Myelodysplastic Syndrome
Myelodysplastic syndrome is a group of clonal hematopoietic stem cell disorders characterized by ineffective hematopoiesis, peripheral cytopenias, and dysplastic changes in one or more myeloid cell lines with a risk of progression to acute myeloid leukemia.
Myelodysplastic Syndrome (MDS)
Myelodysplastic Syndrome — let's break the name down:
- "Myelo" = bone marrow (Greek: myelos)
- "Dys" = abnormal/disordered (Greek: dys)
- "Plastic" = formation/growth (Greek: plasis)
So MDS literally means "disordered bone marrow formation."
MDS is a heterogeneous group of clonal haematopoietic stem cell disorders characterised by ineffective and dysplastic (morphologically abnormal) haematopoiesis, leading to peripheral blood cytopenias despite a usually hypercellular bone marrow, with a propensity to transform into acute myeloid leukaemia (AML). [1][2]
The key conceptual paradox of MDS is this: the bone marrow is busy making cells (hypercellular), but the cells it produces are defective and die prematurely within the marrow (intramedullary apoptosis) before they can be released into the blood — hence "ineffective haematopoiesis." The result is peripheral cytopenias (low blood counts) despite a packed marrow. Think of it as a factory with many workers but terrible quality control — lots of products are made but most are defective and thrown away before they ever leave the factory floor.
Core Concept — Ineffective Haematopoiesis
MDS = hypercellular marrow + peripheral cytopenias. The marrow can make cells, but cannot release functional ones into the circulation. This is fundamentally different from aplastic anaemia (where the marrow is empty) and from myeloproliferative neoplasms (where the marrow overproduces functional cells).
MDS is considered a pre-leukaemic condition — it may transform into acute leukaemia (specifically AML). [1][2][3] The blast percentage must be ≤20% to remain classified as MDS; once it reaches ≥20% blasts in the bone marrow or peripheral blood, it is reclassified as AML (by WHO definition). [2][4]
2. Epidemiology
- Increased incidence with age; median age at diagnosis is approximately 65–70 years. [2]
- Overall incidence: ~3–5 per 100,000/year in the general population, but rises dramatically to 20–50 per 100,000/year in those > 70 years old.
- Male predominance (M > F). [2]
- MDS is one of the most common haematological malignancies in the elderly.
- In Hong Kong specifically, with an ageing population, MDS is an increasingly recognized entity. The incidence mirrors global trends.
| Feature | Detail |
|---|---|
| Median age at diagnosis | ~65–70 years |
| Sex ratio | M > F (approximately 1.5–2:1) |
| Paediatric MDS | Rare; accounts for < 5% of all childhood haematological malignancies |
| Therapy-related MDS | Younger age of onset (depends on primary cancer treatment timing) |
- The ageing demographic in Hong Kong means MDS prevalence is increasing.
- Therapy-related MDS (t-MDS) is seen in patients who have been treated with chemotherapy/radiotherapy for other malignancies (e.g., breast cancer, lymphoma).
- Occupational benzene exposure is less common now due to regulations but historically relevant.
3. Risk Factors
Risk factors for MDS can be divided into de novo (primary) and therapy-related (secondary) categories:
Most cases have no identifiable cause (idiopathic). Risk factors include:
| Risk Factor | Mechanism |
|---|---|
| Advanced age | Accumulated somatic mutations in haematopoietic stem cells over decades (clonal haematopoiesis of indeterminate potential — CHIP — is the precursor state) |
| Male sex | Unclear; may relate to occupational exposures or X-chromosome-linked gene dosage effects |
| Smoking | Benzene and other carcinogens in tobacco cause DNA damage in HSCs |
| Benzene exposure | Directly toxic to haematopoietic stem cells; causes DNA strand breaks |
| Pesticides, solvents | Similar mechanisms to benzene |
| Genetic predisposition | Inherited bone marrow failure syndromes (see below) |
Therapy-related MDS arises following prior chemotherapy or radiotherapy for another malignancy. [3][5]
| Prior Therapy | Typical Latency | Characteristic Cytogenetics |
|---|---|---|
| Alkylating agents (e.g., cyclophosphamide, melphalan, busulfan) | 5–7 years | del(5q), del(7q), complex karyotype |
| Topoisomerase II inhibitors (e.g., etoposide, doxorubicin) | 1–3 years | Balanced translocations (11q23/MLL) — more often presents as t-AML directly |
| Radiotherapy | 5–10 years | Similar to alkylating agents |
High Yield — Therapy-Related MDS/AML
Alkylating agents → latency 5–7 years → often presents as MDS first → then transforms to AML → del(5q), del(7q), complex karyotype → poor prognosis. [3][5] Topoisomerase II inhibitors → shorter latency 1–3 years → often presents as AML directly (skipping MDS) → balanced translocations (11q23). [3][5]
These inherited bone marrow failure syndromes predispose to MDS → AML transformation:
| Syndrome | Inheritance | Key Features | Diagnostic Test |
|---|---|---|---|
| Fanconi anaemia | AR (rarely XR) | Short stature, café-au-lait spots, radial ray anomalies, ↑risk MDS/AML | Diepoxybutane (DEB) chromosomal breakage test [2] |
| Dyskeratosis congenita | XR (usually) | Nail dystrophy, oral leukoplakia, reticular skin pigmentation; mutation in telomere-related genes [2] | Telomere length assay |
| Shwachman-Diamond syndrome | AR | Pancreatic exocrine insufficiency, skeletal abnormalities | Genetic testing (SBDS gene) |
| Diamond-Blackfan syndrome | AD | Pure red cell aplasia in infancy | Elevated erythrocyte adenosine deaminase (eADA) |
| Down syndrome (Trisomy 21) | Chromosomal | 15–20x increased risk of AML/MDS | Karyotype |
4. Anatomy and Function — Normal Haematopoiesis Review
To understand MDS, you must first understand what goes wrong — so let's review normal haematopoiesis.
- The bone marrow is the primary site of haematopoiesis in adults, located within the medullary cavities of flat bones (sternum, iliac crest, vertebrae) and proximal long bones.
- The haematopoietic stem cell (HSC) is a pluripotent cell capable of self-renewal and differentiation into all blood cell lineages.
- MDS arises from a mutated HSC that has acquired somatic mutations, giving it a clonal advantage over normal HSCs.
- The clone expands and dominates the marrow, but the cells it produces are dysplastic (morphologically abnormal) and undergo excessive apoptosis (programmed cell death) within the marrow.
- This affects all three myeloid lineages — erythroid, granulocytic, and megakaryocytic — to varying degrees.
- The lymphoid lineage is generally spared (unlike MPN/MDS overlap syndromes or lymphoid neoplasms).
This is the central paradox:
- The mutated HSC clone proliferates actively → hypercellular marrow
- The dysplastic progeny have abnormal maturation → increased intramedullary apoptosis
- The cells that do mature are often functionally deficient (e.g., hypogranular neutrophils cannot kill bacteria effectively)
- Net result: low blood counts despite high marrow cellularity
5. Etiology and Pathophysiology
5.1 Molecular Pathogenesis
MDS is fundamentally a clonal stem cell disorder driven by acquired somatic mutations. The current understanding involves a multi-step model:
- With ageing, HSCs accumulate somatic mutations.
- When a mutation confers a selective growth advantage, that HSC clone expands — this is called CHIP (or age-related clonal haematopoiesis, ARCH).
- CHIP is defined as the presence of a somatic mutation (typically in DNMT3A, TET2, or ASXL1) at a variant allele frequency (VAF) ≥2% in a person with no haematological malignancy or cytopenia.
- CHIP is extremely common: present in ~10% of people > 65 and > 20% of people > 80.
- Most people with CHIP will never develop MDS — but they have a 0.5–1% per year risk of progression.
- When CHIP is accompanied by unexplained cytopenias but does not yet meet full MDS diagnostic criteria (no definitive dysplasia or diagnostic cytogenetics), it is termed CCUS.
- This is the "grey zone" between CHIP and MDS.
- Additional mutations accumulate → sufficient dysplasia and cytopenias to meet diagnostic criteria for MDS.
- Further mutations (especially in signalling pathway genes like FLT3, RAS, TP53) push the disease towards overt acute leukaemia (≥20% blasts).
| Gene Category | Examples | Function | Consequence of Mutation |
|---|---|---|---|
| Epigenetic regulators | TET2, DNMT3A, IDH1/2, ASXL1, EZH2 | DNA methylation and histone modification | Altered gene expression → dysplastic differentiation |
| Splicing factors | SF3B1, SRSF2, U2AF1, ZRSR2 | Pre-mRNA splicing | Aberrant RNA processing → abnormal protein production |
| Transcription factors | RUNX1, ETV6, GATA2 | Regulate haematopoietic gene expression | Impaired differentiation |
| Tumour suppressors | TP53 | Cell cycle checkpoint, apoptosis | Genomic instability, treatment resistance, very poor prognosis |
| Signalling pathway | NRAS, KRAS, CBL, JAK2 | Growth factor signalling | Proliferative advantage (more prominent in CMML and progression to AML) |
| Cohesin complex | STAG2, RAD21, SMC1A | Chromosome segregation | Aneuploidy, dysregulated gene expression |
High Yield — SF3B1 and Ring Sideroblasts
SF3B1 mutation is found in > 80% of MDS with ring sideroblasts (MDS-RS). It is associated with a favourable prognosis. The mutation disrupts normal iron incorporation into haem within mitochondria of erythroid precursors, leading to iron accumulation around the nucleus — hence ring sideroblasts (≥5 iron granules encircling ≥1/3 of the nucleus on Prussian blue stain). [2]
High Yield — TP53 Mutation in MDS
TP53 mutation (especially biallelic) in MDS is associated with very poor prognosis, complex karyotype, resistance to standard therapy, and rapid AML transformation. It is one of the most important prognostic markers.
Cytogenetic (chromosomal) abnormalities are found in ~50% of de novo MDS and ~80% of therapy-related MDS. They are critical for diagnosis, classification, and prognosis.
| Cytogenetic Abnormality | Frequency | Prognostic Significance |
|---|---|---|
| del(5q) | ~10–15% | Good prognosis [2] — responds to lenalidomide |
| del(20q) | ~5% | Good prognosis |
| -Y (loss of Y chromosome) | ~5% | Good prognosis |
| Normal karyotype | ~50% | Intermediate (depends on molecular mutations) |
| Trisomy 8 | ~5–10% | Intermediate |
| del(7q) / monosomy 7 | ~10% | Poor prognosis |
| Complex karyotype (≥3 abnormalities) | ~10–15% | Very poor prognosis |
| del(17p) / TP53 abnormality | Variable | Very poor prognosis |
Let's trace how the molecular defects lead to the clinical picture:
- Mutated HSC acquires clonal advantage → dominates the marrow (displaces normal haematopoiesis)
- The dysplastic clone proliferates → hypercellular marrow
- Dysplastic cells have impaired maturation and undergo excessive apoptosis in the marrow (especially in early/low-grade MDS) → ineffective haematopoiesis
- This produces:
- Anaemia (most common and earliest cytopenia) — due to ineffective erythropoiesis
- Neutropenia — due to ineffective granulopoiesis; the neutrophils that are produced are often functionally defective (hypogranular, hypolobulated) → increased infection risk
- Thrombocytopenia — due to ineffective megakaryopoiesis → bleeding tendency
- As disease progresses (higher-risk MDS), apoptosis decreases but proliferation increases → blasts accumulate → risk of AML transformation rises
Key Conceptual Shift
In early/low-grade MDS: excessive apoptosis dominates → cytopenias are prominent, blasts are few. In late/high-grade MDS: apoptosis resistance develops (due to additional mutations) → blasts accumulate → approaches AML transformation. This is why low-risk MDS is primarily a disease of "too much cell death" while high-risk MDS is a disease of "too much cell survival."
There is also an immune component:
- In low-risk MDS, there is T-cell mediated autoimmune attack on haematopoietic progenitors (similar to aplastic anaemia), which contributes to the cytopenias. This is why some low-risk MDS patients respond to immunosuppressive therapy (e.g., anti-thymocyte globulin, cyclosporine).
- In high-risk MDS, the immune surveillance is suppressed, allowing accumulation of malignant blasts.
- MDS is associated with autoimmune phenomena in ~10–20% of patients (e.g., vasculitis, seronegative inflammatory arthritis, Sweet syndrome, relapsing polychondritis).
6. Classification
The WHO classification underwent major revision in 2022. The naming system was simplified. Here is the current classification framework:
Classification Principles
The classification of MDS is based on: [2]
- Number of dysplastic lineages (1 vs. multilineage)
- Percentage of ring sideroblasts (≥15% or ≥5% with SF3B1 mutation)
- Percentage of blast cells in bone marrow and peripheral blood (must be ≤20% to rule out AML)
- Cytogenetic abnormalities (especially del(5q) — good prognosis) [2]
- Molecular mutations (especially TP53, SF3B1)
| WHO 2022 Name | Key Features | BM Blasts | PB Blasts |
|---|---|---|---|
| MDS with low blasts (MDS-LB) | Dysplasia in ≥1 lineage; replaces old "RCUD" and "RCMD" | < 5% | < 2% |
| MDS with low blasts and SF3B1 mutation (MDS-SF3B1) | Ring sideroblasts ≥15% (or ≥5% with SF3B1 mutation); favourable prognosis | < 5% | < 2% |
| MDS with low blasts and isolated del(5q) (MDS-5q) | Isolated del(5q) ± 1 additional abnormality (not -7/del(7q)); responds to lenalidomide | < 5% | < 2% |
| MDS with increased blasts-1 (MDS-IB1) | Intermediate risk | 5–9% | 2–4% |
| MDS with increased blasts-2 (MDS-IB2) | High risk; near-AML threshold | 10–19% | 5–19% |
| MDS with biallelic TP53 inactivation (MDS-biTP53) | Any blast %; very poor prognosis; defines its own entity | Any | Any |
| MDS, hypoplastic | Hypocellular marrow ( < 25% cellularity); overlaps with aplastic anaemia | Variable | Variable |
| MDS of childhood | Rare; includes refractory cytopenia of childhood (RCC) | Variable | Variable |
| Feature | MDS | Aplastic Anaemia | MPN | MDS/MPN Overlap |
|---|---|---|---|---|
| Marrow cellularity | Usually hypercellular | Hypocellular ( < 25%) | Hypercellular | Hypercellular |
| Dysplasia | Present (defining feature) | Absent | Absent | Present |
| Peripheral counts | Cytopenic | Cytopenic | Elevated (at least one lineage) | Mixed (some elevated, some low) |
| Blast % | ≤20% (variable) | Normal ( < 5%) | Usually < 5% | < 20% |
| Apoptosis | Increased (ineffective haematopoiesis) | Different mechanism (immune-mediated HSC destruction + empty marrow) | Decreased (effective but excessive haematopoiesis) | Mixed |
| Risk of AML | Yes (10–40% depending on subtype) | Low (~5–10% lifetime) | Variable (depends on type) | Yes |
| Hepatosplenomegaly | No (characteristically absent) [2] | No | Yes (especially CML, PMF) | Variable |
High Yield — No Hepatosplenomegaly in MDS
MDS characteristically does NOT present with hepatosplenomegaly [2]. This is a key distinguishing feature from MPN and MDS/MPN overlap syndromes. If a patient with suspected MDS has massive splenomegaly, think about CMML (MDS/MPN overlap), MPN, or AML with extramedullary disease instead.
