Myelodysplasia

Definition. Myelodysplastic syndromes are clonal haematopoietic stem cell disorders characterised by ineffective haematopoiesis — a hypercellular or normocellular marrow with peripheral cytopenias — morphological dysplasia, and a tendency to transform into acute myeloid leukaemia. It is predominantly a disease of old age, with a median age of 70–75 and incidence rising to over 30 per 100,000 beyond 70 years.

Aetiology. Mostly primary/de novo, arising from age-related clonal haematopoiesis. Secondary (therapy-related) MDS follows alkylating agents (5–7 years later, with del(5q)/del(7q)) and topoisomerase II inhibitors, radiotherapy, and exposure to benzene, organic solvents and tobacco. Common somatic mutations: SF3B1 (favourable, ring sideroblasts), TET2, ASXL1, DNMT3A, RUNX1, TP53 (adverse).

Clinical features. Often discovered incidentally on a routine blood count. Otherwise, symptoms of anaemia (fatigue, dyspnoea, angina, falls, worsening heart failure), recurrent infection from neutropenia and impaired neutrophil function, and bruising and bleeding from thrombocytopenia. Splenomegaly is unusual except in CMML. Autoimmune phenomena (vasculitis, arthritis, pericarditis) occur in about 10%.

Diagnosis. Persistent unexplained cytopenia with a blood film showing oval macrocytes, hypogranular neutrophils and the Pelger-Huët anomaly (bilobed nuclei), giant or hypogranular platelets, and circulating blasts. Bone marrow aspirate and trephine are essential — dysplasia in ≥10% of cells in one or more lineages, blasts <20% (20% or more defines AML), ring sideroblasts on Perls stain, and cytogenetics (del(5q), monosomy 7, trisomy 8, complex karyotype). Always exclude the mimics first — B and folate 12 deficiency, copper deficiency, alcohol, HIV, drugs and recent chemotherapy.

Classification and prognosis. Classified by the WHO 5th edition (2022)/ICC by blast percentage, lineage dysplasia, ring sideroblasts and defining genetic lesions — MDS with low blasts, MDS with SF3B1 mutation, MDS with del(5q), MDS with increased blasts, MDS with biallelic TP53 inactivation. Prognosis uses the Revised International Prognostic Scoring System (IPSS-R) based on cytogenetics, marrow blast percentage, haemoglobin, platelet count and neutrophil count, giving five risk groups from very low to very high, with median survival ranging from about 8.8 years to 0.8 years.

Management (risk-adapted). Lower-risk disease — supportive care with transfusion and iron chelation if more than 20–25 units are transfused; erythropoiesis-stimulating agents if serum EPO <500 mU/mL; lenalidomide for del(5q); luspatercept for anaemia with ring sideroblasts/SF3B1 mutation; immunosuppression in selected hypoplastic MDS. Higher-risk disease — hypomethylating agents (azacitidine or decitabine), which improve survival and are well tolerated in the elderly, or intensive AML-type chemotherapy in the fit. Allogeneic stem cell transplantation with reduced-intensity conditioning is the only curative option and is feasible up to about 70– 75 years in fit patients.

Molecular prognostication and two new drugs. The IPSS-M (Molecular IPSS) incorporates 31 gene mutations with clinical variables and reclassifies about 46% of patients compared with IPSS-R, most often upstaging them and thereby changing transplant timing. For lower-risk transfusion-dependent anaemia: the COMMANDS trial (Lancet Haematol 2024) showed luspatercept is superior to epoetin alfa as first-line therapy, and imetelstat, a telomerase inhibitor, was FDA-approved in June 2024 (IMerge trial, Lancet 2024) for transfusion-dependent lower-risk MDS after ESA failure, giving durable transfusion independence irrespective of ring sideroblast status.