Myelodysplastic syndrome / Myelodysplasia

Clinical picture

Myelodysplastic syndrome (MDS) includes a group of bone marrow disorders that are characterised by the production of abnormal red blood cells.

In healthy patients, the production of blood cells takes place in the bone marrow. Here, stem cells develop to various blood cells, such as red blood cells (erythrocytes), white blood cells (leukocytes) and platelets (platelets). In the case of MDS, mutations are present in the DNA of these stem cells, which results in abnormally formed blood cells that do not mature into healthy cells. Myelodysplastic syndrome is therefore composed of myelos, which means that the condition relates to the bone marrow (dys = abnormal), and plasia, which relates to the formation of cells. A syndrome is a variety of symptoms.

The abnormal blood cells are already destroyed in the bone marrow before they enter the bloodstream. This results in a shortage of blood cells:

deficiency of red blood cells: anaemia
shortage of white blood cells: leukocytopenia
deficiency of platelets: thrombocytopenia
deficiency of all these cells in the blood: pancytopenia

Types of myelodysplastic syndrome

There are several types of myelodysplastic syndrome. In some cases, the disease develops into leukaemia. The different types of MDS are:

refractory anaemia (RA): anaemia that does not respond to administration of iron tablets
refractory anaemia with ringsider oblasts (RARS): anaemia with red blood cells that are surrounded by iron
refractory cytopenia with multilineage dysplasia (RCMD)
refractory anaemia with too many blasts (immature cells) (RAEB)
MDS with isolated 5q-min (del (5q)) abnormality, in which a part of chromosome 5 is missing
do not classify myelodysplastic syndrome (MDS-U)

Furthermore, there are some rare forms of myelodysplastic syndrome:

juvenile myelomonocytic leukaemia (JMML): especially occurs in children aged 0-14 years The blood contains few platelets and many monocytes
chronic myelomonocytic leukaemia (CMML): usually a disease that occurs in people around 70 years of age. The blood and bone marrow show an increased number of monocytes
atypical chronic myeloid leukaemia without cytogenetic abnormality (without Philadelphia chromosome): a very rare condition that is mainly found in the elderly
myelodysplastic / myeloproliferative diseases that cannot be classified

MDS occurs at all ages, but most of the patients are older than 60 years of age. The disease is more common in men than in women.

Symptoms

In the beginning stages of the disease, patients do not have a lot of complaints and the disease can be discovered by accident through routine tests as a result. Gradually, symptoms become more severe and at the time of diagnosis, blood production may already be seriously disrupted. Most complaints are therefore linked to the shortage of blood cells in the blood. However, these complaints do not only occur in patients with MDS, which makes the diagnosis more difficult.

Patients may present the below symptoms:

Fatigue, shortness of breath, weakness and paleness due to a shortage of red blood cells.
Common or severe infections due to a lack of white blood cells (immune cells).
Increased risk of haemorrhages due to the shortage of platelets. For example, bruises, small red spots under the skin (spot bleeding) or wounds that do not stop bleeding.
Fever, weight loss without a clear cause and enlargement of spleen and liver due to increased cell breakdown in these organs.
Pain in the joints and skin. Sometimes myelodysplastic syndrome is associated with an autoimmune disease. The immune system recognises the body’s own cells and substances as foreign and attacks these cells.
Acute myeloid leukaemia (AML). With MDS, the progenitor cells (blasts) can become malignant. This occurs in about a third of patients. In the worst case they develop acute myeloid leukaemia. However, the chance on AML is depending on the type of MDS.

Cause

Often, no cause can be found for the disturbed production of blood cells in myelodysplastic syndrome. It is likely that the error arises in the stem cells of the bone marrow. One theory is that during the many divisions of the bone marrow cells, mutations occur in the DNA. These mutations eventually lead to MDS. For that reason, MDS is also typically a disease of the elderly (older than 60 years), although the disease can also appear in young people.

There also seems to be a connection with the exposure to toxic substances such as pesticides, chemicals (such as benzene) and radiation. It is known that some patients who have been treated with radio or chemotherapy, develop MDS later in life. This is called therapy-related MDS.

Diagnosis

To diagnose myelodysplastic syndrome, several test can be performed:

A structured medical history, taking into account the signs and symptoms of the patient.
Physical examination.
Blood tests for abnormal cells and numbers of blood cells in the bloodstream.
Bone marrow research into the deformed cells and numbers of blasts. An excess of blasts indicates a development towards acute myeloid leukaemia.
Cytogenetic analysis: examination of bone marrow cells for abnormalities of the chromosomes, such as the 5q-min deviation.
Molecular diagnostics: research on specific DNA abnormalities known for MDS.

Treatment

The treatment of patients with myelodysplastic syndrome depends, among other things, on the symptoms and the risk profile of the patient. It may vary from only observation to chemotherapy and stem cell transplantation.

The treatment focuses in particular on keeping the symptoms under control and increasing the quality of life. Patients with a mild form of MDS (with less than 5% blasts in the bone marrow) will receive blood transfusions. In addition, treatment with growth factors (erythropoietin and possibly G-CSF) is possible.

Patients with severe MDS –with more than 5% blasts in the bone marrow- will undergo more aggressive treatment. This treatment may consist of a low dose of chemotherapy or intensive chemotherapy followed by bone marrow transplantation. The choice of treatment depends on the age and physical state of the patient. Because acute leukaemia occurs in approximately 40% of patients with MDS-RAEB (usually AML), MDS is treated in the same way as AML.

Targeted therapies in current development for myelodysplastic syndrome include XPO1, NAE, telomerase and SMO inhibitors.