These are distinct entities that share features of both MDS (dysplasia) and MPN (proliferation). [6]
| Entity | Key Features |
|---|---|
| Chronic myelomonocytic leukaemia (CMML) | Monocytosis ≥1×10⁹/L, dysplastic neutrophils, often with anaemia and/or thrombocytopenia [6] |
| Atypical CML (aCML), BCR-ABL1 negative | Marked neutrophilia with dysgranulopoiesis, but BCR-ABL1 negative [6] |
| Juvenile myelomonocytic leukaemia (JMML) | Disorder of infancy/early childhood with hepatosplenomegaly and lymphadenopathy ± dysgranulopoiesis [6] |
| MDS/MPN with ring sideroblasts and thrombocytosis | MDS features + thrombocytosis ≥450×10⁹/L [6] |
7. Clinical Features
MDS typically presents insidiously in an elderly patient (median age ~65) with progressive cytopenias. [2] Many patients are asymptomatic and diagnosed incidentally on routine blood counts. When symptomatic, the clinical features are attributable to trilineage failure — i.e., the consequences of anaemia, neutropenia, and thrombocytopenia.
Progressive decline in cell counts (trilineage failure) is the hallmark. [2]
7.1 Symptoms (with pathophysiological basis)
Anaemia is due to ineffective erythropoiesis — dysplastic erythroid precursors undergo intramedullary apoptosis.
| Symptom | Mechanism |
|---|---|
| Fatigue and lethargy | Reduced oxygen-carrying capacity → tissue hypoxia → reduced ATP generation |
| Exertional dyspnoea | Tissue oxygen demand exceeds supply during exertion → compensatory increase in respiratory rate |
| Palpitations | Compensatory increase in cardiac output to maintain tissue oxygenation → increased heart rate |
| Dizziness/lightheadedness | Cerebral hypoperfusion/hypoxia |
| Pallor | Reduced haemoglobin concentration → less colour in skin and mucous membranes |
| Angina (in elderly with IHD) | Reduced myocardial oxygen delivery in the setting of pre-existing coronary artery disease |
Even when neutrophil counts appear adequate, the neutrophils in MDS are often functionally defective (hypogranular → cannot kill bacteria effectively; hypolobulated → impaired chemotaxis).
| Symptom | Mechanism |
|---|---|
| Recurrent infections | Quantitative and qualitative neutrophil deficiency → impaired innate immune defence |
| Fever | Infections trigger inflammatory cytokine release (IL-1, IL-6, TNF-α) → hypothalamic set-point elevation |
| Oral ulcers, skin infections | Mucosal and skin barriers are maintained by neutrophil surveillance; when this fails, opportunistic organisms invade |
| Pneumonia, UTI, sepsis | Severe neutropenia ( < 0.5 × 10⁹/L) predisposes to life-threatening bacterial and fungal infections |
Due to ineffective megakaryopoiesis — dysplastic megakaryocytes produce inadequate or dysfunctional platelets.
| Symptom | Mechanism |
|---|---|
| Easy bruising | Insufficient platelets to maintain vascular integrity → petechial bleeding into skin |
| Epistaxis (nosebleeds) | Mucosal bleeding due to inadequate primary haemostasis |
| Gum bleeding | Same mechanism — mucous membranes are particularly susceptible |
| Menorrhagia (in premenopausal women, rare given median age) | Inadequate platelet plug formation |
| Haematuria, GI bleeding | More severe thrombocytopenia → visceral mucosal bleeding |
| Symptom | Mechanism |
|---|---|
| Weight loss | Hypermetabolic state from clonal expansion; cytokine-mediated cachexia |
| Night sweats | Cytokine release (TNF-α, IL-6) from the malignant clone |
| Anorexia | Inflammatory cytokines suppress appetite |
7.2 Signs (with pathophysiological basis)
| Sign | Mechanism |
|---|---|
| Pallor (conjunctival, palmar crease, nail bed) | Reduced haemoglobin → reduced redness of tissues |
| Tachycardia | Compensatory increase in cardiac output |
| Systolic flow murmur | Hyperdynamic circulation with reduced blood viscosity → turbulent flow across valves |
| Wide pulse pressure / bounding pulse | Reduced peripheral vascular resistance (vasodilation to maximise tissue oxygenation) |
| Heart failure signs (in severe/prolonged anaemia) | High-output cardiac failure from chronic compensatory volume overload |
| Sign | Mechanism |
|---|---|
| Fever | Infection or inflammatory cytokines |
| Oral candidiasis | Impaired neutrophil-mediated antifungal defence |
| Skin infections, cellulitis | Breach of cutaneous defence |
| Perianal infections | Common site in neutropenic patients due to commensal flora |
| Sign | Mechanism |
|---|---|
| Petechiae | Capillary bleeding points from inadequate platelet plugging |
| Purpura | Coalesced petechiae |
| Ecchymoses | Larger areas of subcutaneous bleeding |
| Gum bleeding, epistaxis | Mucosal bleeding |
| Sign | Mechanism |
|---|---|
| NO hepatosplenomegaly (characteristically) [2] | Unlike MPN, MDS does not cause extramedullary haematopoiesis in early stages; absence of splenomegaly helps distinguish MDS from MPN and CMML |
| Signs of iron overload (in transfusion-dependent patients) | Repeated RBC transfusions deliver excess iron → haemosiderosis → skin bronze discolouration, liver dysfunction, endocrinopathy, cardiac siderosis |
| Sweet syndrome (acute febrile neutrophilic dermatosis) | Paraneoplastic/autoimmune phenomenon associated with MDS; tender erythematous plaques, fever |
| Autoimmune phenomena (~10–20%) | Immune dysregulation in MDS → vasculitis, relapsing polychondritis, seronegative arthritis |
The peripheral blood smear in MDS shows: [1]
- Significant macrocytosis (MCV > 100 fL) — due to dysplastic erythropoiesis with impaired DNA synthesis and premature release of large, immature red cells
- Hypolobulated neutrophils (Pelger-Huët anomaly — "the French Ray-Ban glasses") — bilobed nuclei instead of normal 3–5 lobes; reflects disordered granulopoiesis [1]
- Hypogranular neutrophils — reduced or absent cytoplasmic granules; functionally defective [1]
- Immature myeloid cells — left shift reflecting disordered maturation [1]
- Nucleated red blood cells — premature release of erythroid precursors [1]
- Pancytopenia [1]
High Yield — Pelger-Huët Anomaly
Pelger-Huët anomaly = hypolobulated neutrophil (typically bilobed, resembling spectacles/"Ray-Ban glasses"). It is a hallmark of MDS-related dysgranulopoiesis. True congenital Pelger-Huët anomaly is rare and autosomal dominant — in clinical practice, if you see it on a blood film, think MDS first. [1]
The bone marrow in MDS is typically hypercellular (reflecting ineffective haematopoiesis — the marrow is making cells, but they are dying before release). [1]
Key morphological features of dysplasia:
| Lineage | Dysplastic Features |
|---|---|
| Erythroid (dyserythropoiesis) | Megaloblastoid changes, nuclear budding, internuclear bridges, multinucleation, ring sideroblasts (iron-laden mitochondria encircling nucleus), irregular nuclear contours |
| Granulocytic (dysgranulopoiesis) | Hypolobulated nuclei (pseudo-Pelger-Huët), hypogranular cytoplasm, abnormal nuclear shapes |
| Megakaryocytic (dysmegakaryopoiesis) | Micromegakaryocytes (small, monolobated), hypolobated nuclei, widely separated nuclear lobes |
Dysplasia must be present in ≥10% of cells in at least one lineage to be diagnostically significant (WHO criterion).
It is important to recognise mimics of dysplasia that are not MDS:
- Vitamin B12/folate deficiency → causes megaloblastic changes mimicking dyserythropoiesis; always check B12/folate before diagnosing MDS
- Copper deficiency → can cause sideroblastic anaemia and neutropenia
- HIV infection → can cause dysplastic changes
- Heavy metal exposure (arsenic, lead) → can cause sideroblastic anaemia
- Medications (methotrexate, azathioprine, mycophenolate, valproate) → can cause cytopenias and dysplasia
- Chronic alcohol use → macrocytosis + ring sideroblasts
- Recent G-CSF administration → causes left shift and transient dysplastic-looking changes
Common Exam Pitfall
Always exclude B12/folate deficiency, copper deficiency, HIV, drugs, and alcohol before diagnosing MDS. Megaloblastic anaemia from B12/folate deficiency can perfectly mimic MDS morphologically. A student who diagnoses MDS without checking B12/folate will lose marks.
| Step | Action | Rationale |
|---|---|---|
| 1 | History: age, prior chemo/RT, occupational exposures, medications, alcohol, constitutional symptoms | Identify risk factors and exclude reversible causes |
| 2 | Examination: pallor, petechiae, infection signs, NO splenomegaly | Confirm cytopenias clinically; absence of organomegaly supports MDS over MPN |
| 3 | CBC + reticulocyte count | Confirm cytopenias; reticulocytes typically LOW (ineffective erythropoiesis) |
| 4 | Peripheral blood smear | Look for macrocytosis, Pelger-Huët cells, hypogranular neutrophils, blasts, nucleated RBCs |
| 5 | Exclude mimics | B12, folate, copper, HIV, iron studies, LFTs, TSH |
| 6 | Bone marrow aspirate + trephine biopsy | Assess cellularity, dysplasia (≥10% in ≥1 lineage), blast %, ring sideroblasts |
| 7 | Cytogenetics (G-banding karyotype) | Identify prognostic chromosomal abnormalities; essential for classification |
| 8 | FISH panel | Targeted for specific abnormalities (del(5q), -7, trisomy 8, del(20q)) |
| 9 | Molecular panel (NGS) | SF3B1, TP53, RUNX1, ASXL1, EZH2, etc. — prognostic and therapeutic implications |
| 10 | Iron stain (Prussian blue) on aspirate | Identify ring sideroblasts |
| 11 | Flow cytometry | Identify aberrant immunophenotype on blasts; helps distinguish from reactive cytopenias |
| 12 | Prognostic scoring (IPSS-R / IPSS-M) | Stratify risk and guide treatment decisions |
High Yield Summary
Definition: MDS = clonal HSC disorder → ineffective/dysplastic haematopoiesis → peripheral cytopenias despite hypercellular marrow → risk of AML transformation (≥20% blasts = AML).
Epidemiology: Median age ~65–70; M > F; one of the most common haematological malignancies in the elderly.
Risk Factors: Most are idiopathic (de novo). Therapy-related MDS follows alkylating agents (5–7 year latency, del(5q)/del(7q)) or topoisomerase II inhibitors (1–3 year latency). Inherited BMF syndromes (Fanconi, dyskeratosis congenita) predispose.
Pathophysiology: Mutated HSC → clonal expansion → dysplastic maturation → increased intramedullary apoptosis (early MDS) → cytopenias. With progression, apoptosis decreases → blast accumulation → AML.
Key Mutations: SF3B1 (ring sideroblasts, good prognosis), TP53 (very poor prognosis, complex karyotype), splicing factors, epigenetic regulators.
Classification (WHO 2022): Based on blast %, dysplastic lineages, ring sideroblasts, del(5q), TP53 biallelic. Blast < 5% = MDS-LB; 5–9% = MDS-IB1; 10–19% = MDS-IB2; ≥20% = AML.
Clinical Features: Insidious onset in elderly; anaemia symptoms (fatigue, dyspnoea, pallor); infections (neutropenia); bleeding (thrombocytopenia). NO hepatosplenomegaly.
Blood Smear: Macrocytosis, Pelger-Huët anomaly, hypogranular neutrophils, nucleated RBCs, pancytopenia.
Marrow: Hypercellular, dysplasia in ≥10% of ≥1 lineage, ring sideroblasts, variable blasts.
Always exclude: B12/folate deficiency, copper deficiency, HIV, drugs, alcohol before diagnosing MDS.
Active Recall — Myelodysplastic Syndrome (Definition to Clinical Features)
[1] Senior notes: Block A - Introduction to Haematological investigations (CBP, Clotting).pdf (MDS peripheral blood smear and bone marrow findings) [2] Senior notes: Maksim Medicine Notes.pdf (MDS definition, clinical features, classification principles) [3] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf (AML etiology including MDS as precursor; therapy-related risk factors) [4] Senior notes: Block A - High white cell count_ acute and chronic leukaemia; bone marrow transplantation; immunogenetics.pdf (blast percentage cutoff for acute vs chronic leukaemia; AML definition) [5] Lecture slides: Block C - A child with cancer_ paediatric cancers.pdf (de novo AML vs MDS-associated AML) [6] Senior notes: Ryan Ho Haemtology.pdf (MDS/MPN overlap syndromes; MPN vs MDS comparison; AML risk factors)
Differential Diagnosis of Myelodysplastic Syndrome (MDS)
The clinical scenario that brings MDS to mind is typically an elderly patient (> 60 years) with unexplained cytopenias — most commonly macrocytic anaemia ± neutropenia ± thrombocytopenia, with or without dysplastic morphology on peripheral blood smear. The differential diagnosis is therefore built around the question:
"What else can cause cytopenias (especially macrocytic anaemia with or without pancytopenia) with or without morphological dysplasia in an elderly patient?"
The differential can be structured into several major categories:
- Conditions mimicking MDS morphologically (reversible causes of "pseudo-MDS")
- Other clonal haematological disorders (malignant mimics)
- Non-clonal bone marrow failure states
- Systemic/secondary causes of cytopenias
These are the most important conditions to exclude first, because they are treatable and reversible. Missing them means subjecting a patient to unnecessary bone marrow biopsies and potentially harmful MDS-directed therapy.
