Our bone marrow is formed by cells that divide and differentiate to transform into mature cells found in our bloodstream. They include red cells, white cells and platelets. The rate of division and differentiation is controlled by many feedback mechanisms which make sure that the rate of division equals the need for new cells, either due to the destruction of old ones or the increased overall needs of the body.
For example, the increased white blood cell count during infections. Disruption of such mechanisms causes what is collectively known as myeloproliferative neoplasms, which is the uncontrolled division of one or more of those cell lines. The reason is at the genetic level in the form of a mutation or a critical change of the genetic constitution of those cells. If you have previous knowledge about leukemia, the mechanism seems familiar, and that is because it is. Acute leukemias are a known consequence of myeloproliferative neoplasms.
Myeloproliferative neoplasms include the following diseases, according to the latest classification:
- Chronic myelogenous leukemia (CML): This is the only myeloproliferative neoplasm with characteristic Philadelphia chromosome mutation.
- Essential thrombocythemia (ET)
- Polycythemia rubra vera (PV)
- Myelofibrosis
There are other minor disorders that may be considered as MPN, including mastocytosis and chronic neutrophilic leukemia, but this is still subject to clinical debate, so we will only focus on the 4 main types.
Myelofibrosis types
1) Primary myelofibrosis
When myelofibrosis is mentioned, it generally refers to primary myelofibrosis. The reason it is called primary or “idiopathic” is that there is no known cause for its occurrence and it is not preceded by another condition that eventually caused it.
2) Secondary myelofibrosis
This refers to myelofibrosis that developed following polycythemia vera or essential thrombocythemia as a complication.
Continue reading to uncover the mechanism of its occurrence now.
Mechanism of its occurrence
As mentioned above, primary myelofibrosis is an uncontrolled division of a line of blood stem cells. However, this is not the only disorder occurring, and the “fibrosis” in the name refers to a fibrous tissue. Fibrous tissue is formed by cells called fibroblasts found all over the body. They are normally activated when a tissue defect occurs to start healing the tissue and forming the scar. In the case of myelofibrosis, however, such activation is uncontrolled and can be as a result of the release of certain chemical substance responsible for the activation of fibroblasts. Those chemical substances are also responsible for the formation of new blood vessels within the bone itself, a characteristic sign seen under the microscope by pathologists. To summarize then: myelofibrosis is a disease of uncontrolled division of blood mother cells, which is also accompanied by excess fibrous tissue as a side effect.
Exposure to radiation and some chemicals can be one of the risk factors of the disease but the main reason remains largely unknown.
Fibrous tissue is not a benign tissue in closed spaces, and its encroachment on the cells that were originally responsible for its formation results in those cells’ death and consequently, a fall in the number of blood cells. The number of cells is controlled by many feedback mechanisms, and the fall of red cell count, for example, can cause their increased formation from other sites than the bone marrow. This is called extramedullary erythropoiesis. The sites of such formation include the liver, the spleen and lymph nodes. This pathway is necessary to comprehend since it reflects on the symptoms the patient feels or the signs that appear on his body.
Myelofibrosis symptoms
One of the challenges for the treatment of myelofibrosis is that many patients don’t show any symptoms, since the anemia is usually compensated for by the extramedullary erythropoiesis. Otherwise, symptoms can be a result of anemia, splenic enlargement, increased cellular production and the energy it requires or deficiency of platelets. The following symptoms are the most common:
1) Splenic enlargement manifestations
The spleen is an organ located just below your diaphragm in the upper left part of your abdomen. When it enlarges, it usually produces no symptoms, however, rapid or massive enlargement can be troublesome. Rapid enlargement can cause pressure upon the capsule of the spleen and a characteristic type of pain called stitching pain. If the spleen enlarges to a massive size, it can also pull the ligament holding it to the diaphragm producing a feeling of heaviness and pain.
2) Indigestion and early satiety
The spleen is close to the stomach, and when it enlarges it presses on the stomach causing early satiety following meals or indigestion, it is also associated with increased acid reflux in the esophagus due to increased intraabdominal pressure.
3) Hypersplenism
The spleen enlarges to be able to produce more red blood cells. However, this can turn up to be a double-edged weapon since the spleen is also the main site of the destruction of aged cells. Its enlargement carries the risk of causing hypersplenism when it destroys red blood cells, exaggerating the condition it was meant to resolve. It can also destroy white blood cells and platelets causing decreased counts and increased susceptibility to infections and bleeding tendency.
4) Anemia
Anemia comes with a wide range of symptoms. Mild anemia is usually asymptomatic, but the more severe the anemia is, the more pronounced the symptoms will be. They include easy fatiguability, intolerance to effort, awareness of heartbeats, shortness of breath and even loss of consciousness. Those symptoms occur because a decrease in the number of red blood cells decreases the capacity of blood to transport oxygen which leads to decreased energy production. Severe anemia can cause heart failure and death.
