Clonal stem cell disorder with ineffective hematopoiesis, cytopenias, dysplasia, and risk of AML transformation.
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Risk factors
- Advanced age
- Prior chemotherapy (alkylating agents — melphalan, cyclophosphamide; topoisomerase II inhibitors — etoposide) or radiotherapy (therapy-related MDS, t-MDS)
- Benzene and other organic solvent exposure
- Tobacco use
- Inherited bone marrow failure syndromes — Fanconi anemia, dyskeratosis congenita, GATA2 mutations
- Prior aplastic anemia
Pathophysiology
Acquired somatic mutations in hematopoietic stem cells (commonly TET2, SF3B1, ASXL1, DNMT3A, SRSF2, RUNX1, TP53) drive clonal expansion and impaired differentiation. The dysfunctional clone produces morphologically abnormal but functionally inadequate blood cells that undergo intramedullary apoptosis — paradoxical bone marrow hypercellularity with peripheral cytopenias. Progressive genetic instability eventually leads to AML in ~30%.
Clinical presentation
Symptoms
- Fatigue and exertional dyspnea from anemia (most common)
- Recurrent or atypical infections from neutropenia or neutrophil dysfunction
- Easy bruising, petechiae, mucosal bleeding from thrombocytopenia
- Often asymptomatic — discovered on routine CBC
Signs / physical exam
- Pallor, petechiae, mucosal bleeding
- Splenomegaly uncommon (more suggestive of MDS/MPN overlap or CMML)
- Skin lesions (Sweet syndrome, leukemia cutis) in advanced disease
Classic findings
Older patient with persistent unexplained macrocytic anemia, bicytopenia, or pancytopenia and dysplastic morphology on smear/marrow.
Differential diagnosis
- Aplastic anemia — Hypocellular marrow with no dysplasia; younger patients; PNH clone screening
- B12 or folate deficiency — Macrocytic anemia with hypersegmented neutrophils; normal copper; replacement reverses morphologic findings
- Copper deficiency — Pancytopenia mimicking MDS; ring sideroblasts; ataxia/myelopathy; check ceruloplasmin and copper
- Acute myeloid leukemia — ≥20% blasts in marrow or blood; certain cytogenetics (t(8;21), inv(16), t(15;17)) define AML regardless of blast count
- Chronic myelomonocytic leukemia (CMML) — Persistent monocytosis ≥1.0 × 10⁹/L and ≥10% of WBC; classified separately (MDS/MPN overlap)
- Paroxysmal nocturnal hemoglobinuria — Coombs-negative hemolysis, thrombosis; flow cytometry for GPI-deficient clone
Diagnostic workup
Diagnostic criteria
WHO 2022 (now ICC 2022) classification — requires persistent cytopenia(s), dysplasia in ≥10% of cells in ≥1 lineage, exclusion of other causes, and <20% blasts in marrow/blood. Specific entities include MDS with low blasts (formerly RA/RCMD), MDS with ring sideroblasts (SF3B1 mutation), MDS with isolated del(5q), MDS with biallelic TP53 inactivation, and MDS with increased blasts (formerly RAEB).
Labs
- CBC with differential — cytopenias affecting ≥1 lineage; MCV often elevated
- Reticulocyte count — inappropriately low for degree of anemia
- Peripheral smear — pseudo-Pelger-Huët neutrophils (bilobed), hypogranular granulocytes, dysplastic platelets, oval macrocytes
- B12, folate, copper, TSH, iron studies, HIV — exclude reversible causes
- LDH, haptoglobin to assess for hemolysis
- Erythropoietin level (predicts response to ESA)
- Bone marrow aspirate and biopsy — hypercellular with dysplasia in ≥10% of cells in ≥1 lineage; blast percentage; ring sideroblasts (iron stain)
- Cytogenetics (conventional karyotype) and FISH — del(5q), -7/del(7q), trisomy 8, complex karyotype
- Molecular panel — TP53, SF3B1, TET2, ASXL1, RUNX1, EZH2, SRSF2
Imaging
- Generally not required for diagnosis
- CT chest/abdomen/pelvis if concern for transformation, infection, or organomegaly
Treatment
First-line
- Risk stratify with IPSS-R (Revised International Prognostic Scoring System) or the newer IPSS-M (molecular)
- Lower-risk MDS — supportive care: transfusions, erythropoiesis-stimulating agents (epoetin alfa, darbepoetin) if EPO <500 mU/mL
- Iron chelation (deferasirox, deferoxamine) for chronic transfusion dependence (>20-30 units RBC or ferritin >2500)
- Higher-risk MDS — hypomethylating agents: azacitidine or decitabine
Lower-risk MDS (IPSS-R very low/low/intermediate)
- Erythropoiesis-stimulating agents (ESA) if symptomatic anemia and EPO <500
- Luspatercept for anemia, especially with ring sideroblasts/SF3B1 mutation
- Lenalidomide for transfusion-dependent del(5q) MDS
- Iron chelation if chronic transfusion dependence
Higher-risk MDS (IPSS-R high/very high)
- Hypomethylating agents — azacitidine (subcutaneous or oral) or decitabine — improve survival
- Allogeneic hematopoietic stem cell transplant — only curative option; offer to transplant-eligible patients
- Venetoclax + HMA combinations under investigation
Therapy-related MDS
- Typically aggressive course with complex/monosomal karyotype, TP53 mutations
- Allo-HSCT if eligible; HMA otherwise
Second-line / adjunct
- Immunosuppression (ATG + cyclosporine) for hypoplastic MDS variant
- Allogeneic stem cell transplant — only curative therapy
- Clinical trial enrollment for novel agents
Complications
- Progression to acute myeloid leukemia (30% overall; higher in high-risk subtypes)
- Severe infections from neutropenia and granulocyte dysfunction
- Bleeding from thrombocytopenia
- Transfusion-related iron overload causing cardiac, hepatic, endocrine dysfunction
- Cardiovascular complications from chronic anemia
- Treatment toxicity: cytopenias from HMA, transplant-related morbidity
PANCE pearls
- Always exclude reversible causes (B12, folate, copper deficiency, HIV, alcohol) before labeling cytopenias as MDS.
- Ring sideroblasts ≥15% and SF3B1 mutation define MDS with ring sideroblasts (favorable subtype).
- Isolated del(5q) MDS — 'classic 5q- syndrome' — presents in older women with macrocytic anemia, normal/elevated platelets, and responds dramatically to lenalidomide.
- Pseudo-Pelger-Huët cells (bilobed neutrophils) on smear should raise suspicion for MDS.
- TP53 mutations carry poor prognosis and may blunt response to standard therapy.
- Allogeneic stem cell transplant is the only cure — refer transplant-eligible higher-risk patients early.
References
- NCCN Guidelines — NCCN Clinical Practice Guidelines in Oncology: Myelodysplastic Syndromes (current version).
- IPSS-M — Bernard E et al. Molecular International Prognostic Scoring System for myelodysplastic syndromes. NEJM Evidence 2022.
- WHO/ICC 2022 — Khoury JD et al. 5th edition WHO Classification of Haematolymphoid Tumours: Myeloid Neoplasms. Leukemia 2022; Arber DA et al. International Consensus Classification. Blood 2022.
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