Haematology

Key Facts

Vitamin B12 (cobalamin) deficiency causes megaloblastic anaemia and potentially irreversible neurological damage. Pernicious anaemia is the commonest cause in the UK.

Epidemiology

• Prevalence: ~6% of >60 years; higher in vegans (~50%)
• Pernicious anaemia: F:M 1.6:1; peak age 60–70; associated with other autoimmune conditions (thyroid, vitiligo, Addison)

Aetiology

• Dietary: vegans, vegetarians (B12 found only in animal products)
• Malabsorption: gastrectomy, ileal resection (terminal ileum), Crohn disease (terminal ileum), bacterial overgrowth, fish tapeworm (Diphyllobothrium latum)
• Drugs: metformin, PPIs, H2 receptor antagonists, nitrous oxide (inactivates B12)

Pathophysiology

• B12 is cofactor for methionine synthase (homocysteine → methionine) and methylmalonyl-CoA mutase
• Deficiency → impaired DNA synthesis (megaloblastic change) and impaired fatty acid metabolism (neurological damage)

• Neurological: accumulation of methylmalonic acid → demyelination of dorsal columns and lateral corticospinal tracts

Haematological

• Gradual onset anaemia symptoms: fatigue, dyspnoea, pallor
• Mild jaundice (lemon-yellow tinge - from ineffective erythropoiesis/haemolysis)
• Glossitis (smooth, beefy-red tongue)
• Angular stomatitis

Neurological (may occur WITHOUT anaemia)

• Subacute combined degeneration of the cord:
  • Dorsal columns: loss of vibration sense, proprioception, positive Romberg, sensory ataxia
  • Lateral corticospinal tracts: upper motor neuron signs (hyperreflexia, extensor plantars, spasticity)
  • Peripheral neuropathy: glove-and-stocking paraesthesiae
• Cognitive: memory impairment, confusion, dementia
• Psychiatric: depression, psychosis ('megaloblastic madness')
• Optic atrophy: rare

Red Flags

• Neurological symptoms (SACD) - treat URGENTLY; may be irreversible
• Cognitive decline in elderly (consider B12 deficiency as reversible cause)
• Young patient with macrocytic anaemia (dietary, autoimmune)

Bloods

• FBC: low Hb, raised MCV (>100 fL), ± low WCC and platelets (pancytopenia in severe cases)
• Blood film: oval macrocytes, hypersegmented neutrophils (≥5 lobes), anisopoikilocytosis
• Serum B12: low (<150 ng/L)
• Methylmalonic acid (MMA): elevated (more sensitive; confirms tissue deficiency)
• Homocysteine: elevated (non-specific; also raised in folate deficiency)
• Anti-intrinsic factor antibodies: ~50% sensitive, highly specific for pernicious anaemia
• Anti-gastric parietal cell antibodies: ~90% sensitive but less specific
• Reticulocyte count: low (inappropriately)
• LDH, bilirubin: elevated (ineffective erythropoiesis/intramedullary haemolysis)
• Serum folate: check simultaneously (treat B12 first if both deficient)

Imaging/Special Tests

• MRI spine: SACD - high signal in dorsal columns and lateral corticospinal tracts on T2
• Gastroscopy: if pernicious anaemia confirmed (risk of gastric carcinoid and gastric adenocarcinoma - but routine surveillance debated)
• Schilling test: historical; no longer used

Pharmacological

No neurological involvement:

• Hydroxocobalamin 1mg IM on alternate days × 2 weeks (loading)
• Then hydroxocobalamin 1mg IM every 2–3 months for life (pernicious anaemia)

WITH neurological involvement (URGENT):

• Hydroxocobalamin 1mg IM on alternate days until no further improvement (may be several weeks/months)
• Then hydroxocobalamin 1mg IM every 2 months for life

Dietary deficiency:

• Oral cyanocobalamin 50–150mcg daily may suffice (if adherent)
• Dietary advice: fortified foods, consider lifelong supplementation for vegans

CRITICAL:

• If B12 and folate both deficient: treat B12 FIRST - giving folate alone may precipitate/worsen SACD
• Hypokalaemia may occur during early treatment (increased erythropoiesis uses potassium) - monitor

Referral Criteria

• Haematology: diagnostic uncertainty, pancytopenia, suspected MDS
• Neurology: SACD or other neurological complications
• Gastroenterology: pernicious anaemia surveillance (debated), malabsorption investigation

• Haematological: excellent response; reticulocyte rise within 5–7 days; Hb normalises in 6–8 weeks
• Neurological: if treated early, many symptoms improve; if delayed (>6 months), may be irreversible
• Pernicious anaemia: lifelong B12 replacement; ~2–3× increased risk of gastric cancer (debated surveillance)
• SACD: early treatment is critical - prognosis directly related to duration before treatment
• Dietary: excellent if supplementation maintained

B12 vs Folate Deficiency Comparison

Key Facts

Folate (vitamin B9) deficiency is a common cause of megaloblastic anaemia. Unlike B12 deficiency, it does not cause neurological damage. Folate supplementation in pregnancy is critical for preventing neural tube defects.

Epidemiology

• Common: estimated ~5% of UK population may have suboptimal folate
• Elderly, alcoholics, and lower socioeconomic groups at highest risk
• Pregnancy: increased demand → deficiency common without supplementation

Aetiology

• Dietary insufficiency (most common): poor intake of green vegetables, liver, fortified foods; alcoholism
• Increased demand: pregnancy, lactation, haemolytic anaemia (sickle cell, thalassaemia), malignancy, psoriasis, exfoliative dermatitis
• Malabsorption: coeliac disease, Crohn disease (proximal jejunum), tropical sprue
• Drugs: methotrexate (DHFR inhibitor), trimethoprim, phenytoin, carbamazepine, sodium valproate

Pathophysiology

• Folate is essential for one-carbon metabolism and DNA synthesis (thymidylate synthesis)

• Nuclear-cytoplasmic dissociation: delayed nuclear maturation with normal cytoplasmic maturation → large cells
• Body stores last only 3–4 months (cf. B12 stores last 3–5 years)
• Folate absorbed in proximal jejunum

Haematological

• Anaemia symptoms: fatigue, dyspnoea, pallor
• Glossitis (smooth, red tongue)
• Mild jaundice (ineffective erythropoiesis)

No Neurological Features

• Key distinction from B12 deficiency
• If neurological signs present: suspect B12 deficiency (or combined)

Red Flags

• Neurological symptoms (suggests B12 deficiency - check both)
• Pancytopenia (severe deficiency; exclude other causes)
• Pregnancy with no folate supplementation (NTD risk)
• Suspected coeliac disease (weight loss, diarrhoea, iron deficiency)

Bloods

• FBC: low Hb, raised MCV (>100 fL), ± pancytopenia
• Blood film: oval macrocytes, hypersegmented neutrophils (identical to B12 deficiency)
• Serum folate: low (<3 µg/L) - affected by recent dietary intake
• Red cell folate: more reliable for tissue stores (low <150 µg/L) - but less commonly available
• Serum B12: MUST check before starting folate (exclude B12 deficiency)
• Homocysteine: elevated (non-specific)
• MMA: NORMAL (distinguishes from B12 deficiency where MMA is elevated)
• LDH, bilirubin: elevated (ineffective erythropoiesis)

Special Tests

• Coeliac screen: anti-tTG (if unexplained folate deficiency)
• Reticulocyte count: low

Pharmacological

• Folic acid 5mg daily for 4 months (standard treatment dose)
• Identify and treat underlying cause (diet, coeliac, drugs)
• CRITICAL: check and correct B12 deficiency BEFORE or alongside folate replacement

Pregnancy/Pre-conception

• All women: folic acid 400mcg daily from pre-conception through first 12 weeks
• High-risk (previous NTD, diabetes, BMI >30, epilepsy on valproate/carbamazepine, sickle cell/thalassaemia, coeliac): folic acid 5mg daily from pre-conception through first 12 weeks

Ongoing Supplementation

• If cause is ongoing (haemolytic anaemia, chronic malabsorption): long-term folic acid 5mg daily
• Methotrexate patients: folic acid 5mg once weekly (not on methotrexate day)

Dietary Advice

• Green leafy vegetables (spinach, broccoli, Brussels sprouts)
• Fortified cereals and bread
• Liver, legumes, oranges

Referral Criteria

• Haematology: pancytopenia, diagnostic uncertainty
• Gastroenterology: suspected coeliac or malabsorption
• Obstetrics: high-risk pregnancy

• Excellent with appropriate replacement
• Reticulocyte count rises within 5–7 days of starting treatment
• Hb normalises within 6–8 weeks
• Stores replenished within 4 months
• Folate supplementation: reduces NTD risk by ~70% (400mcg); high dose (5mg) for high-risk
• If underlying cause treated: folate deficiency unlikely to recur
• Long-term folate needed if ongoing cause (haemolysis, malabsorption)

Drugs Causing Folate Deficiency

Key Facts

Anaemia of chronic disease (ACD), also termed anaemia of inflammation, is the second most common cause of anaemia worldwide. It occurs in the setting of chronic immune activation.

Epidemiology

• Most common cause of anaemia in hospitalised patients
• Prevalence: depends on underlying condition (~30–60% of patients with chronic inflammatory conditions)

Aetiology

• Chronic infections: TB, HIV, osteomyelitis, endocarditis
• Chronic inflammatory disease: RA, SLE, IBD, sarcoidosis
• Malignancy: solid tumours, haematological malignancies
• CKD: reduced EPO production + inflammation

Pathophysiology

• Inflammatory cytokines (IL-6, TNF-α, IL-1) stimulate hepatic hepcidin production
• Hepcidin: master iron regulator - degrades ferroportin on enterocytes and macrophages
  • Blocks intestinal iron absorption
  • Traps iron in macrophages (functional iron deficiency)
• Reduced EPO production and EPO resistance
• Shortened RBC lifespan
• Impaired erythroid progenitor proliferation
• Result: normocytic (or mildly microcytic) anaemia with iron present but sequestered

Symptoms

• Often mild and overshadowed by the underlying disease
• Fatigue, pallor, dyspnoea on exertion
• Usually mild-moderate anaemia (Hb rarely <80 g/L)

Clinical Context

• Patient with known chronic inflammatory/infective/malignant condition
• Anaemia discovered on routine blood tests

Red Flags

• Severe anaemia (Hb <80 g/L) - consider additional cause (iron deficiency, B12/folate, bone marrow infiltration)
• Worsening anaemia in cancer patient (bleeding, bone marrow failure)
• Newly discovered anaemia without obvious cause (investigate for occult malignancy/infection)

Bloods

• FBC: normocytic normochromic anaemia (MCV 75–95 fL); may be mildly microcytic
• Iron studies:
  • Serum iron: LOW
  • Ferritin: NORMAL or RAISED (acute phase reactant)
  • TIBC/transferrin: LOW (key distinguishing feature from IDA)
  • Transferrin saturation: low-normal
• CRP/ESR: elevated (underlying inflammation)
• Reticulocyte count: inappropriately low
• Blood film: normocytic normochromic; no specific features

Special Tests (if diagnostic uncertainty)

• Soluble transferrin receptor (sTfR): raised in true iron deficiency but normal in pure ACD (helps diagnose combined ACD + IDA)
• sTfR/log ferritin ratio: >2 suggests concurrent iron deficiency
• Hepcidin levels: elevated (research/specialist use)
• EPO level: in CKD (low for degree of anaemia)
• Bone marrow: iron stores present (stainable iron in macrophages - Prussian blue); rarely needed

Non-pharmacological

• Treat the underlying cause (most important)
  • Control inflammation (DMARDs for RA, treat infection, cancer treatment)
  • Resolution of underlying cause → anaemia improves

Pharmacological

Mild ACD:

• Often no specific treatment needed; treat underlying cause

Moderate-severe or symptomatic:

• IV iron: if concurrent true iron deficiency (ferritin <100 in inflammatory state; sTfR raised)
  • Ferric carboxymaltose (Ferinject) 1g IV
  • Oral iron poorly absorbed in ACD (hepcidin blocks absorption)

CKD-associated anaemia (NICE NG203):

• Erythropoiesis-stimulating agents (ESAs): epoetin alfa, darbepoetin alfa
  • Target Hb 100–120 g/L (avoid >120 - cardiovascular risk)
  • Ensure iron-replete before starting (transferrin sat >20%, ferritin >200)
• IV iron: first-line in CKD before ESAs (if iron-deficient)

Transfusion:

• Rarely needed; only if symptomatic with very low Hb

Referral Criteria

• Haematology: unexplained anaemia, severe, or diagnostic uncertainty
• Nephrology: CKD-associated anaemia for ESA management

• Prognosis depends on underlying condition
• Anaemia usually mild-moderate and well-tolerated
• Resolves with treatment of underlying cause in many cases
• CKD-anaemia: managed long-term with ESAs and IV iron
• Does not progress to more severe marrow failure

Iron Studies Comparison

Key Facts

Sickle cell disease (SCD) is an autosomal recessive haemoglobinopathy caused by a structural variant of haemoglobin (HbS). It is characterised by chronic haemolysis, vaso-occlusion, and progressive organ damage.

