Aetiology

MDS can occur de novo or secondary to antecedent haematological malignancy or following exposure to chemotherapy or radiotherapy.[3] Most cases of MDS occur de novo, and the exact cause is unknown. However, a number of risk factors (genetic, environmental, and prior medical history) have been identified.

Chromosomal abnormalities

Chromosomal abnormalities are found in approximately 50% of patients with de novo MDS, and in as many as 90% of patients with MDS secondary to previous chemotherapy or radiotherapy.[20][21]​​​​ The most common chromosomal abnormalities include -5, del(5q), -7, del(7q), del(11q), del(12p), -17, del(17p), and del(20q), suggesting a role for tumour suppressor genes located on these chromosomes.[18][22]​​​

Genetic mutations

Somatic mutations are found in 80% to 90% of patients with MDS.[23][24][25]​​​ The most common mutations include DNMT3A, TET2, ASXL1, TP53, and SF3B1.[18][23]​​

Congenital disorder

MDS in children and younger adults is often associated with congenital disorders.[18]

Risk of MDS is increased in those with inherited bone marrow failure syndromes (e.g., Fanconi anaemia, Diamond-Blackfan anaemia, Shwachman-Diamond syndrome, dyskeratosis congenita, severe congenital neutropenia [Kostmann syndrome]), Down syndrome (trisomy 21), ataxia telangiectasia, xeroderma pigmentosum, Bloom syndrome, glutathione transferase theta 1 (GSTT1) gene defect, and Li-Fraumeni syndrome.[15][16][18][26][27][28][29][30]​​​

Previous haematological disorders

Risk of MDS is increased in patients with previous haematological disorders, including aplastic anaemia and paroxysmal nocturnal haemoglobinuria.[18][31]​​

Environmental exposures

Increased risk of MDS has been associated with exposure to tobacco and benzene.[32][33][34]

Previous exposure to chemotherapy or radiotherapy

Alkylating agents (e.g., chlorambucil, cyclophosphamide, melphalan), topoisomerase inhibitors (e.g., etoposide, teniposide), anthracyclines (e.g., doxorubicin, daunorubicin), and platinum agents (e.g., cisplatin, carboplatin) are associated with an increased risk for secondary MDS.[35][36][37] 

Radiotherapy is associated with an increased risk for secondary MDS.[37]​ Radiotherapy combined with chemotherapy increases the risk compared with radiotherapy alone.[38][39]

Autologous haematopoietic stem cell transplantation increases risk, but this is likely related to the use of chemotherapy for conditioning before transplantation.[40]

Pathophysiology

MDS is a heterogeneous group of clonal haematopoietic neoplasms that arise from a multipotent haematopoietic stem cell.[41]​ Sequential acquisition of somatic mutations in haematopoietic stem cells is thought to play a key role in the development and expansion of a malignant stem cell clone. The stem cell clone in MDS gives rise to intermediate cell types that are defective and susceptible to apoptosis, resulting in premature cell death in the bone marrow and ultimately cytopenias.

Dysregulation of the immune system and inflammatory signalling in MDS can result in abnormal haematopoiesis and unbalanced cell death and cell proliferation in the bone marrow, which may contribute to the pathogenesis of MDS.[42][43]

Classification

The 5th edition of the World Health Organization (WHO) classification of haematolymphoid tumours: myeloid and histiocytic/dendritic neoplasms[1]

The WHO classification introduces the term myelodysplastic neoplasms (MDS) to replace myelodysplastic syndromes. MDS is categorised based on defining genetic abnormalities or morphology.

MDS with defining genetic abnormalities

  • MDS with low blasts and isolated 5q deletion (MDS-5q)

    • Blasts: <5% in bone marrow and <2% in peripheral blood

    • Cytogenetics: 5q deletion alone, or with one other abnormality other than monosomy 7 or 7q deletion.

  • MDS with low blasts and SF3B1 mutation (MDS-SF3B1)

    • Blasts: <5% in bone marrow and <2% in peripheral blood

    • Cytogenetics: absence of 5q deletion, monosomy 7, or complex karyotype

    • Mutations: SF3B1 (≥15% ring sideroblasts may substitute for SF3B1 mutation).

  • MDS with biallelic TP53 inactivation (MDS-biTP53)

    • Blasts: <20% in bone marrow and peripheral blood

    • Cytogenetics: usually complex

    • Mutations: two or more TP53 mutations, or one mutation with evidence of TP53 copy number loss or copy neutral loss of heterozygosity.

