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Myelodysplastic Syndromes (MDS)
Essentials
- Myelodysplastic syndromes (MDS) are malignant blood diseases characterized by decreased haematological values and a tendency to develop into acute leukaemia.
- MDS should be suspected particularly in elderly patients with unexplained macrocytic anaemia, which may be associated with leucopenia or thrombocytopenia.
- Abnormal blood values are due to disturbances in the differentiation and maturation of cell lines (dysplasias) in the bone marrow.
Occurrence
- New cases: 3-4/year/100 000 individuals
- The risk of developing the disease increases with age; the median age at diagnosis is 70 years.
Aetiology
- Principally unknown
- Risk factors include a history of cytotoxic therapy, radiotherapy, benzene or insecticide exposure, radiation, autologous stem cell transplant, certain blood diseases and predisposing genetic abnormalities particularly in younger persons.
Symptoms
- One fifth of patients have no symptoms at diagnosis.
- Symptoms are caused by cytopenias.
- The most common symptom is anaemia and the fatigue and debility caused by it.
Diagnosis
- Diagnosis is based on full blood count, bone marrow examination and chromosome analysis and, as necessary, on mutation testing.
- Requires detection of cytopenia or cytopenias in the blood picture and
- bone marrow dysplasia
- excess of ring sideroblasts
- increased blast count or
- detection of certain chromosomal changes.
- Full blood count
- Almost always macrocytic anaemia
- Half of the patients have leucopenia or thrombocytopenia (as an exception del(5q) syndrome in which the number of platelets is usually increased)
- Neutrophils with hypogranular cytoplasm and hypolobated nucleus is a typical feature.
- Solitary blast cells, depending on the disease stage.
- Bone marrow
- 10% or more of dysplastic cells in at least one myeloid cell line (nuclear abnormalities and disturbed maturation, megakaryopoiesis with micromegacaryocytes as the most typical one)
- The number of blasts may be increased, but always less than 20%
- In some cases, ringed sideroblasts are seen on iron stain.
- Chromosome studies
- Abnormal in over half of the patients
- May confirm diagnosis in unclear cases of cytopenia.
- Useful also in estimating the prognosis of the disease
- Mutation testing (gene mutation panel of myeloid blood diseases)
- Useful in differential diagnosis of ring sideroblast anaemia (SF3B1 mutation can be detected in 80% of cases)
- Helps in finding germ line mutations that predispose to MDS.
- Recommended at list for patients for whom allogeneic stem cell transplantation may at some phase be possible (provides a more precise disease prognosis).
- The significane of mutation-related information is increasing in the future.
Differential diagnosis
- In chronic myelomonocytic leukaemia there is absolute monocytosis in the blood picture, dysplasia in the bone marrow, and often splenomegaly.
- Dysplasia may sometimes be associated with deficiency of vitamin B12 or folic acid, excessive alcohol intake, heavy metal poisoning, HIV infection, recent cytotoxic treatment, aplastic anaemia and paroxysmal nocturnal haemoglobinuria.
Classification and prognostic markers
- WHO classification (2016) divides MDS into 7 subgroups:
- MDS with single lineage dysplasia (MDS-SLD)
- MDS with multilineage dysplasia (MDS-MLD)
- MDS with ringed sideroblasts ((SF3B1 mutation or sideroblasts over 15%; MDS-RS)
- MDS with excess blasts (MDS-EB)
- MDS with isolated del(5q) chromosomal change
- MDS, unclassifiable (MDS-U)
- Refractory cytopenia of childhood.
- Either IPSS or IPSS-R risk score should be determined for all patients with MDS http://www.nmds.org/index.php/guidelines.
- Risk points are given for the number of blasts in the bone marrow, the chromosomal findings and the severity of cytopenias.
- Based on the risk points, the patient is classified to having either a lower- or higher-risk disease as regards life expectancy prognosis and the risk of developing leukaemia, which assists in making decisions on treatment choices.
Clinical course
- In the lower-risk disease (70% of patients, IPSS-R score < 4) the life expectancy is 3-12 years.
- The main problem is anaemia, accompanied with increased susceptibility to infections and bleeding.
- Del(5q) syndrome carries the best prognosis as regards life expectancy.
- In the higher-risk disease (30% of patients, IPSS-R score > 4) the life expectancy is only about one year.
- Considerable risk of transformation into leukaemia (30-50%), particularly if there is a high-risk chromosomal change or the number of blasts in bone marrow is > 10%
Treatment and follow-up
- The management approach is decided by a specialist in internal medicine or a haematologist.
- Treatment decisions are also affected by the patient's blood values, risk points, age, other health status and the patient's own desires regarding the treatment.
- An asymptomatic patient should be reviewed every 2-4 months.
- Treatment is started in the case of
- symptomatic cytopenia (usually anaemia, Hb < 100 g/l)
- increasing proportion of blasts in the bone marrow (> 10-15%)
- a higher-risk disease.
Supportive measures
- Treatment of anaemia
- Red blood cell transfusions aim at keeping the haemoglobin level in the range of 80-100 g/l.
- If the life expectancy is > 2 years, the prescription of iron-chelating agents should be considered when plasma ferritin increases to above 1 500-2 000 µg/l.
- In patients suitable for allogeneic transplantation, plasma ferritin target is < 1 000 µg/l.
- Management of bleeding
- Platelet transfusions are usually used only in case of haemorrhage (with the exception of surgical procedures and pharmacotherapy of MDS).
- Eltrombopag (a thrombopoietin receptor antagonist) may be considered for severe thrombocytopenia in non-MDS-EB (not an official indication).
- Treatment of infections
- Should be treated meticulously; infections are the most common cause of death in MDS patients.
- Granulocyte growth factor for neutropenic infections as well as in prevention of recurrent neutropenic infections as decided case by case
Specific MDS treatment
- Higher-risk patient
- Allogeneic stem cell transplantation
- The only curative treatment modality. Should be considered for all patients under 70 years of age, whose other health status is good and a stem cell donor can be found.
- Blast excess of over 10% is treated before the transplantation with a cytostatic drug or azacitidine.
- Azacitidine(for patients not suited for allogeneic stem cell transplantation)
- Administered subcutaneously on an outpatient basis as 5- to 7-day courses; repeated every 4 weeks
- Treatment response is seen slowly and the response can be evaluated only after 4-6 courses.
- The need for erythrocyte transfusions ends in almost half of the patients.
- Prolongs life expectancy by about 10 months, delays leukaemic transformation of the disease and increases the quality of life.
- Lower-risk patient with symptoms (in addition to supportive measures)
- Erythropoietin therapy (epoetin, darbepoetin alpha)
- A treatment trial of 3-4 months, if serum erythropoietin is less than 500 U/l and the percentage of bone marrow blasts is less than 10%
- Treatment response is obtained in half of the patients.
- Sufficient iron stores must be ensured during erythropoietin therapy.
- Other possible treatments to be considered case-by-case
- Del(5q) syndrome: lenalidomide after response to erythropoietin therapy is lost (reimbursement may vary from country to country)
- Lower-risk MDS-RS: luspatercept after response to erythropoietin therapy is lost (reimbursement may vary from country to country)
- Immunosuppressive therapy in severe cytopenias associated with bone marrow hypoplasia, provided that there are no high-risk chromosomal abnormalities (rarely used)
- In severe cytopenias refractory to other treatments, allogeneic stem cell transplantation or azacitidine (no official indication in lower-risk disease).
References