Epidemiology

• ~15,000 affected in the UK; ~300 births/year
• Predominantly Black African/Caribbean populations; also Mediterranean, Middle Eastern, Indian
• Carrier rate ~1 in 4 in West Africa; ~1 in 10 in UK Black African/Caribbean
• Most common genetic disorder in the UK

Aetiology

• Autosomal recessive: HbSS (sickle cell anaemia - most severe), HbSC, HbS-β-thalassaemia

• Sickle trait (HbAS): carrier state; generally asymptomatic but may sickle under extreme conditions

Pathophysiology

• HbS polymerises when deoxygenated → rigid sickle-shaped RBCs
• Vaso-occlusion: sickled cells obstruct microcirculation → ischaemia, infarction, pain
• Chronic haemolysis: RBC lifespan ~10–20 days (normal 120 days)
• Endothelial activation, inflammation, nitric oxide depletion → vasculopathy
• Progressive organ damage: spleen, kidneys, lungs, brain, bones

Acute Presentations

• Vaso-occlusive crisis (VOC): severe bone/joint pain (most common); dactylitis in infants (hand-foot syndrome)
• Acute chest syndrome: fever, cough, dyspnoea, new CXR infiltrate, hypoxia - LEADING CAUSE OF DEATH in adults
• Splenic sequestration: paediatric emergency; rapid splenic enlargement, falling Hb, shock

• Stroke: ~10% of children; silent infarcts in ~30%
• Priapism: sustained painful erection

Chronic Complications

• Autosplenectomy: functional asplenia by age ~5 (fibrosis from repeated infarction)
• Chronic kidney disease: sickle nephropathy, proteinuria
• Avascular necrosis: femoral/humeral head
• Pulmonary hypertension: ~30%
• Leg ulcers, retinopathy, gallstones (pigment stones)
• Iron overload: from chronic transfusion

Red Flags

• Fever in SCD (functional asplenia → sepsis risk - emergency)
• Acute chest syndrome (may rapidly deteriorate)
• Sudden severe headache or neurological deficit (stroke)
• Rapid fall in Hb (sequestration, aplastic crisis)

Bloods

• FBC: Hb 60–80 g/L (baseline); MCV usually normal or slightly raised
• Reticulocyte count: raised (compensatory for haemolysis; 10–20%)
• Blood film: sickle cells, target cells, Howell-Jolly bodies (functional asplenia)
• Hb electrophoresis: HbS ~80–95%, HbF variable, absent HbA in HbSS
• LDH, bilirubin: raised (haemolysis)
• Haptoglobin: low
• Ferritin: may be raised (chronic transfusion → iron overload)

During Acute Crisis

• FBC with reticulocytes: Hb drop from baseline
• CXR: acute chest syndrome
• Group and save/crossmatch: for transfusion
• Blood cultures: if febrile (sepsis risk)
• CT head: if stroke suspected
• ABG/SpO2: hypoxia in ACS

Screening

• Newborn screening: universal UK heel prick test (isoelectric focusing/HPLC)
• Transcranial Doppler: annual in children age 2–16 (stroke risk - velocity >200 cm/s indicates high risk)

Acute VOC

• Strong analgesia within 30 minutes: IV morphine (0.1–0.15mg/kg), PCA; avoid pethidine (seizure risk)
• IV fluids: avoid dehydration
• Oxygen: if SpO2 <95%
• Monitor for ACS: daily CXR if respiratory symptoms, observations

Acute Chest Syndrome

• Oxygen, IV fluids, analgesia
• Antibiotics: cephalosporin + macrolide (atypical cover)
• Exchange transfusion: if deteriorating (aim HbS <30%)
• Incentive spirometry: prevent/treat

Long-term Disease Modification

• Hydroxycarbamide (hydroxyurea): increases HbF; reduces VOC by ~50%, ACS, transfusion need (NICE TA743)
  • Dose: 15–35mg/kg/day; monitor FBC (myelosuppression)
• Crizanlizumab 5mg/kg IV monthly: anti-P-selectin; reduces VOC (SUSTAIN trial; NICE TA743)
• Voxelotor: HbS polymerisation inhibitor; improves Hb

Chronic Management

• Penicillin V prophylaxis: 250–500mg BD lifelong (functional asplenia)
• Vaccinations: pneumococcal, meningococcal (ACWY + B), Hib, annual influenza
• Folic acid 5mg daily: increased erythropoiesis
• Annual screening: renal (ACR, eGFR), ophthalmology (retinopathy), TCD (children), echocardiography (PHT)
• Chronic transfusion programme: for stroke prevention (primary/secondary), recurrent severe crises
• Iron chelation: deferasirox or desferrioxamine if transfusion-related iron overload (ferritin >1000)

Surgical/Interventional

• Allogeneic stem cell transplant: only curative option; best results in children with matched sibling donor
• Gene therapy: emerging (LentiGlobin/lovotibeglogene autotemcel - showing promise)

Referral Criteria

• Specialist haemoglobinopathy centre: all SCD patients
• Emergency: fever, ACS, stroke, priapism >4 hours
• Obstetrics: high-risk pregnancy management

• Median survival: ~45–55 years in UK (improving with modern care)
• Leading causes of death: acute chest syndrome, sepsis, stroke, multi-organ failure
• Hydroxycarbamide: reduces mortality by ~40%
• Stroke: ~10% in children; chronic transfusion reduces recurrence from 70% to <10%
• Quality of life: significantly impacted by chronic pain, organ damage, psychological morbidity
• SCT: ~90% cure rate in children with matched sibling donor

SCD Genotypes

Triggers for VOC

Key Facts

Thalassaemias are inherited haemoglobinopathies characterised by reduced synthesis of globin chains, leading to ineffective erythropoiesis, haemolysis, and anaemia.

Epidemiology

• Most common single-gene disorder worldwide
• β-thalassaemia: Mediterranean, Middle East, South/Southeast Asia
• α-thalassaemia: Southeast Asia, Southern China, Africa
• UK: ~1,000 patients with transfusion-dependent thalassaemia; ~30,000 carriers

Aetiology

β-thalassaemia:

• 200 point mutations in β-globin gene (chromosome 11)

• β⁰: no β-globin production; β⁺: reduced production
• Trait (heterozygous): one abnormal allele
• Major (homozygous β⁰/β⁰ or β⁰/β⁺): severe; transfusion-dependent
• Intermedia: moderate; variable transfusion need

α-thalassaemia:

• Gene deletions on chromosome 16 (4 α-globin genes total: 2 per chromosome)
• 1 deletion: silent carrier
• 2 deletions: α-thal trait (mild microcytosis)
• 3 deletions: HbH disease (moderate haemolytic anaemia)
• 4 deletions: Hb Bart's hydrops fetalis (incompatible with life)

Pathophysiology

• β-thal: excess α-chains → ineffective erythropoiesis + haemolysis

• Increased iron absorption (due to suppressed hepcidin) + transfusion → iron overload

β-Thalassaemia Trait

• Usually asymptomatic; mild microcytic anaemia
• Discovered incidentally on FBC (disproportionately low MCV for Hb level)
• Important to identify for genetic counselling

β-Thalassaemia Major

• Presents at 6–12 months (after HbF declines)
• Severe anaemia, failure to thrive
• Hepatosplenomegaly (extramedullary haematopoiesis)
• Skeletal changes: frontal bossing, maxillary hyperplasia ('chipmunk facies'), 'hair on end' skull X-ray
• Growth retardation, delayed puberty
• Without treatment: death in first decade

β-Thalassaemia Intermedia

• Variable severity between trait and major
• May or may not require regular transfusion

α-Thalassaemia

• Silent carrier/trait: usually asymptomatic
• HbH disease: moderate haemolytic anaemia, splenomegaly
• Hb Bart's: fatal hydrops fetalis in utero

Red Flags

• Severe anaemia in infancy (transfusion-dependent)
• Iron overload complications (cardiac, hepatic, endocrine)
• Non-immune hydrops fetalis (Hb Bart's)

Bloods

• FBC: microcytic hypochromic anaemia; very low MCV for degree of anaemia (often MCV <70 fL with near-normal Hb in trait)
• Blood film: target cells, microcytes, hypochromia; nucleated RBCs in major
• Reticulocyte count: raised
• Iron studies: normal or raised ferritin and transferrin saturation (distinguishes from IDA)
• Hb electrophoresis/HPLC: KEY diagnostic test
  • β-thal trait: HbA2 >3.5% (usually 4–6%)
  • β-thal major: HbF 60–90%, HbA absent or very low, HbA2 variable
  • HbH disease: HbH (β4 tetramers) on electrophoresis

Special Tests

• Genetic testing: definitive diagnosis (prenatal counselling)
• Ferritin: monitor iron overload in transfused patients
• Cardiac MRI T2*: gold standard for myocardial iron overload (<20ms = iron loading; <10ms = severe)
• Liver MRI (FerriScan): liver iron concentration
• Endocrine: glucose, TFTs, gonadotrophins (iron overload endocrinopathy)

β-Thalassaemia Trait

• No treatment needed
• Genetic counselling for couples at risk
• Do NOT give iron (not iron-deficient)

β-Thalassaemia Major

Chronic transfusion:

• Regular RBC transfusions every 2–4 weeks
• Aim pre-transfusion Hb >95–100 g/L
• Suppresses ineffective erythropoiesis and prevents skeletal deformity

Iron chelation (ESSENTIAL):

• Deferasirox 14–28mg/kg/day oral (first-line; NICE TA376)
• Desferrioxamine 20–50mg/kg SC/IV over 8–12 hours, 5–7 nights/week: highly effective but burdensome
• Deferiprone 75mg/kg/day oral: especially for cardiac iron
• Target ferritin <1000 µg/L; cardiac MRI T2* >20ms

Supportive:

• Folic acid 5mg daily
• Hepatitis B vaccination (before transfusion)
• Endocrine monitoring and replacement (growth hormone, sex hormones, thyroxine)
• Bone densitometry

Curative

• Allogeneic stem cell transplant: curative; ~90% success in children <14 with matched sibling donor
• Gene therapy: betibeglogene autotemcel (Zynteglo; NICE HST24) - one-time gene therapy for β-thal
• Luspatercept: reduces transfusion burden in thal intermedia/major (BELIEVE trial; NICE TA872)

Referral Criteria

• Specialist haemoglobinopathy centre: all thalassaemia major/intermedia
• Genetic counselling: all carriers and affected families
• Prenatal diagnosis: CVS or amniocentesis if both parents carriers

• β-thal major without treatment: death in first decade
• With modern transfusion + chelation: median survival >50 years (improving)
• Leading cause of death: cardiac iron overload (cardiac failure, arrhythmia)
• SCT: ~90% cure rate; ~5% transplant-related mortality
• Thal trait: normal life expectancy; no treatment needed
• Quality of life: significantly impacted by transfusion burden and chelation

α-Thalassaemia by Gene Deletion

Key Facts

Hereditary spherocytosis (HS) is the most common inherited haemolytic anaemia in Northern European populations. It is caused by defects in red cell membrane skeleton proteins.

Epidemiology

• Prevalence: ~1 in 2,000–5,000 in Northern Europeans
• Autosomal dominant in ~75%; autosomal recessive or de novo in ~25%

Aetiology

• Mutations in genes encoding membrane skeleton proteins:
  • Ankyrin (ANK1): most common (~40%)
  • Band 3 (SLC4A1): ~25%
  • Spectrin (α or β): ~20%
  • Protein 4.2: ~5%

Pathophysiology

• Spherocytes are rigid, less deformable

• Reduced RBC lifespan (10–30 days vs normal 120 days)

Typical Presentation

• Neonatal jaundice: may be severe; prolonged
• Childhood: anaemia, jaundice, splenomegaly
• Variable severity:
  • Mild (~20–30%): compensated haemolysis, normal Hb, mild reticulocytosis
  • Moderate (~60–70%): mild-moderate anaemia, intermittent jaundice
  • Severe (~5–10%): transfusion-dependent

Complications

• Pigment gallstones: unconjugated bilirubin stones (~50% by adulthood)

• Megaloblastic crisis: folate depletion from chronic haemolysis
• Haemolytic crisis: concurrent infection → increased haemolysis

Red Flags

• Severe neonatal jaundice (kernicterus risk)
• Sudden fall in Hb (aplastic crisis - check reticulocyte count)
• Symptomatic gallstones

Bloods

• FBC: anaemia (variable severity); raised MCHC (>360 g/L - classically associated)
• Reticulocyte count: raised (compensatory; often 5–20%)
• Blood film: spherocytes (small, round, no central pallor), polychromasia
• DAT (Coombs test): NEGATIVE (essential to exclude AIHA)
• LDH, bilirubin (unconjugated): raised (haemolysis)
• Haptoglobin: low

Special Tests

• EMA binding test (flow cytometry): reduced eosin-5-maleimide binding to band 3 on RBCs - gold standard screening test (replaced osmotic fragility)
• Osmotic fragility test: increased (spherocytes lyse at higher NaCl concentrations) - historical; less commonly used now
• SDS-PAGE: membrane protein analysis (specialist)
• Genetic testing: definitive
• USS abdomen: gallstones

Conservative

• Folic acid 5mg daily: prevent megaloblastic crisis
• Monitoring: regular FBC, reticulocyte count, bilirubin, ferritin
• Transfusion: for aplastic crises or severe chronic anaemia

Splenectomy

• Curative for haemolysis (spherocytes no longer destroyed in spleen; anaemia resolves)
• Indications: moderate-severe HS with symptomatic anaemia, growth failure, recurrent gallstones
• Timing: defer until >6 years (infection risk higher in younger children)
• Partial (subtotal) splenectomy: option in children (maintains some splenic function)
• Pre-splenectomy: vaccinations (pneumococcal, meningococcal ACWY + B, Hib, influenza) ≥2 weeks before
• Post-splenectomy: lifelong penicillin V 250–500mg BD; carry alert card; prompt medical attention for fever

Cholecystectomy

• If symptomatic gallstones; may be done at same time as splenectomy

Referral Criteria

• Haematology: all confirmed HS
• Surgery: splenectomy consideration
• Neonatology: severe neonatal jaundice

• Mild HS: normal lifespan; no treatment needed
• Moderate HS: well-managed with folic acid ± splenectomy; normal lifespan after splenectomy
• Severe HS: transfusion-dependent until splenectomy
• Post-splenectomy: excellent haematological outcomes; lifelong OPSI risk (~1–5% lifetime risk, ~50% mortality if occurs)
• Parvovirus B19 aplastic crisis: transient (1–2 weeks); may need transfusion support

Severity Classification

Key Facts

G6PD deficiency is the most common human enzymopathy, an X-linked condition causing episodic haemolytic anaemia when RBCs are exposed to oxidative stress.

