All About Myelofibrosis

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What is myelofibrosis (MF)?

Myelofibrosis is a group of rare cancers of the bone marrow. In MF, the bone marrow is replaced by scar tissue and is not able to make healthy blood cells. It is classified as a type of chronic leukemia and belongs to a group of blood disorders called myeloproliferative disorders. It may also be called primary myelofibrosis, chronic idiopathic myelofibrosis, or myelosclerosis with myeloid metaplasia.

A myeloproliferative disorder happens when the bone marrow produces either too many or too few of certain blood cells, most of which do not function properly (each disorder's name comes from the cells that are affected). Other diseases, including chronic myelogenous leukemia (CML), polycythemia vera (PV), essential thrombocythemia (ET), chronic neutrophilic leukemia, and chronic eosinophilic leukemia are related closely to MF. PV and ET can progress to myelofibrosis and makeup 10-15% of myelofibrosis cases. Myelofibrosis can also progress to other, more aggressive types of leukemia. 

What is bone marrow?

In order to understand myelofibrosis, it is helpful to know how normal bone marrow works. The bone marrow is a spongy area in the center of our bones. Its role is to produce blood cells.

  • White blood cells (also called leukocytes): The body's infection-fighting cells.
  • Red blood cells (also called erythrocytes): Give blood its red color. These cells carry oxygen from the lungs to the rest of the body and return carbon dioxide to the lungs as waste.
  • Platelets (also called thrombocytes): Help the body form blood clots to control bleeding.

Larger bones have more bone marrow and produce more blood cells. The larger bones include the femur (top part of the leg or thigh), the hip bones, and parts of the rib cage. The bone marrow contains hematopoietic stem cells (or blood stem cells). These are cells that can produce one type of blood cell over and over again. The bone marrow also contains a small number of cells that are in development and are not yet mature. These immature cells are called blasts. Once the cell has matured, it moves out of the bone marrow and into the bloodstream. The body knows when more cells are needed and has the ability to produce them in an orderly fashion.

In the case of myelofibrosis, one blood stem cell acquires the ability to reproduce without regulation, producing large numbers of immature blood cells. When looked at under a microscope, these abnormally produced cells do not look or work like normal cells. The body continues to produce these abnormal, non-functional cells, leaving little space for healthy cells. At the same time, these cells release chemicals that cause the bone marrow to become "fibrous" or fill with scar tissue. This also makes it harder to produce healthy blood cells. In addition, these abnormal cells may be produced in other areas of the body, most often the spleen or liver, which results in an enlarged spleen or liver that can be felt by a healthcare provider during a physical exam.

What causes myelofibrosis and am I at risk?

Myelofibrosis is rare, though the exact incidence is not known. It is likely underestimated as less severe and/or asymptomatic disease may go undetected.  It is estimated that the annual incidence in the United States population is 1.5 cases per 100,000 persons in the United States.

Aging is the major risk factor for developing myelofibrosis, as the disorder usually develops in people over age 50. The average age at the time of diagnosis is about 60 years old. About 15% of all patients diagnosed with myelofibrosis are under the age of 50 and about 6% under 40.

Environmental exposures to certain chemicals (benzene, toluene) and radiation may increase the risk of developing MF.

Many cases of MF occur as a result of a genetic mutation in the bone marrow. The genes most frequently associated with MF are Janus kinase 2 gene (JAK2) and calreticulin gene (CALR).  For some patients, the abnormality is found in the MPL gene, which is also involved in the pathway that signals for more blood cells to be produced. There may be other mutations associated with the development of MF. The underlying cause of the gene mutation is not known.

Myelofibrosis often develops without a known cause. This is called primary myelofibrosis. However, other myeloproliferative diseases can progress into myelofibrosis. Ten to fifteen percent of myelofibrosis cases have developed from a diagnosis of polycythemia vera or essential thrombocythemia (called secondary myelofibrosis). Though some families have a predisposition for the disease, it is not passed on or inherited. The disease is caused by a change in a gene that occurs during a person's lifetime. Perhaps this change is due to exposure to something in our environment (which family members may have in common).

What screening tests are used for myelofibrosis?

There is no screening test for the disease. Routine blood work can be used as a screen to check the red and white blood cell counts as well as the platelet count. These tests can prompt other, more invasive testing, such as a bone marrow biopsy.

What are the signs of myelofibrosis?

About one-third of individuals with myelofibrosis have no symptoms. This can make the disease difficult to detect. As the number of abnormal cells increases and healthy cells decreases, symptoms may develop. These symptoms are most often related to a low red blood cell count (anemia) or enlarged spleen. Individuals will anemia may be pale, fatigued, and have shortness of breath with activity. There may also be chest pain or dizziness as the heart has to work harder to get adequate oxygen to the brain and other organs when the red blood cell count is low. Other symptoms can include easy bruising/bleeding, multiple infections, weight loss, low-grade fever, and night sweats. Many patients will also experience intense itching, known as pruritis, caused by inflammation in the body.

