Key Facts

Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal haematopoietic stem cell disorders characterised by ineffective haematopoiesis, peripheral blood cytopenias, and a variable risk of progression to acute myeloid leukaemia.

Epidemiology

• Incidence: ~4–5 per 100,000 per year; increases markedly with age
• Median age at diagnosis: ~70 years
• Male:female ratio ~1.5:1

Aetiology

• De novo (~80%): no identifiable cause
• Therapy-related (~20%): prior chemotherapy (alkylating agents, topoisomerase II inhibitors) or radiotherapy
• Risk factors: benzene exposure, smoking, prior cytotoxic therapy

Pathophysiology

• Acquired somatic mutations in haematopoietic stem cells → clonal expansion
• Common mutations: TET2, ASXL1, SF3B1 (ring sideroblasts), TP53 (high-risk), DNMT3A
• Ineffective haematopoiesis: cells produced but die prematurely in marrow (apoptosis)
• Cytopenias despite hypercellular marrow (paradox)
• Accumulation of additional mutations → AML transformation

Typical Presentation

• Incidental finding: cytopenias on routine blood tests (most common)
• Anaemia symptoms: fatigue, pallor, dyspnoea (most common presentation)
• Infections: recurrent (neutropenia)
• Bleeding: easy bruising, petechiae, mucosal bleeding (thrombocytopenia)

Examination

• Pallor
• Petechiae, bruising
• Splenomegaly (mild, ~10%)

Red Flags

• Progressive cytopenias
• Increasing blast percentage (approaching AML transformation)
• Constitutional symptoms (weight loss, night sweats — transformation)
• Severe neutropenic sepsis

Bloods

• FBC: cytopenias — anaemia (often macrocytic), ± neutropenia, ± thrombocytopenia
• Blood film: dysplastic features
  • Pseudo-Pelger-Huët cells (bilobed neutrophils)
  • Hypogranular neutrophils
  • Oval macrocytes
  • Occasional circulating blasts
• Reticulocyte count: inappropriately low
• B12, folate, iron studies: exclude deficiency
• EPO level: guides ESA use

Bone Marrow (DIAGNOSTIC)

• Aspirate: dysplasia in ≥1 lineage (erythroid, myeloid, megakaryocytic); blast percentage; ring sideroblasts (Prussian blue stain)
• Trephine biopsy: cellularity, architecture
• Cytogenetics: del(5q), del(7q), trisomy 8, complex karyotype
• Molecular: SF3B1 (ring sideroblasts, good prognosis), TP53 (poor prognosis)
• Iron stain: ring sideroblasts (≥15% for MDS-RS; ≥5% if SF3B1 mutated)

Prognostic

• IPSS-R: based on cytogenetics, blast %, Hb, platelets, ANC → very low, low, intermediate, high, very high risk

Low-Risk MDS (IPSS-R very low/low/intermediate)

Supportive:

• Transfusion: RBC and platelets as needed
• Iron chelation: if transfusion-dependent (ferritin >1000; deferasirox)
• EPO ± G-CSF: if EPO level <500 and low transfusion burden

Specific:

• Lenalidomide 10mg daily: for del(5q) MDS (NICE TA322) — ~65% transfusion independence
• Luspatercept: for MDS-RS with low transfusion burden

High-Risk MDS (IPSS-R high/very high)

• Azacitidine 75mg/m² SC × 7 days every 28 days: hypomethylating agent; delays AML transformation, improves survival (NICE TA218)
• Allogeneic SCT: only curative option; consider in fit patients <70 with donor
• Best supportive care: if unfit for intensive therapy

Referral Criteria

• Haematology: all suspected MDS
• Specialist MDS centre: SCT assessment

• Very variable depending on IPSS-R risk group:
  • Very low risk: median survival ~8 years
  • Low risk: ~5 years
  • Intermediate: ~3 years
  • High risk: ~1.5 years
  • Very high risk: ~0.8 years
• AML transformation: ~30% overall; higher in high-risk
• Del(5q): good prognosis; responds well to lenalidomide
• TP53 mutation: poor prognosis regardless of other factors
• SCT: 40–50% 3-year survival in high-risk MDS

WHO 2022 MDS Classification (Simplified)