Epidemiology

• ~400 million affected worldwide
• X-linked recessive: affects males predominantly; females may be affected if homozygous or through lyonisation
• Prevalent in Africa, Mediterranean, Middle East, Southeast Asia
• Evolutionary advantage: protection against Plasmodium falciparum malaria

Aetiology

• Mutations in G6PD gene on X chromosome

• 200 variants classified by WHO into 5 classes:

  • Class I: severe chronic haemolysis (rare)
  • Class II: severely deficient (<10% activity; Mediterranean variant)
  • Class III: moderately deficient (10–60%; African A- variant)

Pathophysiology

• G6PD is rate-limiting enzyme in pentose phosphate pathway (hexose monophosphate shunt)

• Older RBCs more susceptible (G6PD activity declines with RBC age)
• Mediterranean variant: more severe (G6PD activity very low even in reticulocytes)

Acute Haemolytic Crisis

• Occurs 1–3 days after oxidative trigger
• Jaundice (dark urine - intravascular haemolysis/haemoglobinuria), pallor
• Back/abdominal pain
• Fatigue, malaise
• Dark urine ('coca-cola' coloured)
• Self-limiting in African variant (young reticulocytes have adequate G6PD)

Triggers

• Infections: most common trigger (any acute illness)
• Drugs: primaquine, dapsone, ciprofloxacin, nitrofurantoin, sulfasalazine, sulfonamides, rasburicase, methylene blue
• Fava beans (broad beans): favism (especially Mediterranean variant)
• Diabetic ketoacidosis
• Naphthalene (mothballs)

Neonatal

• Prolonged neonatal jaundice (2nd–3rd day)
• May be severe → kernicterus risk

Red Flags

• Severe intravascular haemolysis with renal failure
• Neonatal jaundice requiring exchange transfusion
• Haemolysis after starting a new drug

During Crisis

• FBC: anaemia (may be severe), raised reticulocytes (after 3–5 days)
• Blood film: bite cells (hemighosts), blister cells, polychromasia, contracted cells
• Heinz body preparation (supravital stain): denatured Hb inclusions within RBCs
• LDH: raised (intravascular haemolysis)
• Bilirubin (unconjugated): raised
• Haptoglobin: low/undetectable
• Urinalysis: haemoglobinuria (dark urine)
• DAT: NEGATIVE (not immune-mediated)

Definitive Diagnosis

• G6PD enzyme assay: quantitative measurement of G6PD activity
  • CAUTION: may be falsely normal during/shortly after crisis (reticulocytes have higher G6PD activity)
  • Retest 2–3 months after acute episode for accurate result
• Genetic testing: available for specific variants

Acute Crisis

• Remove trigger: stop offending drug, treat infection
• Supportive: IV fluids, maintain renal perfusion
• Transfusion: if severe anaemia (Hb <70 g/L or symptomatic)
• Folic acid 5mg daily: during recovery
• Monitor renal function: intravascular haemolysis → AKI risk

Prevention (KEY)

• Avoid oxidative triggers: provide drug avoidance list to patient
• Medical alert bracelet/card
• Dietary: avoid fava beans (Mediterranean variant)
• Check G6PD status BEFORE prescribing: primaquine, dapsone, rasburicase, nitrofurantoin
• Neonatal screening: in endemic populations

Referral Criteria

• Haematology: confirmed G6PD deficiency, genetic counselling
• Emergency: severe haemolytic crisis

• Between crises: normal life expectancy; usually completely well
• Acute crisis: self-limiting in most cases (especially African A- variant)
• Mediterranean variant: more severe crises; may require transfusion
• Neonatal: jaundice usually manageable; severe cases rare
• With education and trigger avoidance: excellent prognosis

Common Drug Triggers

Key Facts

Autoimmune haemolytic anaemia (AIHA) is an acquired condition in which autoantibodies directed against RBCs cause haemolysis. It is classified by the thermal reactivity of the autoantibody.

Epidemiology

• Incidence: ~1–3 per 100,000 per year
• Warm AIHA: ~70%; cold AIHA: ~20%; mixed: ~10%
• All ages; warm AIHA peaks in middle age; cold more common in elderly

Aetiology

Warm AIHA (IgG):

• Idiopathic (~50%)
• Secondary: SLE, CLL, lymphoma, drugs (methyldopa, fludarabine), autoimmune disorders

Cold AIHA (IgM):

• Post-infectious: Mycoplasma pneumoniae, EBV (usually transient)
• Chronic cold agglutinin disease: lymphoproliferative disorder (underlying clonal B-cell)

Pathophysiology

Warm:

Cold:

• Agglutination in peripheral circulation → acrocyanosis, livedo

Warm AIHA

• Gradual onset anaemia: fatigue, pallor, dyspnoea
• Jaundice
• Splenomegaly
• Dark urine
• May be precipitated by drug exposure or underlying disease flare

Cold AIHA

• Anaemia + jaundice (often mild)
• Acrocyanosis: blue/purple discolouration of fingers, toes, ears, nose in cold
• Raynaud-like symptoms
• Haemoglobinuria after cold exposure

Red Flags

• Severe acute haemolysis (Hb <60 g/L)
• Evans syndrome (AIHA + ITP - cytopenias)
• Underlying malignancy (CLL, lymphoma)
• Drug-induced (stop offending drug)

Bloods

• FBC: anaemia (severity varies), raised MCV (reticulocytosis)
• Reticulocyte count: raised (usually markedly)
• Blood film: spherocytes (warm), RBC agglutination (cold), polychromasia
• DAT (direct Coombs test): POSITIVE
  • Warm AIHA: IgG ± C3d
  • Cold AIHA: C3d alone (IgM dissociates at lab temperature)
• LDH: raised
• Bilirubin (unconjugated): raised
• Haptoglobin: low/undetectable
• Urinalysis: haemoglobinuria (intravascular haemolysis)

Special Tests

• Cold agglutinin titre: if cold AIHA suspected (high titre >1:64 at 4°C)
• ANA, anti-dsDNA: screen for SLE
• Serum immunoglobulins, SPEP: lymphoproliferative disorder
• CT CAP: lymphoma staging if suspected
• Flow cytometry (peripheral blood): CLL screen
• Bone marrow: if underlying haematological malignancy suspected

Warm AIHA

First-line:

• Prednisolone 1mg/kg/day (max 60mg) for 1–3 weeks; taper over 4–6 months
• Response in ~70–80%

Second-line:

• Rituximab 375mg/m² × 4 weekly (anti-CD20): ~60–80% response

Third-line:

• Splenectomy: ~65–70% response; reserved for refractory
• Mycophenolate, azathioprine, ciclosporin: steroid-sparing alternatives

Drug-induced: Stop offending drug; usually resolves

Cold AIHA

• Avoid cold exposure (most important)
• Corticosteroids usually INEFFECTIVE (not IgG-mediated)
• Rituximab: first-line for chronic cold agglutinin disease
• Sutimlimab (anti-C1s complement inhibitor): NICE TA985 - for cold agglutinin disease
• Transfusion: use blood warmer; crossmatch difficulties (warm sample to 37°C)

Supportive

• Folic acid 5mg daily: increased erythropoiesis
• Thromboprophylaxis: AIHA is prothrombotic
• Transfusion: if severe/symptomatic; crossmatch may be difficult (least incompatible units)

Referral Criteria

• Haematology: all confirmed AIHA
• Emergency: severe acute haemolysis
• Rheumatology: if SLE suspected

• Warm AIHA: ~70–80% respond to steroids; ~50% relapse on taper
• Rituximab: durable remission in ~60% at 2 years
• Chronic relapsing course in ~30–40%
• Cold agglutinin disease: chronic; rituximab effective
• Drug-induced: excellent prognosis on drug withdrawal
• Evans syndrome: more difficult to treat; consider underlying SLE or lymphoma
• Mortality: ~5–10% in severe cases (thromboembolic complications)

Warm vs Cold AIHA

Key Facts

Paroxysmal nocturnal haemoglobinuria (PNH) is a rare acquired clonal haematopoietic stem cell disorder characterised by complement-mediated haemolysis, thrombosis, and bone marrow failure.

Epidemiology

• Rare: incidence ~1–2 per million per year
• Peak onset: 30–50 years; equal sex distribution
• ~30% of aplastic anaemia patients develop PNH clone

Aetiology

• Somatic mutation in PIGA gene (X-linked) in haematopoietic stem cell
• PIGA encodes enzyme required for GPI-anchor biosynthesis

Pathophysiology

• GPI-anchor deficiency → loss of complement regulatory proteins from cell surface:
  • CD55 (DAF): inhibits C3 convertase
  • CD59 (MIRL): inhibits membrane attack complex (MAC)

• Nocturnal: mild respiratory acidosis during sleep → complement activation

• Thrombosis: complement activation on platelet surface + free Hb + nitric oxide depletion

Haemolytic Anaemia

• Chronic haemolysis with intermittent exacerbations
• Dark urine (haemoglobinuria) - classically morning; may be throughout day
• Fatigue (often severe and disproportionate to Hb level)
• Jaundice

Thrombosis (Leading Cause of Death)

• Budd-Chiari syndrome (hepatic vein thrombosis)
• Cerebral venous sinus thrombosis
• Portal/mesenteric vein thrombosis
• DVT/PE
• Unusual sites (dermal veins → skin necrosis)

Bone Marrow Failure

• Cytopenias: anaemia, neutropenia, thrombocytopenia
• May present as or evolve from aplastic anaemia

Smooth Muscle Dystonia (NO depletion)

• Dysphagia, abdominal pain, erectile dysfunction

Red Flags

• Coombs-negative haemolytic anaemia with thrombosis (classic PNH)
• Thrombosis at unusual sites (Budd-Chiari in young patient)
• Cytopenias with haemolysis (aplastic anaemia-PNH overlap)

Bloods

• FBC: anaemia, ± neutropenia, ± thrombocytopenia
• Reticulocyte count: raised
• LDH: markedly raised (intravascular haemolysis)
• Haptoglobin: undetectable
• Bilirubin (unconjugated): raised
• DAT: NEGATIVE (not antibody-mediated)
• Urinalysis: haemoglobinuria, haemosiderinuria

Definitive Diagnosis

• Flow cytometry: GOLD STANDARD - demonstrates absence/reduction of GPI-anchored proteins (CD55, CD59, FLAER) on RBCs, granulocytes, and monocytes
• Quantifies PNH clone size

Other

• Bone marrow biopsy: if aplastic anaemia suspected (hypocellular marrow)
• Imaging: if thrombosis suspected (Doppler, CT, MRI)

Pharmacological

Complement inhibitors (transform prognosis):

• Eculizumab 900mg IV every 2 weeks (after loading) - anti-C5 monoclonal antibody; prevents MAC formation (NICE TA698)
• Ravulizumab: long-acting anti-C5; every 8 weeks (improved convenience)
• Iptacopan, danicopan, pegcetacoplan: newer complement inhibitors targeting C3/factor B; address extravascular haemolysis

CRITICAL: meningococcal vaccination BEFORE starting eculizumab/ravulizumab (C5 blockade → increased meningococcal infection risk)

• MenACWY + MenB vaccines; consider ciprofloxacin prophylaxis

Anticoagulation:

• Warfarin for treatment/prevention of thrombosis (role reduced with complement inhibitors)

Supportive:

• Folic acid 5mg daily
• Iron supplementation (iron lost in haemoglobinuria)
• Transfusion PRN
• EPO if suboptimal erythropoiesis

Curative

• Allogeneic stem cell transplant: only cure; reserved for severe/refractory cases or progressive bone marrow failure

Referral Criteria

• Specialist PNH centre: all confirmed PNH (UK National PNH Service)
• Haematology: urgent for suspected PNH

• Pre-eculizumab median survival: ~10–15 years; thrombosis was leading cause of death (~40–60% of deaths)
• Post-eculizumab: near-normal life expectancy for many patients
• Eculizumab: reduces haemolysis, thrombosis risk, transfusion dependence, and fatigue
• ~15% may undergo spontaneous remission
• ~5% transform to MDS or AML
• Quality of life: significantly improved with complement inhibitors

PNH vs AIHA Comparison

Key Facts

Aplastic anaemia is a bone marrow failure syndrome characterised by pancytopenia (anaemia, leucopenia, thrombocytopenia) with a hypocellular/empty bone marrow.

Epidemiology

• Incidence: ~2 per million per year in Europe
• Bimodal: peak 10–25 years and >60 years
• Higher incidence in East Asia (~5–7 per million)

Aetiology

• Idiopathic (~70%): presumed autoimmune
• Drugs: chloramphenicol, carbamazepine, phenytoin, sulfonamides, NSAIDs, gold, methotrexate (dose-dependent)
• Viral: hepatitis (seronegative - hepatitis-associated aplastic anaemia), parvovirus B19, EBV, HIV
• Chemical: benzene, pesticides
• Inherited: Fanconi anaemia (AR, childhood, skeletal anomalies, café-au-lait), dyskeratosis congenita
• Radiation

Pathophysiology

• Result: empty/fatty marrow → failure of all cell lineages
• Clonal escape: surviving clones may acquire mutations → PNH, MDS, or AML

Insidious Onset

• Anaemia: fatigue, pallor, dyspnoea
• Thrombocytopenia: bruising, petechiae, mucosal bleeding, menorrhagia
• Leucopenia (neutropenia): recurrent/severe infections

Examination

• Pallor
• Petechiae, bruising
• NO hepatosplenomegaly, NO lymphadenopathy (distinguishes from leukaemia/lymphoma)

Red Flags

• Severe bleeding (intracranial, GI)
• Severe neutropenic sepsis
• Pancytopenia in young patient
• Drug history (recent new drug)

Bloods

• FBC: pancytopenia - low Hb, low WCC (neutropenia), low platelets
• Reticulocyte count: low (inappropriately for anaemia)
• Blood film: pancytopenia, no abnormal cells, no dysplasia
• B12, folate, iron studies: exclude deficiency
• LDH, bilirubin, haptoglobin: mild haemolysis markers if PNH clone
• Viral serology: hepatitis B/C, HIV, EBV, parvovirus

Bone Marrow

• Aspirate AND trephine biopsy: ESSENTIAL
  • Hypocellular (<25% cellularity or <50% with <30% haem cells)
  • Fat spaces replacing haematopoietic tissue
  • No dysplasia, no increased blasts
  • No fibrosis, no infiltration

Special Tests

• Flow cytometry: PNH clone screen (GPI-anchored proteins)
• Cytogenetics: exclude MDS (normal karyotype in aplastic anaemia)
• Chromosomal breakage (DEB/MMC test): if Fanconi anaemia suspected (<30 years, physical anomalies)
• Telomere length: dyskeratosis congenita
• HLA typing: for potential SCT

Young Patient (<40 years) with Matched Sibling Donor

• Allogeneic SCT: first-line curative treatment
• ~75–90% long-term survival with matched sibling
• Conditioning: fludarabine + cyclophosphamide ± ATG

Older Patient (>40) or No Matched Sibling

• Horse ATG (ATGAM) + ciclosporin: first-line immunosuppression
  • Response rate: ~60–70% at 6 months
  • Horse ATG superior to rabbit ATG for aplastic anaemia
• Eltrombopag 150mg OD: added to ATG/ciclosporin improves response (NICE TA895)

Refractory:

• Matched unrelated donor SCT (MUD)
• Repeat immunosuppression with rabbit ATG
• Eltrombopag monotherapy

Supportive

• Transfusion: RBC and platelet support (irradiated if pre-SCT)
• Antibiotics: prompt treatment of febrile neutropenia
• Antifungals: if prolonged neutropenia
• G-CSF: may be used short-term for severe infection (not routine)
• Iron chelation: if transfusion-dependent

Referral Criteria

• Haematology: URGENT for all suspected aplastic anaemia
• Specialist bone marrow failure centre: for SCT assessment

• Untreated severe aplastic anaemia: ~70% mortality within 1 year
• Matched sibling SCT: 75–90% 5-year survival
• MUD SCT: 65–75% 5-year survival
• ATG + ciclosporin: 60–70% response; 5-year survival ~75%
• Eltrombopag addition: improves complete response rates
• ~15% develop clonal evolution (MDS, AML, PNH) over 10 years
• Relapse after immunosuppression: ~30–40%

Severity Classification (Modified Camitta Criteria)

Key Facts

Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal haematopoietic stem cell disorders characterised by ineffective haematopoiesis, peripheral blood cytopenias, and a variable risk of progression to acute myeloid leukaemia.

