Primary Myelofibrosis (MF)

What is primary myelofibrosis, (MF)?

Myelofibrosis (MF) is a disorder which affects the way blood cells are produced in the body. People over the age of sixty are most likely to have this disease, with men and women equally at risk.

MF affects the bone marrow, the “factory” inside our bodies which produces blood cells. MF causes scar tissue and fibrous tissue to build up inside the bone marrow, so that the marrow can’t produce blood cells effectively. As a result blood making tissue leaves the bone marrow and takes place elsewhere in the body commonly the spleen, or liver.

MF patients often have low numbers of red blood cells, white blood cells and/or platelets resulting in anaemia, neutropenia and thrombocytopenia respectively.

In MF, there are too many fibroblasts in the marrow. Fibroblasts are cells which produce connective tissue, scar and fibrous tissue. The excess fibroblasts scar the bone marrow and stop the bone marrow from making blood cells. This increase in fibrous tissue is thought to occur due to the abnormal stem cells not abnormal fibroblasts.

MF might adversely affect any one or more of the three types of blood cells

Types of myelofibrosis

MF can develop in several ways:

Primary Myelofibrosis: The disorder can develop spontaneously on its own. In this case we call the disorder “primary” or “idiopathic” myelofibrosis (PMF).
Post ET/PV: People may develop myelofibrosis after they have had another MPN for some time. If MF develops after someone has had Essential Thrombocythaemia (ET) or Polycythaemia Vera (PV), we call the disorder “post ET” or “post PV”myelofibrosis.
With another disease: MF sometimes develops as a result of another disease such as autoimmune or inflammatory conditions, cancers like Hodgkin’s disease, tuberculosis or damage caused by radiation. This type of myelofibrosis is not the same as MF caused by an MPN.

What causes MF?

What causes MF is not fully understood. However, we do know that the disease causes a dysregulated signal in the stem cells (cells that make the red blood cells and platelets in your blood). The signal is called JAK-STAT. Recent research found that about 50% of MF patients have a change (mutation) in a protein that regulates blood cell production (this protein is known as JAK2 and the mutation as JAK2 V617F). However, even MF patients who do not carry this mutation have a dysregulated signal through other mechanisms. A number of people have other recently discovered types of mutations. People are not born with these mutations but acquire them during their lives. These mutations may also be triggered by past exposure to ionizing radiation (a type of radiation that has very high energy, like medical X-rays) or to some chemical substances such as benzene and toluene. It is also important to note that MF is rarely inherited and is not passed on from parents to child, although some families do seem to develop the disease more readily than others.

Diagnostic tests

Your haematologist may recommend some of the following tests to confirm a diagnosis of myelofibrosis:

Full Blood Count (FBC): Your haematologist will review your full blood count for signs of high blood cell counts or low total blood count (called “pancytopenia”). In the early phase of the disease, your bone marrow may be overactive and make too many blood cells. This phase occurs before the fibrous scarring begins to become very prominent and damages the bone marrow. In later stages of the disease, blood cell counts may be low.
JAK2 test: Your haematologist can test your blood to see if you have a change of gene called JAK2 V617F mutation. About 50% of people with MF show this mutation. Your haematologist may also test for other possible mutations in the same way. Recent research has shown that about 50-60% of patients have a mutation (or change) in a protein called JAK2. 25-30% have a mutation in a gene called Calreticulin and another 2-5% of patients have a mutation in a protein called MPL. Both JAK2 and MPL are proteins which regulate blood cell production. Calreticulin is involved in calcium flow within the cell which is also important in growth signals. Researchers don’t currently understand what causes these mutations to occur.
Abdominal ultrasound: If your haematologist suspects that you may have myelofibrosis, he or she will check to see if your spleen is enlarged. This is because in MF your spleen may begin to produce blood cells, and these collect inside the spleen. The ultrasound is a painless test.
Bone Marrow Biopsy (BMB): A bone marrow biopsy is a test of your bone marrow that is done in the hospital. You will not need to stay overnight in the hospital, and you will generally just need local anaesthesia. Your haematologist will give you some medication to prevent pain, and then he or she will extract some bone marrow from your hip bone using a needle. The bone marrow tissue can then be examined in a laboratory so that your haematologist can see how the stem cells in your bone marrow are working, and if there is any fibrosis in your marrow.

How common is MF?

MF is considered to be a rare condition. The number of people diagnosed each year with MF will be two to three cases per 100,000 and it is equally common in men and women. It primarily affects middle-aged and elderly people and is hardly ever diagnosed in children.

