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Q1: Definition, classification and the AML boundary (2 min)
- Define the myelodysplastic syndromes: clonal haematopoietic stem-cell neoplasms defined by dysplastic, ineffective haematopoiesis, peripheral cytopenia(s) and a variable risk of transformation to AML.
- State the three diagnostic requirements: dysplasia at least 10 percent in one or more lineages (or an MDS-defining cytogenetic lesion), persistent unexplained cytopenia, and exclusion of secondary causes.
- Blast threshold: 20 percent marrow or peripheral blasts = AML (WHO lowered the FAB 30 percent). MDS-EB1 is 5 to 9 percent; MDS-EB2 is 10 to 19 percent.
- Outline the WHO 2022 categories: MDS with del(5q), MDS with SF3B1 mutation, MDS with low blasts (single/multilineage), MDS-EB, MDS with biallelic TP53 inactivation (MDS-biTP53), and MDS with fibrosis. Note CMML is now an MDS/MPN overlap neoplasm (monocytosis at least 1 x 10^9/L).
Q2: Pathophysiology and mechanism (3 min)
- Ineffective haematopoiesis: the founding clone proliferates but maturing progenitors undergo excessive intramedullary apoptosis — hence a hypercellular marrow with peripheral cytopenia (the defining paradox).
- Two parallel processes: (1) ineffective haematopoiesis driving the cytopenias (anaemia, infection, bleeding); (2) progressive blast accumulation and clonal evolution driving AML transformation in about 30 percent.
- Cytogenetics: favourable — isolated del(5q), del(20q), -Y, normal; adverse — complex (at least 3 abnormalities), monosomal karyotype, -7/del(7q).
- Genes/molecular: SF3B1 (ringed sideroblasts, favourable); TP53 multi-hit (adverse, complex karyotype, t-MDS); ASXL1, RUNX1, EZH2, NRAS (adverse); TET2/DNMT3A (common, variable).
- CHIP/CCUS/ICUS: the antecedent clonal-haematopoiesis spectrum toward overt MDS.
Q3: Investigations and risk stratification (3 min)
- Bloods + film: macrocytosis, Pelgeroid hypogranular neutrophils, giant/hypogranular platelets, reticulocytes inappropriately low, blast count; plus B12, folate, copper, ferritin, HIV/viral, LDH, EPO level.
- Bone-marrow aspirate/trephine with Prussian-blue iron stain: dysplasia per lineage, blast percent, micromegakaryocytes, ringed sideroblasts.
- Cytogenetics (karyotype + FISH) and molecular NGS (TP53, SF3B1, ASXL1, RUNX1).
- IPSS-R = marrow blast percent + cytogenetic category + haemoglobin + platelet count -> five risk categories (very low to very high) with distinct median survival (about 8.8 years down to about 0.8 years). Mention the newer molecular IPSS-M.
- Pitfall: dysplasia alone is not MDS — always exclude B12, folate, copper deficiency and alcohol first.
Q4: Management — definitive and supportive (3 min)
- Lower-risk (IPSS-R very low/low/intermediate): supportive care plus erythropoiesis-stimulating agents (epoetin/darbepoetin) if serum EPO low and transfusion need low; lenalidomide for del(5q); luspatercept for ringed-sideroblast/SF3B1 ESA-resistant disease; immunosuppression (ATG + ciclosporin) for selected hypocellular, HLA-DR15-positive younger patients.
- Higher-risk (IPSS-R high/very high): hypomethylating agent — azacitidine 75 mg/m2 x 7 days (or decitabine), +/- venetoclax; allogeneic stem-cell transplant is the only cure, for fit patients using reduced-intensity conditioning.
- Supportive: red-cell/platelet transfusion (irradiated if transplant candidate), iron chelation (deferasirox) when ferritin over about 1000 microg/L, antimicrobial prophylaxis, ESA for anaemia. Avoid routine TPO-receptor agonists (blast-progression concern).
Q5: Complications, prognosis and an emergency (2 min)
- Disease complications: progressive cytopenia (infection, bleeding), transfusional iron overload (cirrhosis, cardiac failure, endocrinopathy), and AML transformation in about 30 percent.
- Treatment complications: HMA cytopenias/GI/fatigue; lenalidomide — cytopenias, VTE, rash; deferasirox — renal/hepatic; allogeneic SCT — GVHD, infections, transplant-related mortality.
- Prognosis: IPSS-R drives survival — from near-normal in low-risk del(5q) to under a year in very-high-risk/multi-hit TP53 disease. Allogeneic transplant is the only curative modality.
- Emergency management: febrile neutropenia — cultures and empirical antipseudomonal beta-lactam; severe anaemia — transfuse; major bleeding — platelet support; transfusion-related iron overload — initiate chelation.