Epidemiology

• Incidence: ~4–5 per 100,000 per year; increases markedly with age
• Median age at diagnosis: ~70 years
• Male:female ratio ~1.5:1

Aetiology

• De novo (~80%): no identifiable cause
• Therapy-related (~20%): prior chemotherapy (alkylating agents, topoisomerase II inhibitors) or radiotherapy
• Risk factors: benzene exposure, smoking, prior cytotoxic therapy

Pathophysiology

• Acquired somatic mutations in haematopoietic stem cells → clonal expansion
• Common mutations: TET2, ASXL1, SF3B1 (ring sideroblasts), TP53 (high-risk), DNMT3A
• Ineffective haematopoiesis: cells produced but die prematurely in marrow (apoptosis)
• Cytopenias despite hypercellular marrow (paradox)
• Accumulation of additional mutations → AML transformation

Typical Presentation

• Incidental finding: cytopenias on routine blood tests (most common)
• Anaemia symptoms: fatigue, pallor, dyspnoea (most common presentation)
• Infections: recurrent (neutropenia)
• Bleeding: easy bruising, petechiae, mucosal bleeding (thrombocytopenia)

Examination

• Pallor
• Petechiae, bruising
• Splenomegaly (mild, ~10%)

Red Flags

• Progressive cytopenias
• Increasing blast percentage (approaching AML transformation)
• Constitutional symptoms (weight loss, night sweats - transformation)
• Severe neutropenic sepsis

Bloods

• FBC: cytopenias - anaemia (often macrocytic), ± neutropenia, ± thrombocytopenia
• Blood film: dysplastic features
  • Pseudo-Pelger-Huët cells (bilobed neutrophils)
  • Hypogranular neutrophils
  • Oval macrocytes
  • Occasional circulating blasts
• Reticulocyte count: inappropriately low
• B12, folate, iron studies: exclude deficiency
• EPO level: guides ESA use

Bone Marrow (DIAGNOSTIC)

• Aspirate: dysplasia in ≥1 lineage (erythroid, myeloid, megakaryocytic); blast percentage; ring sideroblasts (Prussian blue stain)
• Trephine biopsy: cellularity, architecture
• Cytogenetics: del(5q), del(7q), trisomy 8, complex karyotype
• Molecular: SF3B1 (ring sideroblasts, good prognosis), TP53 (poor prognosis)
• Iron stain: ring sideroblasts (≥15% for MDS-RS; ≥5% if SF3B1 mutated)

Prognostic

• IPSS-R: based on cytogenetics, blast %, Hb, platelets, ANC → very low, low, intermediate, high, very high risk

Low-Risk MDS (IPSS-R very low/low/intermediate)

Supportive:

• Transfusion: RBC and platelets as needed
• Iron chelation: if transfusion-dependent (ferritin >1000; deferasirox)
• EPO ± G-CSF: if EPO level <500 and low transfusion burden

Specific:

• Lenalidomide 10mg daily: for del(5q) MDS (NICE TA322) - ~65% transfusion independence
• Luspatercept: for MDS-RS with low transfusion burden

High-Risk MDS (IPSS-R high/very high)

• Azacitidine 75mg/m² SC × 7 days every 28 days: hypomethylating agent; delays AML transformation, improves survival (NICE TA218)
• Allogeneic SCT: only curative option; consider in fit patients <70 with donor
• Best supportive care: if unfit for intensive therapy

Referral Criteria

• Haematology: all suspected MDS
• Specialist MDS centre: SCT assessment

• Very variable depending on IPSS-R risk group:
  • Very low risk: median survival ~8 years
  • Low risk: ~5 years
  • Intermediate: ~3 years
  • High risk: ~1.5 years
  • Very high risk: ~0.8 years
• AML transformation: ~30% overall; higher in high-risk
• Del(5q): good prognosis; responds well to lenalidomide
• TP53 mutation: poor prognosis regardless of other factors
• SCT: 40–50% 3-year survival in high-risk MDS

WHO 2022 MDS Classification (Simplified)

Key Facts

Acute lymphoblastic leukaemia (ALL) is a malignancy of lymphoid progenitor cells (lymphoblasts) that accumulate in the bone marrow, blood, and extramedullary sites.

Epidemiology

• Most common childhood cancer: ~400 new cases/year in UK children
• Peak incidence: 2–5 years (B-cell ALL)
• Second peak: >50 years (adult ALL; poorer prognosis)
• Slight male predominance

Aetiology

• Mostly unknown; likely multistep oncogenesis
• Risk factors: Down syndrome (20× risk), radiation, previous chemotherapy
• Genetic: ETV6-RUNX1 t(12;21) - good prognosis; Philadelphia chromosome t(9;22) - poor (adult)

Pathophysiology

• Malignant transformation of lymphoid precursors in bone marrow
• Clonal expansion of lymphoblasts → marrow failure (normal haematopoiesis suppressed)
• Extramedullary infiltration: liver, spleen, lymph nodes, CNS, testes
• B-cell ALL (~85% children), T-cell ALL (~15%)

Typical Presentation

• Bone marrow failure: anaemia (pallor, fatigue), infections (neutropenia), bleeding/bruising (thrombocytopenia)
• Bone pain: especially in children (marrow expansion)
• Hepatosplenomegaly and lymphadenopathy
• Constitutional: fever, weight loss, night sweats

Specific

• Mediastinal mass: T-cell ALL (thymic involvement → SVC obstruction)
• CNS: headache, cranial nerve palsies, vomiting (leptomeningeal infiltration)
• Testicular enlargement: boys; sanctuary site

Red Flags

• Child with pallor, bruising, bone pain, hepatosplenomegaly
• Mediastinal mass with respiratory compromise
• CNS symptoms
• Tumour lysis syndrome at presentation or early treatment

Bloods

• FBC: anaemia, thrombocytopenia, WCC variable (low/normal/very high)
• Blood film: circulating lymphoblasts (large cells, high nuclear:cytoplasmic ratio, fine chromatin)
• LDH, urate: raised (high cell turnover)
• Coagulation: may be deranged
• U&Es, calcium, phosphate: tumour lysis syndrome risk assessment

Bone Marrow

• Aspirate + trephine: ≥20% lymphoblasts (diagnostic)
• Flow cytometry/immunophenotyping: B-cell (CD10, CD19, CD20) vs T-cell (CD3, CD7) lineage
• Cytogenetics: t(12;21) ETV6-RUNX1 (good), t(9;22) BCR-ABL (poor), hyperdiploidy (good), hypodiploidy (poor)
• Molecular: BCR-ABL1, MLL rearrangements, IKZF1

Special Tests

• LP (CSF): CNS involvement assessment
• CXR: mediastinal mass (T-cell ALL)
• Testicular USS: if enlarged (boys)

Childhood ALL (UK UKALL Protocol)

Induction (4–6 weeks):

• Dexamethasone (or prednisolone) + vincristine + asparaginase + daunorubicin
• Aim: complete remission (CR) in ~95%

Consolidation:

• High-dose methotrexate, cyclophosphamide, cytarabine
• Intrathecal methotrexate (CNS prophylaxis)

Maintenance (2–3 years total):

• Daily 6-mercaptopurine + weekly methotrexate

CNS-directed therapy:

• Intrathecal methotrexate/cytarabine/hydrocortisone throughout treatment

Adult ALL

• Similar intensive chemotherapy protocols
• Philadelphia positive: add TKI (imatinib, dasatinib) throughout
• Allogeneic SCT: in first CR for high-risk (Ph+, poor cytogenetics, slow response)

Relapsed/Refractory

• Blinatumomab (bispecific T-cell engager; anti-CD19/CD3; NICE TA450)
• Tisagenlecleucel (CAR-T; anti-CD19; NICE TA554): for relapsed/refractory B-cell ALL in children
• Inotuzumab ozogamicin (anti-CD22-ADC; NICE TA541)
• Allogeneic SCT: post-reinduction

Supportive

• Tumour lysis syndrome prevention: allopurinol/rasburicase, IV fluids
• Infection prevention: PCP prophylaxis (co-trimoxazole), antifungals
• Blood product support

Referral Criteria

• Paediatric oncology: all childhood ALL (principal treatment centres)
• Haematology: adult ALL
• Urgent: suspected acute leukaemia (same-day blood film)

• Childhood ALL: ~90% 5-year survival (one of the great successes of modern oncology)
  • Good risk: age 1–9, WCC <50, hyperdiploidy, ETV6-RUNX1 → >95% cure
  • Poor risk: Ph+, infant (<1 year), hypodiploidy, MLL rearrangement
• Adult ALL: ~40–50% 5-year survival; Ph+ historically ~20% (improved with TKIs to ~60%)
• CNS relapse: reduced to <5% with intrathecal prophylaxis
• Late effects in survivors: secondary cancers, cardiac toxicity, neurocognitive effects, infertility, growth impairment

Prognostic Factors

Key Facts

Acute myeloid leukaemia (AML) is a heterogeneous group of haematological malignancies characterised by clonal proliferation of myeloid blasts in the bone marrow and blood.

Epidemiology

• Most common acute leukaemia in adults: ~3,000 new cases/year in UK
• Median age at diagnosis: 68 years
• Incidence increases with age

Aetiology

• De novo: most cases
• Secondary: prior MDS, myeloproliferative neoplasm, previous chemotherapy/radiation (therapy-related AML)
• Risk factors: benzene, smoking, Down syndrome (10–20× risk), Fanconi anaemia

Pathophysiology

• Two-hit model: (1) class I mutations promoting proliferation (FLT3, RAS) + (2) class II mutations blocking differentiation (PML-RARA, CBF)
• Clonal expansion of myeloid blasts → marrow failure
• Infiltration of organs (liver, spleen, gums, skin, CNS)

Bone Marrow Failure

• Anaemia: fatigue, pallor, dyspnoea
• Neutropenia: recurrent/severe infections
• Thrombocytopenia: bleeding, bruising, petechiae

Tissue Infiltration

• Hepatosplenomegaly
• Gingival hypertrophy (monocytic subtypes - M4/M5)
• Skin infiltration (leukaemia cutis)
• CNS involvement (more common in monocytic)

Specific

• DIC: especially APL t(15;17) - bleeding and thrombosis
• Leucostasis: WCC >100 × 10⁹/L → respiratory distress, neurological symptoms
• Tumour lysis syndrome

Red Flags

• Bleeding with DIC (APL - start ATRA immediately if suspected)
• Leucostasis (WCC >100)
• Febrile neutropenia

Bloods

• FBC: anaemia, thrombocytopenia, WCC variable (low/normal/very high); circulating blasts
• Blood film: myeloid blasts, Auer rods (pathognomonic), cytoplasmic granules
• Coagulation: DIC screen (prolonged PT/APTT, low fibrinogen, high D-dimer) - especially APL
• LDH, urate: raised
• U&Es, Ca, PO4, LFTs: baseline + TLS risk

Bone Marrow

• Aspirate + trephine: ≥20% myeloid blasts
• Flow cytometry: CD13, CD33, CD34, MPO (myeloid markers)
• Cytogenetics: t(15;17) PML-RARA (APL), t(8;21), inv(16) (CBF - good risk), complex karyotype (poor)
• Molecular: FLT3-ITD (~30%), NPM1 (~30%), CEBPA, TP53, IDH1/2, RUNX1

Classification

• WHO 2022: based on genetic abnormalities (not morphology alone)

APL (t(15;17)) - EMERGENCY

• ATRA (all-trans retinoic acid) 45mg/m²/day: start IMMEDIATELY if APL suspected (do NOT wait for cytogenetics)
• ATRA + arsenic trioxide (ATO): standard for low/intermediate risk APL (~90% cure)
• Differentiation syndrome: ATRA/ATO can cause fever, oedema, respiratory distress → dexamethasone 10mg BD

Non-APL AML

Fit for intensive therapy:

• Induction ('3+7'): daunorubicin 60mg/m² × 3 days + cytarabine 100–200mg/m² × 7 days
• FLT3+: add midostaurin 50mg BD (NICE TA823; RATIFY trial)
• CR achieved in ~60–80%
• Consolidation: high-dose cytarabine (HiDAC) or allogeneic SCT (intermediate/poor risk)

Unfit (elderly/comorbid):

• Azacitidine 75mg/m² × 7 days/28 days ± venetoclax (NICE TA957; VIALE-A trial)
• Low-dose cytarabine: alternative
• Best supportive care: transfusions, antibiotics, palliative

Supportive

• TLS prevention: allopurinol (rasburicase if high risk - contraindicated in G6PD deficiency)
• Febrile neutropenia: piperacillin-tazobactam, antifungals
• Blood products, G-CSF

Referral Criteria

• Haematology: URGENT same-day referral for suspected acute leukaemia
• Specialist centre: SCT assessment

• Highly variable by genetics:
  • APL: ~90% cure with ATRA + ATO
  • CBF AML (t(8;21), inv(16)): ~65–75% 5-year survival
  • NPM1+/FLT3-: ~60% 5-year survival
  • FLT3-ITD: ~30–40% (improved with midostaurin)
  • Complex karyotype/TP53: <10% 5-year survival
• Overall 5-year survival: ~30% (all ages); ~50% in <60 years
• Elderly (>70): median survival ~6–12 months with treatment
• Venetoclax + azacitidine: improved median survival from 10 to 15 months in elderly

ELN 2022 Risk Stratification

Key Facts

Chronic lymphocytic leukaemia (CLL) is a low-grade B-cell lymphoproliferative disorder characterised by progressive accumulation of functionally incompetent monoclonal B lymphocytes in the blood, bone marrow, and lymphoid tissues.