High Yield — Always Exclude Before Diagnosing MDS
Always check vitamin B12, folate, copper, zinc, HIV status, drug history, alcohol use, and thyroid function before diagnosing MDS. [7] Megaloblastic anaemia from B12/folate deficiency can perfectly mimic MDS morphologically.
| Condition | Why It Mimics MDS | Key Distinguishing Features |
|---|---|---|
| Megaloblastic anaemia (B12/folate deficiency) [7] | Pancytopenia + macrocytosis + dysplastic erythropoiesis + intramedullary haemolysis; can have hypersegmented neutrophils and megaloblastic changes in marrow that look like dyserythropoiesis | Check serum B12, RBC folate [7]; MCV often > 110–120 fL (higher than typical MDS); hypersegmented neutrophils (≥5 lobes) rather than hypolobulated (Pelger-Huët); responds to replacement therapy within weeks |
| Copper deficiency | Sideroblastic anaemia + neutropenia; ring sideroblasts on iron stain mimicking MDS-RS | History of gastric surgery, zinc supplementation, malabsorption; low serum copper and ceruloplasmin; responds to copper replacement |
| Zinc excess (causes secondary copper deficiency) | Same mechanism as above | Often iatrogenic from zinc supplementation; check zinc and copper levels together |
| HIV infection [7] | Can cause dysplastic haematopoiesis and variable cytopenias [7]; BM can show dysplasia | HIV serology; treat HIV → cytopenias improve; no clonal cytogenetic abnormality |
| Drug-induced cytopenias | Methotrexate, azathioprine, mycophenolate, valproate, hydroxyurea, co-trimoxazole, chemotherapy all cause cytopenias ± morphological dysplasia | Temporal relationship with drug; resolves on discontinuation; no clonal markers |
| Alcohol excess | Macrocytosis + ring sideroblasts + vacuolated erythroid precursors; can cause pancytopenia | Social history; MCV normalises with abstinence (takes ~3 months); no clonal cytogenetics |
| Chronic liver disease | Macrocytosis (from altered lipid metabolism affecting RBC membranes) + cytopenias from hypersplenism/portal hypertension | LFTs deranged; target cells and acanthocytes on smear; clinical signs of liver disease |
| Hypothyroidism | Macrocytic anaemia | Check TSH; responds to thyroid replacement |
| Recent G-CSF administration | Left shift with dysplastic-looking changes; transient blasts in circulation | History of G-CSF use; changes are transient and resolve |
From the lecture material: In the diagnostic pathway for MDS, check vitamin B12, folate ± zinc, copper in all patients with suspected MDS before confirming the diagnosis. [7]
Category 2: Other Clonal Haematological Disorders
These are the malignant conditions that share features with MDS but are fundamentally different diseases requiring different treatment.
| Feature | MDS | AML |
|---|---|---|
| Blast % | < 20% in BM and PB [1][4] | ≥20% in BM or PB, OR AML-defining cytogenetic abnormalities [4][8] |
| Maturation | Dysplastic but some maturation occurs | Maturation arrested at blast stage |
| Clinical tempo | Insidious, chronic | Rapidly progressive, acute onset |
| Extramedullary disease | Absent (no hepatosplenomegaly) [2] | Possible (gum hypertrophy in monoblastic AML, skin, CNS) [4] |
| PBS morphology | Dysplastic mature cells; few blasts | Blasts dominate; Auer rods diagnostic of myeloid lineage [8][9] |
| Cytochemistry | Variable | MPO +ve, Sudan Black B +ve [1][8] |
AML-defining genetic abnormalities include: [8]
- t(8;21)(q22;q22) + RUNX1-RUNX1T1
- inv(16)(p13.1q22) or t(16;16)(p13.1;q22) + CBFB-MYH11
- t(15;17)(q24.1;q21.1) + PML-RARA (diagnostic of APL — a haematological emergency)
These abnormalities are diagnostic of AML even if blast % is < 20%. [8]
High Yield — MDS vs AML Threshold
The blast percentage cutoff of 20% is the critical threshold separating MDS from AML. [1][4] However, some AML-defining cytogenetic abnormalities allow diagnosis of AML even with < 20% blasts. Furthermore, AML with myelodysplasia-related changes (a distinct WHO subtype) has dysplasia in ≥50% of cells in ≥2 lineages — this has poor prognosis. [8]
From GC lecture slides: The workup for suspected acute leukaemia includes CBP + differential + manual count, clotting profile, d-dimer, fibrinogen (to detect DIC in APL), biochemistry (for tumour lysis features), bone marrow examination + cytogenetics + molecular/NGS, CXR, ECG, echocardiogram. [10]
| Feature | MDS | MPN |
|---|---|---|
| Peripheral blood | Cytopenias (low counts) | ↑ cell counts for ≥1 lineage [6] |
| Morphology | Dysplastic | Non-dysplastic (normal maturation) [6] |
| Marrow | Hypercellular, ineffective haematopoiesis | Hypercellular, effective haematopoiesis [6] |
| Splenomegaly | Absent [2] | Often present (especially CML, PMF) [6] |
| Key mutations | Splicing factors, epigenetic regulators, TP53 | BCR-ABL1 (CML), JAK2 (PV, ET, PMF), CALR, MPL [6] |
| AML risk | 10–40% depending on subtype | Variable (> 90% for untreated CML; < 5% for ET) [6] |
The key conceptual difference: MPN cells differentiate normally but proliferate excessively → high counts. MDS cells differentiate abnormally (dysplasia) and die prematurely in the marrow → low counts.
These entities have features of BOTH MDS (dysplasia) and MPN (proliferation). [6][7]
| Entity | Distinguishing Features |
|---|---|
| Chronic myelomonocytic leukaemia (CMML) | Monocytosis ≥1×10⁹/L + dysplastic neutrophils ± anaemia/thrombocytopenia [6]; can have splenomegaly |
| Atypical CML (aCML), BCR-ABL1 negative | Marked neutrophilia + dysgranulopoiesis, but BCR-ABL1 negative [6] |
| JMML | Infancy/early childhood + hepatosplenomegaly + lymphadenopathy ± dysgranulopoiesis [6] |
| MDS/MPN with ring sideroblasts and thrombocytosis | MDS features + thrombocytosis ≥450×10⁹/L [6] |
Key differentiator: If a patient with suspected MDS has ↑monocyte count > 1×10⁹/L → think CMML (MDS/MPN), not pure MDS. If there is significant thrombocytosis a/w megakaryocyte proliferation, leukocytosis, ± prominent splenomegaly → think MDS/MPN overlap. [7]
| Feature | MDS | PMF |
|---|---|---|
| Marrow fibrosis | Mild in 10–15% of MDS | Significant reticulin/collagen fibrosis |
| Splenomegaly | Absent | Prominent (extramedullary haematopoiesis) |
| PBS | Dysplastic cells | Leukoerythroblastic picture (left shift + nucleated RBCs + tear-drop RBCs/dacryocytes) [9] |
| Key mutations | Splicing/epigenetic | JAK2 (60-65%), CALR (20-25%), MPL (7%) [6] |
Myelofibrosis can occur in MDS (usually mild/moderate), but there should NOT be significant splenomegaly and characteristic MPN genetic changes (e.g., JAK2 mutation) in MDS. [7]
This is a critically important differential, especially for hypoplastic MDS.
| Feature | MDS | Aplastic Anaemia |
|---|---|---|
| Marrow cellularity | Usually hypercellular (paradox of ineffective haematopoiesis) | Hypocellular (< 25%) with fat replacement [11][12] |
| Dysplasia | Present (≥10% in ≥1 lineage) | Absent — residual cells are morphologically NORMAL [11] |
| Cytogenetics | Abnormal in ~50% | Normal [11] |
| Blasts | Variable (up to 19%) | Normal (< 5%) |
| Hepatosplenomegaly | No | No [11] |
| PBS | Dysplastic cells, macrocytes | Normal morphology; no abnormal cells [11] |
| Reticulocytes | Low (ineffective erythropoiesis) | Low (production failure) [11] |
Some MDS cases have hypoplastic marrow ("hypoplastic MDS"), especially if therapy-related. These cases should still have morphologically/karyotypically abnormal marrow cells, which are NOT present in AA. [7]
Hypoplastic MDS vs Aplastic Anaemia
Both present with pancytopenia and hypocellular marrow. The key distinguisher is dysplasia and clonal cytogenetic abnormalities — present in hypoplastic MDS, absent in AA. Flow cytometry showing aberrant immunophenotype also supports MDS. This distinction matters because AA responds to immunosuppression (ATG + cyclosporine), while MDS requires different management.
- A clonal T-cell or NK-cell disorder causing cytopenias (especially neutropenia, sometimes anaemia) through immune-mediated mechanisms.
- Can coexist with MDS or mimic it.
- Distinguish by flow cytometry showing expanded clonal T-LGL (CD3+/CD8+/CD57+) or NK-LGL population.
- A rare B-cell lymphoproliferative disorder causing pancytopenia + splenomegaly + monocytopenia.
- Distinguished by "hairy" projections on lymphocytes, BRAF V600E mutation, and characteristic immunophenotype.
- The monocytopenia is a key distinguishing feature (MDS does not typically cause monocytopenia; CMML causes monocytosis).
- Can cause cytopenias through marrow infiltration.
- Distinguished by monoclonal paraprotein on serum protein electrophoresis (SPEP), ≥10% clonal plasma cells in BM, and end-organ damage (CRAB criteria). [13]
- MDS does NOT produce a paraprotein.
| Condition | Key Distinguishing Feature |
|---|---|
| Bone marrow infiltration by solid tumours (e.g., prostate, breast, lung metastases) | Leukoerythroblastic picture on PBS; tumour cells visible on BM biopsy; clinical history of known malignancy |
| Myelofibrosis (secondary) | Due to infiltration or marrow damage; leukoerythroblastic picture + tear-drop RBCs [9] |
| Granulomatous disease (TB, sarcoidosis) | Granulomata visible on BM biopsy; clinical context |
| Storage diseases (Gaucher's) | Characteristic storage cells on BM biopsy |
These are conditions where cytopenias are due to causes outside the bone marrow:
| Condition | Mechanism | Distinguishing Feature |
|---|---|---|
| Hypersplenism | Splenic sequestration of blood cells | Splenomegaly present (absent in MDS); all counts low but marrow is reactive/normal |
| Anaemia of chronic disease (ACD) | Hepcidin-mediated iron restriction + blunted EPO response | Usually normocytic (can be mildly microcytic); elevated ferritin, low TIBC; no dysplasia |
| Chronic kidney disease | Reduced EPO production | Predominantly anaemia (not pancytopenia); elevated creatinine; responds to EPO |
| Autoimmune cytopenias (ITP, AIHA, Evans syndrome) | Immune-mediated peripheral destruction | Positive DAT (AIHA); antiplatelet antibodies (ITP); reticulocytosis in haemolysis (vs. reticulocytopenia in MDS) |
| Viral infections (hepatitis, parvovirus B19, EBV, CMV) | Direct marrow suppression or immune-mediated | Serologies; transient cytopenias; resolves with viral clearance |
| Sepsis/severe infection | Consumptive cytopenias, marrow suppression | Acute clinical picture; positive cultures; resolves with treatment |
| Diagnosis | Marrow Cellularity | Dysplasia | Blast % | Splenomegaly | Key Distinguisher |
|---|---|---|---|---|---|
| MDS | Hypercellular | Yes | < 20% | No | Clonal cytogenetics, dysplasia ≥10% in ≥1 lineage |
| AML | Hypercellular | ± | ≥20% | ± | Blast ≥20% or AML-defining genetics; Auer rods |
| Aplastic anaemia | Hypocellular | No | < 5% | No | Empty marrow, normal morphology, no clonal markers |
| MPN | Hypercellular | No | < 5% | Yes | ↑ blood counts, JAK2/CALR/MPL/BCR-ABL |
| MDS/MPN (CMML) | Hypercellular | Yes | < 20% | ± | Monocytosis ≥1×10⁹/L |
| PMF | Fibrotic | ± | < 20% | Massive | Tear-drop RBCs, JAK2/CALR/MPL, dry tap |
| B12/folate deficiency | Hypercellular (megaloblastic) | "Pseudo-dysplasia" | < 5% | No | Low B12/folate; hypersegmented neutrophils; reversible |
| HIV | Variable | ± dysplasia | < 5% | ± | HIV serology positive; no clonal cytogenetics |
| Drug-induced | Variable | ± | < 5% | No | Temporal drug relationship; resolves on cessation |
High Yield Summary — Differential Diagnosis of MDS
-
Always exclude reversible causes first: B12, folate, copper, zinc, HIV, drugs, alcohol, hypothyroidism, liver disease.
-
Distinguish from AML: blast ≥20% = AML, not MDS. AML-defining cytogenetics (e.g., t(15;17), t(8;21)) diagnose AML even with < 20% blasts.
-
Distinguish from aplastic anaemia: AA = hypocellular marrow with NO dysplasia and NO clonal cytogenetics. Hypoplastic MDS exists but will still show dysplasia and/or clonal abnormalities.
-
Distinguish from MPN: MPN = elevated cell counts, no dysplasia, splenomegaly, gain-of-function mutations (JAK2, BCR-ABL). MDS = cytopenias, dysplasia, no splenomegaly.
-
Distinguish from MDS/MPN overlap: if monocytosis ≥1×10⁹/L → CMML; if thrombocytosis ≥450 + dysplasia → MDS/MPN-RS-T; if proliferative features + dysplasia → overlap syndrome.
-
Distinguish from PMF: significant splenomegaly + tear-drop RBCs + leukoerythroblastic picture + JAK2/CALR/MPL = PMF, not MDS (even though mild fibrosis can occur in MDS).
-
MDS characteristically has NO hepatosplenomegaly — if present, reconsider diagnosis.
Active Recall — Differential Diagnosis of MDS
References
[1] Senior notes: Block A - Introduction to Haematological investigations (CBP, Clotting).pdf (MDS peripheral blood smear findings, AML vs ALL cytochemistry) [2] Senior notes: Maksim Medicine Notes.pdf (MDS definition, classification, no hepatosplenomegaly) [4] Senior notes: Block A - High white cell count_ acute and chronic leukaemia; bone marrow transplantation; immunogenetics.pdf (blast percentage cutoff acute vs chronic; AML features) [6] Senior notes: Ryan Ho Haemtology.pdf (MPN overview, MDS/MPN overlap, classification of myeloid neoplasms, PMF/ET criteria, MDS diagnostic pathway and differential diagnoses) [7] Senior notes: Ryan Ho Haemtology.pdf, p.83 (MDS differential diagnosis list: AML, MDS/MPN, AA, PMF, HIV, megaloblastic anaemia) [8] Senior notes: Ryan Ho Haemtology.pdf, p.53-54 (AML subtypes, AML-defining cytogenetics, laboratory features) [9] Senior notes: Ryan Ho Fundamentals.pdf, p.390 (leukoerythroblastic picture, PBS interpretation, dysplastic WBCs in MDS) [10] Lecture slides: GC 060. High white cell count.pdf (workup for suspected acute leukaemia) [11] Senior notes: Adrian Lui Pediatrics Notes.pdf, p.369 (aplastic anaemia clinical features, labs, diagnostic criteria, no lymphadenopathy/hepatosplenomegaly) [12] Senior notes: Block A - Family history of anaemia_ inherited causes of anaemia; haemolytic anaemia; aplastic anaemia.pdf (aplastic anaemia definition, causes) [13] Senior notes: Block A - An old man with bone pain and anaemia_ multiple myeloma; monoclonal gammopathy.pdf (MGUS/myeloma spectrum)
Diagnostic Criteria, Diagnostic Algorithm, and Investigations for Myelodysplastic Syndrome (MDS)
1. Diagnostic Criteria for MDS
Diagnosing MDS requires establishing three things simultaneously:
- Unexplained, persistent cytopenias — at least one lineage must be affected
- Evidence of clonal, dysplastic haematopoiesis — morphological dysplasia ± clonal genetic markers
- Exclusion of other causes — both reversible mimics (B12, folate, copper, HIV, drugs) and other clonal disorders (AML, MPN, MDS/MPN)
Think of it as a diagnosis that sits at the intersection of clinical, morphological, and genetic evidence — no single test is sufficient on its own.
