Myelodysplastic syndromes

01OverviewDefinition, clinical context and the essential points that orientate the chapter.

MDS is a family of clonal myeloid neoplasms defined by persistent cytopenia with diagnostic dysplasia, excess blasts or qualifying genetic abnormality. The label should not be applied until common reversible mimics have been assessed. Macrocytosis is frequent but neither necessary nor sufficient. Marrow aspirate evaluates cell morphology and blasts, trephine shows cellularity and fibrosis, cytogenetics detects prognostic structural change and sequencing identifies biologically important mutations. These results must be integrated rather than interpreted as independent positive tests.

Risk predicts both marrow-failure mortality and AML transformation. IPSS-R combines cytogenetics, blasts and depth of cytopenias; IPSS-M adds molecular data. A low score does not mean trivial disease when transfusion dependence, infection or bleeding dominates daily life. Higher-risk genetics or increasing blasts should trigger early transplant review before repeated therapy erodes fitness. Germline predisposition is considered with young age, family history, lifelong cytopenia, physical features or characteristic mutation and affects donor selection.

Support is phenotype driven. Red-cell transfusion thresholds are individualised to symptoms, cardiovascular reserve and quality of life. Erythropoiesis-stimulating agents work best with lower endogenous erythropoietin and modest transfusion need; response is reassessed and ineffective treatment stopped. Platelets are given for bleeding, procedures or protocol prophylaxis, not solely because MDS exists. Recurrent infection prompts antimicrobial and selected G-CSF strategies. Iron chelation is considered when long expected survival and transfusion burden make organ iron clinically relevant.

Disease modification is risk led. Azacitidine can prolong survival in higher-risk MDS but requires repeated cycles and proactive infection and transfusion support because counts may worsen initially. Intensive AML-like therapy suits a smaller fit subgroup and may bridge to transplant. Allogeneic transplant offers cure but its non-relapse mortality competes with MDS risk, so timing is an MDT decision. Clinical trials are particularly important for adverse molecular disease, treatment failure and lower-risk transfusion dependence lacking a standard targeted option.

Key points

Suspect MDS with persistent unexplained macrocytic anaemia, bi- or pancytopenia, hypogranular neutrophils, pseudo-Pelger-Huët cells, abnormal platelets or circulating blasts.
First-line assessment excludes B12, folate, iron and copper deficiency, alcohol, medicines, renal, liver, thyroid, infection, autoimmune and splenic causes before marrow interpretation.
Confirm with marrow aspirate and trephine for morphology, cellularity, fibrosis and blasts plus cytogenetics and a myeloid molecular panel; one dysplastic-looking film is insufficient.
Use WHO or ICC subtype with IPSS-R or IPSS-M risk, performance, frailty, transfusion burden and patient goals rather than blast percentage alone.
Lower-risk care aims to improve cytopenia and quality of life using individualised transfusion, erythropoiesis-stimulating treatment in selected low-EPO anaemia and subtype-directed options.
Higher-risk disease requires early transplant assessment; azacitidine is a standard disease-modifying option for eligible adults not immediately receiving curative allogeneic transplantation.
Azacitidine is commonly 75 mg/m² subcutaneously or intravenously daily on days 1 to 7 every 28 days; assess response only after sufficient cycles unless progression or unacceptable toxicity occurs.
Allogeneic stem-cell transplantation is the only established curative treatment but eligibility depends on biological risk, comorbidity, donor, fitness and informed preference.

02AetiologyUnderlying causes, associations and risk factors, with why each one matters.

Acquired clonal haematopoiesis

MDS arises when a myeloid stem or progenitor clone acquires mutations that impair maturation, increase apoptosis and create ineffective blood-cell production.

Age-related risk

Incidence rises with age as clonal haematopoiesis accumulates; most patients have no single exposure that explains the disease.

Therapy-related and inherited risk

Previous cytotoxic chemotherapy, radiotherapy, benzene and germline marrow-failure or cancer-predisposition syndromes create biologically high-risk subsets requiring specialist genetic assessment.

03PathophysiologyThe causal sequence from the underlying abnormality to symptoms and harm.

1
Ineffective haematopoiesis
Dysplastic precursors die or mature abnormally in marrow, causing peripheral cytopenia despite normal or increased cellularity.
2
Clonal maturation block
Spliceosome, epigenetic, transcription and signalling lesions shape morphology, sideroblasts, fibrosis, blast accumulation and response to targeted or hypomethylating therapy.
3
Progression to AML
Subclonal evolution increases blasts and proliferative fitness; selected defining genetic lesions can establish AML even when the historical 20% blast threshold is not reached.

04Clinical features and red flagsSymptoms, examination findings, patterns of presentation and time-critical warnings.