Epidemiology

• Most common leukaemia in Western countries: ~3,500/year in UK
• Median age: ~72 years; rare <40
• Male:female 2:1

Aetiology

• Unknown; familial clustering (5–10× risk in first-degree relatives)
• NOT associated with radiation or benzene (unlike other leukaemias)

Pathophysiology

• Clonal expansion of mature CD5+ B cells that accumulate due to defective apoptosis (overexpression of BCL-2)

• Autoimmune phenomena: AIHA (~10%), ITP (~5%)
• Microenvironment interactions promote CLL cell survival

Often Asymptomatic

• Incidental lymphocytosis on routine FBC (~80% at diagnosis)

Symptomatic

• Lymphadenopathy: painless, symmetrical, rubbery
• Splenomegaly (~50%)
• Hepatomegaly (~15%)
• B symptoms: weight loss >10%, drenching night sweats, fever >38°C
• Recurrent infections: hypogammaglobulinaemia (sinopulmonary)
• Autoimmune: AIHA (warm), ITP

Red Flags

• Richter transformation: rapid lymph node enlargement, B symptoms, rising LDH
• Severe autoimmune cytopenias
• Recurrent severe infections

Bloods

• FBC: lymphocytosis ≥5 × 10⁹/L (often 20–100+)
• Blood film: small mature lymphocytes, smudge/smear cells
• Flow cytometry: CD5+, CD19+, CD23+, weak sIg - CLL immunophenotype score (≥4/5 = CLL)
• Immunoglobulins: often low (hypogammaglobulinaemia)
• DAT: if AIHA suspected
• LDH, β2-microglobulin: prognostic markers

Prognostic

• IGHV mutation status: mutated (good prognosis); unmutated (poor)
• Cytogenetics (FISH): del(13q) = good; trisomy 12 = intermediate; del(11q) = poor; del(17p)/TP53 mutation = very poor (resistant to FCR)
• TP53 mutation analysis: critical for treatment decisions

Staging

• Binet staging (Europe): A (lymphocytosis ± ≤2 areas), B (≥3 lymphoid areas), C (anaemia/thrombocytopenia)
• Rai staging (USA): 0–IV
• Bone marrow biopsy and CT: not routinely needed for diagnosis; used if treatment planned

Watch and Wait (Binet A/B asymptomatic)

• NO treatment benefit from early intervention
• Monitor FBC every 3–6 months
• Treat only when indications arise

Treatment Indications

• Progressive marrow failure (Hb <100, platelets <100)
• Massive/progressive lymphadenopathy (>10cm) or splenomegaly
• Constitutional symptoms (B symptoms)
• Lymphocyte doubling time <6 months
• Autoimmune cytopenias not responding to steroids

First-line Treatment

Del(17p)/TP53:

• Ibrutinib (BTK inhibitor; continuous) or venetoclax + obinutuzumab (fixed duration; NICE TA663)

Without del(17p)/TP53:

• Ibrutinib (NICE TA689) or venetoclax + obinutuzumab
• FCR (fludarabine, cyclophosphamide, rituximab): young, fit, IGHV mutated (potential cure for some; ~60% 10-year PFS)

Supportive

• Immunoglobulin replacement: if hypogammaglobulinaemia with recurrent infections
• Vaccination: annual influenza, pneumococcal, COVID (response may be impaired)
• Infection prophylaxis: aciclovir (herpes), co-trimoxazole (PCP) during/after treatment

Referral Criteria

• Haematology: all confirmed CLL
• Urgent: Richter transformation, severe cytopenias

• Highly variable: early stage may never need treatment; median survival Binet A >10 years
• Binet C: median survival ~3–5 years (improving with novel agents)
• IGHV mutated: ~85% 10-year survival
• Del(17p)/TP53: historically very poor (~2–3 years); improved with ibrutinib/venetoclax (~60–70% 5-year)
• FCR in young IGHV mutated: potential cure (~60% 10-year PFS)
• Richter transformation: median survival ~6–12 months
• Novel agents (BTK inhibitors, BCL-2 inhibitors): transforming CLL outcomes

Binet Staging

Key Facts

Chronic myeloid leukaemia (CML) is a myeloproliferative neoplasm characterised by the Philadelphia chromosome and its BCR-ABL1 fusion gene. TKI therapy has revolutionised outcomes.

Epidemiology

• Incidence: ~1 per 100,000 per year; ~700 new cases/year in UK
• Median age at diagnosis: 55–60 years; all ages affected
• Slight male predominance

Aetiology

• Philadelphia chromosome t(9;22)(q34;q11): reciprocal translocation creating BCR-ABL1 fusion gene
• BCR-ABL1 encodes constitutively active tyrosine kinase
• Risk factor: ionising radiation (only established)

Pathophysiology

• BCR-ABL1 tyrosine kinase → uncontrolled myeloid proliferation, reduced apoptosis, impaired adhesion
• Clonal expansion of myeloid cells at all stages of maturation
• Three phases:
  1. Chronic phase (~90% at diagnosis): controlled proliferation
  2. Accelerated phase: increasing blasts (10–19%), basophilia, additional cytogenetic changes
  3. Blast crisis: ≥20% blasts (myeloid ~60%, lymphoid ~30%) - resembles acute leukaemia

Chronic Phase (Most Common Presentation)

• Often incidental: raised WCC on routine blood test (~50%)
• Symptomatic: fatigue, weight loss, sweating, abdominal fullness
• Massive splenomegaly: may extend to pelvis
• Leucocytosis: WCC 50–400+ × 10⁹/L
• Gout: hyperuricaemia from high cell turnover

Accelerated/Blast Crisis

• Worsening symptoms, increasing spleen, fever
• Bleeding, infections
• Bone pain, lymphadenopathy
• Blast crisis: behaves like acute leukaemia

Red Flags

• Leucostasis (WCC >300): respiratory distress, altered consciousness, visual changes
• Blast crisis features
• Splenic infarction (acute left upper quadrant pain)

Bloods

• FBC: leucocytosis (often 50–400+); full range of myeloid maturation - myelocytes, metamyelocytes, neutrophils, basophilia, eosinophilia
• Blood film: leucocytosis with orderly left shift; basophilia; no maturation gap (unlike AML)
• LDH, urate: raised

Definitive

• BCR-ABL1 by RT-PCR (peripheral blood): most sensitive; quantitative monitoring
• Cytogenetics (bone marrow): Philadelphia chromosome t(9;22)
• FISH: BCR-ABL1 fusion

Bone Marrow

• Hypercellular with granulocytic hyperplasia
• Cytogenetics: for additional chromosomal abnormalities

Monitoring on TKI

• BCR-ABL1 RT-qPCR: every 3 months
  • Major molecular response (MMR): BCR-ABL1 ≤0.1% IS
  • Deep molecular response (MR4/MR4.5): ≤0.01%/0.0032%
  • Treatment milestones: BCR-ABL1 ≤10% at 3 months, ≤1% at 6 months, ≤0.1% at 12 months

Pharmacological

First-line (chronic phase):

• Imatinib 400mg OD: first-generation TKI (NICE TA251)
  • ~95% complete haematological response
  • ~85% complete cytogenetic response at 5 years

Second-generation TKIs (faster/deeper responses):

• Dasatinib 100mg OD (NICE TA426)
• Nilotinib 300mg BD (NICE TA251)
• Bosutinib: for resistance/intolerance

Resistance/intolerance:

• Switch to alternative TKI
• Ponatinib: for T315I 'gatekeeper' mutation (resistant to all other TKIs)
• Asciminib: novel allosteric BCR-ABL1 inhibitor (NICE TA969)

Blast crisis:

• TKI + acute leukaemia-type chemotherapy; allogeneic SCT if possible

Treatment-Free Remission (TFR)

• Patients with sustained deep molecular response (MR4/MR4.5 for ≥2 years) may attempt TKI discontinuation
• ~50% maintain TFR; ~50% lose MMR and need to restart (virtually all re-respond)
• STIM and EURO-SKI trials

Supportive

• Allopurinol: prevent gout/TLS at diagnosis
• Monitoring: FBC, LFTs, lipase (TKI side effects)

Referral Criteria

• Haematology: all confirmed/suspected CML
• Specialist CML centre for treatment decisions

• Pre-imatinib era: median survival ~3–5 years
• Imatinib era: 10-year survival ~85–90%; near-normal life expectancy for most chronic phase patients
• Chronic phase responding to TKI: life expectancy approaches general population
• Accelerated phase: reduced survival (~2–3 years historically; improved with TKIs)
• Blast crisis: median survival ~6–12 months
• T315I mutation: poor (addressed by ponatinib/asciminib)
• TFR achievable in ~50% of eligible patients

CML Phase Criteria

TKI Treatment Milestones

Key Facts

Hodgkin lymphoma (HL) is a lymphoid neoplasm characterised by the presence of Reed-Sternberg cells within a reactive inflammatory background. It is one of the most curable cancers.

Epidemiology

• ~2,000 new cases/year in the UK
• Bimodal: peak 20–30 years, second peak >60 years
• Slight male predominance
• EBV-associated in ~40% of classical HL

Aetiology

• EBV: detected in ~40% of HL (higher in mixed cellularity subtype)
• Immunosuppression: HIV, post-transplant
• Genetic: slightly increased risk in siblings

Pathophysiology

• Reed-Sternberg cells are derived from germinal centre B cells
• RS cells secrete cytokines → recruit reactive inflammatory infiltrate (T cells, eosinophils, histiocytes)
• RS cells constitute <1% of tumour mass; the rest is reactive
• Classical HL (95%): nodular sclerosis (most common), mixed cellularity, lymphocyte-rich, lymphocyte-depleted
• Nodular lymphocyte-predominant HL (5%): LP cells ('popcorn cells'), CD20+, indolent

Typical Presentation

• Painless lymphadenopathy: cervical (~70%), mediastinal, axillary
• Nodes: rubbery, non-tender
• Mediastinal mass (bulky): especially nodular sclerosis subtype

B Symptoms (~30–40%)

• Fever >38°C (Pel-Ebstein fever: cyclical, rare but classic)
• Drenching night sweats
• Weight loss >10% in 6 months

Other

• Alcohol-induced lymph node pain (rare but specific)
• Pruritus (sometimes severe)
• Fatigue

Red Flags

• Mediastinal mass with SVC obstruction
• Progressive lymphadenopathy with B symptoms
• Young adult with unexplained lymphadenopathy >2 weeks

Bloods

• FBC: may be normal; eosinophilia, lymphopenia
• ESR: elevated (prognostic; >30 mm/hr is adverse)
• LDH: prognostic marker
• Albumin: low = adverse
• LFTs, U&Es: baseline
• HIV: screen

Biopsy

• Excision lymph node biopsy: ESSENTIAL (core biopsy may be inadequate)
• Reed-Sternberg cells: CD15+, CD30+, CD20-/weak, CD45-
• Nodular lymphocyte-predominant: LP cells, CD20+, CD15-, CD30-

Staging (Ann Arbor/Lugano)

• PET-CT: gold standard for staging
  • Stage I: single lymph node region
  • Stage II: ≥2 regions, same side of diaphragm
  • Stage III: both sides of diaphragm
  • Stage IV: diffuse extranodal involvement (liver, bone marrow)
  • Add 'A' (no B symptoms) or 'B' (B symptoms present)
  • 'X' or 'bulky' if >10cm mass

Fertility

• Semen cryopreservation / oocyte preservation BEFORE chemotherapy

Early Stage (I/II) - Favourable

• ABVD × 2–4 cycles + involved-field radiotherapy (IFRT)
• ~95% cure rate

Early Stage - Unfavourable

• ABVD × 4–6 cycles ± IFRT

Advanced Stage (III/IV)

• ABVD × 6 cycles (standard)
• Escalated BEACOPP × 6: more intensive; higher response but more toxicity (used in some centres for high-risk)
• PET-adapted: interim PET after 2 cycles guides therapy (if PET-negative, may omit bleomycin - RATHL trial)

Relapsed/Refractory

• Salvage chemotherapy (DHAP, ICE, GDP) → autologous SCT (~50% cure in relapse)
• Brentuximab vedotin (anti-CD30 ADC): post-ASCT consolidation or relapsed HL (NICE TA524)
• Pembrolizumab/nivolumab (anti-PD-1): relapsed after ASCT + brentuximab (NICE TA540)

Supportive

• Fertility preservation before treatment
• Bleomycin lung toxicity monitoring (PFTs)
• Long-term follow-up: second cancers, cardiac disease, thyroid dysfunction

Referral Criteria

• Haematology/oncology: urgent for suspected lymphoma
• 2-week-wait referral: unexplained lymphadenopathy

• Overall cure rate: ~85–90%
• Early stage favourable: >95% cure
• Advanced stage: ~75–85% cure with ABVD
• Relapsed after ASCT: ~50% salvage with brentuximab/checkpoint inhibitors
• Late effects in survivors: secondary malignancy (breast, lung - 10–20 years), cardiac disease (anthracycline, radiotherapy), hypothyroidism, infertility
• Long-term survival: requires lifelong surveillance for late complications

IPS-7 (International Prognostic Score for Advanced HL)

Key Facts

Non-Hodgkin lymphoma (NHL) encompasses a large, heterogeneous group of lymphoid neoplasms arising from B cells, T cells, or NK cells. They range from indolent to highly aggressive.

Epidemiology

• ~14,000 new cases/year in UK; 5th most common cancer
• Median age: 65–70 years
• Incidence increases with age
• 85% B-cell, 15% T/NK-cell

Aetiology

• Most idiopathic
• Infections: EBV (Burkitt, PTLD), H. pylori (gastric MALT), HCV (splenic marginal zone), HTLV-1 (adult T-cell leukaemia/lymphoma), HHV-8 (primary effusion lymphoma)
• Immunosuppression: HIV, post-transplant, autoimmune
• Autoimmune: Sjögren (MALT), coeliac (EATL), RA

Pathophysiology

• Malignant transformation of lymphocytes at various stages of differentiation
• Characteristic chromosomal translocations:
  • t(14;18) BCL2: follicular lymphoma (anti-apoptotic)
  • t(11;14) cyclin D1: mantle cell lymphoma
  • t(8;14) MYC: Burkitt lymphoma (proliferation)
  • t(11;18): MALT lymphoma
• Indolent NHL: accumulate slowly; incurable but long survival
• Aggressive NHL: rapid growth; curable with intensive treatment

Indolent NHL (e.g., Follicular)

• Painless lymphadenopathy (often waxing and waning)
• Often widespread at diagnosis (stage III/IV)
• Fatigue
• May be asymptomatic for years

Aggressive NHL (e.g., DLBCL)

• Rapidly enlarging lymph nodes
• B symptoms: fever, night sweats, weight loss
• Extranodal involvement: GI, CNS, bone, skin
• LDH raised

Burkitt Lymphoma

• Endemic (African): jaw/facial mass (EBV-associated)
• Sporadic: abdominal mass (ileocaecal region)
• HIV-associated: widespread
• Tumour doubling time ~24–48 hours (fastest growing human tumour)

Gastric MALT

• Dyspepsia, epigastric pain
• Often localised (stage I/II)
• H. pylori positive in ~90%

Red Flags

• Rapidly enlarging nodes
• B symptoms
• Cord compression
• SVC obstruction
• TLS (Burkitt, high-grade)

Biopsy

• Excision lymph node biopsy: ESSENTIAL for accurate subtyping (core biopsy often insufficient)
• Histopathology + immunohistochemistry: defines subtype

