Primary myelofibrosis

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Primary myelofibrosis
Other namesPMF, Overt PMF, Myelofibrosis
Specialty Oncology and Hematology

Primary myelofibrosis (PMF) is a rare bone marrow blood cancer. [1] It is classified by the World Health Organization (WHO) as a type of myeloproliferative neoplasm, a group of cancers in which there is activation and growth of mutated cells in the bone marrow. This is most often associated with a somatic mutation in the JAK2 , CALR , or MPL genes. In PMF, the bony aspects of bone marrow are remodeled in a process called osteosclerosis; in addition, fibroblast secrete collagen and reticulin proteins that are collectively referred to as (fibrosis). These two pathological processes compromise the normal function of bone marrow resulting in decreased production of blood cells such as erythrocytes (red cells), granulocytes and megakaryocytes, the latter cells responsible for the production of platelets.

Contents

Signs and symptoms include fever, night sweats, bone pain, fatigue, and abdominal pain. Increased infections, bleeding and an enlarged spleen (splenomegaly) are also hallmarks of the disease. Patients with myelofibrosis have an increased risk of acute meyloid leukemia and frank bone marrow failure.

In 2016, prefibrotic primary myelofibrosis was formally classified as a distinct condition that progresses to overt PMF in many patients, the primary diagnostic difference being the grade of fibrosis. [2]

Signs and symptoms

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

Causes

The underlying cause of PMF is almost always related to an acquired mutation in JAK2, CALR or MPL in a hematopoietic stem/progenitor cell in the bone marrow. [5] There is an association between mutations to the JAK2 , CALR , or MPL genes and myelofibrosis. [6] Approximately 90% of those with myelofibrosis have one of these mutations; 10% do not have mutations in these three genes. These mutations are not specific to myelofibrosis, but are observed in other myeloproliferative neoplasms, specifically polycythemia vera and essential thrombocythemia. [3]

The JAK2 protein is mutated giving risk to a variant protein with an amino acid substistution commonly referred to as V617F; the mutation causing this variant is found in approximately half of individuals with primary myelofibrosis. [7] The V617F subsitution is an amino acid change of valine to phenylalanine at the 617 position in the JAK2 protein. Janus kinases (JAKs) are non-receptor tyrosine kinase part of the signaling pathway activated by receptors that recognize cytokines and growth factors. These include receptors for erythropoietin, thrombopoietin, most interleukins and interferon. [7] JAK2 mutations play a significant role in the pathogenesis of all the MPNs because the recognized mutations all cause constitutive activation of the pathway controlling the production of blood cells arising from hematopoietic stem cells. The V617F subsustition also renders hematopoietic cells more sensitive to growth factors that use JAK2 for signal transduction, which include erythropoietin and thrombopoietin. [8]

The MPL gene codes for a protein that acts as a receptor for thrombopoietin, a growth factor that enhances production of platelets. A mutation in that gene, resulting in the subsitution W515L, results in thrombopoietin receptor that is constitutively active even in the absence of thrompoietin. Abnormal megakaryocytes redominate in the bone marrow and platelet production is enhanced. The mutant megakaryocytes also release growth factors that stimulate other cells in the bone marrow including fibroblasts, the cells that are stimulated to secrete excess collagen, [9] by secreting PDGF and TGF-β1. [10]

Mechanism

Myelofibrosis is a clonal neoplastic disorder of hematopoiesis, the formation of blood cellular components. It is one of the myeloproliferative disorders, diseases of the bone marrow in which excess cells are produced at some stage. Production of cytokines such as fibroblast growth factor by the abnormal hematopoietic cell clone (particularly by megakaryocytes) [11] 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.[ citation needed ]

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

Myelofibrosis can be a late complication of other myeloproliferative disorders, such as polycythemia vera, and less commonly, essential thrombocythemia. 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. [12]

Sites of hematopoiesis

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 due to interrupted oxygen supply to the spleen partial or complete tissue death happens. On the cellular level, the spleen contains red blood cell precursors, granulocyte precursors and megakaryocytes, with the megakaryocytes 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 "Mechanism" 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.[ citation needed ]