Anaemic presentation

Fatigue, dyspnoea, angina, dizziness and falls accompany persistent macrocytic or normocytic anaemia after common deficiencies are excluded.

Neutropenic infection

Recurrent oral, skin or respiratory infection may occur at modest counts because dysplastic neutrophils can also function poorly.

Platelet failure

Petechiae, bruising, epistaxis or procedure bleeding reflects thrombocytopenia, dysfunctional platelets or concurrent antithrombotic treatment.

Film dysplasia

Hypogranular or hypolobated neutrophils, anisopoikilocytosis, large abnormal platelets and blasts support urgent marrow assessment but are not diagnostic alone.

Transformation patternRed flag

Rapid worsening cytopenia, new blasts, fever, bone pain or tissue disease suggests AML evolution and accelerates classification.

Red flags requiring action

Fever, rigors, hypotension or confusion with neutropenia is a medical emergency requiring immediate empiric intravenous antibiotics.
Active bleeding with severe thrombocytopenia or coagulopathy requires urgent transfusion-laboratory and haematology coordination rather than waiting for routine marrow review.
New circulating blasts, rapid count deterioration, bone pain or rising LDH may represent AML transformation and requires urgent marrow and molecular classification.

05InvestigationsWhat to request, why it matters and how to interpret it.

Investigation order

Read from the initial assessment onwards. Tests may run in parallel in urgent care; first-line, preferred, confirmatory, definitive and gold-standard labels appear only when the chapter explicitly states them.

01
First-line reversible-cause screenFirst stepFirst line
Why
Prevent nutrient, medicine, infection or organ disease being mislabelled as a clonal neoplasm.
Interpretation and limitations
Use repeat FBC, reticulocytes and film, ferritin and iron, B12, folate, renal, liver, thyroid and context-directed copper, viral, autoimmune and haemolysis tests.
02
Confirmatory marrow aspirate and trephineConfirmatory
Why
Assess multilineage morphology, blast percentage, cellularity, fibrosis and alternative infiltration.
Interpretation and limitations
Review through expert haemato-pathology; dilute aspirate or patchy disease requires trephine correlation and blast findings must be reconciled with defining AML genetics.
03
Cytogenetic and molecular classification
Why
Establish diagnostic lesions, prognosis, germline concern and potential targeted treatment.
Interpretation and limitations
Perform karyotype or appropriate FISH plus myeloid sequencing; variant allele fraction and phenotype help distinguish somatic clone from possible germline predisposition.
04
Risk and treatment baseline
Why
Combine disease risk with the person's ability to tolerate transplant or disease modification.
Interpretation and limitations
Calculate IPSS-R or IPSS-M, record transfusion burden, infections, bleeding, performance, frailty, comorbidity, HLA pathway, ferritin and reproductive goals.

06Differential diagnosisRealistic alternatives and the features that help distinguish them.

Nutritional and toxic cytopenia

B12, folate and copper deficiency, alcohol, zinc excess and medicines can produce cytopenia and dysplasia but improve when the cause is removed.

Infection and inflammation

HIV, hepatitis, parvovirus, severe infection, autoimmune disease and hypersplenism suppress counts and require directed clinical and laboratory testing.

Other marrow neoplasms

AML, aplastic anaemia, myelofibrosis, PNH, plasma-cell disease and MDS or MPN overlap are separated by marrow, flow, cytogenetic and molecular findings.

Clonal cytopenia states

Clonal haematopoiesis and clonal cytopenia of undetermined significance have mutations without full MDS morphology or genetics and require surveillance, not automatic treatment.

07ManagementImmediate care, first-line treatment, alternatives and escalation.

01Persistent unexplained cytopeniaExclude mimics then examine marrowFirst stepOne or more blood counts remain low without a clear transient cause.

1Repeat FBC, reticulocytes and film and assess nutrition, medicines, alcohol, organs, infection, autoimmune disease and spleen.
2Perform marrow aspirate and trephine with morphology, flow, cytogenetics and molecular testing when cytopenia remains unexplained.
3Integrate subtype and risk and identify germline clues before counselling or donor testing.

02Lower-risk symptomatic diseaseImprove the limiting cytopeniaProgression risk is lower but anaemia, infection, bleeding or transfusion burden impairs health.

1Define the dominant cytopenia, endogenous erythropoietin, transfusion need, iron state and patient-valued outcome.
2Use individualised component support and a subtype-appropriate ESA or other commissioned treatment with a prespecified response review.
3Stop ineffective therapy, reassess clone and risk and consider trials or transplant if disease biology or functional burden changes.

03Higher-risk diseasePlan disease modification and cure earlyAdverse genetics, excess blasts or high IPSS risk predicts near-term AML or marrow-failure mortality.

