Myelofibrosis overview

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Sabawoon Mirwais, M.B.B.S, M.D.[2], Sujit Routray, M.D. [3]

Overview

Myelofibrosis is a hematological disorder in which the bone marrow is replaced with collagenous connective tissue and progressive fibrosis, replacing the bone marrow with a scar tissue and hence disrupting the normal production of blood cells which leads to pancytopenia. It is also classified as a myeloproliferative disorder. The term myelofibrosis alone usually refers to primary myelofibrosis (PMF), also known as chronic idiopathic myelofibrosis (CIMF); the terms idiopathic and primary mean that the disease is of unknown or spontaneous origin. This is in contrast with myelofibrosis that develops secondary to polycythemia vera, essential thrombocythemia, leukemia, or lymphoma (secondary myelofibrosis). Myelofibrosis is a form of myeloid metaplasia, which refers to a change in cell type in the blood-forming tissue of the bone marrow, and often the two terms are used synonymously. Genes involved in the pathogenesis of myelofibrosis include JAK2, CALR, and MPL. Myelofibrosis must be differentiated from other diseases that cause diffuse bone sclerosis, such as sickle cell disease, hyperthyroidism, sclerosing bone dysplasia, osteoblastic metastases, and Paget's disease.Myelofibrosis must be differentiated from other diseases that cause splenomegaly, such as anemia, CML, polycythemia rubra vera, cirrhosis, infections, neoplastic, and lipid storage disorders. The prevalence of myelofibrosis is approximately 1 per 100,000 individuals worldwide. Myelofibrosis is a disease that tends to affect the middle-aged and elderly population. The mean age at diagnosis is 60 years. Males are more commonly affected with myelofibrosis than females. The male to female ratio is approximately 1.5 to 1. Myelofibrosis usually affects individuals of the Ashkenazi Jews race. African American, Latin American, and Asian individuals are less likely to develop myelofibrosis. Common risk factors in the development of myelofibrosis may be age, other myeloproliferative disorders, radiation, or industrial chemical exposure. Myelofibrosis has a very indolent course. If left untreated, myelofibrosis may progress to develop acute myelogenous leukemia, thrombohemorrhagic events, and progressive marrow failure. Common complications of myelofibrosis include infections, bleeding, hepatic failure, heart failure, and gout. Prognosis is generally poor and the median survival for myelofibrosis is 3.5 years to 5.5 years, but patients younger than 55 years have a median survival of 11 years. According to the World Health Organization (WHO) diagnostic criteria for primary myelofibrosis, polycythemia vera, and essential thrombocythemia, the diagnosis of primary myelofibrosis is made when all three of the following major diagnostic criteria and at least two minor criteria are met. Symptoms of myelofibrosis include left upper quadrant abdominal pain, bruising, easy bleeding, pale skin, and frequent infections. Common physical examination findings of myelofibrosis include pallor, petechiae, lymphadenopathy, hepatomegaly, and splenomegaly. Laboratory findings consistent with the diagnosis of myelofibrosis include decreased red blood cells, normochromic normocytic anemia, tear-drop shaped RBCs, thrombocytopenia, and raised levels of lactate dehydrogenase. X-ray may be helpful in the diagnosis of myelofibrosis. Findings on x-ray suggestive of myelofibrosis include osteosclerosis at different sites of the body, which tends to be diffuse and devoid of architectural distortion. CT scan and MRI may be helpful in the diagnosis of myelofibrosis. Findings on CT scan suggestive of myelofibrosis include diffuse bone sclerosis. Findings on MRI suggestive of myelofibrosis include diffuse decrease bone marrow signal intensity. Bone marrow biopsy is the imaging modality of choice for myelofibrosis. A bone marrow biopsy will reveal collagen fibrosis that has replaced the bone marrow. Other diagnostic studies for myelofibrosis include JAK2 mutation analysis testing and bone scan. Red blood cell transfusion, danazol therapy, or thalidomide are recommended for patients who develop anemia. Ruxolitinib, an inhibitor of JAK1 and JAK2, can reduce the splenomegaly and the debilitating symptoms of weight loss, fatigue, and night sweats for patients with JAK2-positive or JAK2-negative primary myelofibrosis, post–essential thrombocythemia myelofibrosis, or post–polycythemia vera myelofibrosis. Hydroxyurea, chemotherapy, radiotherapy, or splenectomy are recommended for patients who develop splenomegaly. Surgery is not the first-line treatment option for patients with myelofibrosis. Splenectomy is usually reserved for patients with massive splenomegaly unresponsive to conservative treatment. The only known cure is allogeneic stem cell transplantation, but this approach involves significant risks.Future and investigational therapies involve immunomodulatory drugs, histone deacetylase inhibitors, newer generation drugs of already existing medications and drugs targeting pathways other than the JAK/STAT. The goal is to limit the need for allogeneic stem cell transplantation.