An enlarged spleen (splenomegaly) and/or liver (hepatomegaly) can also be symptoms of MF. When the bone marrow scars, the liver, and spleen try to make blood cells to compensate (called extramedullary hematopoiesis). This causes these organs to swell. Approximately 25-50% of patients will have symptoms from an enlarged spleen at diagnosis, including pain with deep breaths, loss of appetite and feeling full after eating a small amount (called early satiety). Extramedullary hematopoiesis can also occur in other parts of the body (lymph nodes, spinal cord, lungs), causing swelling in these areas, leading to symptoms.

How is myelofibrosis diagnosed?

Blood tests are used to diagnose MF. These tests include:

  • Complete Blood Count (CBC):  CBC is the most common blood test. It uses a machine to see the number of red blood cells, platelets, and white blood cells circulating in the blood. The amount of hemoglobin, the substance which carries oxygen in red blood cells, is also assessed on a CBC. The platelet counts and white blood cells counts can either be elevated or low.
  • Peripheral Blood Smear:  A small sample of blood can be smeared on a slide and examined under a microscope to count cells by hand and to look for changes. Red blood cells often look abnormal in myelofibrosis on a peripheral smear with unusual shapes and sizes, reflecting defective production of the red blood cells. Changes in the appearance of the platelets and white blood cells can also be seen on a peripheral smear. 
  • Bone Marrow Biopsy/Aspiration:  A bone marrow biopsy/aspiration is needed for the diagnosis of myelofibrosis. During a bone marrow biopsy, a local anesthetic will be given into the buttock region to numb the area. A small core of bone marrow will be taken out of the pelvic bone using a needle. With MF, the bone marrow biopsy usually shows fibrosis, or scarring, of the marrow. Hyperplasia, which is an increase in the precursor cells (the cells that develop into mature red & white blood cells and platelets), is usually seen as well. This increase in precursor cells can be in one or multiple cell lines. For example, an increase in the number of megakaryocytes, which will go on to form platelets in the blood, is known as megakaryocyte hyperplasia. These megakaryocytes may also appear abnormal under the microscope. Increased (thrombocytosis) or decreased (thrombocytopenia) platelets can be seen in the peripheral blood of individuals as well.
  • Molecular Testing:  Testing for gene mutations including JAK2, CALR, and MPL are also important in the diagnosis of MF. 

The World Health Organization (WHO) has developed the following criteria for the diagnosis of myelofibrosis. A patient must meet all 3 major criteria as well as 1 minor criterion for a diagnosis of primary myelofibrosis.

Major Criteria

  • Proliferation and atypia of megakaryocytes accompanied by either reticulin and/or collagen fibrosis grades 2 or 3 on a scale of 0-3.
  • Not meeting WHO criteria for ET, PV, BCR-ABL1 positive chronic myelogenous leukemia, myelodysplastic syndromes, or other myeloid neoplasms.
  • Presence of JAK2, CALR, or MPL mutation or in the absence of these mutations, the presence of another clonal marker or absence of reactive myelofibrosis.

Minor Criteria

  • Anemia not attributed to a comorbid condition.
  • Leukocytosis ≥ 11 x 109/L.
  • Palpable splenomegaly.
  • LDH increased to above upper normal limit of institutional reference range.
  • Leukoerythroblastosis.

What are the treatments for MF?

Most therapies for MF are aimed at minimizing symptoms through supportive care. The primary goal of supportive care is limiting the symptoms associated with decreased blood counts, improving quality of life, and decreasing the risk of progression to acute leukemia. Individuals are usually not treated until they have symptoms unless they are a candidate for a stem cell transplant (see below).

Targeted Therapies

The discovery of JAK2 mutations in 2005 opened the door to the development of targeted therapy for people with MF. Ruxolitinib is currently the only medication with FDA approval specifically for the treatment of MF. Other medications in this class are currently being studied in clinical trials.

Other medications called immunomodulators, including lenalidomide and thalidomide, are also used in the treatment of symptomatic myelofibrosis.

Interferon is an immune therapy that works by reducing the overabundance of unhealthy blood cells and reduces the cytokines that lead to fibrosis in the marrow. It appears to work best in those with early myelofibrosis secondary to PV or ET. Interferon has significant side effects that can be difficult to tolerate.

Stem Cell Transplant

Currently, the only curative treatment is allogeneic stem cell transplant (where the bone marrow comes from a donor). Stem cell transplants have risks related to complications. For this reason, they are generally reserved for individuals in good health, who are younger than 60 and have a "matched" donor. Current guidelines recommend stem cell transplant only in young patients with high-risk disease.

Supportive Care

Given that most people present with MF at an older age and that MF is a chronic disease, supportive care is extremely important to limit symptoms and maintain a high quality of life. Supportive care treatments include the following:

  • Androgen therapy (oxymetholone, danazol), a synthetic version of male hormones) can be used to improve anemia.
  • Erythropoietin is a medication that stimulates the body to make red blood cells and has been shown to improve anemia in 30-50% of patients.
  • Hydroxyureais a medication that is thought to interfere with the synthesis of DNA and is used in the treatment of other blood disorders. It has been shown to decrease the size of the spleen and help control platelet and WBC counts.
  • Cladribine: is a medication that may be able to prevent cells from reproducing by inhibiting DNA synthesis.
  • Bisphosphonates (Aredia, Zometa): a type of medication that can relieve bone pain and help to prevent bone loss.
  • Splenectomy: Because an enlarged spleen can be a source of discomfort, its removal can relieve symptoms. Patients with MF and an enlarged spleen, low platelets, and needing frequent transfusions despite drug therapies may get some symptom relief from the removal of their spleen.