Bloods

• FBC, blood film: cytopenias if marrow involvement; circulating lymphoma cells in some
• LDH: raised (prognostic; reflects tumour burden)
• β2-microglobulin: prognostic
• Urate: raised in high-turnover lymphomas
• HIV, Hep B/C: screen (reactivation risk with rituximab)

Staging

• PET-CT: for FDG-avid subtypes (DLBCL, follicular, Burkitt)
• CT CAP: if PET not indicated
• Bone marrow biopsy: if relevant to treatment
• LP: CNS involvement risk (DLBCL with specific risk factors, Burkitt)
• Ann Arbor staging: I–IV (as per HL)

Prognostic Scores

• IPI (DLBCL): age >60, LDH elevated, ECOG ≥2, stage III/IV, >1 extranodal site
• FLIPI (follicular): age >60, LDH elevated, Hb <120, stage III/IV, >4 nodal areas

DLBCL (Aggressive)

• R-CHOP × 6 cycles (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone)
• ± involved-site radiotherapy
• CNS prophylaxis: intrathecal methotrexate ± high-dose IV methotrexate (if high CNS risk)
• Cure rate: ~60–65%

Follicular Lymphoma (Indolent)

• Asymptomatic, low burden: watch and wait (no survival benefit to early treatment)
• Symptomatic: R-CHOP, R-CVP, or R-bendamustine × 6 cycles
• Maintenance rituximab: every 2 months for 2 years (prolongs PFS)
• Localised (stage I/II): radiotherapy (potentially curative)

Burkitt Lymphoma

• Intensive chemotherapy: R-CODOX-M/R-IVAC or similar intensive regimen
• TLS prevention: critical (rasburicase, aggressive hydration)
• CNS prophylaxis: intrathecal chemotherapy
• Highly curable: ~80–90% in children; ~60–80% in adults

Gastric MALT

• H. pylori eradication: first-line for localised H. pylori+ gastric MALT (~60–90% respond)
• Radiotherapy: if H. pylori negative or eradication failure
• R-chlorambucil or R-CVP: advanced stage

Relapsed/Refractory

• Salvage chemotherapy + autologous SCT: DLBCL
• CAR-T therapy (axicabtagene ciloleucel, tisagenlecleucel): relapsed/refractory DLBCL (NICE TA895)
• Bispecific antibodies: glofitamab, epcoritamab (emerging)

Referral Criteria

• Haematology/oncology: all suspected lymphoma (2-week-wait referral for unexplained lymphadenopathy)

• DLBCL: ~60–65% 5-year survival with R-CHOP; IPI score predicts outcome (0–1: ~75%; 4–5: ~30%)
• Follicular: median survival >15 years; incurable but long natural history; ~3% per year transform to DLBCL
• Burkitt: ~80–90% cure in children; ~60–80% in adults with intensive chemo
• Gastric MALT: excellent prognosis; ~90% cure with H. pylori eradication (if localised)
• Mantle cell: median survival ~5–7 years (improving with BTK inhibitors)
• CAR-T: ~40% long-term remissions in relapsed/refractory DLBCL

NHL Subtypes Overview

Key Facts

Multiple myeloma is a haematological malignancy characterised by clonal proliferation of plasma cells in the bone marrow, producing a monoclonal immunoglobulin (paraprotein). It causes a constellation of features including bone destruction, renal failure, anaemia, and immunosuppression.

Epidemiology

• Approximately 5,900 new cases per year in the UK
• Median age at diagnosis: 70 years
• More common in males (M:F ratio 1.5:1)
• 2-3 times more common in Black African/Caribbean populations
• Incidence is rising due to ageing population and improved detection

Aetiology

• Risk factors: increasing age, male sex, Black ethnicity, family history, obesity, prior MGUS
• MGUS progresses to myeloma at a rate of approximately 1% per year
• Genetic abnormalities: t(4;14), t(14;16), del(17p) confer high-risk disease

Pathophysiology

• Clonal plasma cells proliferate in the bone marrow and produce monoclonal immunoglobulin (paraprotein/M-protein)
• Bone destruction: myeloma cells activate osteoclasts (via RANKL) and inhibit osteoblasts → lytic lesions, pathological fractures, hypercalcaemia
• Renal impairment: light chain deposition, hypercalcaemia, hyperuricaemia, amyloidosis, cast nephropathy
• Anaemia: marrow infiltration, chronic disease, renal impairment
• Immunoparesis: suppression of normal immunoglobulins → recurrent infections
• Hyperviscosity: rare, more common in IgA myeloma and Waldenström macroglobulinaemia

Bone Disease

• Bone pain (most common presenting symptom, ~70%) – especially back and ribs
• Pathological fractures – vertebral compression fractures, long bone fractures
• Spinal cord compression – oncological emergency

Systemic Features

• Fatigue and lethargy (anaemia)
• Recurrent infections (immunoparesis) – pneumonia, UTIs
• Weight loss

Renal Disease

• Present in 20-30% at diagnosis
• May present as AKI or CKD
• Myeloma kidney (cast nephropathy) – most common cause

Hypercalcaemia

• Confusion, constipation, polyuria, polydipsia, nausea
• Present in ~30% at diagnosis

Hyperviscosity Syndrome (rare)

• Visual disturbance, headache, mucosal bleeding, confusion

Red Flags

• Spinal cord compression: back pain with leg weakness, saddle anaesthesia, urinary retention → MRI spine within 24 hours
• Hypercalcaemia with confusion → medical emergency
• Neutropenic sepsis during treatment
• Acute renal failure with disproportionately raised urea/creatinine

Bedside

• Urine dipstick: may be negative (Bence Jones protein not detected by standard dipstick)
• ECG: hypercalcaemia (short QT), hyperkalaemia

Bloods

• FBC: normocytic normochromic anaemia, may show rouleaux on blood film
• U&Es: renal impairment, raised calcium
• Bone profile: hypercalcaemia, raised ALP (if fractures)
• Serum protein electrophoresis (SPEP): M-protein band
• Serum free light chains (sFLC): kappa/lambda ratio (abnormal ratio confirms clonality)
• Serum immunoglobulins: immunoparesis (low uninvolved Ig classes)
• Beta-2 microglobulin: prognostic marker (ISS staging)
• LDH and albumin: for staging
• Blood film: rouleaux formation
• ESR: markedly elevated (often >100 mm/h)
• Serum viscosity: if hyperviscosity suspected

Imaging

• Whole-body low-dose CT (preferred over skeletal survey per NICE NG35) – detects lytic lesions
• MRI whole spine: if spinal cord compression suspected
• PET-CT: for solitary plasmacytoma or suspected extramedullary disease

Special Tests

• Bone marrow aspirate and trephine: ≥10% clonal plasma cells confirms diagnosis; cytogenetics/FISH for risk stratification
• Urine Bence Jones protein: urine protein electrophoresis for light chains
• 24-hour urine protein: quantify proteinuria

Non-pharmacological

• MDT discussion at specialist haematology centre
• Adequate hydration: ≥3L/day to prevent renal complications
• Avoid nephrotoxic drugs: NSAIDs, aminoglycosides, IV contrast with caution
• Spinal precautions if vertebral disease
• Psychological support and patient education

Pharmacological

First-line (transplant-eligible, typically <70 years):

• Induction: VRd regimen – bortezomib 1.3 mg/m² SC (days 1, 4, 8, 11) + lenalidomide 25mg OD (days 1-14) + dexamethasone 40mg weekly × 4-6 cycles
• Followed by autologous stem cell transplant (ASCT)
• Lenalidomide maintenance 10mg OD until progression

First-line (transplant-ineligible):

• VRd (dose-attenuated) or VMP (bortezomib, melphalan, prednisolone)
• Daratumumab-VMP (ALCYONE trial) or Daratumumab-Rd (MAIA trial) now standard

Supportive care:

• Zoledronic acid 4mg IV monthly for bone protection (continue for 2 years minimum)
• Erythropoietin for anaemia if Hb <100 g/L
• Prophylactic aciclovir 400mg BD (VZV reactivation with bortezomib)
• Thromboprophylaxis: aspirin 75mg OD or LMWH with lenalidomide/thalidomide
• IV immunoglobulin replacement if recurrent infections with low IgG

Relapsed disease:

• Carfilzomib, pomalidomide, isatuximab, elotuzumab, selinexor, CAR-T therapy (ide-cel, cilta-cel)

Referral Criteria

• All suspected myeloma → urgent 2-week-wait haematology referral
• Spinal cord compression → emergency oncology/neurosurgery
• Acute renal failure → nephrology

• Median overall survival: 5-7 years with modern therapy
• Transplant-eligible patients: median survival 7-10 years
• High-risk cytogenetics [t(4;14), del(17p), t(14;16)]: median survival 2-3 years
• ISS Stage I (β2M <3.5, albumin ≥35): median survival 62 months
• ISS Stage III (β2M ≥5.5): median survival 29 months
• R-ISS now incorporates cytogenetics and LDH for improved prognostication
• 10-year survival approximately 30% overall

International Staging System (ISS)

CRAB Criteria for End-Organ Damage

Landmark Trials

Key Facts

Waldenström macroglobulinaemia is a lymphoplasmacytic lymphoma characterised by infiltration of the bone marrow by clonal lymphoplasmacytic cells and secretion of monoclonal IgM. The large pentameric IgM molecule predisposes to hyperviscosity syndrome.

Epidemiology

• Rare: approximately 1,500 people living with WM in the UK
• Median age at diagnosis: 65-70 years
• Male predominance (M:F ratio 2:1)
• More common in White European populations
• Accounts for 1-2% of haematological malignancies

Aetiology

• Exact cause unknown; often preceded by IgM MGUS
• IgM MGUS progresses to WM at 1.5% per year
• MYD88 L265P mutation is present in >90% (activates NF-κB signalling)
• CXCR4 mutations in ~30% (associated with resistance to ibrutinib)
• Familial clustering observed; first-degree relatives have 20-fold increased risk

Pathophysiology

• Clonal B-cell lymphoplasmacytic proliferation in bone marrow
• Overproduction of monoclonal IgM (pentameric) → markedly raised serum viscosity
• Hyperviscosity: IgM is the largest immunoglobulin → sludging of blood in microcirculation
• Bone marrow infiltration → cytopenias (anaemia most common)
• IgM may act as autoantibody → cold agglutinin disease, peripheral neuropathy, cryoglobulinaemia
• Unlike myeloma, lytic bone lesions are rare

Constitutional Symptoms

• Fatigue (most common, due to anaemia)
• Weight loss, night sweats
• Hepatosplenomegaly and lymphadenopathy (more common than in myeloma)

Hyperviscosity Syndrome (10-30%)

• Visual disturbance: blurred vision, diplopia
• Headache, confusion, somnolence
• Mucosal bleeding: epistaxis, gingival bleeding
• Fundoscopy: engorged retinal veins ("sausage-link" appearance), papilloedema, retinal haemorrhages

IgM-Related Complications

• Peripheral neuropathy (20-25%): anti-MAG antibodies → sensorimotor neuropathy
• Cold agglutinin disease: Raynaud phenomenon, acrocyanosis, haemolytic anaemia in cold
• Cryoglobulinaemia: purpura, arthralgia, renal involvement
• AL amyloidosis (rare)

Red Flags

• Rapidly worsening cytopenias → marrow failure
• Unexplained neuropathy with IgM paraprotein → investigate for WM

Bedside

• Fundoscopy: hyperviscosity changes (dilated veins, haemorrhages)
• Peripheral neurological examination: neuropathy assessment

Bloods

• FBC: anaemia (normocytic), may show rouleaux
• SPEP and immunofixation: monoclonal IgM band
• Serum IgM level: typically >30 g/L
• Serum free light chains
• Serum viscosity: >4 cP associated with hyperviscosity symptoms
• Beta-2 microglobulin: prognostic
• LDH: prognostic
• DAT (Coombs test): if cold agglutinin disease suspected
• Cryoglobulins: if cryoglobulinaemia suspected
• Hepatitis B and C serology: exclude HCV-associated cryoglobulinaemia

Imaging

• CT neck/chest/abdomen/pelvis: lymphadenopathy, hepatosplenomegaly
• MRI brain: if CNS involvement suspected (Bing-Neel syndrome)

Special Tests

• Bone marrow aspirate and trephine: lymphoplasmacytic infiltrate, confirm clonality
• MYD88 L265P mutation testing: present in >90% (helps distinguish from marginal zone lymphoma)
• CXCR4 mutation testing: treatment implications
• Nerve conduction studies: if neuropathy present
• Anti-MAG antibodies: if peripheral neuropathy

Non-pharmacological

• Watch and wait if asymptomatic (smouldering WM) – regular monitoring
• Treatment indicated for: symptomatic hyperviscosity, cytopenias, neuropathy, constitutional symptoms, amyloidosis, cryoglobulinaemia

Pharmacological

First-line:

• DRC regimen: dexamethasone 20mg IV day 1 + rituximab 375 mg/m² IV + cyclophosphamide 100 mg/m² BD PO days 1-5, q21 days × 6 cycles
• Alternative: bendamustine-rituximab (BR): bendamustine 90 mg/m² IV days 1-2 + rituximab, q28 days × 6
• Ibrutinib 420mg OD – increasingly used first-line, particularly if MYD88 mutated
• Avoid rituximab monotherapy initially if IgM >40 g/L (risk of IgM flare)

Hyperviscosity emergency:

• Urgent plasmapheresis to rapidly reduce IgM levels
• Followed by systemic chemotherapy

Relapsed disease:

• Ibrutinib, zanubrutinib, venetoclax, bortezomib-based regimens
• Zanubrutinib 160mg BD (ASPEN trial) – second-generation BTK inhibitor

Referral Criteria

• All patients with IgM paraprotein → haematology
• Acute visual loss or neurological symptoms → urgent assessment for plasmapheresis

• Median overall survival: 5-8 years with modern therapy
• International Prognostic Scoring System for WM (IPSSWM): age >65, Hb ≤115 g/L, platelets ≤100, β2M >3, IgM >70 g/L
• Low-risk IPSSWM: 5-year survival 87%
• High-risk IPSSWM: 5-year survival 36%
• Risk of transformation to DLBCL (diffuse large B-cell lymphoma) in 5-10%
• Neuropathy can be debilitating and may not fully resolve with treatment

IPSSWM Prognostic Scoring

Key Differences: WM vs Multiple Myeloma

Key Facts

Polycythaemia vera is a chronic myeloproliferative neoplasm characterised by uncontrolled production of red blood cells, often accompanied by leucocytosis and thrombocytosis. It carries a significant risk of thrombotic events.