Historical Perspective

The first description of primary myelofibrosis (PMF) is credited to a German surgeon, Gustav Heuck, who described the concept in 1879. Additional work and discoveries started to get documented at the beginning of the twentieth century. The substantial contribution came from Max Askanazy, a German pathologist and Herbert Assmann, an Internist from Germany. The condition was given several pseudonyms before the International Working Group for Myelofibrosis Research and Treatment decided in 2006 to use the term primary myelofibrosis (PMF).

Classification

Myelofibrosis is subclassified into primary and secondary types with the primary type being more common and a high proportion of the cases resulting from mutations in the Janus kinase 2 (JAK2) gene. It can be secondary to a variety of malignant, non-malignant, and hematologic conditions. It can also be secondary to malignancies, infections, toxins, autoimmune, and endocrine diseases.

Pathophysiology

Myelofibrosis, a myeloproliferative disorder, is characterized by the proliferation of megakaryocytes in the bone marrow, disrupted cytokine production, and reactive fibrosisresulting in bone marrow failure. The fibrosed and scarred bone marrow produces fewer and fewer normal functioning blood cells leading to pancytopenia and extramedullary hematopoiesis (EMH). It can mainly be associated with somatic mutation of the myeloproliferative leukemia virus (MPL) oncogene, the calreticulin (CALR) gene, or Janus kinase 2 (JAK2) gene but other genes can also be involved and it can also result in the setting of another primary insult.

Causes

Myelofibrosis is most commonly caused by somatic mutations in the myeloproliferative leukemia virus (MPL) oncogene, the calreticulin (CALR) gene, or Janus kinase 2 (JAK2) gene. Less common mutations in other genes have also been documented. It can also be the result of other primary disorders manifesting as a complication or part of the disease process.

Differentiating Myelofibrosis from other Diseases

Myelofibrosis must be differentiated from other diseases that cause diffuse bone sclerosis, such as sickle cell disease, hyperthyroidism, sclerosing bone dysplasia, osteoblastic metastases, and Paget's disease. Myelofibrosis must be differentiated from other diseases that cause splenomegaly, such as anemia, CML, polycythemia rubra vera, cirrhosis, infections, neoplastic, and lipid storage disorders.

Epidemiology and Demographics

The prevalence of myelofibrosis is approximately 1 per 100,000 individuals worldwide. Myelofibrosis is a disease that tends to affect the middle-aged and elderly population. The mean age at diagnosis is 60 years. Males are more commonly affected with myelofibrosis than females. The male to female ratio is approximately 1.5 to 1. Myelofibrosis usually affects individuals of the Ashkenazi Jews race. African American, Latin American, and Asian individuals are less likely to develop myelofibrosis.

Risk Factors

Common risk factors in the development of myelofibrosis may be age, other myeloproliferative disorders, radiation, or industrial chemical exposure.

Screening

There is insufficient evidence to recommend routine screening for myelofibrosis and there is no screening test currently available for the disease. Routine blood work can be used to check the blood cell counts which can further warrant a bone marrow biopsy.

Natural History, Complications, and Prognosis

The development of myelofibrosis is a a slow process and it does not cause early symptoms. A significant proportion of the patients can be asymptomatic and the diagnosis is usually made in the setting of an unrelated condition. The most overlapping and common findings encountered are anemia and splenomegaly presenting as weakness, easy fatigability, palpitations, and dyspnea in the case of anemia and early satiety with possible accompanying left upper quadrant discomfort if splenomegaly is present.

The disease has a progressive course and can result in pancytopenia as the bone marrow failure ensues. This can result in bleeding complications, easy bruising, increase in the susceptibility to infections, and worsening anemia. The bone marrow failure paves the way for extramedullary hematopoiesis (EMH) which mainly occurs in the reticuloendothelial tissues.

If left untreated, myelofibrosis can lead to severe complications, the most feared of which are acute leukemia, heart failure, and portal hypertension.