Clinical Trials

Clinical trials are extremely important in furthering our knowledge of this disease. It is through clinical trials that we know what we do today, and many exciting new therapies are currently being tested. Talk to your healthcare provider about participating in clinical trials in your area. You can also explore currently open clinical trials using the OncoLink Clinical Trials Matching Service

Follow Up Care and Survivorship

Because of the complexity of treating and monitoring MF, patients with MF will see their healthcare providers for physical examination and lab testing on a frequent basis (sometimes monthly). Your healthcare team will monitor your blood counts and symptoms for signs of progression as well as the need for supportive care treatment interventions.

Fear of recurrence, relationship challenges, the financial impact of cancer treatment, employment issues, and coping strategies are common emotional and practical issues experienced by MF survivors. Your healthcare team can identify resources for support and management of these practical and emotional challenges faced during and after cancer.

Cancer survivorship is a relatively new focus of oncology care. With some 17 million cancer survivors in the US alone, there is a need to help patients transition from active treatment to survivorship. What happens next, how do you get back to normal, what should you know and do to live healthy going forward? A survivorship care plan can be a first step in educating yourself about navigating life after cancer and helping you communicate knowledgeably with your healthcare providers. Create a survivorship care plan today on OncoLink

Resources for More Information

MPN Research Foundation

Started by patients, an advocacy organization that promotes research funding in pursuit of new treatments – and eventually a cure – for myeloproliferative neoplasms (MPNs)

http://www.mpnresearchfoundation.org/Primary-Myelofibrosis

MPN Education Foundation

Run by volunteer MF patients, offers MPN-Net online support group with approximately 3000 members from around the world information

https://mpninfo.org/

Leukemia and Lymphoma Society

Provides disease information and support resources.

http://www.lls.org/

Referencias

Cordoba, R., Garcia-Gutierrez, V., & Alonso-Dominguez, J. M. (2020). Chronic Myelogenous Leukemia and Myeloproliferative Disorders in Older Adults. Geriatric Oncology, 535-547.

Harrison, C., Kiladjian, J. J., Al-Ali, H. K., Gisslinger, H., Waltzman, R., Stalbovskaya, V., ... & Cervantes, F. (2012). JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis. New England Journal of Medicine366(9), 787-798.

Deisseroth, A., Kaminskas, E., Grillo, J., Chen, W., Saber, H., Lu, H. L., ... & Bullock, J. (2012). US Food and Drug Administration approval: ruxolitinib for the treatment of patients with intermediate and high-risk myelofibrosis. Clinical Cancer Research18(12), 3212-3217.

Kröger, N., Giorgino, T., Scott, B. L., Ditschkowski, M., Alchalby, H., Cervantes, F., ... & Maffioli, M. (2015). Impact of allogeneic stem cell transplantation on survival of patients less than 65 years of age with primary myelofibrosis. Blood125(21), 3347-3350.

Mesa, R. A., Gotlib, J., Gupta, V., Catalano, J. V., Deininger, M. W., Shields, A. L., ... & Harvey, J. H. (2013). Effect of ruxolitinib therapy on myelofibrosis-related symptoms and other patient-reported outcomes in COMFORT-I: a randomized, double-blind, placebo-controlled trial. Journal of Clinical Oncology31(10), 1285-1292.

Tefferi, A. (2013). Primary myelofibrosis: 2013 update on diagnosis, risk‐stratification, and management. American Journal of Hematology88(2), 141-150.

Tefferi, A., Guglielmelli, P., Larson, D. R., Finke, C., Wassie, E. A., Pieri, L., ... & Ketterling, R. P. (2014). Long-term survival and blast transformation in molecularly annotated essential thrombocythemia, polycythemia vera, and myelofibrosis. Blood,124(16), 2507-2513.

Tefferi, A., Lasho, T. L., Finke, C. M., Knudson, R. A., Ketterling, R., Hanson, C. H., ... & Pardanani, A. (2014). CALR vs JAK2 vs MPL-mutated or triple-negative myelofibrosis: clinical, cytogenetic, and molecular comparisons. Leukemia28(7), 1472-1477.

World Health Organization (2016). Diagnostic criteria for primary myelofibrosis, polycythemia vera, and essential thrombocytopenia. Retrieved from https://www.mpnconnect.com/pdf/who-diagnostic-criteria-mf-pv-et.pdf

Xu, P., Shen, P., Yu, B., Xu, X., Ge, R., Cheng, X., ... & Wang, J. (2020). Janus kinases (JAKs): The efficient therapeutic targets for autoimmune diseases and myeloproliferative disorders. European Journal of Medicinal Chemistry, 112155.

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