Primary Myelofibrosis (MF)

WHAT IS PRIMARY MYELOFIBROSIS (MF)?

Primary myelofibrosis (MF) is a chronic blood cancer in which excessive scar tissue forms in the bone marrow and impairs its ability to produce normal blood cells.

Researchers believe MF may be caused by abnormal blood stem cells in the bone marrow. The abnormal stem cells produce mature cells that grow quickly and take over the bone marrow, causing both fibrosis (scar tissue formation) and chronic inflammation. As a result, it becomes more difficult for the bone marrow to create normal blood cells and blood cell production may move to the spleen (causing enlargement) or to other areas of the body.

Classified as a myeloproliferative neoplasm (MPN), MF can arise on its own or as a progression of polycythemia vera (post-PV-MF) or essential thrombocythemia (post-ET-MF). The manifestations of MF, post-PV-MF and post-ET-MF are virtually identical and treatment is generally the same for all three.

WHAT CAUSES MF?

No one knows exactly what triggers the start of myelofibrosis or other myeloproliferative neoplasms. In the majority of cases, myelofibrosis is not inherited genetically — you cannot pass the disease on to your children or inherit it from your parents (although some families do demonstrate a clear predisposition).

Recently, researchers have discovered that these diseases may be caused by acquired gene mutations (changes in DNA that not inherited). Some of these mutations affect proteins that work in signaling pathways in your cells.

Risk factors associated with MF include:

Age
Myelofibrosis is most often diagnosed in people over the age of 60, although there are known cases of myelofibrosis in the young.

Environment
Exposure to petrochemicals (e.g., benzene and toluene) and ionizing radiation may increase the risk of developing MF.

JAK2 Mutation
Approximately 50% to 60% of people with MF have a mutation of the JAK2 gene within their blood-forming cells. Mutant JAK2 tells blood cells to grow and divide even when the body is not asking for more blood cells. Between 5 and 10% of patients will have a mutation in another gene named MPL, which also affects the JAK signaling pathway.

CALR
About 23.5% of people with myelofibrosis and essential thrombocythemia have a mutation called Calreticulin, or CALR. This genetic marker was discovered in 2013. Research is still ongoing, but there are potential implications for treatments and prognosis for those with the CALR mutation.

HOW IS MF DIAGNOSED?

Physicians review a wide range of factors before making a diagnosis of myelofibrosis. Since every case of MF is different, a medical history, a physical examination, laboratory tests and a bone marrow examination are usually required to diagnose the disease.

Even though some people living with myelofibrosis may not have symptoms (things you feel), they frequently exhibit signs (things a doctor notices during a physical examination).

Common signs of MF during physical examinations may include:

• An enlarged spleen (splenomegaly)
• Pale mucous membranes (pallor), if anemia is present
• Loss of muscle mass
• Cachexia (wasting syndrome characterized by weight loss, muscle atrophy, weakness and fatigue)

Common lab tests to diagnose MF include:

Blood Tests

A complete blood count (CBC) often shows abnormal blood cell counts. Red blood cells (erythrocytes), white blood cells (leukocytes), platelets (thrombocytes) or other blood cell types are commonly affected by MF, and counts may be either too high or too low.

Bone Marrow Biopsy

An examination of bone marrow under a microscope may reveal that suggest MF, including scar tissue formation and the atypical appearance of bone marrow precursors

Gene Mutation Analysis of Blood Cells

Specific mutations associated with some cases of MF (e.g., JAK2, CALR, and MPL) can be identified through gene mutation analysis.

Imaging Tests

An ultrasound of the spleen or other tests may be done to determine whether the spleen is enlarged.

WHAT ARE THE SYMPTOMS OF MF?

Myelofibrosis symptoms are often caused by an enlarged spleen and/or insufficient numbers of normal blood cells and chronic inflammation.

Common MF symptoms and signs may include:

• Tiredness, weakness, or shortness of breath with mild exertion
• Fullness, discomfort or pain in the left upper area of the abdomen
• Fever
• Night sweats
• Weight loss or malnutrition
• Bone pain
• Itching (pruritus)
• Easy bleeding or bruising
• Susceptibility to infection
• Joint pain or gout
• Abdominal distension/fluid retention (if portal hypertension or increased blood pressure within the portal vein is present)
• Compromised liver function
• Abnormal growth of blood forming cells outside of the bone marrow

Routine medical examinations including complete blood counts (CBCs) are important for diagnosing MF and other MPNs, since some MF patients exhibit no symptoms (especially during the early course of the disease).

WHAT IS THE PROGNOSIS FOR MF?

There is no single prognosis for people who suffer from myelofibrosis– the prognosis of MF is different for every patient. While some individuals live for many years without developing major symptoms, others find that the disease progresses more quickly.

Factors that can influence an MF prognosis are age, white blood cell counts, number of “blasts” (immature blood cells) in the blood, “constitutional symptoms” (e.g., night sweats, weight loss, fever), anemia (low red blood cells), transfusion dependence, low platelets and abnormal chromosome analysis.