MDS, morphologically defined

  • MDS with low blasts (MDS-LB)

    • Blasts: <5% in bone marrow and <2% in peripheral blood.

  • MDS, hypoplastic (MDS-h)

    • Blasts: <5% in bone marrow and <2% in peripheral blood

    • Bone marrow cellularity ≤25% (age adjusted).

  • MDS with increased blasts (MDS-IB)

    • MDS-IB1

      • Blasts: 5% to 9% in bone marrow or 2% to 4% in peripheral blood.

    • MDS-IB2

      • Blasts: 10% to 19% in bone marrow or 5% to 19% in peripheral blood or Auer rods.

    • MDS with fibrosis (MDS-f)

      • Blasts: 5% to 19% in bone marrow; 2% to 19% in peripheral blood.

International Consensus Classification (ICC) of myeloid neoplasms and acute leukaemias[2]

The ICC categorises MDS based on cytogenetic abnormalities, morphological dysplasia, or presence of excess blasts. The statement 'therapy-related' is added to specific classifications as a diagnostic qualifier if MDS is therapy related.

MDS with mutated SF3B1 (MDS-SF3B1)

  • Dysplastic lineages: typically ≥1

  • Cytopenias: ≥1

  • Cytoses: 0

  • Blasts: <5% in bone marrow; <2% in peripheral blood

  • Cytogenetics**: any, except isolated del(5q), -7/del(7q), abn3q26.2, or complex

  • Mutations: SF3B1 (≥10% variant allele frequency [VAF]), without multi-hit TP53, or RUNX1.

MDS with del(5q) [MDS-del(5q)]

  • Dysplastic lineages: typically ≥1

  • Cytopenias: ≥1

  • Cytoses: thrombocytosis allowed

  • Blasts*: <5% in bone marrow; <2% in peripheral blood

  • Cytogenetics**: del(5q), with up to 1 additional, except -7/del(7q)

  • Mutations: any, except multi-hit TP53.

MDS, not otherwise specified (NOS) without dysplasia

  • Dysplastic lineages: 0

  • Cytopenias: ≥1

  • Cytoses: 0

  • Blasts*: <5% in bone marrow; <2% in peripheral blood

  • Cytogenetics**: -7/del(7q) or complex

  • Mutations: any, except multi-hit TP53 or SF3B1 (≥10% VAF).

MDS, NOS with single lineage dysplasia

  • Dysplastic lineages: 1

  • Cytopenias: ≥1

  • Cytoses: 0

  • Blasts*: <5% in bone marrow; <2% in peripheral blood

  • Cytogenetics**: any, except not meeting criteria for MDS-del(5q)

  • Mutations: any, except multi-hit TP53; not meeting criteria for MDS-SF3B1.

MDS, NOS with multilineage dysplasia

  • Dysplastic lineages: ≥2

  • Cytopenias: ≥1

  • Cytoses: 0

  • Blasts*: <5% in bone marrow; <2% in peripheral blood

  • Cytogenetics**: any, except not meeting criteria for MDS-del(5q)

  • Mutations: any, except multi-hit TP53; not meeting criteria for MDS-SF3B1.

MDS with excess blasts (MDS-EB)

  • Dysplastic lineages: typically ≥1

  • Cytopenias: ≥1

  • Cytoses: 0

  • Blasts*: 5% to 9% in bone marrow; 2% to 9% in peripheral blood. For paediatric patients (aged <18 years), the blast thresholds for MDS-EB are 5% to 19% in bone marrow and 2% to 19% in peripheral blood, and the entity MDS/AML does not apply

  • Cytogenetics**: any

  • Mutations: any, except multi-hit TP53.

MDS/AML

  • Dysplastic lineages: typically ≥1

  • Cytopenias: ≥1

  • Cytoses: 0

  • Blasts: 10% to 19% in bone marrow or peripheral blood. For paediatric patients (aged <18 years), the blast thresholds for MDS-EB are 5% to 19% in bone marrow and 2% to 19% in peripheral blood, and the entity MDS/AML does not apply

  • Cytogenetics**: any, except AML-defining cytogenetic abnormalities (see Acute myeloid leukaemia)

  • Mutations: any, except NPM1, bZIP CEBPA, or TP53.

*Presence of 1% blasts in peripheral blood confirmed on two separate occasions also qualifies for MDS-EB.

**BCR::ABL1 rearrangement or any of the rearrangements associated with myeloid/lymphoid neoplasms with eosinophilia and tyrosine kinase gene fusions exclude a diagnosis of MDS, even in the context of cytopenia.

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