Diagnosis

Diagnostic Study of Choice

Diagnosis of myelofibrosis may be made based upon a thorough clinical evaluation, detailed patient history, and specialized tests. The World Health Organization (WHO) has set the criteria for diagnosing primary myelofibrosis (PMF). It has determined set rules for distinguishing the prefibrotic/early (pre-primary myelofibrosis) phase and the overtly fibrotic (overt primary myelofibrosis) phase. The World Health Organization (WHO) has also introduced a proposed revised criteria for primary myelofibrosis (PMF).

History and Symptoms

A significant proportion of patients with myelofibrosis can be asymptomatic. The hallmark of the disease is pancytopenia. A positive history of fatigue, recurring infections, and bleeding complications is suggestive of myelofibrosis. The most common symptom is fatigue which is prominent enough as it remarkably affects the quality of life. Fatigue, a result of anemia, leads to the associated complaints of weakness, palpitations, and dyspnea on exertion. Other nonspecific symptoms such as fever, night sweats, and weight loss can also be present at diagnosis.

Physical Examination

Patients with myelofibrosis usually appear pale and chronically ill. Physical examination of patients with myelofibrosis is usually remarkable for splenomegaly, hepatomegaly, skin pallor, petechiae and ecchymoses, and lymphadenopathy.

Laboratory Findings

Peripheral blood smear and bone marrow examination helps in making the diagnosis of myelofibrosis. Various tests performed to aid in reaching the diagnosis include complete blood count, peripheral blood smear and bone marrow examination, comprehensive metabolic panel, and leukocyte alkaline phosphatase (LAP) test. Laboratory findings consistent with the diagnosis of myelofibrosis include decreased red blood cells, normochromic normocytic anemia, tear-drop shaped RBCs, thrombocytopenia, and raised levels of lactate dehydrogenase.

Electrocardiogram

There are no ECG findings associated with myelofibrosis.

X Ray

X-ray may be

Echocardiography or Ultrasound

There are no echocardiography/ultrasound findings associated with myelofibrosis. However, an echocardiography/ultrasound may be helpful in the diagnosis of complications of myelofibrosis, which include heart failure, splenic rupture, pulmonary hypertension, intestinal obstruction, splenomegaly, hepatomegaly, ureteral obstruction, and thromboticevents.

helpful in the diagnosis of myelofibrosis. Findings on x-ray suggestive of myelofibrosis include osteosclerosis at different sites of the body, which tends to be diffuse and devoid of architectural distortion.

CT

CT scan may be helpful in the diagnosis of myelofibrosis. Findings on CT scan suggestive of myelofibrosis include diffuse bone sclerosis.

MRI

MRI may be helpful in the diagnosis of myelofibrosis. Findings on MRI suggestive of myelofibrosis include diffuse decrease bone marrow signal intensity.

Other Imaging Findings

There are no other imaging findings associated with myelofibrosis.

Other Diagnostic Studies

Other diagnostic studies for myelofibrosis include genetic testing, which demonstrates JAK2^V617F mutation, hybrid imaging, which demonstrates increased uptake of the radionuclides by the extramedullary hematopoietic foci, and bone scintigraphy and positron emission tomography (PET), both of which demonstrate fibrosis.

Treatment

Medical Therapy

Red blood cell transfusion, danazol therapy, or thalidomide are recommended for patients who develop anemia. Ruxolitinib, an inhibitor of Janus kinase 1 (JAK1) and Janus kinase 2 (JAK2), can reduce the splenomegaly and the constitutional symptoms of weight loss, fatigue, and night sweats for patients with Janus kinase 2 (JAK2)-positive or Janus kinase 2 (JAK2)-negative primary myelofibrosis (PMF), post–essential thrombocythemia myelofibrosis, or post–polycythemia vera myelofibrosis. Hydroxyurea, chemotherapy, or radiotherapy are recommended for patients who develop splenomegaly.

Surgery

Surgery is not the first-line treatment option for patients with myelofibrosis. Splenectomy is usually reserved for patients with massive splenomegaly unresponsive to conservative treatment. The only known cure is allogeneic stem cell transplantation, but this approach involves significant risks.

Primary Prevention

There are no established measures for the primary prevention of myelofibrosis. Avoidance of radiation may be helpful, as radiation exposure can induce bone marrow fibrosis.

Secondary Prevention

There are no established measures for the secondary prevention of myelofibrosis.

Myelofibrosis Future or Investigational Therapies

Future and investigational therapies involve immunomodulatory drugs, histone deacetylase inhibitors, newer generation drugs of already existing medications and drugs targeting pathways other than the JAK/STAT. The goal is to limit the need for allogeneic stem cell transplantation.