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The treatment options for patients with MDS are currently very limited. There is therefore great pressure to develop new, well-tolerated and effective drugs. In the Department of Internal Medicine III at Ulm University Hospital, we are conducting several therapy studies for low-risk and high-risk MDS. You can find a current overview here:

Study Centre >> Active Clinical Trials >> MDS

Myelodysplastic syndrome (MDS) is a clonal disease of the bone marrow. Genetic changes in the blood stem cells lead to malformations (dysplasia) of the cells with a differentiation defect. This leads to an uncontrolled proliferation of stem cells (blasts) and a quantitative deficiency of mature blood cells (cytopenias). MDS can progress in the course of the disease with a proliferation of blasts and develop into so-called secondary acute myeloid leukaemia (sAML).

In Germany, MDS has an incidence of approx. 4/100,000 inhabitants measured against the total population. However, as with most cancers, the incidence of MDS increases with age. On average, patients are around 75 years old when they are diagnosed with MDS.

MDS is caused by genetic changes in the blood stem cells. Genetic changes (mutations) in the DNA are acquired randomly in every cell in the course of life and accumulate accordingly with increasing age, which explains why the risk of developing MDS increases with age. Risk factors for the development of MDS are all influences that promote the development of genetic changes in the blood stem cells. These include ionising radiation and chemotherapeutic agents, which are used, for example, in the treatment of cancer. Accordingly, the risk of developing MDS is increased after such tumour therapy. MDS that occurs after such a therapy is called therapy-associated MDS (tMDS). tMDS often has high-risk genetic markers (see below) and therefore responds poorly to therapy.

The symptoms of MDS are mainly due to the inadequate formation of mature blood cells:

Leukopenia = lack of white blood cells: The leukocytes (white blood cells) are responsible for the defence against infections. A lack of such cells therefore leads to an immunodeficiency, which increases the risk of developing serious infections caused by bacteria, fungi and viruses.

Anaemia = lack of red blood cells (erythrocytes). Erythrocytes transport oxygen from the lungs to the organs in the body. A deficiency leads to weakness, tiredness and shortness of breath under stress.

Thrombocytopenia = lack of blood platelets (thrombocytes). Platelets are an important component of blood clotting, so that a reduced platelet count increases the tendency to bleed. The first sign may be dot-shaped haemorrhages on the lower legs (petechiae).

Patients often come to the doctor because of one of the symptoms mentioned above, who then carries out a blood count in which the cytopenia is then revealed. There may be a deficiency in one, two or all cell lines, but sometimes cytopenia is also detected during a routine blood test without any symptoms. The next step in the diagnosis is a microscopic differential blood count and a bone marrow examination (cytology and histology). In myelodysplastic syndrome, dysplastic cells are typically seen, and immature cells [blasts] may also be present. Molecular biological examinations are also carried out on the bone marrow to detect changes in genes and chromosomes in the MDS cells. However, the diagnosis is not always clear and it is important to exclude possible differential diagnoses, especially if no genetic changes are detected. For example, an iron or vitamin deficiency, bleeding, alcohol consumption and certain medications can also lead to anaemia and sometimes also dysplasia in the bone marrow.

Acquired chromosomal changes are found in 50% of patients with MDS, and gene mutations in approx. 80-90%. On the one hand, the genetic changes help with the diagnosis of MDS. They also have prognostic significance in some cases.

According to the WHO 2016 classification, MDS is divided into several subgroups based on morphology, blast content and genetic changes.

• MDS with dysplasia of one lineage (MDS-SLD)
• MDS with dysplasia of several lines (MDS-MLD)
• MDS with ring sideroblasts (MDS-RS)
• MDS with isolated deletion of chromosome 5q
• MDS with excess of blasts (MDS-EB1/2)
• Unclassified MDS

Patients with MDS have a very variable course in terms of progression to AML and overall survival. The risk can be estimated with the help of prognosis scores such as the IPSS-R. The variables included in this score are the number of blasts, genetics and the number and severity of cytopenias. Accordingly, patients can be categorised into those with a low and high risk of transitioning to AML and the risk of dying.

Most patients with MDS suffer from one or more cytopenias and their consequences. Symptomatic, supportive therapy consists of substituting blood cells through transfusions. Erythrocytes are transfused if the haemoglobin level is below 7 g/dl or if symptoms occur. If the transfusion takes a long time, it is important to pay attention to an inevitable iron overload and to treat this if necessary.

There are no clear recommendations for platelets. As sensitisation and rejection of the foreign platelets can occur with an increasing number of transfusions, the transfusions lose their effect with regular substitution. Therefore, restraint is generally recommended. It is unclear whether substitution should be carried out at a certain limit of 10 G/L platelets or only in the event of bleeding, regardless of the platelet count. One of the factors to be considered is how far the patient is from a hospital where a transfusion can be carried out quickly in an emergency.

In order to treat immunodeficiency due to the lack of leucocytes, antibiotic therapy must be started quickly in the event of infections and fever. However, it is not certain whether long-term antibiotic prophylaxis is beneficial, as the development of pathogen resistance is to be expected.

The further treatment of MDS depends on the risk constellation. Patients with low-risk MDS can be treated with growth factors such as erythropoietin in addition to transfusions, which in some patients leads to freedom from transfusions or a reduction in the frequency of transfusions. MDS with isolated loss of chromosome 5q is a special case. In this case, treatment with the thalidomide (thalidomide) analogue lenalidomide can lead to freedom from transfusion in around 60% of patients. In the absence of symptoms and transfusion requirements, low-risk MDS does not necessarily have to be treated.

In high-risk MDS, there is usually always an indication for treatment, as there is a high risk of transition to acute myeloid leukaemia in addition to cytopenias. A curative approach is allogeneic stem cell transplantation, in which stem cells are transferred from a family or unrelated donor. However, this is a very risky procedure and is only suitable for otherwise healthy, biologically young patients. Further information on this intensive therapy can be found here. For older patients with previous illnesses or organ disorders, however, this type of therapy is too risky. In this case, azacytidine is a substance that is generally well tolerated and can be administered on an outpatient basis. Approximately 50% of patients respond with an improvement in cytopenias. Although a cure cannot be achieved with azacytidine, it does lead to a prolongation of overall survival.

In addition to the clinical studies, various research groups at the Department of Internal Medicine III and the University of Ulm are conducting experimental work on the development and treatment of MDS. A particular focus is on the mechanism of action and resistance mechanisms of the drug lenalidomide, which is approved for the treatment of MDS with del(5q).

https://www.onkopedia.com

https://www.kompetenznetz-leukaemie.de

http://www.mds-register.de/

https://www.leukaemie-hilfe.de

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