Epidemiology

• Incidence: 2 per 100,000/year in the UK
• Median age at diagnosis: 60 years
• Slight male predominance
• Prevalence approximately 22 per 100,000

Aetiology

• JAK2 V617F mutation in >95% of PV cases (exon 14)
• JAK2 exon 12 mutations in ~3% of JAK2 V617F-negative PV
• Gain-of-function mutation → constitutive activation of JAK-STAT signalling
• Results in cytokine-independent erythroid proliferation

Pathophysiology

• Mutant JAK2 → constitutive activation of erythropoietin receptor signalling

• Leucocytosis and thrombocytosis also common (trilineage proliferation)

• Platelet dysfunction → paradoxical bleeding risk (especially if platelets >1500 × 10⁹/L due to acquired von Willebrand disease)
• Late-phase: bone marrow fibrosis (post-PV myelofibrosis) or leukaemic transformation

Common Presentations

• Incidental finding on FBC (raised Hb/Hct)
• Facial plethora (ruddy complexion)
• Aquagenic pruritus (itch after bathing – highly characteristic)
• Headache, dizziness, visual disturbance (hyperviscosity)
• Splenomegaly (present in ~70%)
• Erythromelalgia (burning pain and redness of extremities)

Thrombotic Complications

• Stroke, TIA
• MI, angina
• DVT/PE
• Budd-Chiari syndrome (hepatic vein thrombosis) – consider PV in young patients
• Portal/splenic vein thrombosis

Late-Phase Disease

• Progressive splenomegaly (post-PV myelofibrosis)
• Worsening cytopenias
• Constitutional symptoms (weight loss, night sweats)

Red Flags

• Budd-Chiari syndrome in young patient → test JAK2
• Erythrocytosis with low EPO → strongly suggests PV
• Rapidly increasing spleen size → transformation to myelofibrosis
• New pancytopenia in known PV → leukaemic transformation

Bedside

• SpO₂: exclude hypoxic secondary polycythaemia
• Weight/BMI: obesity associated with apparent polycythaemia

Bloods

• FBC: raised Hb (>165 g/L males, >160 g/L females), raised Hct (>0.49 males, >0.48 females); often WCC and platelets also raised
• JAK2 V617F mutation: positive in >95%
• JAK2 exon 12: if V617F negative but PV still suspected
• Serum erythropoietin (EPO): low or low-normal in PV (raised in secondary causes)
• Serum ferritin: often low (iron depletion from erythrocytosis or venesection)
• LDH: may be elevated
• Uric acid: often raised

Imaging

• Abdominal ultrasound: splenomegaly, hepatomegaly
• CT abdomen: if Budd-Chiari or splanchnic thrombosis suspected

Special Tests

• Bone marrow biopsy: hypercellular with trilineage proliferation, pleomorphic megakaryocytes; confirms diagnosis if EPO and JAK2 equivocal
• Cytogenetics: for risk stratification
• Red cell mass study: rarely performed now; replaced by JAK2 testing

Non-pharmacological

• Venesection: target haematocrit <0.45 (regardless of sex) – CYTO-PV trial demonstrated reduced thrombotic events
• Initially weekly 400-500mL until target achieved, then as needed
• Cardiovascular risk factor management: smoking cessation, BP control

Pharmacological

All patients:

• Aspirin 75mg OD (unless contraindicated) – reduces thrombotic risk
• Avoid aspirin if platelets >1500 × 10⁹/L (acquired vWD risk)

High-risk patients (age >60 OR prior thrombosis):

• Hydroxycarbamide (hydroxyurea) 500mg-2g OD – first-line cytoreductive therapy
• Titrate to maintain Hct <0.45, WCC <10, platelets <400

Hydroxycarbamide-intolerant/resistant:

• Ruxolitinib 10mg BD (JAK1/2 inhibitor) – RESPONSE trial: superior to best available therapy
• Interferon alfa (ropeginterferon alfa-2b): preferred in younger patients, pregnancy-safe
• Busulfan 2-4mg OD – in elderly/frail patients

Aquagenic pruritus:

• Antihistamines, SSRIs, narrow-band UVB phototherapy, ruxolitinib

Referral Criteria

• All patients with confirmed/suspected PV → haematology
• Splanchnic thrombosis with erythrocytosis → urgent haematology + hepatology

• Median survival: 14-20 years (near-normal life expectancy with good control)
• Major cause of death: thrombotic events (30-40% of deaths)
• Risk of myelofibrotic transformation: 10-20% at 20 years
• Risk of AML transformation: 5-10% at 20 years (increased with alkylating agents)
• CYTO-PV trial: maintaining Hct <0.45 reduces cardiovascular death and major thrombosis by 60%
• Prognosis significantly worse with high-risk cytogenetics or leukaemic transformation

WHO Diagnostic Criteria for PV (2016)

Major criteria (all 3 required, or first 2 + minor criterion):

Minor criterion: Low serum EPO

Risk Stratification

Landmark Trials

Key Facts

Essential thrombocythaemia is a myeloproliferative neoplasm characterised by megakaryocyte proliferation leading to persistent thrombocytosis. The main clinical consequences are thrombosis and haemorrhage.

Epidemiology

• Incidence: 1-2.5 per 100,000/year in the UK
• Median age at diagnosis: 55-60 years (bimodal: peak at 30 and 55)
• Slight female predominance
• Most common MPN at presentation

Aetiology

• JAK2 V617F: ~60% (shared with PV and PMF)
• CALR mutations (calreticulin): ~25% (type 1 and type 2)
• MPL mutations (thrombopoietin receptor): ~5%
• Triple-negative: ~10% (no known driver mutation)

Pathophysiology

• Driver mutations cause cytokine-independent megakaryocyte proliferation
• Increased platelet production → sustained thrombocytosis
• Abnormal platelet function → paradoxical thrombosis AND bleeding

• Leukoerythroblastic change and fibrosis suggest transformation to myelofibrosis

Common Presentations

• Incidental finding of raised platelet count on FBC (~50%)
• Microvascular symptoms: erythromelalgia, headache, dizziness, visual disturbance, acral paraesthesiae
• Thrombotic events: stroke, TIA, MI, DVT/PE, splanchnic vein thrombosis
• Haemorrhagic events: mucosal bleeding, bruising (especially with very high platelets)
• Splenomegaly (mild, in ~40%)

Red Flags

• Splanchnic vein thrombosis in a young patient → screen for MPNs
• Platelets >1500 × 10⁹/L with bleeding → acquired von Willebrand disease
• Rapidly rising platelets with constitutional symptoms → consider transformation
• Leukoerythroblastic blood film → myelofibrotic transformation

Bedside

• Examination for splenomegaly, evidence of thrombosis or bleeding

Bloods

• FBC: sustained platelets ≥450 × 10⁹/L on two occasions at least 1 month apart
• Blood film: large platelets, platelet clumps; exclude leukoerythroblastic features
• JAK2 V617F: first-line molecular test
• CALR mutation: if JAK2 negative
• MPL mutation: if JAK2 and CALR negative
• BCR-ABL: to exclude CML (mandatory)
• Iron studies, CRP, ESR: exclude reactive causes
• LDH: raised in MPNs
• vWF activity/antigen and ristocetin cofactor: if platelets >1000 and bleeding

Imaging

• Abdominal ultrasound: splenomegaly assessment

Special Tests

• Bone marrow biopsy: proliferation of large mature megakaryocytes with hyperlobulated nuclei; no significant fibrosis (reticulin grade 0-1); mandatory for diagnosis
• Cytogenetics: exclude MDS, CML

Non-pharmacological

• Cardiovascular risk factor modification: smoking cessation, weight management
• Low-risk patients may require observation only

Pharmacological

Low-risk (age <60, no prior thrombosis):

• Aspirin 75mg OD (if microvascular symptoms or cardiovascular risk factors)
• Some very low-risk patients (CALR-mutated, young) may not need aspirin

High-risk (age ≥60 OR prior thrombosis):

• Hydroxycarbamide 500mg-1g OD – first-line cytoreductive therapy (PT-1 trial)
• Target platelet count <400 × 10⁹/L
• Plus aspirin 75mg OD

Hydroxycarbamide-intolerant/resistant:

• Anagrelide 0.5mg BD (titrate to response, max 10mg/day) – PT-1 trial showed non-inferiority but more arterial thrombosis and fibrosis
• Interferon alfa (pegylated): preferred in younger patients and pregnancy
• Busulfan: elderly patients, short course

Very high platelets (>1500 × 10⁹/L):

• Withhold aspirin (acquired vWD risk → bleeding)
• Check vWF activity: restore aspirin when platelets reduced and vWF normalised

Referral Criteria

• All patients with sustained thrombocytosis >450 → haematology
• Thrombotic or haemorrhagic events → urgent haematology

• Median survival: >20 years (near-normal life expectancy for low-risk)
• Thrombosis risk: 10-25% at 10 years (higher in JAK2-positive)
• Transformation to myelofibrosis: 3-10% at 10 years
• Transformation to AML: 1-3% at 10 years
• CALR-mutated ET has best prognosis and lowest thrombotic risk
• IPSET-thrombosis score guides risk stratification: age, JAK2 status, prior thrombosis, cardiovascular risk factors

IPSET-Thrombosis Risk Stratification

Driver Mutation Comparison

Key Facts

Myelofibrosis is characterised by progressive replacement of bone marrow by fibrotic tissue, leading to bone marrow failure and extramedullary haematopoiesis (predominantly in the spleen and liver). It can present de novo (primary MF) or evolve from PV or ET.

Epidemiology

• Incidence: 0.5-1 per 100,000/year in the UK
• Median age at diagnosis: 65-70 years
• Slight male predominance
• Rarest of the classic MPNs

Aetiology

• JAK2 V617F: ~60%
• CALR: ~25% (type 1 has better prognosis than type 2)
• MPL: ~7%
• Triple-negative: ~8% (worst prognosis)
• Additional mutations (ASXL1, EZH2, SRSF2, IDH1/2) modify prognosis

Pathophysiology

• Clonal stem cell disorder with abnormal megakaryocyte proliferation
• Megakaryocytes release fibrogenic cytokines (TGF-β, PDGF, VEGF) → progressive marrow fibrosis
• Marrow failure → cytopenias
• Extramedullary haematopoiesis → massive splenomegaly, hepatomegaly
• Altered stem cell niche → leukoerythroblastic picture in peripheral blood
• Constitutional symptoms driven by pro-inflammatory cytokine excess

Common Presentations

• Massive splenomegaly (often below umbilicus) – most prominent finding
• Constitutional symptoms: fatigue, weight loss, night sweats, fevers (up to 30%)
• Anaemia symptoms: fatigue, dyspnoea
• Abdominal discomfort/early satiety (from splenic enlargement)
• Bone pain (marrow fibrosis)

Complications

• Splenic infarction: acute left upper quadrant pain
• Portal hypertension: ascites, variceal bleeding
• Extramedullary haematopoiesis: pulmonary hypertension, spinal cord compression
• Transformation to AML: 10-20% at 10 years

Red Flags

• Rapidly increasing spleen size → disease progression or blast transformation
• New cytopenias with circulating blasts → leukaemic transformation
• Severe thrombocytopenia (<50 × 10⁹/L) → high bleeding risk

Bedside

• Physical examination: splenomegaly (often massive), hepatomegaly

Bloods

• FBC: anaemia (normocytic, often severe), WCC variable (raised or low), platelets variable
• Blood film: leukoerythroblastic picture – tear-drop poikilocytes (dacrocytes), nucleated RBCs, immature myeloid cells, large platelets
• LDH: elevated (marrow turnover)
• Uric acid: often raised
• JAK2 V617F, CALR, MPL mutations
• Additional molecular profiling: ASXL1, SRSF2, EZH2, IDH1/2 (prognostic)

Imaging

• Abdominal ultrasound/CT: splenomegaly, hepatomegaly, portal hypertension
• MRI: assess extramedullary haematopoiesis if clinically indicated

Special Tests

• Bone marrow biopsy (trephine essential): reticulin/collagen fibrosis (graded MF-0 to MF-3), megakaryocyte atypia, reduced haematopoietic tissue
• Cytogenetics: complex karyotype is adverse
• Dry tap on aspirate is common due to fibrosis

Non-pharmacological

• Risk stratification using DIPSS or DIPSS-Plus before treatment decisions
• Observation if asymptomatic, low-risk disease
• Red cell transfusion support for symptomatic anaemia

Pharmacological

JAK inhibitors (COMFORT-I/II, SIMPLIFY trials):

• Ruxolitinib 15-20mg BD (based on platelet count): reduces spleen size by ≥35% in ~40% and improves constitutional symptoms
• Start at 20mg BD if platelets >200, 15mg BD if 100-200
• Monitor FBC closely (dose-limiting cytopenias)
• Fedratinib 400mg OD: second-line JAK inhibitor (JAKARTA trial)

Anaemia management:

• Erythropoiesis-stimulating agents: if EPO <500 and low transfusion burden
• Danazol 200mg TDS: may improve anaemia
• Thalidomide 50mg OD + prednisolone – can improve anaemia and splenomegaly
• Luspatercept for transfusion-dependent anaemia

Splenomegaly:

• Ruxolitinib (first-line for symptomatic splenomegaly)
• Splenectomy: considered for refractory symptomatic splenomegaly, transfusion-dependent anaemia (high perioperative risk ~9% mortality)
• Splenic irradiation: for non-surgical candidates

Surgical/Interventional

• Allogeneic stem cell transplant: only curative option; consider in intermediate-2/high-risk patients aged <70 with suitable donor
• Transplant-related mortality ~20-30%

Referral Criteria

• All suspected MF → haematology
• Intermediate-2/high-risk → consider transplant referral early

• Median survival varies widely by risk group:
  • DIPSS Low risk: >15 years
  • DIPSS Intermediate-1: 6-7 years
  • DIPSS Intermediate-2: 2.5-4 years
  • DIPSS High risk: 1-2 years
• Overall median survival for primary MF: 3.5-5.5 years
• AML transformation: 10-20% at 10 years (prognosis very poor once transformed)
• Post-PV/ET MF generally has better prognosis than primary MF
• Allogeneic SCT can cure but significant morbidity/mortality

DIPSS Prognostic Scoring

Landmark Trials

Key Facts

ITP is an acquired autoimmune disorder characterised by isolated low platelet count resulting from immune-mediated platelet destruction and impaired platelet production. It is a diagnosis of exclusion.