There are also reports of hematopoiesis taking place in the lungs. These cases are associated with hypertension in the pulmonary arteries. [13]

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.[ citation needed ]

Diagnosis

Epidemiologically, the disorder usually develops slowly and is mainly observed in people over the age of 50. [14]

Diagnosis is made on the basis of bone marrow biopsy. Fibrosis grade 2 or 3 defines overt PMF whereas grade 0 or 1 defines prefibrotic primary myelofibrosis.[ citation needed ]

A physical exam of the abdomen may reveal enlargement of the spleen, the liver, or both. [3] Fibrosis with scattered linear reticulin in the early stages. In this patient, the symptoms and findings are consistent with primary myelofibrosis (PMF). PMF is a clonal myeloproliferative disorder that is often associated with a JAK2 mutation. One of the key features of PMF is the development of fibrosis in the bone marrow. In the early stages of the disease, the fibrosis is characterized by scattered linear reticulin fibers. This can be observed on a bone marrow biopsy. The other answer options are not consistent with the findings seen in PMF. Essential thrombocytopenia,would show hypercellularity with numerous abnormal megakaryocytes on bone marrow biopsy. Polycythemia vera ,would show hypercellularity with fibrosis in later stages. Myelodysplastic syndromes,

would show ringed sideroblasts and less than 20% myeloblasts. Aplastic anemia , would show a hypocellular bone marrow.

Treatment

The one known curative treatment is allogeneic stem cell transplantation, but this approach involves significant risks. [15] Other treatment options are largely supportive, and do not alter the course of the disorder (with the possible exception of ruxolitinib, as discussed below). [16] These options may include regular folic acid, [17] allopurinol [18] or blood transfusions. [19] Dexamethasone, alpha-interferon and hydroxyurea (also known as hydroxycarbamide) may play a role. [20] [21] [22]

Lenalidomide and thalidomide may be used in its treatment, though peripheral neuropathy is a common troublesome side-effect. [22]

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. [23]

In November 2011, the US Food and Drug Administration (FDA) approved ruxolitinib (Jakafi) as a treatment for intermediate or high-risk myelofibrosis. [24] [25] Ruxolitinib serves as an inhibitor of JAK 1 and 2. Data from two phase III studies of ruxolitinib showed that the treatment significantly reduced spleen volume, improved symptoms of myelofibrosis, and was associated with much improved overall survival rates compared to placebo. [26] [27] However, the beneficial effect of ruxolitinib on survival has been recently questioned. [28]

In August 2019, the FDA approved fedratinib (Inrebic) as a treatment for adults with intermediate-2 or high-risk primary or secondary (post-polycythemia vera or post-essential thrombocythemia) myelofibrosis (MF). [29]

In March 2022, the FDA approved pacritinib (Vonjo) with an indication to treat adults who have intermediate or high-risk primary or secondary myelofibrosis and who have platelet (blood clotting cells) levels below 50,000/µL. [30]

Momelotinib (Ojjaara) was approved for medical use in the United States in September 2023. [31] It is indicated for the treatment of intermediate or high-risk myelofibrosis, including primary myelofibrosis or secondary myelofibrosis [post-polycythemia vera and post-essential thrombocythemia], in adults with anemia. [31] [32]

History

Myelofibrosis was first described in 1879 by Gustav Heuck. [33] [34] Eponyms for the disease are Heuck-Assmann disease or Assmann's Disease, for Herbert Assmann, [35] who published a description under the term "osteosclerosis" in 1907. [36]

It was characterised as a myeloproliferative condition in 1951 by William Dameshek. [37] [38]

The disease was also known as myelofibrosis with myeloid metaplasia and agnogenic myeloid metaplasia [39] The World Health Organization utilized the name chronic idiopathic myelofibrosis until 2008, when it adopted the name of primary myelofibrosis.

In 2016, the WHO revised their classification of myeloproliferative neoplasms to define Prefibrotic primary myelofibrosis as a distinct clinical entity from overt PMF. [2]

Related Research Articles

<span class="mw-page-title-main">Haematopoiesis</span> Formation of blood cellular components

Haematopoiesis is the formation of blood cellular components. All cellular blood components are derived from haematopoietic stem cells. In a healthy adult human, roughly ten billion to a hundred billion new blood cells are produced per day, in order to maintain steady state levels in the peripheral circulation.