The WHO 5th Edition (2022) and the International Consensus Classification (ICC 2022) provide parallel but broadly similar frameworks. The WHO 2022 criteria are the standard used in clinical practice.
Minimum diagnostic requirements for MDS:
| Criterion | Detail | Why This Matters |
|---|---|---|
| 1. Persistent cytopenia in ≥1 lineage | Hb < 10 g/dL, ANC < 1.8 × 10⁹/L, or PLT < 100 × 10⁹/L (thresholds are guidelines; clinical judgement applies) | Confirms the clinical problem — haematopoiesis is failing |
| 2. Morphological dysplasia in ≥10% of cells in ≥1 lineage | Assessed on BM aspirate smear (≥500 nucleated cells and ≥100 erythroid precursors counted) | Confirms the morphological hallmark of abnormal maturation |
| 3. Blast percentage < 20% in BM and PB [1][2] | If ≥20% → reclassify as AML | The critical threshold separating MDS from AML |
| 4. Exclusion of reactive/reversible causes | B12, folate, copper, zinc, HIV, drugs, alcohol, thyroid, liver disease | Prevents misdiagnosis of a treatable condition |
| 5. Supportive evidence of clonality (if dysplasia is borderline) | Cytogenetic abnormalities (e.g., del(5q), -7, +8) and/or somatic mutations (e.g., SF3B1, TET2, ASXL1) and/or abnormal flow cytometry | Especially important when morphological dysplasia is subtle or equivocal |
High Yield — Diagnostic Pillars of MDS
MDS diagnosis rests on: [1][2][6]
- Persistent unexplained cytopenias
- Morphological dysplasia ≥10% in ≥1 lineage on BM aspirate
- Blast count < 20% (to rule out AML)
- Exclusion of reversible causes (B12, folate, copper, HIV, drugs)
- Supportive: MDS-defining cytogenetic abnormalities and/or somatic mutations
Certain cytogenetic abnormalities are considered presumptive evidence of MDS even when morphological dysplasia is borderline (i.e., < 10% in any lineage). These are called "MDS-defining cytogenetic abnormalities":
| Abnormality | Notes |
|---|---|
| del(5q) | Isolated or with 1 additional abnormality (not -7/del(7q)); good prognosis [2] |
| Monosomy 7 / del(7q) | Poor prognosis |
| del(20q) | Good prognosis |
| Trisomy 8 | Intermediate prognosis |
| i(17q) / del(17p) | Very poor prognosis (often a/w TP53) |
| del(12p) / del(11q) | Variable |
| Complex karyotype (≥3 abnormalities) | Very poor prognosis |
| del(13q) | Intermediate |
| -Y as sole abnormality | Good prognosis (but be cautious — age-related Y loss in elderly men can be non-clonal) |
If a patient has persistent cytopenias and one of these cytogenetic abnormalities but dysplasia < 10%, they can still be diagnosed with MDS. Conversely, if cytogenetics are normal and morphological dysplasia is minimal, the diagnosis may fall under CCUS (clonal cytopenia of undetermined significance) rather than overt MDS.
Understanding where MDS sits on the spectrum is critical:
| Entity | Somatic Mutation | Cytopenia | Dysplasia ≥10% | MDS Diagnosis |
|---|---|---|---|---|
| CHIP | Present (VAF ≥2%) | No | No | No |
| CCUS | Present | Yes | No (or equivocal) | No — but at risk |
| ICUS | Absent | Yes | No | No — idiopathic cytopenia |
| MDS | Usually present | Yes | Yes (or MDS-defining cytogenetics) | Yes |
2. Diagnostic Algorithm
Detailed Explanation of Each Step
This is where MDS is first suspected. The typical "trigger" is an incidental finding of cytopenias in an elderly patient.
CBC findings:
- Anaemia — usually macrocytic (MCV > 100 fL) [1]; the most common and earliest cytopenia
- Neutropenia (ANC < 1.8 × 10⁹/L)
- Thrombocytopenia (PLT < 100 × 10⁹/L)
- One, two, or all three lineages can be affected (uni-, bi-, or pancytopenia)
Reticulocyte count: Characteristically low or inappropriately normal for the degree of anaemia — because the marrow is making cells but they are dying before release (ineffective erythropoiesis). This distinguishes MDS from haemolytic anaemia (where reticulocytes are elevated) and blood loss (where reticulocytes should be rising).
Peripheral blood smear (PBS) findings in MDS: [1]
| Finding | Pathophysiological Basis |
|---|---|
| Significant macrocytosis (> 100 fL) [1] | Dysplastic erythropoiesis with impaired DNA synthesis; premature release of large, immature red cells |
| Hypolobulated neutrophils (Pelger-Huët anomaly — "the French Ray-Ban glasses") [1] | Dysgranulopoiesis; failure of normal nuclear segmentation |
| Hypogranular neutrophils [1] | Failure of granule production; cells are functionally defective |
| Immature myeloid cells [1] | Left shift from disordered maturation |
| Nucleated red blood cells [1] | Premature release of erythroid precursors |
| Pancytopenia [1] | Net result of trilineage ineffective haematopoiesis |
| Circulating blasts (< 20%) | If present, suggests higher-risk MDS (MDS-IB1/IB2) |
| Dysplastic WBCs [9] | Key PBS finding suggestive of MDS |
From the workup mnemonic: MCICM = Morphology (PBS, BM), Cytochemistry, Immunophenotype, Cytogenetics, Molecular genetics [9][14]
This step is mandatory before proceeding to bone marrow examination. The following must be checked:
| Test | Purpose | Why It Matters |
|---|---|---|
| Serum B12 / holotranscobalamin | Exclude B12 deficiency | B12 deficiency causes megaloblastic changes mimicking MDS; bone marrow examination is not routinely needed for pernicious anaemia except when findings are incompatible or when thinking of MDS [15] |
| RBC folate | Exclude folate deficiency | Same rationale; rare cause in practice but must be excluded |
| Serum copper and zinc | Exclude copper deficiency (± zinc excess) | Copper deficiency causes ring sideroblasts + neutropenia mimicking MDS-RS |
| TSH | Exclude hypothyroidism | Hypothyroidism causes macrocytic anaemia |
| HIV serology | Exclude HIV | HIV causes dysplastic haematopoiesis and variable cytopenias |
| LFTs | Exclude liver disease | Chronic liver disease causes macrocytosis and cytopenias from hypersplenism |
| Iron studies (ferritin, TIBC, serum iron) | Baseline iron status | Important for assessing iron overload risk if transfusion-dependent; also excludes iron deficiency as cause of concurrent microcytosis |
| Haemolysis screen (LDH, haptoglobin, reticulocyte count, bilirubin, DAT) | Exclude haemolytic anaemia | Intramedullary haemolysis in MDS causes elevated LDH and bilirubin but with LOW reticulocytes (unlike peripheral haemolysis) |
| Drug history | Exclude drug-induced cytopenias | Methotrexate, azathioprine, valproate, hydroxyurea — all can cause cytopenias and morphological dysplasia |
| Alcohol history | Exclude alcohol-related changes | Alcohol causes macrocytosis, ring sideroblasts, vacuolated erythroid precursors |
High Yield — B12/Folate and MDS
Bone marrow examination is not routinely needed for suspected pernicious anaemia — except when laboratory findings are incompatible with PA, or when you are thinking of MDS (which can also cause pancytopenia with macrocytosis), or when the patient does not improve after parenteral B12 replacement. [15] This is a crucial clinical decision point.
Bone marrow examination is mandatory/required for the diagnosis of MDS. [6][11][14]
Both aspirate and trephine biopsy should be obtained, ideally from different sites 1–2 cm apart at the posterior iliac crest [14].
| Component | What It Provides | Key MDS Findings |
|---|---|---|
| BM Aspirate [14] | Cytology (cell morphology), blast %, flow cytometry, genetic studies | Dysplasia in ≥1 lineage (≥10% of cells); blast % < 20%; ring sideroblasts on iron stain |
| BM Trephine Biopsy [14] | Histological examination — marrow cellularity, architecture, fibrosis, bone structure, immunohistochemistry | Usually hypercellular [1] (paradox of ineffective haematopoiesis); may be hypocellular in hypoplastic MDS; degree of fibrosis; architectural distortion |
Contraindications to BM examination: Only absolute C/I is severe bleeding disorder (severe haemophilia, DIC) — thrombocytopenia of any severity is NOT a contraindication (just top up platelets to > 20 × 10⁹/L prior to the procedure). [14]
Morphological dysplasia assessment on BM aspirate:
| Lineage | Dysplastic Features (≥10% of cells in that lineage) |
|---|---|
| Erythroid (dyserythropoiesis) | Megaloblastoid changes, nuclear budding, internuclear bridges, multinucleation, karyorrhexis, irregular nuclear contours, ring sideroblasts (≥5 iron granules encircling ≥1/3 of nucleus on Prussian blue stain) [2] |
| Granulocytic (dysgranulopoiesis) | Hypolobulated nuclei (pseudo-Pelger-Huët) [1], hypogranular cytoplasm [1], ring-shaped nuclei, nuclear sticks, abnormal nuclear shapes |
| Megakaryocytic (dysmegakaryopoiesis) | Micromegakaryocytes (small, monolobated), hypolobated nuclei, widely separated nuclear lobes, multinucleated forms |
Blast percentage determination: Count ≥500 nucleated cells on the aspirate. Blast percentage must be < 20% to diagnose MDS; ≥20% = AML. [1][2][6]
Bone marrow cellularity:
- Typically hypercellular (ineffective haematopoiesis — can make, but can't release into circulation) [1]
- Age-adjusted cellularity should be considered (expected cellularity = 100 − age, ±10%)
- Rarely hypocellular → hypoplastic MDS (distinguish from aplastic anaemia by presence of dysplasia and clonal cytogenetic changes) [6]
- 10–15% of MDS may show mild/moderate myelofibrosis [6]
Hypercellular Marrow + Pancytopenia = Think MDS
Pancytopenia + hypercellular marrow is classical for MDS (due to ineffective haematopoiesis), cf. aplastic anaemia which is hypocellular. [6] This paradox is the morphological signature of MDS and reflects the core pathophysiology: the marrow is working hard but producing defective cells that die before entering the circulation.
Step 4: Ancillary Studies on BM Specimen
These are performed on the aspirate material and/or biopsy to complete the diagnostic workup.
| Stain | Purpose | Findings in MDS |
|---|---|---|
| Prussian blue (iron stain) | Detect ring sideroblasts | Ring sideroblasts = erythroid precursors with ≥5 iron granules encircling ≥1/3 of the nucleus [2]; defines MDS-RS subtype if ≥15% (or ≥5% with SF3B1 mutation) |
| MPO / Sudan Black B [1][9] | Confirm myeloid lineage of blasts | +ve staining = myeloid lineage [1]; important to distinguish myeloblasts from lymphoblasts if blasts are approaching the 20% threshold |
Why do we need cytochemistry? Because morphologically, myeloblasts and lymphoblasts can look identical under light microscopy. MPO positivity confirms myeloid origin, ruling out ALL. Auer rods, if present, also confirm myeloid lineage and are diagnostic of AML. [9]
Flow cytometry on the aspirate identifies aberrant antigen expression on haematopoietic cells, which supports clonality even when morphological dysplasia is borderline.
| Application | Detail |
|---|---|
| Blast immunophenotype | CD34+, CD117+, HLA-DR+, CD13+, CD33+ (myeloid markers); aberrant expression of lymphoid markers or loss of normal markers suggests clonality |
| Dysplastic granulocytes | Abnormal patterns of CD10, CD11b, CD13, CD16 expression |
| Dysplastic monocytes | Abnormal CD14, CD36, HLA-DR expression |
| PNH clone detection | GPI-anchored protein deficiency (↓CD55/CD59) — MDS can coexist with PNH clone |
Immunophenotyping is non-diagnostic on its own but can help support the diagnosis and has prognostic value. [6]
Cytogenetics is essential for MDS classification, prognosis, and distinguishing from AML. [6]
| Principle | Detail |
|---|---|
| Method | Conventional G-banding karyotype on BM aspirate cells (requires dividing cells; failure rate ~10–20%) |
| Abnormal in ~50% of de novo MDS | Higher in therapy-related MDS (~80%) |
| Provides both diagnostic and prognostic information | del(5q), -7, +8, del(20q), complex karyotype — all have defined prognostic significance |
| Characteristic MDS cytogenetics include: del(5q), del(7q), monosomy 5/7 [6] | These help distinguish from AML and classify MDS with prognostic value [6] |
| Principle | Detail |
|---|---|
| Method | Targeted probes for specific abnormalities; does NOT require dividing cells (advantage over karyotype) |
| Advantages | Higher sensitivity for specific abnormalities; can be used when karyotype fails |
| Standard MDS FISH panel | del(5q), -7/del(7q), trisomy 8, del(20q), del(17p) |
| When used | Complements karyotype; particularly useful if karyotype fails or is normal but clinical suspicion is high |
This has become increasingly central to MDS diagnosis, classification, and prognosis.
| Principle | Detail |
|---|---|
| Method | Targeted NGS panel of 30–50 genes commonly mutated in myeloid neoplasms |
| Key genes tested | SF3B1 (ring sideroblasts, good prognosis), TP53 (very poor prognosis), ASXL1, RUNX1, EZH2, TET2, DNMT3A, SRSF2, U2AF1, IDH1/2 |
| Diagnostic role | Supports clonality when morphological dysplasia is borderline; SF3B1 now defines a specific WHO subtype |
| Prognostic role | Incorporated into IPSS-M (molecular prognostic model) |
| TP53 biallelic inactivation | Defines its own entity in WHO 2022 (MDS-biTP53); very poor prognosis regardless of blast % |
From the workup mnemonic: MCICM = Morphology, Cytochemistry, Immunophenotype, Cytogenetics, Molecular genetics [9][14]. This systematic approach applies to ALL suspected haematological malignancies, including MDS.
