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TimoSiitonen

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 an elderly patient with unexplained macrocytic anaemia, which may be associated with leucopenia or thrombocytopenia.
  • Cytopenias in the blood count result from inefficient bone marrow function caused by dysplasia i.e. a disorder of differentiation and maturation of myeloid cell lines.

Occurrence

  • The average number of new cases is 4 per 100 000 people per year. The risk of developing the disease increases with age.
  • At detection the average age is 70 years.

Aetiology

  • Principally unknown
  • Risk factors include a history of cytostatic therapy, radiotherapy, benzene or other solvent exposure, insecticide exposure, radiation, autologous stem cell transplant, certain blood diseases and hereditary genetic abnormalities predisposing to blood diseases particularly in younger persons.

Symptoms

  • One fifth of patients have no symptoms at diagnosis.
  • Symptoms from cytopenias; most commonly fatigue and debility due to anemia.

Diagnosis

  • Cytopenias in the blood count raise a suspicion of the disease, but diagnosis requires a bone marrow sample.
  • The bone marrow sample is examined for morphology and chromosomal analysis and, more often than before, gene panel analysis for myeloid mutations is performed.
  • Full blood count and a blood smear
    • Normocytic or macrocytic anaemia almost always
    • Half of the patients have leucopenia or thrombocytopenia
      • Neutrophils with hypogranular cytoplasm and hypolobated nucleus is a typical feature.
    • Solitary blast cells, depending on the disease stage.
  • Bone marrow examination
    • Usually, MDS diagnosis requires that 10% or more of dysplastic cells are detected 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 (suggests MDS-SF3B1).
  • Bone marrow chromosome study
    • Abnormal in half of the patients
    • Useful in estimating the prognosis of the disease
    • May confirm MDS diagnosis in unclear cases of cytopenia.
  • Mutation testing (gene panel examination for myeloid mutations)
    • Usually tested from bone marrow, but it is possible to test also from blood.
    • Somatic mutations in 90% of cases
    • Refines the classification and prognosis.
    • Helps in finding also germ line mutations that predispose to MDS and that about 10% of patients have.
    • Performed in all patients for whom allogeneic stem cell transplantation may be possible as well as, on an individual basis, older patients.

Differential diagnosis

  • 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.
  • Clonal cytopenia of uncertain significance (CCUS) is a precursor to MDS in which somatic myeloid mutations are found in addition to cytopenia in the blood count, but the criteria for MDS are not met in terms of dysplasia.
  • In chronic myelomonocytic leukaemia, there is absolute monocytosis in the blood picture, dysplasia in the bone marrow, and in the majority of cases splenomegaly.

Classification and prognostic markers

  • Two classifications published in 2022 are used: the WHO classification and the ICC classification.
  • Both classifications use both morphological and genetic information.
  • Based on genetics, there are 3 groups of MDS in which a diagnosis of MDS can be made even without detection of dysplasia.
    • MDS with TP53 mutation (MDS-TP53)
    • MDS with SF3B1 mutation (MDS-SF3B1)
    • MDS with del(5q) chromosome aberration (MDS-5q)
  • Otherwise, MDS is divided according to dysplasia and blast count into:
    • MDS with low (< 5%) blast count (MDS-LB), or
    • MDS with increased (> 5%) blast count (MDS-IB).
  • The WHO classification limits MDS and acute myeloid leukaemia (AML) to a blast share of 20%, but the ICC classification has introduced a new MDS/AML category for the blast level of 10-20%.
  • The WHO classification distinguishes also hypoplastic MDS and fibrotic MDS as separate subgroups.
  • IPSS-R and/or IPSS-M risk score should be determined for all patients with MDS http://www.nmds.org/index.php/guidelineshttp://mds-risk-model.com/.
    • The IPSS-R risk score is calculated from the bone marrow blast share, the chromosomal finding and the number and severity of cytopenias.
    • IPSS-M is based on the IPSS-R risk classification, but adds the mutation finding.
    • The risk score classifies the patient 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 (60% of patients, IPSS-R score HASH(0x2fd5bc8) 3.5, IPSS-M HASH(0x2fd5bc8) 0) the life expectancy is 3.5-12 years. Life expectancy is longest in the MDS-5q and MDS-SF3B1 groups.
    • The main problem is usually anaemia. In addition, there may be increased susceptibility to infections and bleeding.
    • The aim of treatment is to correct anaemia and improve quality of life.
  • In the higher-risk disease (40% of patients, IPSS-R score > 3.5, IPSS-M > 0) the life expectancy is less than two years.
    • Considerable risk of transformation into leukaemia (30-50%), particularly if there is a high-risk chromosomal or mutation finding or the number of blasts in bone marrow is > 10%.
    • The aim of treatment is to inhibit progression to acute leukaemia and prolong the patient's life.

Treatment and follow-up

  • The management approach is decided by a specialist in internal medicine or a haematologist.
  • In addition to the risk classification, the need for transfusions, the patient's age, other underlying conditions, general health and personal wishes for treatment influence the choice of treatment line.
  • The blood count of an asymptomatic lower-risk patient should be reviewed every 2-4 months.
  • Treatment is started if the patient has
    • symptomatic cytopenia (usually anaemia, Hb < 100 g/l)
    • increasing proportion of blasts in the bone marrow (> 10%)
    • a higher-risk disease.

Supportive measures

  • Used regardless of risk classification.
  • 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

  • Lower-risk patient with symptoms
    • Erythropoietin therapy (epoetin, darbepoetin alpha)
      • A treatment trial of 3-4 months, if serum erythropoietin is <500 U/l and the percentage of bone marrow blasts is <10%
      • Treatment response is obtained in half of the patients.
      • Aim to raise Hb to the level of 100-120 g/l (higher Hb may increase the risk of occlusions)
      • Sufficient iron stores must be ensured during erythropoietin therapy.
    • Other treatments to be considered case-by-case
      • MDS-5q: lenalidomide after response to erythropoietin therapy is lost (response to treatment in even 70% of the patients)
      • Lower-risk MDS-SF3B1: luspatercept after response to erythropoietin therapy is lost (if medicine available)
      • Immunosuppressive therapy in lower-risk hypoplastic MDS with severe cytopenias as a problem (used more seldom)
      • In deep cytopenias refractory to other treatments, allogeneic stem cell transplantation or azacitidine (no official indication in lower-risk disease) can be considered.
  • 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 usually with 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.

Palliative care

  • Remember palliative care especially in high-risk MDS, when the disease progresses and there are no good treatment options left, or when age or debility prevents treatment.

    References

    • Nordic MDS Group http://www.nmds.org/index.php/guidelines
    • Garcia-Manero G. Myelodysplastic syndromes: 2023 update on diagnosis, risk-stratification, and management. Am J Hematol 2023;98(8):1307-1325. [PubMed]
    • Saygin C, Carraway HE. Current and emerging strategies for management of myelodysplastic syndromes. Blood Rev 2021;48:100791. [PubMed]