1Refer for transplant eligibility and donor assessment at diagnosis rather than after multiple failed cycles.
2DefinitiveUse azacitidine, trial or selected intensive therapy as definitive non-transplant treatment or a bridge based on fitness and biology.
3Support infection, bleeding and anaemia during early cycles and assess marrow response at the protocol landmark.

Key medicines and prescribing safety3 treatments · regimens, roles and cautions

Disease-modifying first-line treatment for defined higher-risk MDS and related myeloid disease when immediate curative transplantation is not used.

Azacitidine

Give 75 mg/m² subcutaneously once daily on days 1 to 7, followed by 21 treatment-free days in each 28-day cycle; continue for at least 6 cycles and thereafter while benefit persists or until disease progression.

Premedicate for nausea, monitor FBC, creatinine, bicarbonate and liver tests before each cycle and apply SmPC count and renal delay or reduction rules. Do not interchange this injection schedule with oral azacitidine; avoid pregnancy and breastfeeding and discuss fertility.

Reduces transfusion need in selected symptomatic lower-risk anaemia, particularly with lower endogenous erythropoietin and modest prior transfusion burden.

Epoetin alfa

A common lower-risk MDS starting regimen is 30,000 international units subcutaneously once weekly, escalating to 60,000 units weekly if protocol response is inadequate after 8 weeks; stop if no meaningful erythroid response after the defined trial.

Correct iron, B12 and folate deficiency, monitor haemoglobin and blood pressure and avoid haemoglobin overshoot. Review thrombosis risk and do not persist when response criteria are not met.

Relieves symptomatic cytopenia while disease-directed therapy takes effect or when supportive care is the principal strategy.

Transfusion and iron support

Give red cells in one-unit increments with reassessment when clinically appropriate, using an individual haemoglobin and symptom plan; platelet dose and threshold follow bleeding, procedure and prophylactic transfusion guidance rather than a fixed MDS number.

Prevent TACO with rate, volume and diuretic planning, monitor alloantibodies and platelet refractoriness and consider iron assessment and chelation only when cumulative burden, life expectancy and organ risk justify it.

08ComplicationsImportant consequences, why they occur and why they matter clinically.

Anaemia and transfusion dependence

Fatigue, angina, falls and reduced function arise from anaemia, while repeated red-cell support can cause alloimmunisation and clinically significant iron overload.

Infection and bleeding

Neutropenia and dysfunctional neutrophils cause bacterial and fungal infection; thrombocytopenia and abnormal platelets cause mucosal or major bleeding.

AML transformation

Increasing blasts and adverse molecular evolution produce acute leukaemia with worsening marrow failure and reduced treatment tolerance.

Treatment toxicity

Hypomethylating therapy initially worsens cytopenia and infection risk, while transplant carries graft-versus-host disease, organ toxicity, relapse and infertility.

09Monitoring and follow-upTreatment response, safety checks and longer-term review.

During observation, trend FBC, reticulocytes, symptoms, infection, bleeding, transfusion need and new blasts at an interval based on risk and count stability.
During azacitidine, check counts and infection before every cycle and more often during nadir, documenting dose delays, transfusions and antimicrobial support.
Reassess marrow when counts deteriorate unexpectedly, blasts appear, treatment response is due or transplant timing depends on disease burden.
Track red-cell and platelet units, alloantibodies, ferritin trend, cardiac and liver context and TACO history rather than using ferritin alone to mandate chelation.
Recalculate risk after meaningful clonal or marrow change and revisit transplant, trial and goals before functional decline closes options.

10Special situationsVariants, exceptions and circumstances that change the usual approach.

Dysplasia has mimics

B12, copper, alcohol and medicines can produce striking morphological abnormalities, so clonality and clinical context matter.

Marrow components answer different questions

Aspirate shows morphology and blasts, trephine shows cellularity and fibrosis, and genetics establishes clonal biology.

Low risk can still mean high burden

Severe transfusion dependence or infection may dominate quality of life despite a lower predicted AML risk.

Azacitidine needs time

Early cytopenia does not prove failure; adequate cycles with support are needed unless clear progression or intolerable harm occurs.

Transplant referral precedes failure

Donor search and comorbidity work-up take time, so higher-risk disease is referred before repeated treatment erodes fitness.

11Common pitfallsFrequent interpretation and management errors.

01
Diagnosing MDS from macrocytosis before excluding B12, folate, copper, alcohol and medicines.
02
Using aspirate morphology without trephine and genetics.
03
Treating a risk score rather than the person's cytopenia burden and goals.
04
Declaring azacitidine failure after one cytopenic cycle.
05
Delaying transplant assessment until advanced progression.
06
Giving recurrent transfusions without TACO, alloimmunisation and iron planning.