Definition and epidemiology
Myelodysplastic syndrome (MDS) is a group of clonal myeloid neoplasms arising from an abnormal hematopoietic stem cell, resulting in dysplasia (abnormal maturation) of one or more cell lines and peripheral blood cytopenias. The bone marrow is typically normocellular or hypercellular, reflecting ineffective hematopoiesis rather than marrow failure from aplasia.
- Median age at diagnosis is around 70 years; it is uncommon before age 50 except in therapy-related or genetic-predisposition cases.
- Incidence increases steeply with age, estimated at roughly 20-50 per 100,000 per year in patients over 70.
- Slight male predominance.
- MDS is considered a premalignant/malignant myeloid neoplasm and is classified alongside AML and myeloproliferative neoplasms in the WHO classification.
- MDS marrow blasts must be <20%; ≥20% reclassifies as AML
- Dysplastic marrow is normo/hypercellular, unlike the hypocellular marrow of aplastic anemia
- del(5q) MDS responds specifically well to lenalidomide
- SF3B1 mutation correlates with ring sideroblasts and favorable prognosis
- TP53 mutation and complex karyotype predict poor prognosis and AML transformation
- IPSS-R integrates cytogenetics, blast %, and cytopenia severity for risk stratification
- Hypomethylating agents (azacitidine, decitabine) are first-line for higher-risk MDS
- Allogeneic stem cell transplant is the only curative option
Etiology and risk factors
Most cases are primary (de novo), arising without an identifiable cause, likely from age-related clonal hematopoiesis (CHIP) progressing to MDS. A minority are secondary/therapy-related, which tend to behave more aggressively.
Risk factors
- Advanced age
- Prior cytotoxic chemotherapy (especially alkylating agents, topoisomerase II inhibitors) — therapy-related MDS (t-MDS)
- Prior ionizing radiation exposure
- Occupational exposure to benzene and other solvents
- Cigarette smoking
- Inherited bone marrow failure syndromes (e.g., Fanconi anemia, Diamond-Blackfan anemia) in younger patients
- Germline predisposition syndromes (e.g., GATA2 deficiency, telomere biology disorders)
Therapy-related MDS classically appears 3-7 years after alkylating agent exposure (often with complex karyotype, including -5/5q- or -7/7q-) or 1-3 years after topoisomerase II inhibitor exposure (often with 11q23/KMT2A rearrangements).
Pathophysiology
MDS originates from a single mutated hematopoietic stem cell that acquires a survival or proliferative advantage, forming a dominant clone. This clone undergoes ineffective differentiation, producing morphologically abnormal (dysplastic) precursors that undergo excessive intramedullary apoptosis before reaching the peripheral blood — explaining the paradox of a cellular marrow with peripheral cytopenias.
Common mutations
- Splicing factor genes: SF3B1, SRSF2, U2AF1 — among the most frequent
- Epigenetic regulators: TET2, DNMT3A, ASXL1, EZH2
- Transcription factors: RUNX1
- TP53 mutations — associated with complex karyotype and poor prognosis
SF3B1 mutations are strongly associated with the ring sideroblast phenotype and tend to carry a more favorable prognosis. As additional mutations accumulate and genomic instability increases, the clone can acquire a proliferative advantage and progress to AML (a process sometimes called clonal evolution).
Clinical features
Symptoms reflect which cell lines are deficient and are often insidious in onset, discovered incidentally on routine blood counts.
- Anemia (most common): fatigue, dyspnea, pallor
- Neutropenia: recurrent or severe infections
- Thrombocytopenia: easy bruising, petechiae, mucosal bleeding
- Splenomegaly is uncommon in classic MDS (more typical of overlap myeloproliferative/myelodysplastic syndromes like CMML)
- Many patients are asymptomatic at diagnosis, with cytopenia found on routine labs
Physical exam is often unremarkable beyond signs of anemia or bleeding; significant lymphadenopathy or hepatosplenomegaly should prompt consideration of an alternative or overlap diagnosis.
