvenile myelomonocytic leukemia, Chronic myelomonocytic leukemia) Other Histiocytosis CFU-Baso AML (Acute basophilic) CFU-Eos AML (Acute eosinophilic) MP (Chronic eosinophilic leukemia/Hypereosinophilic syndrome) MEP CFU-Meg AML (AMKL/M7) MP (Essential thrombocytosis) CFU-E 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) 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 Multiple/unknown AML (Acute panmyelosis with myelofibrosis, Myeloid sarcoma) · MP (Myelofibrosis) · Acute biphenotypic leukaemia M: MYL cell/phys (coag, heme, immu, gran), csfs rbmg/mogr/tumr/hist, sysi/epon, btst drug (B1/2/3+5+6), btst, trns

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