After all the above investigations are complete, the data is integrated to classify MDS according to the WHO 2022 system:
| WHO 2022 Subtype | Blast % (BM/PB) | Key Defining Feature |
|---|---|---|
| MDS with low blasts (MDS-LB) | < 5% / < 2% [2] | Dysplasia in ≥1 lineage |
| MDS with low blasts and SF3B1 mutation (MDS-SF3B1) | < 5% / < 2% | SF3B1 mutation ± ring sideroblasts ≥15% (or ≥5% with mutation); favourable prognosis |
| MDS with isolated del(5q) (MDS-5q) | < 5% / < 2% | Isolated del(5q) ± 1 additional abnormality (not -7/del(7q)); good prognosis [2] |
| MDS with increased blasts-1 (MDS-IB1) | 5–9% / 2–4% | Intermediate risk |
| MDS with increased blasts-2 (MDS-IB2) | 10–19% / 5–19% | High risk; near-AML threshold |
| MDS with biallelic TP53 inactivation (MDS-biTP53) | Any | Biallelic TP53 loss; very poor prognosis |
| MDS, hypoplastic | Variable | Marrow cellularity < 25%; overlap with aplastic anaemia |
Once classified, risk stratification guides treatment decisions.
IPSS-R (Revised International Prognostic Scoring System):
The IPSS-R uses 5 variables:
| Variable | Categories |
|---|---|
| Cytogenetic risk group | Very good / Good / Intermediate / Poor / Very poor |
| BM blast % | ≤2% / > 2 – < 5% / 5–10% / > 10% |
| Haemoglobin | ≥10 / 8– < 10 / < 8 g/dL |
| Platelet count | ≥100 / 50– < 100 / < 50 × 10⁹/L |
| ANC | ≥0.8 / < 0.8 × 10⁹/L |
| Risk Category | Score | Median Survival |
|---|---|---|
| Very low | ≤1.5 | 8.8 years |
| Low | > 1.5–3.0 | 5.3 years |
| Intermediate | > 3.0–4.5 | 3.0 years |
| High | > 4.5–6.0 | 1.6 years |
| Very high | > 6.0 | 0.8 years |
IPSS-M (Molecular IPSS):
- A newer model that integrates molecular mutations (e.g., TP53, SF3B1, ASXL1, RUNX1) alongside the IPSS-R variables
- Provides more refined risk stratification — approximately 25% of patients are reclassified into a different risk category compared to IPSS-R alone
- Particularly important for identifying patients with TP53 biallelic mutations (very poor prognosis) and SF3B1 mutations (favourable prognosis)
| Investigation | Expected Finding in MDS | Interpretation / Why |
|---|---|---|
| CBC | Cytopenia(s): anaemia (macrocytic), ± neutropenia, ± thrombocytopenia | Trilineage failure from ineffective haematopoiesis |
| Reticulocyte count | Low or inappropriately normal | Ineffective erythropoiesis — cells die in marrow before release |
| PBS [1] | Macrocytosis > 100 fL, Pelger-Huët anomaly, hypogranular neutrophils, nucleated RBCs, immature myeloid cells, pancytopenia [1] | Morphological evidence of dysplasia visible in peripheral blood |
| B12, folate, copper, zinc | Normal (if truly MDS) | Excludes reversible causes of dysplasia |
| HIV serology | Negative (if truly MDS) | Excludes HIV-associated dysplasia |
| LDH, bilirubin | May be elevated | Intramedullary haemolysis (cells die in marrow → release LDH and unconjugated bilirubin) |
| Serum EPO | Variable; often elevated | Kidneys sense anaemia → increase EPO → but marrow cannot respond effectively; EPO level can guide treatment (low EPO → better response to ESAs) |
| BM aspirate [6][14] | Dysplasia ≥10% in ≥1 lineage; blast < 20%; ring sideroblasts on iron stain | Mandatory for diagnosis; permits classification |
| BM trephine biopsy [6][14] | Usually hypercellular; may show mild fibrosis; architecture assessment | Cellularity, fibrosis degree, exclude infiltrative disease |
| Prussian blue iron stain | Ring sideroblasts (≥5 iron granules encircling ≥1/3 nucleus) [2] | Defines MDS-RS / MDS-SF3B1 subtype |
| MPO / Sudan Black B [1] | Positive in myeloid blasts | Confirms myeloid lineage; excludes ALL |
| Flow cytometry | Aberrant immunophenotype on blasts/progenitors | Supports clonality; non-diagnostic alone but useful in borderline cases |
| Cytogenetics (G-banding) [6] | Abnormal in ~50% de novo; del(5q), -7, +8, del(20q), complex | Diagnostic, classification, and prognostic value [6] |
| FISH | Targeted confirmation of specific abnormalities | Higher sensitivity for specific loci; complements karyotype |
| NGS molecular panel | SF3B1, TP53, ASXL1, RUNX1, TET2, SRSF2, etc. | Classification (SF3B1 → MDS-SF3B1; biTP53 → MDS-biTP53), prognosis (IPSS-M), potential therapeutic targets |
| PNH flow cytometry | GPI-anchored protein deficiency (↓CD55/CD59) | MDS can coexist with a PNH clone; important to screen |
| HLA typing | For patients who are candidates for HSCT | Required for transplant planning in higher-risk MDS |
| Serum ferritin | May be elevated (especially if transfusion-dependent) | Monitor iron overload risk |
| Feature | MDS | Aplastic Anaemia | AML | MPN | Megaloblastic Anaemia |
|---|---|---|---|---|---|
| Cellularity | Hypercellular [1] | Hypocellular (< 25%) [11] | Hypercellular | Hypercellular | Hypercellular |
| Dysplasia | Yes (≥10% in ≥1 lineage) | No — morphologically normal residual cells [11] | ± (in AML-MRC) | No [6] | "Pseudo-dysplasia" (megaloblastic changes) |
| Blast % | < 20% [1][2] | < 5% | ≥20% [1] | < 5% | < 5% |
| Ring sideroblasts | ± (defines subtype) | No | Rare | No | No (but copper deficiency does) |
| Fibrosis | Mild in 10–15% | No (fat replacement) | Variable | Significant in PMF | No |
| Cytogenetics | Abnormal ~50% | Normal [11] | Abnormal (AML-defining) | JAK2/CALR/MPL/BCR-ABL | Normal |
| Key PBS feature | Pelger-Huët, hypogranular [1] | No abnormal cells [11] | Blasts ≥20%, Auer rods [9] | ↑ cell counts, no dysplasia [6] | Hypersegmented neutrophils, macro-ovalocytes |
High Yield Summary — Diagnosis of MDS
Diagnostic requirements:
- Persistent cytopenia(s) in ≥1 lineage
- Morphological dysplasia ≥10% in ≥1 lineage on BM aspirate
- Blast % < 20% (≥20% = AML)
- Exclusion of reversible causes (B12, folate, copper, HIV, drugs, alcohol)
- Supportive: clonal cytogenetics and/or somatic mutations
Mandatory investigations: BM aspirate + trephine biopsy (with cytogenetics, FISH, molecular panel, iron stain, flow cytometry)
Key PBS findings: Macrocytosis, Pelger-Huët anomaly, hypogranular neutrophils, nucleated RBCs, pancytopenia
BM hallmark: Hypercellular marrow + pancytopenia = ineffective haematopoiesis = MDS
Workup mnemonic: MCICM = Morphology, Cytochemistry, Immunophenotype, Cytogenetics, Molecular genetics
Prognostic scoring: IPSS-R (clinical + cytogenetic) → IPSS-M (adds molecular mutations) → guides treatment
Classification determines subtype and prognosis: MDS-LB, MDS-SF3B1, MDS-5q, MDS-IB1, MDS-IB2, MDS-biTP53
Active Recall — MDS Diagnostic Criteria and Investigations
References
[1] Senior notes: Block A - Introduction to Haematological investigations (CBP, Clotting).pdf (MDS PBS findings, blast % in AML, MPO/SBB cytochemistry) [2] Senior notes: Maksim Medicine Notes.pdf (MDS definition, classification principles, ring sideroblast definition, del(5q) prognosis, blast < 20%) [6] Senior notes: Ryan Ho Haemtology.pdf (MDS key features, diagnosis pathway, BM findings, cytogenetics role, MDS vs AA vs MPN vs MDS/MPN comparison table, overview of myeloid malignancies) [9] Senior notes: Ryan Ho Fundamentals.pdf (MCICM workup, PBS interpretation including dysplastic WBCs in MDS, leukoerythroblastic picture, Auer rods, BM examination technique and contraindications) [11] Senior notes: Adrian Lui Pediatrics Notes.pdf (aplastic anaemia BM findings, diagnostic criteria, PBS findings — no abnormal cells) [14] Senior notes: Ryan Ho Fundamentals.pdf, p.391 (BM aspirate vs trephine, site, contraindications, complications, further haematological workup) [15] Senior notes: Block A - Pallor_ diagnosis of anaemia; nutritional anaemia; anaemia of systemic diseases.pdf (when BM is indicated in suspected PA vs MDS, intramedullary haemolysis DDx)
Management of Myelodysplastic Syndrome (MDS)
Before diving into specific therapies, let's establish the conceptual framework that governs all MDS management decisions:
-
MDS is a heterogeneous disease — prognosis ranges from > 10 years survival (lower-risk) to < 1 year (very high-risk). Treatment must be tailored to the individual's risk category.
-
NOT ALL MDS requires treatment. [6] A substantial subset of patients can survive for ≥10 years even with supportive therapy alone. [6]
-
No current therapy is curative except allogeneic HSCT — and even that is only feasible in a subset of patients. [6]
-
There is no evidence that treating asymptomatic patients prolongs survival — the main goal is to control symptoms and improve quality of life (QoL). [6]
-
The first decision point is risk stratification (IPSS-R / IPSS-M), which divides patients into lower-risk (very low, low, intermediate) and higher-risk (high, very high) categories.
-
The second decision point is fitness for intensive therapy — determined by age, performance status, comorbidities, and patient preference.
High Yield — MDS Management Philosophy
Management of MDS is risk-stratified: [6]
3. Detailed Treatment Modalities
3.1 Supportive Care — The Foundation for ALL Patients
Supportive care is the backbone of MDS management at every risk level. Even patients receiving disease-modifying therapy need ongoing supportive measures.
| Aspect | Detail |
|---|---|
| Indication | Symptomatic anaemia unresponsive to other measures; transfusion threshold is individualised (typically Hb < 7–8 g/dL, or higher in patients with cardiovascular comorbidities) |
| Goal | Symptom relief — maintain functional capacity and QoL |
| Risk | Transfusional iron overload (haemosiderosis) — each unit of RBCs contains ~200–250 mg iron; the body has no mechanism to excrete excess iron |
| Monitoring | Serial serum ferritin levels; consider iron chelation when ferritin > 1000 μg/L and patient has received > 20 units |
| Aspect | Detail |
|---|---|
| Why | Repeated RBC transfusions → excess iron deposition in heart (cardiac siderosis → cardiomyopathy), liver (cirrhosis), and endocrine organs (diabetes, hypogonadism) |
| Indication | Transfusion-dependent patients with ferritin > 1000 μg/L and expected survival long enough to benefit (typically lower-risk MDS with reasonable prognosis) |
| Agents | Deferasirox (oral, once daily — most commonly used); Desferrioxamine (SC/IV infusion — older agent, less convenient); Deferiprone (oral — risk of agranulocytosis, rarely used in MDS) |
| Contraindications | Severe renal impairment (deferasirox is nephrotoxic — monitor creatinine); high-risk MDS with very short expected survival (no time to benefit) |
Long-term transfusion ± iron chelation to prevent haemosiderosis is a key supportive measure. [16]
| Aspect | Detail |
|---|---|
| Indication | Active bleeding with thrombocytopenia; prophylactic transfusion if PLT < 10 × 10⁹/L (or < 20 × 10⁹/L with fever/infection) |
| Limitation | Repeated platelet transfusions can lead to alloimmunisation → platelet refractoriness; use HLA-matched platelets if this occurs |
| Measure | Rationale |
|---|---|
| Empirical broad-spectrum antibiotics for febrile neutropenia | Febrile neutropenia (ANC < 0.5 × 10⁹/L + fever) is a medical emergency requiring blood cultures and broad-spectrum antibiotics within one hour [17] |
| Antifungal prophylaxis | In patients with prolonged and profound neutropenia [4] — risk of invasive aspergillosis and candidiasis |
| Proper nursing care | Reverse isolation, face mask, hand hygiene, low-bacteria diet [4] |
| G-CSF | Can be used short-term for severe neutropenia/recurrent infections; NOT routinely recommended as long-term monotherapy (concern about stimulating the malignant clone — though evidence is limited) |
| Vaccinations | Influenza, pneumococcal, COVID-19 — as appropriate for age and comorbidities |
High Yield — Febrile Neutropenia in MDS
Febrile neutropenia is a medical emergency. ANC < 0.5 × 10⁹/L + fever → immediate blood cultures and empirical broad-spectrum antibiotics within one hour. [17] Do not wait for culture results. Delayed treatment significantly increases mortality. The same principles from acute leukaemia management apply to MDS patients with severe neutropenia.
| Measure | Detail |
|---|---|
| Stop smoking [6] | Reduces further mutagenic insult to HSCs |
| Exclude and correct reversible causes [6] | B12, folate, copper, thyroid — ongoing reassessment |
| Vaccinations as appropriate [6] | Especially important given immune dysfunction |
| Regular monitoring | Usually by regular CBC with differential and PBS [6] — frequency depends on risk category and clinical stability |
3.2 Lower-Risk MDS — Treatment of Symptomatic Cytopenias
The goal in lower-risk MDS is NOT to cure (HSCT is generally not indicated for lower-risk disease) but to improve blood counts, reduce transfusion dependence, and improve QoL.
| Aspect | Detail |
|---|---|
| Agents | Erythropoietin (EPO) alfa/beta; Darbepoetin alfa (longer half-life) |
| Mechanism | Recombinant EPO binds to EPO receptors on erythroid progenitors in the marrow → promotes survival, proliferation, and differentiation of erythroid precursors → ↑ RBC production |
| Indication | Isolated anaemia with serum EPO ≤ 500 mU/mL [6] — patients with low endogenous EPO are more likely to respond because there is "room" for exogenous EPO to have an effect |
| Response rate | ~40–60% in selected patients (low EPO, low transfusion burden, lower blast %) |
| Non-responders | EPO > 500 mU/mL, high transfusion burden (≥ 2 units/month), higher blast %, ring sideroblasts (these patients respond better to luspatercept) |
| Combination | ESA + G-CSF can be synergistic — G-CSF enhances erythropoiesis when combined with ESA (through a synergistic signalling mechanism in erythroid progenitors) |
| Duration | Trial for ≥12 weeks before declaring failure; continue indefinitely if responding |
Why does serum EPO level matter? Because if the kidneys are already producing massive amounts of EPO ( > 500 mU/mL) in response to the anaemia, adding more exogenous EPO is unlikely to help — the problem is not insufficient EPO but the marrow's inability to respond to it.