Diagnosis
Diagnosis requires demonstrating peripheral cytopenia(s) with marrow dysplasia and excluding other causes of cytopenia.
Peripheral blood
- Complete blood count: one or more cytopenias (anemia most common)
- Peripheral smear: macrocytosis, dimorphic red cells, hypogranular/hyposegmented neutrophils (pseudo-Pelger-Huët cells), large or agranular platelets
Bone marrow examination (required for diagnosis)
- Hypercellular or normocellular marrow with dysplastic changes in ≥1 lineage (erythroid, myeloid, megakaryocytic)
- Ring sideroblasts on iron stain in some subtypes
- Blast percentage quantified — must be less than 20% (≥20% defines AML)
- Cytogenetics: karyotype and/or FISH to detect recurrent abnormalities (del(5q), -7/del(7q), trisomy 8, complex karyotype)
- Molecular/NGS panel for prognostic and diagnostic mutations (SF3B1, TP53, etc.)
Risk stratification
The Revised International Prognostic Scoring System (IPSS-R) incorporates cytogenetic risk group, percentage of marrow blasts, and severity of cytopenias (hemoglobin, platelets, absolute neutrophil count) to stratify patients into very low to very high risk categories, which guides treatment intensity and prognosis.
Diagnosis is one of exclusion — nutritional deficiencies, infections, drug effects, and other marrow disorders must be ruled out before attributing dysplasia to MDS.
Differential diagnosis
- Vitamin B12 or folate deficiency — can cause megaloblastic changes mimicking dysplasia; must be excluded with levels
- Copper deficiency or zinc toxicity — can cause acquired sideroblastic changes
- Aplastic anemia — hypocellular marrow (vs normo/hypercellular in MDS)
- Acute myeloid leukemia — marrow blasts ≥20%
- Chronic myelomonocytic leukemia (CMML) — overlap syndrome with monocytosis and myeloproliferative features
- Paroxysmal nocturnal hemoglobinuria — flow cytometry for GPI-anchored protein loss
- Drug-induced cytopenia/dysplasia — recent chemotherapy, alcohol, or certain medications (e.g., mycophenolate)
- HIV infection — can cause marrow dysplasia and cytopenias
- Congenital dyserythropoietic anemia — in younger patients
Management
Treatment is risk-adapted, based primarily on IPSS-R category, patient age, performance status, and comorbidities. There is no universal cure outside of allogeneic stem cell transplant; most management is aimed at reducing transfusion needs, infection risk, and delaying progression to AML.
Lower-risk disease
- Observation for asymptomatic, low-risk cytopenias
- Erythropoiesis-stimulating agents (epoetin, darbepoetin) for symptomatic anemia with low endogenous erythropoietin
- Lenalidomide — particularly effective in MDS with isolated del(5q) and transfusion-dependent anemia
- Luspatercept — for transfusion-dependent anemia, especially with ring sideroblasts/SF3B1 mutation
- Supportive care: red cell and platelet transfusions, iron chelation if transfusion-dependent, growth factors (G-CSF) for severe neutropenic infection
Higher-risk disease
- Hypomethylating agents (azacitidine, decitabine) — standard first-line therapy to delay AML progression and improve survival
- Allogeneic hematopoietic stem cell transplant — the only potentially curative option; reserved for eligible (typically younger, fit) patients given treatment-related morbidity/mortality
- Intensive chemotherapy (AML-like regimens) may be used as a bridge to transplant in select higher-risk or blast-excess cases
- Clinical trial enrollment is encouraged given evolving targeted therapies
Guideline bodies (NCCN, ELN, ESMO) broadly agree on this risk-adapted framework; specific drug sequencing and transplant eligibility criteria vary somewhat by region and center.