Epidemiology

• Adult incidence: 3-4 per 100,000/year in the UK
• Childhood ITP: typically post-viral, acute, self-limiting (80% resolve within 6 months)
• Adult ITP: more likely chronic (lasting >12 months)
• Female predominance in adults (F:M 2:1)
• Prevalence increases with age

Aetiology

• Primary ITP: idiopathic (no identifiable trigger)
• Secondary ITP: associated with SLE, antiphospholipid syndrome, CLL, HIV, hepatitis C, H. pylori, drugs (heparin excluded – separate entity)
• Post-viral ITP common in children (follows URTI)

Pathophysiology

• Autoantibodies (usually IgG) target platelet surface glycoproteins (GPIIb/IIIa, GPIb/IX)
• Antibody-coated platelets phagocytosed by splenic macrophages (Fc receptor-mediated)
• Reduced platelet production: autoantibodies also inhibit megakaryocyte function
• T-cell-mediated platelet destruction also contributes
• Relative thrombopoietin deficiency (inadequate compensatory production)

Mild Thrombocytopenia (50-100 × 10⁹/L)

• Often asymptomatic
• Mild bruising

Moderate (20-50 × 10⁹/L)

• Petechiae (non-blanching pinpoint lesions)
• Purpura and easy bruising
• Mucosal bleeding: epistaxis, gingival bleeding, menorrhagia

Severe (<20 × 10⁹/L)

• Spontaneous bleeding
• Haemorrhagic bullae in the mouth
• Haematuria, gastrointestinal bleeding
• Intracranial haemorrhage (rare, <1%, but potentially fatal)

Red Flags

• Platelets <10 × 10⁹/L → highest risk of life-threatening bleeding
• Wet purpura (oral haemorrhagic bullae) → predictor of severe bleeding
• Headache or neurological symptoms → intracranial haemorrhage until proven otherwise
• Splenomegaly → unusual in ITP, consider alternative diagnosis

Bedside

• Examination: petechiae, purpura, mucosal bleeding; no splenomegaly expected

Bloods

• FBC: isolated thrombocytopenia – other cell lines normal
• Blood film: large platelets, no fragments (rules out TTP), no blast cells
• Reticulocyte count: normal (helps exclude marrow failure)
• Coagulation screen: normal (PT, APTT) – differentiates from DIC
• LDH, haptoglobin, bilirubin: to exclude haemolysis/TTP
• HIV, Hepatitis B and C serology: exclude secondary causes
• H. pylori testing: treat if positive (may improve platelet count)
• ANA, antiphospholipid antibodies: if SLE suspected
• Immunoglobulins: exclude CVID or CLL
• Thyroid function: associated autoimmune thyroid disease

Imaging

• Not routinely required
• CT if lymphoproliferative disorder suspected

Special Tests

• Bone marrow biopsy: not routinely required in typical ITP; indicated if age >60 (exclude MDS), atypical features, or pre-splenectomy
• Antiplatelet antibodies: poor sensitivity and specificity – NOT recommended routinely

Non-pharmacological

• Avoid contact sports and activities with high bleeding risk
• Avoid antiplatelet agents and anticoagulants
• No treatment if platelets >30 × 10⁹/L and asymptomatic (watch and wait)

Pharmacological

First-line (platelets <30 or significant bleeding):

• Prednisolone 1mg/kg/day PO for 2 weeks, then taper over 4-8 weeks; OR
• Dexamethasone 40mg OD for 4 days (may be repeated q14-28 days × 1-4 cycles)
• Response rate: 60-80%, but relapse common on taper

Emergency (life-threatening bleeding or <10 with wet purpura):

• IV immunoglobulin (IVIg) 1g/kg (single dose or 2 consecutive days) – rapid rise within 24-48h
• Platelet transfusion: only in life-threatening haemorrhage (short-lived effect)
• Tranexamic acid 1g TDS PO/IV – adjunct for mucosal bleeding
• Methylprednisolone 1g IV for 3 days

Second-line (relapsed/refractory):

• Eltrombopag 50mg OD (TPO receptor agonist, oral)
• Romiplostim 1-10mcg/kg SC weekly (TPO receptor agonist)
• Rituximab 375mg/m² IV weekly × 4 (response rate ~60%, durable in ~30%)
• Splenectomy: considered after 12 months if refractory; cure rate ~60-70%
• Fostamatinib 100-150mg BD (SYK inhibitor)

Referral Criteria

• All new cases of confirmed ITP → haematology
• Life-threatening bleeding → emergency haematology and critical care

• Childhood ITP: 80% resolve spontaneously within 6 months
• Adult ITP: chronic course in ~60-70%
• Mortality from bleeding: <1-2% overall (intracranial haemorrhage is main concern)
• Splenectomy achieves long-term remission in 60-70%
• TPO receptor agonists maintain response in 70-80% while on treatment
• Spontaneous remission can occur even years after diagnosis

ASH Guidelines Treatment Algorithm

Key Drug Summary

Key Facts

TTP is a thrombotic microangiopathy characterised by systemic platelet-rich microvascular thrombosis due to severe deficiency of the vWF-cleaving protease ADAMTS13. Without treatment it is almost universally fatal.

Epidemiology

• Rare: incidence approximately 4-6 per million/year in the UK
• Peak age: 30-50 years
• Female predominance (F:M 2-3:1)
• More common in Black African/Caribbean populations (3-fold increased risk)
• Pregnancy is a recognised trigger

Aetiology

• Acquired TTP (~95%): autoantibodies (IgG) against ADAMTS13 → severe deficiency (<10% activity)
• Congenital TTP (~5%): homozygous/compound heterozygous ADAMTS13 gene mutations (Upshaw-Schulman syndrome)
• Triggers: pregnancy, infection, autoimmune disease (SLE), drugs (quinine, ticlopidine)

Pathophysiology

• ADAMTS13 normally cleaves ultra-large vWF multimers (ULvWF) into smaller fragments
• Severe ADAMTS13 deficiency → accumulation of ULvWF multimers
• ULvWF causes spontaneous platelet adhesion and aggregation in the microcirculation
• Platelet-rich microthrombi → mechanical shearing of RBCs (schistocytes/MAHA)
• Microvascular occlusion → end-organ ischaemia (brain, kidneys, heart)
• Consumptive thrombocytopenia (platelets consumed in microthrombi)

Typical Presentation

• Fatigue and malaise (anaemia)
• Petechiae and purpura (thrombocytopenia)
• Neurological features (60-70%): confusion, headache, focal deficits, seizures, coma
• Jaundice (haemolysis)
• Dark urine (haemoglobinuria)
• Fever (less common than historically described)

Organ Involvement

• CNS: most common site of ischaemia – fluctuating neurological signs
• Renal: usually mild impairment (creatinine rarely >300 µmol/L; if severe, consider HUS)
• Cardiac: troponin elevation in ~50%, myocardial ischaemia
• GI: abdominal pain, pancreatitis

Red Flags

• Thrombocytopenia + schistocytes on blood film → assume TTP until proven otherwise
• NEVER transfuse platelets – potentially fatal
• Neurological deterioration → urgent PEX
• Raised troponin → cardiac involvement (poor prognostic sign)

Bedside

• Blood pressure: may be normal or mildly elevated (severe hypertension suggests alternative diagnosis)
• Neurological assessment: GCS, focal deficits
• Urine dipstick: haemoglobinuria

Bloods

• FBC: thrombocytopenia (often <30 × 10⁹/L), anaemia
• Blood film: schistocytes (fragmented red cells) – essential diagnostic finding
• LDH: markedly elevated (haemolysis + tissue ischaemia)
• Haptoglobin: undetectable (consumed in haemolysis)
• Reticulocyte count: elevated (appropriate response to haemolysis)
• Unconjugated bilirubin: raised
• DAT (Coombs test): negative (distinguishes from AIHA)
• Coagulation screen: normal PT and APTT (distinguishes from DIC)
• Fibrinogen: normal (low in DIC)
• ADAMTS13 activity: <10% confirms TTP (send BEFORE starting PEX)
• ADAMTS13 inhibitor/antibody: identifies acquired TTP
• Troponin: cardiac involvement assessment
• U&Es: usually mild renal impairment

Imaging

• CT head: if neurological symptoms (exclude intracranial haemorrhage)
• MRI brain: if focal neurological deficits

Special Tests

• PLASMIC score: clinical prediction tool (score ≥6 suggests TTP)
• Components: platelet count <30, haemolysis markers, no cancer, no transplant, MCV <90, INR <1.5, creatinine <177

Non-pharmacological

• Haematological emergency – do not delay treatment while awaiting ADAMTS13 result
• Daily plasma exchange (PEX): commence within hours of clinical suspicion
  • Removes autoantibodies and ULvWF; replaces ADAMTS13
  • 1.5 plasma volume exchanges daily until platelet count >150 × 10⁹/L for ≥2 consecutive days
  • Then taper (alternate day, then stop)

Pharmacological

Acute management:

• Methylprednisolone 1g IV daily for 3 days then prednisolone 1mg/kg/day (taper over weeks)
• Caplacizumab 11mg IV (first dose before PEX), then 11mg SC OD for 30 days after last PEX (HERCULES trial: faster platelet recovery, reduced exacerbations)

Refractory/relapsing:

• Rituximab 375mg/m² IV weekly × 4 – targets B-cells producing anti-ADAMTS13 antibodies
• Increasingly used as part of first-line in severe cases

Supportive:

• Folic acid 5mg OD (increased erythropoiesis)
• VTE prophylaxis once platelets >50 × 10⁹/L
• Red cell transfusion for symptomatic anaemia
• DO NOT transfuse platelets unless life-threatening haemorrhage

Referral Criteria

• Suspected TTP → immediate haematology and arrange PEX
• Refractory TTP → tertiary centre with TTP expertise
• All patients require long-term haematology follow-up (relapse risk 20-50%)

• Untreated mortality: >90%
• With plasma exchange: mortality ~10-20%
• With PEX + caplacizumab + rituximab: mortality <5%
• Relapse rate: 20-50% in acquired TTP (highest in first 2 years)
• Congenital TTP: requires regular plasma infusions, generally good prognosis
• Cardiac involvement (raised troponin) associated with worse outcomes
• Long-term neurocognitive sequelae in survivors

PLASMIC Score

Key Distinction: TTP vs HUS vs DIC

Key Facts

HUS is a thrombotic microangiopathy (TMA) characterised by the triad of MAHA, thrombocytopenia, and AKI. It is the most common cause of AKI in children in the UK.

Epidemiology

• Typical STEC-HUS: mainly children aged 6 months to 5 years; ~100-150 cases/year in UK
• Atypical HUS: all ages, including adults; rarer (~2 per million/year)
• Seasonal peaks in summer/autumn (STEC infections)
• UK outbreaks linked to undercooked meat, unpasteurised dairy, contaminated water

Aetiology

• Typical HUS (90%): Shiga toxin-producing E. coli (STEC), mainly O157:H7; also O104:H4; rarely Shigella dysenteriae type 1
• Atypical HUS (10%): dysregulation of alternative complement pathway
  • Mutations in complement regulators: CFH, CFI, MCP (CD46), CFB, C3, THBD
  • Anti-factor H autoantibodies (~5-10% of aHUS)
• Secondary HUS: drugs (calcineurin inhibitors, quinine), malignancy, pregnancy (HELLP), bone marrow transplant

Pathophysiology

• Platelet consumption in microthrombi → thrombocytopenia
• Mechanical shearing of RBCs through damaged vasculature → schistocytes and haemolysis

Typical STEC-HUS

• Prodromal illness: bloody diarrhoea (usually 5-7 days before HUS onset)
• Pallor and jaundice (haemolysis)
• Oliguria/anuria (AKI)
• Oedema and hypertension
• Petechiae/bruising (thrombocytopenia)
• Irritability, lethargy in children

Atypical HUS

• No diarrhoeal prodrome (or non-bloody diarrhoea)
• May present at any age
• Often relapsing course
• Severe AKI
• Hypertension
• Extra-renal involvement: CNS (seizures, stroke), cardiac, hepatic

Red Flags

• Anuria lasting >24 hours → may require dialysis
• Seizures or altered consciousness → CNS involvement
• No improvement after 7-10 days → consider atypical HUS
• Adult presentation without typical diarrhoeal prodrome → atypical HUS or TTP

Bedside

• Blood pressure: hypertension common
• Urine output: oliguria/anuria monitoring
• Stool sample: send for STEC culture and PCR (before antibiotics)

Bloods

• FBC: anaemia, thrombocytopenia
• Blood film: schistocytes (fragmented RBCs)
• LDH: markedly elevated
• Haptoglobin: low/undetectable
• Reticulocytes: elevated
• DAT (Coombs test): negative
• Coagulation screen: normal (distinguishes from DIC)
• U&Es: raised creatinine (often severe in HUS, >300 µmol/L)
• ADAMTS13: >10% (distinguishes from TTP)
• Complement studies (for atypical HUS): C3, C4, factor H, factor I, anti-factor H antibodies

Imaging

• Renal ultrasound: enlarged echogenic kidneys

Special Tests

• STEC PCR/culture: confirms typical HUS
• Complement genetic testing: if aHUS suspected (CFH, CFI, MCP, C3 mutations)
• Renal biopsy: rarely needed acutely; may help distinguish TMA subtypes

Non-pharmacological

• Supportive care is mainstay for typical STEC-HUS
• Fluid and electrolyte management: careful IV fluids, avoid overhydration
• Blood pressure control
• Dialysis (peritoneal or haemodialysis) if severe AKI: indications include hyperkalaemia, fluid overload, uraemia
• Red cell transfusion for symptomatic anaemia
• Avoid platelet transfusion unless life-threatening bleeding

Pharmacological

Typical STEC-HUS:

• Avoid antibiotics during E. coli O157 infection (may increase Shiga toxin release and worsen HUS)
• Supportive management with excellent outcomes

Atypical HUS (complement-mediated):

• Eculizumab (anti-C5 monoclonal antibody): 900mg IV weekly × 4 weeks, then 1200mg every 2 weeks
• Dramatically improves outcomes; prevents complement-mediated endothelial damage
• Ravulizumab (longer-acting anti-C5): 8-weekly dosing
• Meningococcal vaccination required before eculizumab (risk of meningococcal disease) – MenACWY + MenB + prophylactic antibiotics
• Plasma exchange: may be used while awaiting eculizumab or if diagnosis uncertain

Referral Criteria

• All cases of HUS → paediatric/adult nephrology
• Suspected atypical HUS → specialist complement centre
• PHE notification: STEC infection is notifiable

• Typical STEC-HUS: mortality 3-5%; full renal recovery in 70-80% of children
• 15-25% of typical HUS patients develop long-term renal sequelae (proteinuria, hypertension, CKD)
• ~5% progress to ESRD
• Atypical HUS: without treatment, >50% progress to ESRD or death
• With eculizumab, aHUS outcomes dramatically improved (>90% haematological response)
• Recurrence risk in aHUS: 30-50% (depends on mutation type); CFH mutations have highest recurrence risk

Typical vs Atypical HUS

Complement Mutations in aHUS