For most patients, an MF prognosis requires the management of several symptoms and signs, including:

• Anemia (not enough red blood cells to carry oxygen)
• Splenomegaly (enlarged spleen)
• Extramedullary hematopoiesis (production of blood cells in organs outside the bone marrow, such as the spleen and liver)
• Thrombosis and thrombohemorrhagic complications (blood clotting or bleeding complications)
• Leukocytosis (too many white blood cells)
• Thrombocytosis (too many platelets) or thrombocytopenia (low platelet counts)
• Constitutional and systemic (“whole body”) symptoms (e.g., fatigue, night sweats, weight loss, pruritus, fever, bone and joint pain)
• Gout

For a small number of patients, MF can transform to acute myeloid leukemia (AML), a serious blood and bone marrow cancer. When AML does arise from MF, it progresses quickly and can be difficult to treat.

WHAT ARE THE AVAILABLE TREATMENTS FOR MF?

There is no single treatment that is effective for all MF sufferers. Each patient has a unique set of symptoms and circumstances that require different treatment options, as prescribed by a doctor. Also, some patients with MF remain symptom-free for many years and may not require immediate treatment. However, anyone who has been diagnosed with MF needs to be monitored over time for signs or symptoms that suggest the disease has worsened.

Available treatments and therapies for MF include:

Jakafi

Jakafi (ruloxitinib) is the first drug approved by the FDA for treating MF patients. Jakafi is indicated for treatment of patients with intermediate or high-risk myelofibrosis (MF), including primary MF, post–polycythemia vera MF and post–essential thrombocythemia MFAs a targeted therapy, Jakafi is designed to be more specific for abnormal cells. Taken orally, Jakafi partially inhibits the activity of JAK2 and the related protein JAK1. During clinical trials, it was shown to reduce spleen size, abdominal discomfort, early satiety, bone pain, night sweats and itching in MF patients as well as the level of “pro-inflammatory cytokines” in the blood, which may cause some symptoms such as fatigue, fever, night sweats and weight loss. Patients are observed for low blood counts, headache, dizziness, bruising or infection. For more about Jakafi, click here (will be directed to the manufacturer’s website).

Allogenic Stem Cell Transplantation (ASCT)

Allogenic Stem Cell Transplantation is the only curative treatment for MF. ASCT, hematopoietic (blood-forming) stem cells are transferred from a donor to the patient, essentially replacing defective stem cells with healthy ones. Before the stem cell infusion, the patient receives chemotherapy and/or radiation therapy to eradicate diseased bone marrow. In an effort to improve stem cell transplant outcomes for MF patients, MPNRF created a Stem Cell Transplant Timing Tool. The SSTT is a portable on-line tool based on a clinically validated scale. It provides a color signal in response to information entered by a patient, that indicates a risk level and median survival times without a stem cell transplant. A patient can then take what they’ve learned and use it to facilitate a meaningful dialogue between themselves and their physician about their treatment options.An examination of bone marrow under a microscope may reveal that suggest MF, including scar tissue formation and the atypical appearance of bone marrow precursors

Symptom-Specific Treatments
In many cases, therapies for MF patients target specific signs. These signs and related treatments can include:

Anemia may be treated with corticosteroids, androgens (including danazol and halotestin), thalidomide, lenalidomide, blood transfusions, or erythropoiesis stimulating agents (ESAs). There are also some drugs currently in clinical trial that aim to improve anemia for people with myelofibrosis.•
Splenomegaly may be treated with Jakafi, hydroxyurea (HU), cladibrine, interferon, or, in severe cases when drug therapy has failed, radiation or splenectomy.
Risk of thrombosis may be managed with low-dose aspirin therapy or hydroxyurea.
Non-liver and spleen extramedullary hematopoiesis may be treated with radiation therapy.
Constitutional symptoms, such as night sweats, pruritus, weight loss and fever may be treated with Jakafi.

Novel Approaches and Clinical Trials

For many patients with MF, available treatment approaches may not be effective, and experimental treatments (which involve receiving a novel drug or treatment on a clinical trial), may be an appropriate option.

So far, only Jakafi (ruxolitinib) has been FDA approved for MF therapy. But other novel therapies are currently in clinical trial, including multiple mechanisms of action:

JAK Inhibitors

A number of other drugs that inhibit JAK2 (“JAK inhibitors”) are currently in clinical trials, including momelotinib, pacrtinib and NS-018. The results of these studies will determine whether these drugs may also be effective for treating MF patients.

Epigenetic Drugs

Epigenetic drugs change the way genes are organized to make them more or less accessible for use by the cell. Recent studies with epigenetic drugs have found that the HDAC inhibitor, Givinostat, and two hypomethylating agents, azacitidine and decitabine, were minimally effective in treating MF in early studies (in contrast to their effectiveness in treating PV). Another HDAC inhibitor, panobinostat, is under study.

Pomalidomide

Pomalidomide has been shown to effectively treat anemia in early studies. It targets the patient’s immune system to attack abnormal cells in order to make room for the normal cells that make red blood cells. With enhanced anti-cancer activity and lower toxicity compared to the other drugs in its class, pomalidomide has shown promise in initial studies and is now in phase 3 clinical trials for its use as first line therapeutic for treating anemia in MF patients who have the V617F mutation.

Everolimus
Everolimus (also known as RAD001) is an inhibitor of the mTOR/AKT pathway, which is highly active in MF blood producing cells and appears to contribute to abnormal cell growth. In phase 1 and 2 clinical trials, Everolimus was well tolerated and able to reduce both spleen size and systemic symptoms