Complications and prognosis
- Transformation to AML — occurs in a significant proportion of patients, more likely with higher blast percentage, complex karyotype, or TP53 mutation
- Infection — leading cause of morbidity/mortality from neutropenia
- Bleeding — from thrombocytopenia
- Iron overload — from chronic transfusions, risking cardiac and hepatic toxicity if untreated
- Transfusion dependence — associated with worse quality of life and prognosis
Prognosis is highly variable: IPSS-R very-low-risk patients may have median survival exceeding 8 years, while very-high-risk patients may survive less than 1 year without transplant. Overall, MDS behaves as a chronic but potentially fatal clonal disorder, with disease biology (genetics, blast count, cytopenia severity) driving outcomes far more than any single symptom.
"BLAST" to recall MDS red flags: Blasts <20% (diagnostic cutoff), Lineage dysplasia (≥1 cell line), Age (older adults), Secondary causes excluded (B12, drugs, alcohol), Transfusion dependence predicts worse prognosis.
Practice questions
1. A 72-year-old man is found to have persistent macrocytic anemia and mild thrombocytopenia on routine labs. Vitamin B12, folate, and iron studies are normal. Peripheral smear shows hypogranular neutrophils and occasional pseudo-Pelger-Huët cells. Bone marrow biopsy reveals a hypercellular marrow with dysplastic changes in erythroid and myeloid lineages and 8% blasts. Which of the following best confirms this patient's diagnosis?
2. A 65-year-old woman with transfusion-dependent anemia is diagnosed with MDS. Cytogenetic analysis reveals an isolated deletion of chromosome 5q as the sole abnormality, with no excess blasts. Which treatment is most specifically effective for this cytogenetic subtype?
3. A 68-year-old man with higher-risk MDS (IPSS-R high risk, 15% marrow blasts, complex karyotype with TP53 mutation) is being evaluated for treatment. He is otherwise fit with good performance status and has an HLA-matched sibling donor. Which treatment offers the only potential for cure?
Frequently asked questions
What causes myelodysplastic syndrome?
Most MDS arises de novo from age-related mutations in hematopoietic stem cells without a clear trigger. A minority is therapy-related, following prior chemotherapy (alkylating agents, topoisomerase II inhibitors) or radiation. Other risk factors include benzene exposure, smoking, and inherited bone marrow failure syndromes in younger patients. The underlying mechanism is clonal expansion of a mutated stem cell with ineffective maturation.
What are the first symptoms of MDS?
The earliest symptoms are usually fatigue, pallor, and shortness of breath from anemia, since anemia is the most common initial cytopenia. Some patients present with recurrent infections from neutropenia or easy bruising and bleeding from thrombocytopenia. Many cases are detected incidentally when routine blood counts show unexplained cytopenia before any symptoms develop.
How is myelodysplastic syndrome diagnosed?
MDS is diagnosed through a combination of persistent peripheral cytopenia and bone marrow biopsy showing dysplastic changes in one or more cell lines with less than 20% blasts. Cytogenetic and molecular testing (karyotype, FISH, NGS panel) help confirm the clonal nature and guide prognosis via the IPSS-R score. Other causes of cytopenia, especially B12/folate deficiency and drug effects, must be excluded first.
Is myelodysplastic syndrome curable?
MDS is generally not curable except through allogeneic hematopoietic stem cell transplant, which carries significant risks and is only offered to select eligible patients. For most patients, treatment focuses on controlling cytopenias, reducing transfusion needs, and delaying progression to acute leukemia rather than cure. Lower-risk disease can be managed for years with supportive therapies.
MDS vs AML — what is the difference?
The key distinction is bone marrow blast percentage: MDS has fewer than 20% blasts, while AML is defined by 20% or more (or specific recurrent genetic abnormalities regardless of blast count). MDS is a chronic disorder of ineffective, dysplastic blood cell production, whereas AML is an acute, rapidly progressive leukemia. MDS can transform into AML over time as the clone acquires additional mutations.
Key drugs
Related conditions and differentials
Sources and further reading
StatPearls (NCBI Bookshelf)MedlinePlusWHO ICD-10: D46
Educational content for medical students, prepared by the WhiteCoat Pro editorial team with AI assistance; every page is reviewed by a second AI model for factual errors. It is not medical advice and does not replace the product label, local guidelines or a clinician.