| Aspect | Detail |
|---|---|
| Drug class | Immunomodulatory drug (IMiD) — "lenalidomide" = a thalidomide analogue |
| Mechanism | Binds cereblon (CRBN, an E3 ubiquitin ligase component) → targets the del(5q)-associated protein casein kinase 1α (CK1α) for ubiquitination and proteasomal degradation → selectively kills the del(5q) clone while sparing normal haematopoiesis. It also has immunomodulatory and anti-angiogenic effects |
| Indication | del(5q) MDS (MDS-5q) [6] — FDA/EMA approved specifically for transfusion-dependent lower-risk MDS with del(5q) |
| Response rate | ~65–75% achieve transfusion independence; ~50% achieve cytogenetic response |
| Side effects | Neutropenia and thrombocytopenia (paradoxically, in the first weeks — due to initial cytotoxic effect before normal haematopoiesis recovers); thromboembolism (requires prophylactic aspirin or anticoagulation); teratogenicity (absolute contraindication in pregnancy — thalidomide catastrophe legacy) |
| Contraindications | Pregnancy (teratogenic); del(5q) with TP53 mutation (poor response, higher risk of AML transformation on lenalidomide) |
High Yield — Lenalidomide for del(5q) MDS
Lenalidomide is a targeted therapy specifically for MDS with isolated del(5q). [6] It works by degrading CK1α through the cereblon-ubiquitin pathway. Del(5q) is associated with good prognosis [2] and excellent response to lenalidomide. However, concurrent TP53 mutation increases the risk of AML transformation on lenalidomide — always check TP53 status before starting.
| Aspect | Detail |
|---|---|
| Drug class | Recombinant fusion protein — acts as a "ligand trap" for TGF-β superfamily members |
| Mechanism | Binds and neutralises activins (especially activin A) and GDF11/GDF8 → these TGF-β superfamily ligands normally inhibit late-stage erythropoiesis (they suppress terminal erythroid differentiation). By trapping them, luspatercept releases the brake on erythroid maturation → ↑ effective erythropoiesis → ↑ Hb |
| Indication | MDS with ring sideroblasts (MDS-RS / MDS-SF3B1) [6] — especially those who have failed or are unlikely to respond to ESAs |
| Response rate | ~40–50% achieve transfusion independence or significant Hb rise |
| Administration | Subcutaneous injection every 3 weeks |
| Side effects | Fatigue, headache, diarrhoea, bone pain; hypertension; thromboembolic events (rare) |
| Contraindications | Pregnancy (insufficient data); uncontrolled hypertension |
TGF-β inhibitor luspatercept is an emerging therapy specifically positioned for MDS-RS. [16]
| Aspect | Detail |
|---|---|
| Agents | Anti-thymocyte globulin (ATG) + Cyclosporine [6] |
| Mechanism | ATG depletes autoreactive T-cells that are attacking haematopoietic progenitors (similar to the autoimmune mechanism in aplastic anaemia); Cyclosporine inhibits calcineurin → suppresses T-cell activation → reduces immune-mediated marrow suppression |
| Indication | Selected low-risk MDS patients [6] — particularly those with: hypoplastic MDS (overlaps with aplastic anaemia); younger age ( < 60); HLA-DR15 positive; PNH clone present; low blast % |
| Response rate | ~30–40% in selected patients |
| Rationale | In early/low-risk MDS, there is an autoimmune T-cell-mediated component contributing to the cytopenias — similar to aplastic anaemia. IST addresses this component |
| Contraindications | Higher-risk MDS (blasts > 5%); active infection; renal impairment (cyclosporine is nephrotoxic) |
The rationale mirrors aplastic anaemia management: Triple therapy immunosuppression: ATG + cyclosporine A ± eltrombopag is the standard for AA [2], and the same agents can benefit the subset of MDS patients with an autoimmune component.
| Aspect | Detail |
|---|---|
| Agents | Azacitidine (5-azacitidine); Decitabine (5-aza-2'-deoxycytidine) [6] |
| Mechanism | ↓ Methylation of CpG islands → ↓ gene silencing [6]. CpG islands are DNA regions with high frequency of C-(phosphodiester)-G sequences; cytosine residues here are often methylated to silence tumour suppressor genes. HMAs are incorporated into DNA during replication and irreversibly inhibit DNA methyltransferases (DNMTs) → passive demethylation → re-expression of silenced tumour suppressor and differentiation genes |
| Indication in lower-risk | Other low-risk patients with bi/pancytopenia who have no actionable mutation and have failed or are not candidates for growth factors or targeted therapy [6] |
| Note | Not curative but shown to improve survival in MDS [6]; apparent efficacy may not be entirely related to methylation [6] (cytotoxic effect at higher doses; immunomodulatory effects) |
| Administration | Azacitidine: SC or IV, 75 mg/m²/day × 7 days, every 28-day cycle; Decitabine: IV, 20 mg/m²/day × 5 days, every 28-day cycle; Oral decitabine/cedazuridine (Inqovi) — oral formulation now available |
| Response | Typically requires ≥4–6 cycles before response assessment; continue until loss of response or unacceptable toxicity |
| Side effects | Myelosuppression (worsening of cytopenias initially — expected), nausea, injection site reactions (SC azacitidine), fatigue, constipation |
| Contraindications | Advanced hepatic impairment (liver metabolised); active uncontrolled infection |
High Yield — How HMAs Work
Hypomethylating agents (azacitidine, decitabine) work by decreasing methylation of CpG islands, thereby decreasing gene silencing of tumour suppressors. [6] They are not curative but improve survival and reduce transfusion dependence. They are the backbone of MDS therapy for both lower-risk patients with refractory cytopenias and higher-risk patients unfit for HSCT.
| Aspect | Detail |
|---|---|
| Agents | Eltrombopag; Romiplostim |
| Mechanism | Bind and activate the thrombopoietin (TPO) receptor (c-MPL) on megakaryocytes → stimulate megakaryocyte proliferation and differentiation → ↑ platelet production |
| Indication | Isolated thrombocytopenia refractory to transfusion [6] |
| Caution | Concerns for ↑ transformation to AML as it may stimulate growth of leukemic blasts [6] — TPO receptor is expressed on some MDS/AML blast cells; theoretical risk of promoting blast proliferation |
| Use in practice | Reserved for select patients; more established role in aplastic anaemia (where high-dose eltrombopag is part of first-line therapy: ATG + cyclosporine ± eltrombopag) [2] |
3.3 Higher-Risk MDS — Disease-Modifying Therapy
The goal in higher-risk MDS shifts from pure symptom control to altering disease trajectory — reducing blast burden, delaying/preventing AML transformation, and potentially achieving long-term remission (via HSCT).
| Aspect | Detail |
|---|---|
| Agents | Azacitidine (most evidence; preferred); Decitabine |
| Indication | Higher-risk MDS patients — first-line for those unfit for HSCT; bridging therapy before HSCT [6] |
| Evidence | AZA-001 trial: azacitidine vs conventional care → azacitidine improved median OS from 15 months to 24.5 months in higher-risk MDS |
| Combination | Azacitidine + Venetoclax — an emerging standard: venetoclax (BCL-2 inhibitor) promotes apoptosis of MDS/AML cells; synergistic with azacitidine; adopted from AML protocols for unfit patients |
| Duration | Continue until disease progression, transformation to AML, or unacceptable toxicity; responses may take 4–6 cycles |
Allogeneic HSCT is the only potentially curative treatment for MDS. [4][6]
| Aspect | Detail |
|---|---|
| Mechanism | Replace the patient's diseased marrow with a healthy donor's haematopoietic stem cells. The donor immune system also provides a graft-versus-leukaemia (GVL) effect — donor T-cells recognise and destroy residual MDS/leukaemic cells |
| Indication | MDS — high risk at first diagnosis [4]; higher-risk MDS (IPSS-R high/very high); also intermediate-risk patients with poor prognostic molecular features (e.g., TP53 biallelic); should be considered early — ideally before AML transformation |
| Patient selection | Age (historically < 65–70, but this is evolving with reduced-intensity conditioning); performance status; comorbidity burden (HCT-CI score); availability of a suitable donor |
| Donor sources | HLA-matched sibling (best outcomes); matched unrelated donor (MUD); haploidentical donor (half-matched, now increasingly feasible) |
| Conditioning regimen | Myeloablative conditioning (MAC) — for younger/fitter patients; Reduced-intensity conditioning (RIC) — for older patients or those with comorbidities (lower treatment-related mortality but slightly higher relapse risk) |
| Pre-HSCT considerations | Cytoreduction with HMA bridging therapy if needed (to reduce blast burden before transplant); HLA typing early in disease course for all potentially eligible patients |
| Major risks | Treatment-related mortality (TRM): 10–30% depending on conditioning intensity and patient factors; Graft-versus-host disease (GVHD) — acute and chronic; relapse post-transplant; infections during immunosuppression |
| Contraindications | Very poor performance status; severe uncontrolled comorbidities; active uncontrolled infection; patient refusal |
Indications for allogeneic HSCT (adult): [4]
- AML/ALL — high risk at first remission or at relapse
- MDS — high risk
- CML (T315I, accelerated phase/blast crisis)
- Transformed MPN
- Relapsed lymphoma
- Aplastic anaemia
High Yield — Allo-HSCT in MDS
Allogeneic HSCT is the ONLY potentially curative therapy for MDS and is indicated for high-risk MDS. [4][6] The decision involves balancing transplant-related mortality against the risk of disease progression/AML transformation. HLA typing should be performed early for all patients who are potential transplant candidates. [10]
| Aspect | Detail |
|---|---|
| Regimen | 7+3 regimen: 7 days cytarabine infusion + 3 days IV anthracycline (same as AML induction) [8] |
| Indication | Selected higher-risk MDS patients who are fit for intensive therapy but for whom HSCT is planned as consolidation; can be used as a bridge to HSCT |
| Response rate | CR rates of 40–60% — BUT responses are often short-lived compared to de novo AML; therapy-related and secondary MDS/AML tend to be more resistant |
| Major risks | GI toxicity; marked BM hypocellularity (expected); tumour lysis syndrome; neutropenic infections (bacteria and fungi) [8] |
| Limitations | MDS blasts are often more resistant to chemotherapy than de novo AML blasts (especially in TP53-mutated or complex-karyotype MDS); not curative without subsequent HSCT |
| Alternatives for unfit patients | Low-intensity treatment: Azacitidine, Decitabine, low-dose cytarabine; Best supportive care for very poor performance status (including hydroxyurea for symptom control) [8] |
The therapeutic landscape for MDS is evolving rapidly. Several newer agents are now available or in clinical trials:
| Agent | Target | Indication in MDS | Mechanism |
|---|---|---|---|
| Lenalidomide | Cereblon/CK1α | del(5q) MDS | Degrades CK1α in del(5q) clone → selective cytotoxicity |
| Luspatercept | TGF-β superfamily (activin trap) | MDS-RS / SF3B1 | Releases brake on terminal erythroid differentiation |
| Venetoclax | BCL-2 | Higher-risk MDS (+ azacitidine) | Inhibits anti-apoptotic BCL-2 → restores apoptosis in MDS/AML blasts |
| Ivosidenib / Enasidenib | IDH1 / IDH2 | IDH-mutated MDS | IDH mutations produce oncometabolite 2-hydroxyglutarate → blocks differentiation; IDH inhibitors restore normal differentiation |
| Imetelstat | Telomerase | Lower-risk MDS (transfusion-dependent) | Inhibits telomerase → selectively targets cells with high telomerase activity (malignant clones) |
| Magrolimab | CD47 ("don't eat me" signal) | Higher-risk MDS (+ azacitidine) | Blocks CD47 on MDS blasts → allows macrophage-mediated phagocytosis ("eat me" signal restored); clinical trials ongoing |
5. Special Situations
- Arises after prior chemotherapy (alkylating agents, topoisomerase II inhibitors) or radiotherapy
- Generally poorer prognosis than de novo MDS — often complex karyotype, TP53 mutations
- Treated with same principles as higher-risk MDS — HMA ± venetoclax, HSCT if fit
- Patients with prior alkylating agent exposure: often del(5q), del(7q), complex karyotype
- Overlaps clinically and morphologically with aplastic anaemia
- Key distinction: presence of dysplasia and/or clonal cytogenetic changes
- Immunosuppressive therapy (ATG + cyclosporine) may be effective [6] — targeting the autoimmune T-cell component
- If high-risk features present → manage as higher-risk MDS
- Very poor prognosis regardless of blast %
- Resistant to standard chemotherapy and HMAs
- HSCT outcomes are also poor (high relapse rate)
- Clinical trials of novel agents (e.g., eprenetapopt/APR-246 — restores p53 function; magrolimab) are being explored
| Risk Category | Treatment Approach | Key Agents |
|---|---|---|
| Lower-risk, asymptomatic | Monitor — regular CBC/PBS [6] | None (watchful waiting) |
| Lower-risk, isolated anaemia, EPO ≤ 500 | ESA ± G-CSF [6] | EPO alfa, darbepoetin |
| Lower-risk, del(5q) | Lenalidomide [6] | Lenalidomide |
| Lower-risk, MDS-RS / SF3B1 | Luspatercept [6] | Luspatercept |
| Lower-risk, hypoplastic, selected | IST: ATG + Cyclosporine [6] | ATG, cyclosporine |
| Lower-risk, bi/pancytopenia, no target | HMA [6] | Azacitidine, decitabine |
| Higher-risk, fit for HSCT | Allo-HSCT (± HMA bridging) [4][6] | Conditioning + donor HSCs |
| Higher-risk, unfit for HSCT | HMA ± Venetoclax [6] | Azacitidine + venetoclax |
| Higher-risk, very poor PS | Best supportive care [8] | Transfusions, hydroxyurea |
| All patients | Supportive care | Transfusions, iron chelation, infection management, G-CSF prn |
High Yield Summary — Management of MDS
Guiding principles:
- Risk stratify ALL patients using IPSS-R / IPSS-M
- Not all MDS needs treatment — asymptomatic lower-risk → monitor
- No therapy is curative except allo-HSCT
- Goal in lower-risk: improve QoL, reduce transfusion dependence
- Goal in higher-risk: alter disease course, prevent AML transformation
Lower-risk MDS:
- ESA (if EPO ≤ 500) → Lenalidomide (if del(5q)) → Luspatercept (if MDS-RS/SF3B1) → IST (if hypoplastic) → HMA (if refractory)
Higher-risk MDS:
- Allo-HSCT if fit (only curative option)
- HMA ± venetoclax if unfit for HSCT
- Intensive chemotherapy (7+3) as bridge to HSCT in selected cases
- Best supportive care if very poor performance status
Supportive care for ALL:
- RBC/platelet transfusions; iron chelation (deferasirox) if ferritin > 1000
- Febrile neutropenia → emergency → blood cultures + empirical antibiotics within 1 hour
- Antifungal prophylaxis for prolonged neutropenia
- HLA typing early for potential HSCT candidates
Key drugs and their targets:
- Lenalidomide → del(5q) / CK1α
- Luspatercept → TGF-β / activin trap → MDS-RS
- HMAs (azacitidine/decitabine) → DNA methyltransferase → CpG island demethylation
- Venetoclax → BCL-2 → restores apoptosis
- ATG + cyclosporine → T-cell-mediated marrow suppression
Active Recall — Management of MDS
References
[2] Senior notes: Maksim Medicine Notes.pdf (MDS classification, del(5q) good prognosis, ring sideroblast definition, aplastic anaemia management: ATG + cyclosporine ± eltrombopag) [4] Senior notes: Block A - High white cell count_ acute and chronic leukaemia; bone marrow transplantation; immunogenetics.pdf (supportive treatment of acute leukaemia, antifungal prophylaxis, nursing care, haematological emergencies, indications for allo-HSCT including high-risk MDS) [6] Senior notes: Ryan Ho Haemtology.pdf (MDS management principles, risk stratification, monitor if asymptomatic, ESA for EPO ≤ 500, lenalidomide for del(5q), luspatercept for MDS-RS, HMA mechanism and role, IST for selected patients, allo-HSCT for high-risk, TPO-RA caution) [8] Senior notes: Ryan Ho Haemtology.pdf, p.56 (AML/MDS intensive induction: 7+3 regimen, alternatives for unfit patients, major risks, post-remission strategy) [10] Lecture slides: GC 060. High white cell count.pdf (workup for acute leukaemia including HLA typing for HSCT candidates) [16] Senior notes: Block A - Splenomegaly_ common causes of splenomegaly; myeloproliferative diseases.pdf (PMF supportive care: long-term transfusion ± iron chelation, EPO, TGF-β inhibitor luspatercept, JAK2 inhibitors) [17] Senior notes: Learning_Points_All_Lectures.txt (febrile neutropenia: ANC < 0.5 + fever → blood cultures + empirical antibiotics within 1 hour)
Complications of Myelodysplastic Syndrome (MDS)
The complications of MDS can be organised into three major domains:
- Complications arising directly from cytopenias (the disease itself)
- Transformation to acute myeloid leukaemia (the natural history of the disease)
- Complications arising from treatment (iatrogenic)
Understanding these complications requires circling back to the core pathophysiology: MDS is a clonal marrow disorder causing ineffective haematopoiesis → cytopenias → the body fails in its three fundamental haematological tasks: oxygen delivery (RBCs), immune defence (WBCs), and haemostasis (platelets). Meanwhile, the malignant clone itself can acquire additional mutations and evolve toward overt leukaemia.