<span class="mw-page-title-main">Polycythemia vera</span> Overproduction of red blood cells by the bone marrow

In oncology, polycythemia vera (PV) is an uncommon myeloproliferative neoplasm in which the bone marrow makes too many red blood cells. The majority of cases are caused by mutations in the JAK2 gene, most commonly resulting in a single amino acid change in its protein product from valine to phenylalanine at position 617.

<span class="mw-page-title-main">Polycythemia</span> Laboratory diagnosis of high hemoglobin content in blood

Polycythemia is a laboratory finding in which the hematocrit and/or hemoglobin concentration are increased in the blood. Polycythemia is sometimes called erythrocytosis, and there is significant overlap in the two findings, but the terms are not the same: polycythemia describes any increase in hematocrit and/or hemoglobin, while erythrocytosis describes an increase specifically in the number of red blood cells in the blood.

<span class="mw-page-title-main">Megakaryocyte</span> Type of bone marrow cell

A megakaryocyte is a large bone marrow cell with a lobated nucleus that produces blood platelets (thrombocytes), which are necessary for normal clotting. In humans, megakaryocytes usually account for 1 out of 10,000 bone marrow cells, but can increase in number nearly 10-fold during the course of certain diseases. Owing to variations in combining forms and spelling, synonyms include megalokaryocyte and megacaryocyte.

<span class="mw-page-title-main">Essential thrombocythemia</span> Overproduction of platelets in the bone marrow

In hematology, essential thrombocythemia (ET) is a rare chronic blood cancer characterised by the overproduction of platelets (thrombocytes) by megakaryocytes in the bone marrow. It may, albeit rarely, develop into acute myeloid leukemia or myelofibrosis. It is one of the blood cancers wherein the bone marrow produces too many white or red blood cells, or platelets.

<span class="mw-page-title-main">Myeloproliferative neoplasm</span> Overproduction of blood cells in the bone marrow

Myeloproliferative neoplasms (MPNs) are a group of rare blood cancers in which excess red blood cells, white blood cells or platelets are produced in the bone marrow. Myelo refers to the bone marrow, proliferative describes the rapid growth of blood cells and neoplasm describes that growth as abnormal and uncontrolled.

<span class="mw-page-title-main">Extramedullary hematopoiesis</span> Medical condition

Extramedullary hematopoiesis refers to hematopoiesis occurring outside of the medulla of the bone. It can be physiologic or pathologic.

<span class="mw-page-title-main">GATA1</span> Protein-coding gene in humans

GATA-binding factor 1 or GATA-1 is the founding member of the GATA family of transcription factors. This protein is widely expressed throughout vertebrate species. In humans and mice, it is encoded by the GATA1 and Gata1 genes, respectively. These genes are located on the X chromosome in both species.

Myelophthisic anemia is a severe type of anemia found in some people with diseases that affect the bone marrow. Myelophthisis refers to the displacement of hemopoietic bone-marrow tissue by fibrosis, tumors, or granulomas. The word comes from the roots myelo-, which refers to bone marrow, and phthysis, shrinkage or atrophy.

<span class="mw-page-title-main">Thrombopoietin receptor</span> Protein-coding gene in the species Homo sapiens

The thrombopoietin receptor also known as the myeloproliferative leukemia protein or CD110 is a protein that in humans is encoded by the MPL oncogene.

<span class="mw-page-title-main">Basophilia</span> Medical condition

Basophilia is the condition of having greater than 200 basophils/μL in the venous blood. Basophils are the least numerous of the myelogenous cells, and it is rare for their numbers to be abnormally high without changes to other blood components. Rather, basophilia is most often coupled with other white blood cell conditions such as eosinophilia, high levels of eosinophils in the blood. Basophils are easily identifiable by a blue coloration of the granules within each cell, marking them as granulocytes, in addition to segmented nuclei.

