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.

Exam domain	One-glance essentials
Definition / diagnosis	Clonal HSC disorders causing dysplastic, ineffective haematopoiesis → cytopenias despite usually hypercellular marrow ^[1] Pre-leukaemic: ≥20% blasts reclassifies disease as AML
Epidemiology / risks	Predominantly elderly (median ~65–70), male; prior chemotherapy/radiotherapy and benzene increase risk ^[1] Alkylators: 5–7-year latency with del(5q)/del(7q); topoisomerase-II inhibitors: shorter latency
Core mechanism	Mutated HSC clone expands but dysplastic progeny undergo intramedullary apoptosis → low peripheral counts SF3B1 associates with ring sideroblasts/favourable disease; biallelic TP53 with complex karyotype/poor prognosis
Clinical picture	Insidious macrocytic anaemia ± infection from neutropenia and bleeding from thrombocytopenia ^[1] No hepatosplenomegaly is characteristic—reconsider MPN/overlap if present
Investigations	Film: macrocytosis, pseudo-Pelger–Huët/hypogranular neutrophils, nucleated RBCs ^[2] BM aspirate/trephine: dysplasia ≥10% in ≥1 lineage, blast < 20%, usually hypercellular ^[1] Cytogenetics/NGS + Prussian blue; exclude B12/folate, copper, HIV, drugs and alcohol
Management	Risk-stratify with IPSS-R/IPSS-M; asymptomatic lower-risk disease may be observed Lower risk: ESA if EPO ≤500; lenalidomide for del(5q); luspatercept for SF3B1/ring sideroblasts ^[3] Higher risk: azacitidine/decitabine; allo-HSCT is the only cure
Complications	Infection is a leading cause of death; bleeding and transfusion dependence are common AML transformation risk rises with blasts, complex karyotype and TP53 mutation Chronic transfusion → cardiac, hepatic and endocrine iron overload
Prevention / follow-up	Minimise avoidable benzene/tobacco exposure and unnecessary cytotoxic radiation Monitor CBC, blasts and molecular/cytogenetic risk; vaccinate and treat febrile neutropenia urgently
Exam traps	Always exclude reversible pseudo-MDS before diagnosing a clone ^[1] Hypoplastic MDS still has dysplasia/clonal cytogenetics; aplastic anaemia has normal residual cells A hypercellular marrow does not imply high counts—MDS haematopoiesis is ineffective

References

^[1] Senior notes: Maksim Medicine Notes.pdf (MDS definition, classification and differential) ^[2] Senior notes: Block A - Introduction to Haematological investigations (CBP, Clotting).pdf (MDS peripheral blood and marrow morphology) ^[3] Senior notes: Ryan Ho Haemtology.pdf (MDS risk-stratified management)

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

Blast percentage cutoffs: ^[2]^[4]

< 5% BM blasts and < 2% PB blasts → MDS with low blasts

5–9% BM blasts or 2–4% PB blasts → MDS-IB1

10–19% BM blasts or 5–19% PB blasts → MDS-IB2

≥20% BM or PB blasts → AML (no longer MDS)

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]

Lower-risk MDS → Supportive care ± low-intensity therapy (growth factors, targeted agents, HMAs)
Higher-risk MDS → Hypomethylating agents (HMAs), intensive chemotherapy, or allogeneic HSCT
Allogeneic HSCT is the only potentially curative option, reserved for high-risk MDS ^[4]^[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]

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)