1. Complications of Anaemia / Ineffective Erythropoiesis
- Mechanism: Dysplastic erythroid precursors undergo intramedullary apoptosis → inadequate RBC production → progressive anaemia
- Clinical impact: Fatigue, reduced exercise tolerance, exertional dyspnoea, reduced QoL — this is often the primary reason patients seek medical attention
- Consequence: Many patients become transfusion-dependent — requiring regular packed RBC transfusions to maintain functional haemoglobin levels. Transfusion dependence itself is an independent adverse prognostic factor in MDS
This is one of the most important long-term complications, especially in lower-risk MDS patients who survive long enough to accumulate significant iron burden.
Each unit of blood contains approximately 200 mg of iron. The body normally excretes only ~1 mg of iron per day. [18] Therefore, chronic transfusion leads to inevitable iron accumulation with no physiological mechanism for excretion.
| Organ Affected | Consequence | Pathophysiological Mechanism |
|---|---|---|
| Liver | Liver fibrosis → cirrhosis → HCC [18] | Iron deposits in hepatocytes → generates reactive oxygen species (ROS) via Fenton reaction → oxidative damage → hepatocyte necrosis → stellate cell activation → fibrosis |
| Heart | Heart failure (dilated cardiomyopathy), arrhythmias [18] | Iron deposits in cardiomyocytes → ROS-mediated damage to contractile proteins and mitochondria → impaired systolic function; iron in the conduction system → arrhythmias |
| Endocrine organs | Diabetes mellitus, hypogonadism, growth retardation (in children) [18] | Iron deposits in pancreatic β-cells → β-cell destruction → DM; iron in pituitary/gonads → hypogonadotropic hypogonadism |
| Skin | Bronze skin discolouration | Iron deposition in dermal macrophages → haemosiderin pigmentation |
For long-term transfusion patients such as thalassemia and MDS, they will inevitably develop iron overload. [18] Iron chelation therapy (deferasirox, desferrioxamine) is indicated when ferritin > 1000 μg/L and expected survival is sufficient to benefit.
High Yield — Iron Overload in MDS
Iron overload is a slow but devastating complication of chronic transfusion dependence. It is most clinically significant in lower-risk MDS patients who have longer survival (and therefore more time to accumulate iron). Higher-risk MDS patients often succumb to disease progression or AML transformation before iron overload becomes the dominant problem. The key target organs are liver (fibrosis/HCC), heart (failure/arrhythmias), and endocrine organs (DM, hypogonadism). [18]
- Mechanism: Chronic severe anaemia → compensatory increase in cardiac output (increased heart rate + stroke volume + vasodilation) → sustained volume overload → ventricular dilation → eventually decompensation
- Risk factors: Pre-existing cardiovascular disease (common in the elderly MDS population), coexisting iron-mediated cardiomyopathy
- Prevention: Maintain Hb above symptomatic threshold with transfusions or ESAs; avoid over-transfusion (volume overload)
2. Complications of Neutropenia / Immune Dysfunction
Infections are the leading cause of death in MDS, accounting for approximately 20–35% of all deaths.
- Mechanism (quantitative): Ineffective granulopoiesis → reduced absolute neutrophil count (ANC) → inadequate innate immune surveillance
- Mechanism (qualitative): Even when ANC is numerically adequate, MDS neutrophils are hypogranular [1] and hypolobulated [1] — they are functionally defective: impaired phagocytosis, reduced oxidative burst, defective chemotaxis. This means the infection risk is higher than the ANC alone would suggest
- Types of infections:
| Severity of Neutropenia | Predominant Infections |
|---|---|
| Mild (ANC 1.0–1.5) | Typical community-acquired bacterial infections (sinusitis, UTI, pneumonia) |
| Moderate (ANC 0.5–1.0) | Increased frequency and severity of bacterial infections |
| Severe (ANC < 0.5) | Bacterial sepsis (gram-negative organisms, Pseudomonas, E. coli) and invasive fungal infections (Aspergillus, Candida) — these become the leading cause of mortality |
| Profound/prolonged (ANC < 0.1 for > 7 days) | Highest risk of invasive aspergillosis and disseminated candidiasis |
High Yield — Febrile Neutropenia
Febrile neutropenia (ANC < 0.5 × 10⁹/L + fever ≥38°C) is a medical emergency. Requires blood cultures and empirical broad-spectrum antibiotics within one hour. Delayed treatment significantly increases mortality. [17] This principle applies equally to MDS patients as to acute leukaemia patients. Invasive fungal infection is an important cause of death in prolonged neutropenia. [11]
MDS is associated with immune dysregulation that goes beyond simple neutropenia. Approximately 10–20% of MDS patients develop autoimmune or inflammatory conditions.
| Condition | Mechanism | Key Features |
|---|---|---|
| Sweet syndrome (acute febrile neutrophilic dermatosis) | Paraneoplastic neutrophilic inflammation; exact mechanism unclear but involves cytokine dysregulation from the MDS clone | Tender, erythematous, well-demarcated plaques/nodules + fever + neutrophilia (paradoxically, despite background neutropenia from MDS); biopsy shows dense dermal neutrophilic infiltrate without vasculitis |
| Relapsing polychondritis | Autoimmune attack on cartilage; T-cell mediated | Auricular chondritis (red, swollen ears), nasal/tracheal chondritis, inflammatory arthritis |
| Vasculitis (cutaneous or systemic) | Immune complex-mediated or T-cell-mediated | Purpura, skin ulcers, polyarteritis-like syndrome |
| Seronegative inflammatory arthritis | T-cell-mediated synovitis | Inflammatory joint pain without positive RF/ACPA |
| Behçet-like syndrome | Immune dysregulation | Oral/genital ulcers, skin lesions |
| Pyoderma gangrenosum | Neutrophilic dermatosis | Painful, rapidly progressive ulcers with undermined borders |
The autoimmune component is more prominent in low-risk MDS (where T-cell-mediated autoimmunity contributes to cytopenias) and may actually improve with immunosuppressive therapy (ATG + cyclosporine).
3.1 Haemorrhagic Complications
- Mechanism: Ineffective megakaryopoiesis → reduced platelet count AND qualitative platelet defects (dysplastic megakaryocytes produce dysfunctional platelets)
- Clinical spectrum:
- Mild: petechiae, purpura, easy bruising, gum bleeding, epistaxis
- Moderate: haematuria, GI bleeding (melaena, haematemesis)
- Severe: intracranial haemorrhage (rare but potentially fatal, especially with PLT < 10 × 10⁹/L)
- Risk escalation: Bleeding risk increases exponentially as PLT falls below 20 × 10⁹/L, and further below 10 × 10⁹/L
- Confounders: Concurrent medications (aspirin, anticoagulants), concurrent infection (which increases capillary fragility and consumptive coagulopathy), and acquired platelet function defects specific to MDS
4. Transformation to Acute Myeloid Leukaemia (AML)
MDS is a pre-leukaemic condition — it may transform to acute leukaemia. [2]
This is arguably the most clinically important complication and the one that defines MDS as a malignant, rather than simply benign, condition.
The multi-step mutational model explains why MDS transforms to AML:
- The initial MDS clone has mutations that impair differentiation (dysplasia) but the cells still retain some capacity for apoptosis → low blast count, cytopenias
- Over time, additional mutations accumulate — particularly in signalling pathway genes (FLT3, RAS, KIT) and anti-apoptotic genes (BCL-2) → these mutations confer proliferative advantage and resistance to apoptosis
- When blasts accumulate to ≥20% in bone marrow or peripheral blood, the disease is reclassified as AML (secondary AML / AML-MRC — AML with myelodysplasia-related changes)
Think of it as the MDS clone "learning" how to survive AND proliferate, rather than just surviving poorly (as in early MDS).