Symptoms

About 10-20% of people with MF do not exhibit any symptoms. Their condition may be found by chance, for instance during a routine blood test. The other 80-90% of people diagnosed with MF may experience some of the following symptoms:

Excessive tiredness, weakness or shortage of breath as a result of anaemia
Pain or fullness below the ribs due to an enlarged spleen
Easy bruising or bleeding
Excessive sweating especially during sleep (night sweats)
Bone pain
Frequent infections
Unexplained weight loss
Heavy periods
Fever
Sweating
Fatigue not related to anaemia

Complications

There are a number of complications associated with MF:

Fatigue: Anaemia can cause fatigue.
Spleen enlargement: An enlarged spleen can cause discomfort and shortness of breath.
Gout: MF can increase the body’s production of uric acid which in turn can cause joint pain and inflammation.
Infections: Myelofibrosis can reduce the production of white blood cells, cells that fight off infection. Mutated or overproduction of white cells or insufficiently formed white cells will lead to a decreased ability of your body to resist infections.
Bleeding complications: In advanced stages of MF, a lower platelet count or impaired platelet function may lead to uncontrolled or easy bleeding or bruising.
Bone pain: Can occur and may need strong pain killers.
Thrombosis: The risk of a blood clot is increased in patients with MF.
AML: Between 20-30% of patients will develop leukaemia.

“There is a significant need to improve our ability to more accurately predict those individuals who are at high risk for evolution to MPN-BP, and who could benefit from earlier intervention. Currently such intervention is limited to allogeneic SCT, and the recently proposed MIPSS score if validated, may be useful in refining transplant decisions in the chronic phase in PMF. The molecular mechanisms underlying transformation to blast phase are increasingly being understood, and will pave the way for more effective treatment approaches, but much remains to be accomplished” (Odenike 2018, p.18)

Treatment

The main aims of the treatment are to control symptoms of the disease, including low blood counts and the size of the spleen. Additional treatments may be considered to control the disease as it progresses.

Treatment to control symptoms

These treatments will help to reduce the unpleasant symptoms you may experience with MF, such as fatigue. Treatments include:

Blood Transfusions: Your consultant will use blood transfusions to treat severe anaemia. If your platelet count is very low or if you have problems with bleeding, you may need platelet transfusions.
Danazol: This is a hormone that is made naturally by the body. This hormone can stimulate the production of red cells and can sometimes make the haemoglobin level rise. Some patients are given danazol to prevent the need for blood transfusions. This drug is given orally. Side effects include weight gain due to fluid retention and a slight increase in facial hair growth in women. It can also affect the liver or kidneys.
Erythropoetin: Sometimes anaemia is the main problem for MF patients. In this case treatment with erythropoetin (EpO) can be effective. EpO is the hormone naturally produced by the body that stimulates the bone marrow to make red cells. This drug is given by injection under the skin.
Aspirin: Low-dose aspirin (75mg once a day) may be given if the platelet count is high and there is a risk of blood clots (thrombosis).
Splenectomy/Splenic Irradiation: If the main symptom is abdominal pain and discomfort due to a very large spleen, or if the need for blood and platelet transfusions is very high, or if there is no response to medical treatment, it may be beneficial to remove the spleen. There are risks of bleeding and infections with this operation. Occasionally radiotherapy can be given to try to reduce the size of the spleen.

Prognosis

MF is a progressive disorder which is irreversible in most cases.

What determines prognosis

The prognosis depends on your age, the results of your blood and bone marrow tests and your symptoms. Your haematologist can evaluate your haemoglobin level, white cell count, age and bone marrow cytogenetic (chromosome orgenetic analysis) results and will take all these factors into account to decide your prognosis and appropriate treatment regime.

Prognosis varies by person

The progression of MF is very variable. People in a good prognostic group can have up to at least fifteen years of being well. Those in the poor prognosis group may have a survival of about twelve to eighteen months. Between 10 to 20% of MF patients may develop acute myeloid leukaemia (AML), a type of blood and bone marrow cancer that progresses rapidly.

Scoring system

A scoring system is often used by haematologists to gauge prognosis the most recent one relies upon whether any other of the following factors are present:

White cell count OVER 25
Haemoglobin LESS than 100g/L or 10g/dl
Blasts (immature cells in blood) MORE than 1%
Disease related symptoms
Age over 65 years

Your haematologist may give you a prognostic score. These scores are divided into low, intermediate 1, intermediate 2 or high risk disease. People with high risk disease have a shorter life expectancy. Up to 25% of people with MF may develop acute myeloid leukaemia (AML); this a type of blood and bone marrow cancer that progresses rapidly and has a poor prognosis. As prognosis can vary significantly from patient to patient, it’s best to talk with your haematologist for information specific to your situation.

We are learning more but additional research needs to be done to determine the causes of MF.

