Myelofibrosis

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 collagenous connective tissue fibers.^[2] The term myelofibrosis alone usually refers to primary myelofibrosis (PMF) (chronic idiopathic myelofibrosis [cIMF]), the idiopathic form of the disease, in contrast with myelofibrosis secondary to polycythemia vera or essential thrombocythaemia. Myelofibrosis is a form of myeloid metaplasia, and often the two terms are used synonymously. Agnogenic myeloid metaplasia and myelofibrosis with myeloid metaplasia (MMM) also overlap on the same spectrum.

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
• 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.^[3]:746

Pathophysiology

Myelofibrosis is a clonal neoplastic disorder of haematopoiesis, and is one of the myeloproliferative disorders. Production of cytokines such as fibroblast growth factor by the abnormal hematopoietic cell clone (particularly by megakaryocytes)^[4] 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.

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 result as a late complication of other myeloproliferative disorders, such as polycythemia vera, and less commonly as a late complication of essential thrombocythaemia, by means of somatic evolution (clonal evolution) of the underlying abnormal hematopoietic stem cell clone, and possibly accelerated by the oral chemotherapy drug hydroxyurea in some cases.^[5]

The cause and risk factors for primary myelofibrosis are unknown.

Sites of hematopoesis

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.^[6]

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

• Primary myelofibrosis can begin with a blood picture suggestive of Polycythemia Vera or Chronic myelogenous leukemia
• Most patients have moderate to severe anemia
• Eventually the patient develops thrombocytopenia
• The peripheral smear appears markedly abnormal, with presentation of pancytopenia
• 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 biopsy.

Treatment

The one known curative treatment is allogeneic stem cell transplantation, but this approach involves significant risks.^[7] Other treatment options are largely supportive, and do not alter the course of the disorder (with the possible exception of ruxolitinib, as discussed below).^[8] These options may include regular folic acid,^[9] allopurinol^[10] or blood transfusions.^[11] Dexamethasone, alpha-interferon and hydroxyurea (also known as hydroxycarbamide) may play a role.^[12][13][14]

Lenalidomide and thalidomide may be used in its treatment, though peripheral neuropathy is a common troublesome side-effect.^[14]

Frequent blood transfusions may also be required.^[11] If the patient is diabetic and is taking sulfonylureas medication this should be stopped periodically to rule out drug-induced thrombocytopenia.

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.^[15]

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.

History

Myelofibrosis was first described in 1879 by Gustav Heuck.^[21][22]

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,^[23] who published a description under the term "osteosclerosis" in 1907.^[24]

It was characterised as a myeloproliferative condition in 1951 by Dameshek.^[25][26] The Leukemia and Lymphoma Society describes myelofibrosis as a rare type of blood cancer, manifesting as a type of chronic leukemia.^[27]

References

External links

• PV Reporter - Myeloproliferative Neoplasm Website, MPN Patient Research Hub