5) Bleeding tendency
One of the cells affected by fibrosis in the bone marrow are the megakaryocytes. They are the mother cells of platelets and a decreased platelet count affects bleeding. This can manifest as increased bleeding after minor injuries or even spontaneous bleeding in the gums, vagina, or visible in the urine or stool. Also in the skin in the form of petechiae, which are small red dots.
6) Increased body metabolism
We have to remember that myelofibrosis is a neoplasm and any condition that causes uncontrolled cellular division puts a heavy toll on the body’s energy resources. Patients can present with weight loss, fever and night sweating.
7) Gout and kidney stones
When metabolism is excessive and large numbers of cells are destroyed on a daily basis, their basic components are metabolized extensively. The DNA of cells is formed by small units called purines and pyrimidines. Purines re metabolized to uric acid which if excessive, can deposit in body’s tissues especially joints causing the characteristic pain and swelling of joints of the leg and arm “gouty arthritis”. Uric acid is also excreted in large amount in urine causing ureter stones and even in severe cases, kidney failure.
8) DIC
DIC stands for disseminated intravascular coagulopathy, and this condition has been associated with myelofibrosis. In short, it is a condition with a dysregulated clot formation. Small clots are unnecessarily formed, and the body becomes unable to form an appropriate clot when needed, causing bleeding due to a clotting disorder. Those blood clots dislodge in various blood vessels across the body causing many organs to die and multiple system to shut down. It can be fatal unless properly treated.
Myelofibrosis diagnosis
Diagnosing myeloproliferative neoplasms in general relies on good history taking and examination supplemented by blood tests. Your doctor will ask you about your symptoms and will order needed tests.
1) Physical examination
Your doctor will examine your skin for signs of hemorrhage and your eyes and hands for the paleness of anemia. They will also examine your abdomen searching for an enlarged spleen and liver, as well as your joints for signs of gout. They may also check your enlarged lymph nodes since they may become larger as a manifestation of extramedullary erythropoiesis or for differentiating it from other malignant conditions that may or may not be a result of myelofibrosis like acute leukemias.
2) Laboratory investigations
The most basic lab investigation is a CBC which count the number of blood cells, mostly by using an automated analyzer. In myelofibrosis it may show anemia -which a decreased hemoglobin level and red cell count- and thrombocytopenia -which is a decreased platelet count- or thrombocytosis -elevated platelet count-. Although it seems more logical that platelets should be less, it is actually more common to have elevated platelet count since these cells are most commonly uncontrollably dividing. A falling platelet count indicates that the fibrosis of the bone marrow has become more extensive and the disease has progressed.
Those finding are not enough to diagnose myelofibrosis, but should direct the physician to a diagnosis of aplastic anemia, a type of anemia caused by a problem in the manufacturing plant, the bone marrow.
The second step after counting the number of cells is to check them under the microscope by a professional pathologist, this is called blood film. In myelofibrosis, white blood cells show certain abnormalities that suggest the condition.
3) Genetic testing
The doctor may order a genetic testing. This is mainly used to exclude the presence of the only leukemia that has a similar presentation, chronic myeloid leukemia. The genetic test looks for a certain mutation called Philadelphia chromosome, or BCR/ABL fusion gene. If the gene is present, a diagnosis of CML is established.
4) Bone marrow aspiration and biopsy
Myelofibrosis literally means fibrosis of the bone marrow, and to confirm the diagnosis, a bone marrow aspiration or a biopsy is required. The procedure involves sampling a piece of the bone marrow or aspirating it using special needles going through the iliac crest, that is the upper part of your hip bone. The procedure is done under local anesthesia and is generally considered safe.
The main difference between bone marrow aspiration and biopsy is the technique. Bone marrow aspiration relies of the liquidity of the bone marrow to aspirate a number of cells and examine under the microscope while bone marrow biopsy samples a piece of the bone and the underlying marrow, and is especially useful when the bone marrow has fewer cells as is the case in late myelofibrosis. Trying to aspirate in such cases can produce what is called a “dry tap”.
Bone marrow biopsy examination under the microscope shows increased number of mother cells especially those of the platelets as well as significant fibrous tissue and blood vessels. The presence of this triad is a sure sign of myelofibrosis. Genetic tests may be carried out on the specimen since some chromosomal abnormalities can indicate the outcome, but that is not the rule for diagnosis.
5) Imaging
Imaging studies are not necessary for the diagnosis; however, they can add a few clues regarding the progression of the disease or to help exclude some differential diagnoses “which are probable diagnoses with similar symptoms”.
X-rays can show increased bone density, a feature of a condition called osteosclerosis. It is a complication of the condition and can indicate poor outcome. Magnetic resonant imaging can also be used to visualize the bone marrow as a whole and CT scans for the liver and spleen can help delineate the progression of the disease.