Greater awareness and research is urgently needed to stop the rising number of Australians dying from blood cancer says Leukaemia Foundation (SBS 2017)

Ruxolitinib

Ruxolitinib is a medication used to treat myeloproliferative neoplasms (MPNs). It is licensed for the treatment of patients with myelofibrosis (MF) either primary or occurring after polycythaemia vera (PV) or essential thrombocythaemia (ET). It is under investigation in clinical trials for patients with PV and ET. The drug is known by several names. It goes under the brand name Jakavi® and the molecule is called ruxolitinib, before this it was known as INC18424 or INC424.

How it works

Ruxolitinib works by interfering with the function of JAK2 and its relation JAK1. This slows down blood cell production and also the production of signalling chemicals known as cytokines.

When you take ruxolitinib the number of blood cells being made decreases so that your bloodstream will be less crowded, your blood will flow more freely, and you will be less likely to suffer a blood clot or thrombosis. Treatment with ruxolitinib also reduces the size of most patients’ spleens towards a more normal size. In addition, many of the symptoms of an MPN, for example sweating, itching, tiredness and pain and fullness after eating which with MF and other MPN patients suffer, improve with ruxolitinib therapy.

Common side effects

Approximately one person in 100 up to one person in five (1- 20%) of people taking ruxolitinib will experience some of these common side effects:

Reduced red blood cells. If your red blood cells drop too low (anaemia) you may notice that you are becoming breathless and tire easily.
Reduced platelets. If your platelet count drops too low you may experience nose bleeds, bleeding gums when you clean your teeth, a rash of tiny red spots or increased bruising.
Reduced white blood cells. If your white blood cells drop too low you may have an increased risk of developing infections. You may experience a high temperature, fever, shivers or chills.

If you experience any of the symptoms above you must contact your hospital immediately. Sudden and unexpected changes in blood cell levels may occur, although this is uncommon, therefore it is important to attend appointments to have your blood counts checked and to discuss any symptoms with your haematologist.

Causes

Recent research shows that about 50-60% of people with MF have a mutation (or change) in a protein called JAK2, a protein that regulates blood cell production. A further 30% of patients have mutations in a gene called calreticulin referred to as CALR, between 5-10% of patients have mutations in the platelet hormone receptor called MPL. Other mutations in many genes are found in patients with MF but these are also seen in blood diseases. Current research is focused upon whether different patterns of mutations might be important for outcome or prognosis of the disease and also response to treatment.

Patients with MF are not born with these mutations but acquire them during their lives. It is also important to note that MF is rarely inherited and is not passed on from parent to child, although some families do seem to develop the disease more readily than others.

We are learning more but additional research needs to be done to determine the causes of MF.

Management of an enlarged spleen

An enlarged spleen is a common symptom of MF, often leading to pain and discomfort and a feeling of fullness or loss of appetite. Treatment options include:

JAK inhibitor (currently only Ruxolitinib or Jakavi is approved): This tablet reduces the effect of JAK activity and reduces the spleen as well as symptoms and it may also prolong survival. Side effects include low blood counts, risks of infection, headaches and dizziness.
Splenectomy (surgical removal of the spleen): This is considered if the spleen is painful and causing complications and due to the risks all surgical procedures carry, it is quite common not to recommend splenectomy until other treatment options have been exhausted.
Radiotherapy: Radiotherapy or radiation of the spleen is an option if splenectomy is ruled out. Performed in hospital, radiotherapy helps to reduce the size of the spleen and can also relieve other related symptoms, such as bone pain. Radiation kills cells using high strength laser-beams such as x-rays. It usually provides temporary relief that lasts between three and six months.

Management of anaemia

Anaemia is common in people with MF. Symptoms include excessive tiredness, weakness and shortness of breath. If these are causing difficulties, the haematologist may suggest blood transfusions.

Blood transfusions are relatively safe and usually done in an out-patients’ clinic involving the transfer of red blood cells from a compatible donor into the MF patient. This can quickly reduce the symptoms of anaemia and don’t usually cause serious complications. However there is a risk of iron overload for patients who may receive a series of transfusions over several years and this will be discussed with the managing haematologist. Other options are danazol, Erythropoietin, thalidomide.

Bone Marrow Transplants (BMT)

Bone marrow transplants, are the only treatment that can cure MF, but have significant risks.

One of the main reasons why a small group of Australian MPN patients is attempting to create a massive awareness and Fundraising Campaign, is really quite simple…

Presently, in Australia, success rates of BMTs is as low as circa 50%, and rejection, and the threat of Graft Versus Host Disease, (GVHD), is an ever present danger with these procedures.

We desire to find much better outcomes than this, and better treatment regimes too…