| MDS Subtype / Feature | Approximate Risk of AML Transformation |
|---|---|
| MDS-LB (low blasts) | ~5–10% |
| MDS-SF3B1 (ring sideroblasts) | ~2–5% (lowest risk) |
| MDS-5q (del(5q)) | ~5–10% |
| MDS-IB1 (excess blasts 1) | ~25% |
| MDS-IB2 (excess blasts 2) | ~35–50% |
| MDS-biTP53 | Very high (~50–70%+) |
| Therapy-related MDS | ~30–50% |
| Factor | Higher Risk of AML Transformation |
|---|---|
| Higher blast % | More blasts → closer to the 20% threshold |
| Complex karyotype (≥3 abnormalities) | Genomic instability → more rapid acquisition of additional oncogenic mutations |
| TP53 mutation (especially biallelic) | Loss of the "guardian of the genome" → no cell cycle arrest or apoptosis in response to DNA damage → unchecked proliferation |
| Prior alkylating agent therapy | DNA damage accelerates mutational burden |
| Monosomy 7 / del(7q) | Associated with aggressive disease biology |
| RUNX1 mutation | Master regulator of haematopoiesis; mutation impairs differentiation |
Secondary AML arising from MDS is biologically and clinically distinct from de novo AML:
| Feature | s-AML (from MDS) | De novo AML |
|---|---|---|
| Prognosis | Poor [6] | Variable (depends on genetics) |
| Response to chemotherapy | Lower CR rates (~40–50%) | Higher CR rates (~60–80%) |
| Cytogenetics | Often complex, unfavourable | More often has favourable genetics |
| Molecular profile | TP53, ASXL1, RUNX1, EZH2 common | FLT3, NPM1, CEBPA more common |
| Residual dysplasia | Present (≥50% in ≥2 lineages — defining feature of AML-MRC) | Absent or minor |
| Treatment | HMA ± venetoclax for unfit; intensive chemo + HSCT for fit | Standard 7+3 induction often effective |
High Yield — AML Transformation in MDS
MDS is pre-leukaemic and may transform to AML. [2] The risk depends on blast %, cytogenetics, and molecular mutations. Secondary AML arising from MDS has a worse prognosis than de novo AML due to unfavourable genetics, prior clone resistance, and residual dysplasia. Allo-HSCT is the only curative option if feasible. [6]
5. Treatment-Related Complications
| Complication | Mechanism | Management |
|---|---|---|
| Myelosuppression | HMAs are cytotoxic to rapidly dividing haematopoietic cells (both malignant and normal) → transient worsening of cytopenias, especially in the first 1–2 cycles | Expected and managed with supportive care (transfusions, G-CSF, antibiotics); does not necessarily warrant dose reduction |
| Infections | Worsened neutropenia from myelosuppression | Febrile neutropenia protocol; antifungal prophylaxis |
| GI toxicity | Direct cytotoxicity to rapidly dividing GI epithelium | Anti-emetics (ondansetron); supportive care |
| Injection site reactions (azacitidine SC) | Local inflammatory response | Rotate injection sites; topical ice |
| Complication | Mechanism |
|---|---|
| Neutropenia and thrombocytopenia | Initial cytotoxic effect on dysplastic and normal haematopoietic cells; transient and expected |
| Thromboembolism (DVT/PE) | Prothrombotic effect of IMiDs — multifactorial (endothelial activation, increased tissue factor, decreased thrombomodulin); requires aspirin or anticoagulant prophylaxis |
| Teratogenicity | Direct — thalidomide analogue; absolutely contraindicated in pregnancy |
| AML transformation (with TP53-mutated del(5q)) | Lenalidomide may selectively eliminate the del(5q) clone but allow expansion of a pre-existing TP53-mutant subclone → AML |
For patients who undergo the only curative therapy, the complications are significant: [19]
Early complications ( < 1 year):
| Complication | Mechanism |
|---|---|
| Cytopenia-related | Expected — conditioning regimen ablates marrow; engraftment takes 2–4 weeks |
| Bleeding: 26% in first year, 9% life-threatening; sites: lung (16%), GI (14%), CNS (12%) [19] | Thrombocytopenia from conditioning and delayed engraftment |
| Neutropenic infections: bacterial and fungal [19] | Profound neutropenia during the engraftment period |
| Oral mucositis | Due to conditioning regimen [19]; managed with ice cubes, pre-treatment by laser, IV palifermin ± TPN |
| Veno-occlusive disease (VOD) of liver | Conditioning damaged hepatic venous endothelium [19]; presents with painful hepatomegaly, ascites, jaundice ± fulminant failure; treated with urso/heparin for prophylaxis, defibrotide + supportive Tx [19] |
| Graft rejection (host-versus-graft) [19] | Residual host immune cells reject the donor graft |
| Acute graft-versus-host disease (aGVHD) [19] | Donor T-cells attack host tissues (primarily skin, gut, liver) |
Late complications ( > 1 year):
| Complication | Mechanism |
|---|---|
| Cardiovascular disease: 5% at 5y, 9% at 15y [19] | Most common cause of morbidity/non-relapse mortality [19]; due to metabolic effects of immunosuppressants, ↑CV risk factors, chronic GVHD |
| Endocrine dysfunction | T2DM (3× risk), hypothyroidism, hypogonadism (active cGVHD + conditioning), infertility [19] |
| Second malignancy | Post-transplant lymphoproliferative disease (PTLD), post-treatment MDS/AML, solid organ tumours (SCC of skin/oral cavity) [19] |
| Cataract | From total body irradiation (part of some conditioning regimens) [19] |
| Chronic GVHD [19] | Donor T-cells cause chronic fibrotic and inflammatory damage to skin, eyes (dry eyes), mouth (xerostomia), lungs (bronchiolitis obliterans), liver, joints |
| Osteoporosis and AVN | Due to steroid use (for GVHD prophylaxis/treatment) [19] |
| Relapse of primary disease [19] | MDS/AML relapse post-transplant — poor prognosis; may attempt donor lymphocyte infusion (DLI) or second transplant |
High Yield — HSCT Complications
The most important early complications of allo-HSCT are neutropenic infections, GVHD (acute), and veno-occlusive disease. The most important late complication is chronic GVHD (a multi-system fibrotic/inflammatory disease) and cardiovascular disease (most common cause of non-relapse mortality). Disease relapse remains a major concern. [19]
| Agent | Key Toxicity | Monitoring |
|---|---|---|
| Deferasirox | Nephrotoxicity (acute kidney injury, tubulopathy); hepatotoxicity; GI disturbance | Monthly creatinine; LFTs every 2 weeks initially, then monthly |
| Desferrioxamine | Ototoxicity (sensorineural hearing loss); retinal toxicity; Yersinia and mucormycosis susceptibility (iron-dependent organisms thrive when chelator-bound iron is available) | Annual audiology and ophthalmology review |
| Deferiprone | Agranulocytosis (weekly FBC monitoring mandatory) | Weekly CBC |
6. Other Notable Complications
- MDS can coexist with a PNH clone — a subset of haematopoietic cells lacking GPI-anchored proteins (CD55, CD59) on their surface
- These cells are susceptible to complement-mediated lysis → intravascular haemolysis, haemoglobinuria, thrombosis
- Detected by flow cytometry showing ↓CD55/CD59
- The PNH clone may expand over time, particularly in hypoplastic MDS and aplastic anaemia
- Treatment: complement inhibitors (eculizumab, ravulizumab) if clinically significant PNH
- 10–15% of MDS patients develop mild-to-moderate reticulin fibrosis in the marrow
- This is distinct from primary myelofibrosis (PMF) — MDS-associated fibrosis is typically less severe, without massive splenomegaly or the characteristic leukoerythroblastic picture
- Fibrosis in MDS is an adverse prognostic factor — associated with more severe cytopenias and poorer response to treatment
| Category | Complication | Mechanism | Key Points |
|---|---|---|---|
| Anaemia | Symptomatic anaemia, transfusion dependence | Ineffective erythropoiesis | Most common presenting feature |
| Iron overload | Haemosiderosis (liver, heart, endocrine) | Chronic RBC transfusions; ~200 mg iron/unit | Chelation if ferritin > 1000 and sufficient survival expected |
| Neutropenia | Recurrent/severe infections (leading cause of death) | Quantitative + qualitative neutrophil defects | Febrile neutropenia is an emergency |
| Autoimmune | Sweet syndrome, vasculitis, polychondritis | Immune dysregulation from MDS clone | ~10–20% of patients; more in low-risk MDS |
| Thrombocytopenia | Bleeding (petechiae → ICH) | Ineffective megakaryopoiesis + dysfunctional platelets | Risk escalates below PLT 20 × 10⁹/L |
| AML transformation | Secondary AML | Acquisition of additional oncogenic mutations | 10–40% depending on subtype; worse prognosis than de novo AML |
| Treatment-related | HMA toxicity, lenalidomide toxicity, HSCT complications | Drug-specific mechanisms | GVHD, infections, VOD, second malignancies post-HSCT |
| Iron chelation toxicity | Nephro/hepatotoxicity, agranulocytosis | Agent-specific | Monitor renal/hepatic function, FBC |
| PNH clone | Haemolysis, thrombosis | GPI-anchor deficiency on coexisting clone | Screen with flow cytometry |
High Yield Summary — Complications of MDS
Infections are the leading cause of death in MDS — due to both quantitative neutropenia and qualitative neutrophil dysfunction (hypogranular, hypolobulated). Febrile neutropenia is a medical emergency.
Iron overload from chronic transfusions damages the liver (fibrosis → HCC), heart (cardiomyopathy, arrhythmias), and endocrine organs (DM, hypogonadism). Each unit contains ~200 mg iron; the body excretes only ~1 mg/day.
AML transformation is the defining malignant potential of MDS. Risk depends on blast %, cytogenetics (complex = worse), and mutations (TP53 = worst). Secondary AML from MDS has worse prognosis than de novo AML.
Autoimmune complications (~10–20%) include Sweet syndrome, vasculitis, relapsing polychondritis — more common in low-risk MDS and may respond to immunosuppression.
HSCT complications include early (infections, GVHD, VOD) and late (cardiovascular disease, second malignancies, chronic GVHD, endocrine dysfunction, relapse).
Active Recall — Complications of MDS
References
[1] Senior notes: Block A - Introduction to Haematological investigations (CBP, Clotting).pdf (MDS PBS findings: hypogranular and hypolobulated neutrophils) [2] Senior notes: Maksim Medicine Notes.pdf (MDS pre-leukaemia, may transform to acute leukaemia, no hepatosplenomegaly) [6] Senior notes: Ryan Ho Haemtology.pdf (MDS management principles, risk stratification, MPN AML transformation rates, MDS prognosis, s-AML characteristics) [11] Senior notes: Adrian Lui Pediatrics Notes.pdf (aplastic anaemia: invasive fungal infection important cause of death; supportive care principles) [17] Senior notes: Learning_Points_All_Lectures.txt (febrile neutropenia: ANC < 0.5 + fever → blood cultures + empirical antibiotics within 1 hour) [18] Senior notes: Block A - Fever after a blood transfusion_ transfusion and related problems.pdf (transfusion haemosiderosis: 200 mg iron/unit, iron excretion 1 mg/day, target organs: liver fibrosis/HCC, endocrine DM/hypogonadism, heart failure) [19] Senior notes: Ryan Ho Haemtology.pdf, p.156 (HSCT complications: early — bleeding, neutropenic infections, oral mucositis, VOD, acute GVHD; late — cardiovascular disease, endocrine dysfunction, second malignancy, chronic GVHD, cataracts, osteoporosis, relapse)
High Yield Summary
Definition: MDS = clonal HSC disorder → ineffective/dysplastic haematopoiesis → peripheral cytopenias despite hypercellular marrow → risk of AML transformation (≥20% blasts = AML).
Epidemiology: Median age ~65–70; M > F; one of the most common haematological malignancies in the elderly.
Risk Factors: Most are idiopathic (de novo). Therapy-related MDS follows alkylating agents (5–7 year latency, del(5q)/del(7q)) or topoisomerase II inhibitors (1–3 year latency). Inherited BMF syndromes (Fanconi, dyskeratosis congenita) predispose.
Pathophysiology: Mutated HSC → clonal expansion → dysplastic maturation → increased intramedullary apoptosis (early MDS) → cytopenias. With progression, apoptosis decreases → blast accumulation → AML.
Key Mutations: SF3B1 (ring sideroblasts, good prognosis), TP53 (very poor prognosis, complex karyotype), splicing factors, epigenetic regulators.
Classification (WHO 2022): Based on blast %, dysplastic lineages, ring sideroblasts, del(5q), TP53 biallelic. Blast < 5% = MDS-LB; 5–9% = MDS-IB1; 10–19% = MDS-IB2; ≥20% = AML.
Clinical Features: Insidious onset in elderly; anaemia symptoms (fatigue, dyspnoea, pallor); infections (neutropenia); bleeding (thrombocytopenia). NO hepatosplenomegaly.
Blood Smear: Macrocytosis, Pelger-Huët anomaly, hypogranular neutrophils, nucleated RBCs, pancytopenia.
Marrow: Hypercellular, dysplasia in ≥10% of ≥1 lineage, ring sideroblasts, variable blasts.
Always exclude: B12/folate deficiency, copper deficiency, HIV, drugs, alcohol before diagnosing MDS.
High Yield Summary — Differential Diagnosis of MDS
-
Always exclude reversible causes first: B12, folate, copper, zinc, HIV, drugs, alcohol, hypothyroidism, liver disease.
-
Distinguish from AML: blast ≥20% = AML, not MDS. AML-defining cytogenetics (e.g., t(15;17), t(8;21)) diagnose AML even with < 20% blasts.
-
Distinguish from aplastic anaemia: AA = hypocellular marrow with NO dysplasia and NO clonal cytogenetics. Hypoplastic MDS exists but will still show dysplasia and/or clonal abnormalities.
-
Distinguish from MPN: MPN = elevated cell counts, no dysplasia, splenomegaly, gain-of-function mutations (JAK2, BCR-ABL). MDS = cytopenias, dysplasia, no splenomegaly.
-
Distinguish from MDS/MPN overlap: if monocytosis ≥1×10⁹/L → CMML; if thrombocytosis ≥450 + dysplasia → MDS/MPN-RS-T; if proliferative features + dysplasia → overlap syndrome.
-
Distinguish from PMF: significant splenomegaly + tear-drop RBCs + leukoerythroblastic picture + JAK2/CALR/MPL = PMF, not MDS (even though mild fibrosis can occur in MDS).
-
MDS characteristically has NO hepatosplenomegaly — if present, reconsider diagnosis.
High Yield Summary — Diagnosis of MDS
Diagnostic requirements:
- Persistent cytopenia(s) in ≥1 lineage
- Morphological dysplasia ≥10% in ≥1 lineage on BM aspirate
- Blast % < 20% (≥20% = AML)
- Exclusion of reversible causes (B12, folate, copper, HIV, drugs, alcohol)
- Supportive: clonal cytogenetics and/or somatic mutations
Mandatory investigations: BM aspirate + trephine biopsy (with cytogenetics, FISH, molecular panel, iron stain, flow cytometry)
Key PBS findings: Macrocytosis, Pelger-Huët anomaly, hypogranular neutrophils, nucleated RBCs, pancytopenia
BM hallmark: Hypercellular marrow + pancytopenia = ineffective haematopoiesis = MDS
Workup mnemonic: MCICM = Morphology, Cytochemistry, Immunophenotype, Cytogenetics, Molecular genetics
Prognostic scoring: IPSS-R (clinical + cytogenetic) → IPSS-M (adds molecular mutations) → guides treatment
Classification determines subtype and prognosis: MDS-LB, MDS-SF3B1, MDS-5q, MDS-IB1, MDS-IB2, MDS-biTP53
High Yield Summary — Management of MDS
Guiding principles:
- Risk stratify ALL patients using IPSS-R / IPSS-M
- Not all MDS needs treatment — asymptomatic lower-risk → monitor
- No therapy is curative except allo-HSCT
- Goal in lower-risk: improve QoL, reduce transfusion dependence
- Goal in higher-risk: alter disease course, prevent AML transformation
Lower-risk MDS:
- ESA (if EPO ≤ 500) → Lenalidomide (if del(5q)) → Luspatercept (if MDS-RS/SF3B1) → IST (if hypoplastic) → HMA (if refractory)
Higher-risk MDS:
- Allo-HSCT if fit (only curative option)
- HMA ± venetoclax if unfit for HSCT
- Intensive chemotherapy (7+3) as bridge to HSCT in selected cases
- Best supportive care if very poor performance status
Supportive care for ALL:
- RBC/platelet transfusions; iron chelation (deferasirox) if ferritin > 1000
- Febrile neutropenia → emergency → blood cultures + empirical antibiotics within 1 hour
- Antifungal prophylaxis for prolonged neutropenia
- HLA typing early for potential HSCT candidates
Key drugs and their targets:
- Lenalidomide → del(5q) / CK1α
- Luspatercept → TGF-β / activin trap → MDS-RS
- HMAs (azacitidine/decitabine) → DNA methyltransferase → CpG island demethylation
- Venetoclax → BCL-2 → restores apoptosis
- ATG + cyclosporine → T-cell-mediated marrow suppression
High Yield Summary — Complications of MDS
Infections are the leading cause of death in MDS — due to both quantitative neutropenia and qualitative neutrophil dysfunction (hypogranular, hypolobulated). Febrile neutropenia is a medical emergency.
Iron overload from chronic transfusions damages the liver (fibrosis → HCC), heart (cardiomyopathy, arrhythmias), and endocrine organs (DM, hypogonadism). Each unit contains ~200 mg iron; the body excretes only ~1 mg/day.
AML transformation is the defining malignant potential of MDS. Risk depends on blast %, cytogenetics (complex = worse), and mutations (TP53 = worst). Secondary AML from MDS has worse prognosis than de novo AML.
Autoimmune complications (~10–20%) include Sweet syndrome, vasculitis, relapsing polychondritis — more common in low-risk MDS and may respond to immunosuppression.
HSCT complications include early (infections, GVHD, VOD) and late (cardiovascular disease, second malignancies, chronic GVHD, endocrine dysfunction, relapse).
Essential Thrombocythaemia
Essential thrombocythaemia is a chronic myeloproliferative neoplasm characterized by sustained clonal proliferation of megakaryocytes in the bone marrow, leading to persistently elevated platelet counts and an increased risk of thrombosis and hemorrhage.
Lymphadenopathy
Lymphadenopathy is the abnormal enlargement of one or more lymph nodes, often indicating infection, inflammation, or malignancy.