Write a short note on myelodysplastic syndrome.

Definition

The myelodysplastic syndromes (MDS) are a group of clonal haematopoietic stem cell disorders characterised by:

1. Ineffective haemopoiesis — a hypercellular (or normocellular) marrow with peripheral cytopenias, the central paradox of the disease

2. Morphological dysplasia in one or more myeloid lineages

3. A propensity to transform into acute myeloid leukaemia

They are predominantly diseases of the elderly, with a median age at diagnosis of about 70 years.

Aetiology

• Primary (de novo) — the majority; associated with age-related clonal haematopoiesis and acquired somatic mutations in genes of RNA splicing (SF3B1, SRSF2), epigenetic regulation (TET2, ASXL1, DNMT3A), and TP53.
• Secondary (therapy-related) — after alkylating agents, topoisomerase II inhibitors or radiotherapy, typically 5–7 years later; carries a markedly worse prognosis with adverse cytogenetics.
• Environmental: benzene and organic solvents, tobacco smoking, prior chemotherapy.
• Inherited predisposition: Fanconi anaemia, Down syndrome, germline GATA2 and RUNX1 mutations.

Clinical Features

Insidious onset, often detected on a routine blood count in an elderly patient:

• Anaemia — the commonest presentation (80%): fatigue, pallor, exertional dyspnoea, angina in those with coronary disease. It is typically macrocytic and refractory to haematinics.
• Neutropenia — recurrent bacterial infections despite a normal or near-normal total white count (function is also impaired).
• Thrombocytopenia — bruising, petechiae, mucosal bleeding.
• Splenomegaly is usually absent (its presence suggests a myeloproliferative overlap such as chronic myelomonocytic leukaemia).
• Autoimmune phenomena — vasculitis, arthritis, pericarditis, and Sweet's syndrome (acute febrile neutrophilic dermatosis) — recognised associations.
• Progressive transfusion dependence with consequent iron overload.

Investigations

• CBC: cytopenias in one or more lineages; macrocytosis with a normal or raised MCV; reticulocytopenia.
• Peripheral smear — dysplastic features:
• Red cells: anisopoikilocytosis, macrocytes, basophilic stippling, nucleated red cells
• Neutrophils: hypogranular cytoplasm and hypolobated nuclei — the "pseudo-Pelger–Huët anomaly" (bilobed, pince-nez nuclei), a characteristic finding
• Platelets: giant and hypogranular forms
• Blasts may be present but are < 20% (≥ 20% defines acute leukaemia)
• Bone marrow aspiration and trephine biopsy — diagnostic: hypercellular marrow with dysplasia in ≥ 10% of cells in one or more lineages; ring sideroblasts on Perls' (Prussian blue) staining (iron-laden mitochondria encircling the nucleus, associated with SF3B1 mutation and a better prognosis); blast percentage determines subtype.
• Cytogenetics — essential for prognosis: isolated del(5q) carries a favourable prognosis and a specific treatment; monosomy 7, complex karyotype and TP53 abnormality are adverse.
• Molecular panel for prognostically and therapeutically relevant mutations.
• Exclude reversible causes of dysplasia and cytopenias: vitamin B12 and folate deficiency, copper deficiency, HIV, alcohol excess, recent chemotherapy, and drug effects — all can mimic MDS morphologically.

Prognosis

Stratified by the Revised International Prognostic Scoring System (IPSS-R), which uses marrow blast percentage, cytogenetics, and the depth of cytopenias to predict overall survival and the risk of leukaemic transformation. Outcomes range from many years of stable disease to rapid progression. Around 30% transform to acute myeloid leukaemia, and much of the remaining mortality is from infection and bleeding due to marrow failure rather than from transformation.

Management

Treatment is determined by risk category, age and comorbidity, and for many patients the goal is quality of life rather than cure.

Lower-risk disease — supportive and quality-of-life focused:

• Red cell transfusion for symptomatic anaemia, with iron chelation for those receiving long-term transfusion.
• Erythropoiesis-stimulating agents (with G-CSF in selected cases) — effective in those with a low endogenous erythropoietin level and low transfusion burden.
• Luspatercept — for anaemia in MDS with ring sideroblasts.
• Lenalidomide — strikingly effective in del(5q) MDS, often producing transfusion independence.
• Immunosuppressive therapy (ATG, ciclosporin) — for hypoplastic MDS in younger patients.
• Antibiotics for infection; platelet transfusion for bleeding.

Higher-risk disease:

• Hypomethylating agents — azacitidine or decitabine — the standard of care; they delay progression and improve survival but are not curative.
• Intensive AML-type chemotherapy in selected fit patients.
• Allogeneic haematopoietic stem cell transplantation — the ONLY curative treatment, offered to fit patients with higher-risk disease and a suitable donor; age and comorbidity limit eligibility, which is a particular constraint given the elderly population affected.