Myelofibrosis treatment
Ten years ago, if you had asked a specialist hematologist about the treatment of myelofibrosis, you would have received a sad face and a multitude of medications that do not directly deal with the disease. Myelofibrosis is a genetic problem with manifestations at a cellular level, and unless the treatment tackles the genetic problem, it will persist and progress. Targeted genetic therapy greatly improves the outcome of myelofibrosis and all myeloproliferative neoplasms.
Treatment is usually tailored according to the severity of the condition as well as the presence of complications. Some complications such as the enlargement of the spleen may need surgical treatment especially if it causes hypersplenism. To understand how treatment works, we have to deal with 2 main problems, the genetic one and the one related to the symptoms. Both approaches are done at the same time.
1) Ruxolitinib
Ruxolitinib is a chemotherapeutic agent that belongs to a class called JAK inhibitiors. JAK stand for Janus associated kinases and such enzymes play a central role in the development of myelofibrosis. However, the mutation that the drug deals with is only found in half the cases of myelofibrosis. Another sibling to Ruxolitinib is fedratinib, and it has shown great promise in initial trials, which is why it has been recently recommended for some advanced cases. It has to be understood though that those 2 drugs have not yet proved an effect like that of tyrosine kinase inhibitor drugs like imatinib or nilotinib on chronic leukemias, but they are the first step towards a specific treatment for myelofibrosis.
2) Hydroxyurea
Hydroxyurea is one of the oldest chemotherapeutic agents to be used for hematological malignancies, and it is still used in myelofibrosis. It acts mainly as a nonspecific cytoreductive agent, which means that it decreases the number of excessive blood cells like megakaryocytes and red cells which ultimately can result in remission. This class of chemotherapeutic agents is still very non specific that they can even cause severe cellular deficiencies in the form of bone marrow toxicity, but it can’t be replaced due to the fact that even the targeted therapy (ruxolitinib) isn’t successful in many cases.
3) Interferon
Interferon is a magical drug. It is used in a large variety of conditions including viral hepatitis, autoimmune disorders and cancers, and the reason of its effectiveness is that it is the same molecule produced by our body in such conditions, only slightly modified. Interferon can be used instead of hydroxyurea in some cases especially young individuals who can handle its side effects and benefit from its increasing survival odds.
4) Androgenic steroids (testosterone and analogues)
When you pick up a blood count, you will always find that males have a higher reference range for red cells and hemoglobin than females. That is mainly for 2 reasons, the first is that males don’t menstruate and the second is that men have much higher levels of testosterone, and testosterone is an anabolic steroid that stimulates cells to divide more rapidly and produce more protein. That is why it is used and abused by fitness models and medically useful to stimulate the bone marrow to produce more blood cells especially in the case of anemia.
5) Surgery
Surgery is not a line of treatment of myelofibrosis itself, but it can be a line of therapy for the enlarged spleen. The reason why we remove the spleen is that it can cause hypersplenism. Its removal can cause a dramatic improvement of cellular deficiencies. The second situation is when the spleen is so large that it produces a dragging pain and a feeling of heaviness that sometimes becomes unbearable.
6) Radiation therapy
Radiation therapy can be an optimal therapy for many cancers, but in myelofibrosis, it serves a much lesser role. The main organ that can benefit from radiation is the spleen to reduce its size and its manifestations, however it comes with the significant risk of causing a severe drop of blood count and that is why it is much less preferable than surgery.
7) Stem cell transplantation
Stem cell transplantation remains one of the greatest advances of modern medicine and the most curative option for myelofibrosis. The basic principle is that ablating or destroying the old bone marrow which has the genetic defect responsible for myelofibrosis and replacing it with another one, thereby eliminating the cause of the disease. Most of the complications of the main condition become reversible after successful transplantation.
Stem cell transplantation is not the ultimate solution for all cases, however, and many patients may not be ideal candidates since it depends on the acceptance of the grafted marrow to the body. If the grafted marrow develops an autoimmune reaction towards the body, a condition called graft-versus-host disease can develop which is potentially fatal. Ideal patients for stem cell transplantation are young, with minimal complications and a relatively normal hemoglobin level especially if their donors are siblings.
Outcome
Primary myelofibrosis is a disease of variable outcomes and those outcomes are dependent on various factors including age, type of genetic abnormalities and the severity of cellular deficiencies. Overall about fifth of patients survive for more than 10 years. This outcome can be drastically improved with successful therapy especially stem cell transplantation. The main causes of death due to myelofibrosis are infections -due to the decreased white blood cells-, hemorrhage -due to the deficient platelets or DIC- and leukemic transformation.
As mentioned before, myeloproliferative neoplasms are genetically cancers and conversion of myelofibrosis to acute leukemia occurs in about 8%-23% of patients. With all that said, hope of a better cure for myelofibrosis is in the works and genetic therapy is taking long strides that we won’t be surprised if therapy as effective as that of chronic myeloid leukemia will be available for myelofibrosis within the next 10 years.