<span class="mw-page-title-main">Acute megakaryoblastic leukemia</span> Medical condition

Acute megakaryoblastic leukemia (AMKL) is life-threatening leukemia in which malignant megakaryoblasts proliferate abnormally and injure various tissues. Megakaryoblasts are the most immature precursor cells in a platelet-forming lineage; they mature to promegakaryocytes and, ultimately, megakaryocytes which cells shed membrane-enclosed particles, i.e. platelets, into the circulation. Platelets are critical for the normal clotting of blood. While malignant megakaryoblasts usually are the predominant proliferating and tissue-damaging cells, their similarly malignant descendants, promegakaryocytes and megakaryocytes, are variable contributors to the malignancy.

<span class="mw-page-title-main">Lestaurtinib</span> Chemical compound

Lestaurtinib is a tyrosine kinase inhibitor structurally related to staurosporine. This semisynthetic derivative of the indolocarbazole K252a was investigated by Cephalon as a treatment for various types of cancer. It is an inhibitor of the kinases fms-like tyrosine kinase 3 (FLT3), Janus kinase 2 (JAK2), tropomyosin receptor kinase (trk) A (TrkA), TrkB and TrkC.

Acute panmyelosis with myelofibrosis (APMF) is a poorly defined disorder that arises as either a clonal disorder, or following toxic exposure to the bone marrow.

<span class="mw-page-title-main">Ruxolitinib</span> Medication

Ruxolitinib, sold under the brand name Jakafi among others, is a medication used for the treatment of intermediate or high-risk myelofibrosis, a type of myeloproliferative neoplasm that affects the bone marrow; polycythemia vera, when there has been an inadequate response to or intolerance of hydroxyurea; and steroid-refractory acute graft-versus-host disease. Ruxolitinib is a Janus kinase inhibitor. It was developed and marketed by Incyte Corp in the US under the brand name Jakafi, and by Novartis elsewhere in the world, under the brand name Jakavi.

<span class="mw-page-title-main">Fedratinib</span> Chemical compound

Fedratinib, sold under the brand name Inrebic, is an anti-cancer medication used to treat myeloproliferative diseases including myelofibrosis. It is used in the form of fedratinib hydrochloride capsules that are taken by mouth. It is a semi-selective inhibitor of Janus kinase 2 (JAK-2). It was approved by the FDA on 16 August 2019.

<span class="mw-page-title-main">Momelotinib</span> Medication

Momelotinib, sold under the brand name Ojjaara, is an anticancer medication used for the treatment of myelofibrosis. It is a Janus kinase inhibitor and it is taken by mouth.

Clonal hypereosinophilia, also termed primary hypereosinophilia or clonal eosinophilia, is a grouping of hematological disorders all of which are characterized by the development and growth of a pre-malignant or malignant population of eosinophils, a type of white blood cell that occupies the bone marrow, blood, and other tissues. This population consists of a clone of eosinophils, i.e. a group of genetically identical eosinophils derived from a sufficiently mutated ancestor cell.

Prefibrotic primary myelofibrosis (Pre-PMF) is a rare blood cancer, classified by the World Health Organization as a distinct type of myeloproliferative neoplasm in 2016. The disease is progressive to overt primary myelofibrosis, though the rate of progression is variable and not all patients progress. Symptoms and presentation can mimic essential thrombocythemia, with the main differentiator for pre-PMF being the presence of fibrosis in the bone marrow.

Transient myeloproliferative disease (TMD) occurs in a significant percentage of individuals born with the congenital genetic disorder, Down syndrome. It may occur in individuals who are not diagnosed with the syndrome but have some hematological cells containing genetic abnormalities that are similar to those found in Down syndrome. TMD usually develops in utero, is diagnosed prenatally or within ~3 months of birth, and thereafter resolves rapidly and spontaneously. However, during the prenatal-to-postnatal period, the disease may cause irreparable damage to various organs and in ~20% of individuals death. Moreover, ~10% of individuals diagnosed with TMD develop acute megakaryoblastic leukemia at some time during the 5 years following its resolution. TMD is a life-threatening, precancerous condition in fetuses as well as infants in their first few months of life.

References

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  31. 1 2 "FDA Roundup: September 19, 2023". U.S. Food and Drug Administration (FDA) (Press release). 19 September 2023. Retrieved 20 September 2023.PD-icon.svg This article incorporates text from this source, which is in the public domain .
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