High White Cell Count
Leukocytosis is an elevation of the total white blood cell count above the normal range (typically >11,000/μL), indicating infection, inflammation, stress, or hematologic malignancy.
High White Cell Count: Acute & Chronic Leukaemia, Bone Marrow Transplantation, Immunogenetics
Lecture Map
A high white cell count (leukocytosis) is one of the most common laboratory abnormalities you will encounter. The majority of cases are reactive (e.g., infection, inflammation, drugs). However, the exam stakes are highest when the cause is neoplastic — i.e., leukaemia. This lecture systematically covers:
- How to classify leukaemias (WHO 2022)
- How to manage acute and chronic leukaemias (supportive + specific)
- Haematological emergencies that can kill before you even make a diagnosis
- Haematopoietic stem cell transplantation (HSCT) — how and why it cures leukaemia
- HLA and immunogenetics — the transplant science underpinning donor selection
1. Leukaemia classification (WHO 2022) 2. General principles in managing patients with leukaemia 3. Role of haematopoietic stem cell transplantation in leukaemia treatment 4. Importance of histocompatibility in transplantation immunology
Past papers heavily test: recognition of leukaemia subtypes from a clinical vignette + CBP, identification of haematological emergencies (tumour lysis syndrome, neutropenic fever, leukostasis, DIC in APL), Philadelphia chromosome / BCR-ABL and TKI therapy for CML, HLA matching principles, and HSCT indications/complications. [6][7][8]
Leukaemia is a clonal malignant disease of the haematopoietic system. It may arise from the lymphoid or myeloid lineage. [1]
Why "clonal"? A single haematopoietic progenitor acquires a genetic hit (mutation, translocation) that confers a proliferative or survival advantage. All daughter cells carry the same abnormality — this is the clone. Over time, the clone expands, crowds out normal haematopoiesis, and spills into the peripheral blood.
Why does lineage matter? Because the lineage dictates the clinical features, diagnostic markers, treatment, and prognosis. Myeloid leukaemias behave differently from lymphoid ones.
| Myeloid | Lymphoid | |
|---|---|---|
| Acute | Acute Myeloid Leukaemia (AML) | Acute Lymphoblastic Leukaemia (ALL) |
| Chronic | Chronic Myeloid Leukaemia (CML) | Chronic Lymphocytic Leukaemia (CLL) |
This simple matrix is the foundation. [1]
Acute vs Chronic — what does this really mean?
- Acute: the malignant cells are immature blasts that cannot differentiate. They accumulate rapidly, cause bone marrow failure, and are fatal within weeks if untreated.
- Chronic: the malignant cells retain some capacity to differentiate. The disease progresses slowly over months to years. Patients may be asymptomatic at diagnosis.
ACUTE LEUKAEMIA — AML and ALL
Clinical Features of Acute Leukaemia [1]
There are two broad mechanisms producing symptoms:
| Normal lineage lost | Consequence | Clinical feature |
|---|---|---|
| Red cells ↓ | Anaemia | Pallor, fatigue, dyspnoea |
| Neutrophils ↓ | Neutropenia → infection | Fever, sepsis |
| Platelets ↓ | Thrombocytopenia → bleeding | Petechiae, bruising, mucosal bleeding |
DIC is characteristically seen in Acute Promyelocytic Leukaemia (APL) — a specific emergency. [1]
Blasts can infiltrate liver, spleen, lymph nodes, skin, gums. [1]
AML-specific features:
- Gum hypertrophy — classically seen in acute monoblastic/monocytic leukaemia (AML-M4/M5 in old FAB). The monocytic blasts have a tropism for gingival tissue. [1]
ALL-specific features:
- Hepatosplenomegaly, lymphadenopathy — ALL blasts home to lymphoid organs more than AML blasts do
- Mediastinal mass — characteristic of T-ALL. The thymus is the normal developmental site for T-cells; a T-cell neoplasm expands there.
- CNS involvement, testicular involvement — these are "sanctuary sites" with blood-tissue barriers that standard chemotherapy does not penetrate well; hence CNS prophylaxis is essential in ALL. [1]
Exam Discriminator: AML vs ALL Clinical Features
If the vignette mentions gum hypertrophy → think AML (monocytic subtype). If it mentions mediastinal mass, lymphadenopathy, or CNS/testicular infiltration → think ALL.
Workup for Suspected Acute Leukaemia [1]
The lecture organises this into three goals: (1) Make the diagnosis, (2) Watch for haematological emergencies, (3) Prepare the patient for treatment.
| Category | Tests | Why |
|---|---|---|
| CBP + differential + manual count | WBC (may be high, normal, or LOW), Hb, platelets | Establish cytopenias; identify circulating blasts |
| Coagulation | PT, APTT, D-dimer, fibrinogen | Screen for DIC — urgent in APL |
| Biochemistry | RFT (Cr, K⁺, Ca²⁺, PO₄³⁻, urate), LDH | Features of tumour lysis syndrome (TLS) |
| Bone marrow examination | Aspirate + trephine biopsy | Gold standard for diagnosis — see below |
| CXR | Mediastinal mass, infections, pulmonary infiltrates | T-ALL mass, leukostasis |
| ECG + echocardiogram | Baseline cardiac function | Anthracyclines are cardiotoxic — must check LVEF before starting daunorubicin |
| Hepatitis B/C, HIV serology | Pre-chemo screening | Chemo-induced immunosuppression can reactivate Hep B |
| G6PD status | Before giving co-trimoxazole (PJP prophylaxis) or rasburicase | G6PD-deficient patients risk oxidative haemolysis |
| Central venous catheter | For chemo administration | Vesicant drugs + frequent blood draws |
| HLA typing | For patients who are HSCT candidates (high-risk disease) | Early donor search |
The slide explicitly lists G6PD as a required check — this is a favourite exam point. [1]
| Layer | Method | What it tells you |
|---|---|---|
| Morphology | Light microscopy of PB/BM smears | Identify blasts, Auer rods (AML), abnormal promyelocytes (APL) |
| Cytochemistry | MPO (myeloperoxidase), SBB (Sudan Black B) | MPO/SBB positive → AML; negative → ALL |
| Flow cytometry | Immunophenotyping | Sub-classification: which lineage, which stage of maturation (B-ALL vs T-ALL, etc.) |
| Cytogenetics | Karyotype, FISH | Detect specific chromosomal abnormalities — diagnostic AND prognostic |
| Molecular genetics | PCR, NGS | Gene mutations (FLT3, NPM1, PML-RARA, etc.) — diagnostic AND prognostic |
High Yield
MPO/SBB distinguishes AML from ALL. Flow cytometry specifies the lineage. Cytogenetics and molecular genetics determine risk stratification and targeted therapy eligibility.
The WHO 2022 approach to AML classification prioritises defining genetic abnormalities over morphology. The hierarchy is:
- AML with recurrent genetic abnormalities (specific translocations/mutations define distinct entities)
- e.g., APL with t(15;17)/PML-RARA
- e.g., AML with t(8;21), inv(16), etc.
- AML with myelodysplasia-related changes
- Therapy-related AML
- AML, not otherwise specified (NOS) — classified by morphology only when no defining genetic abnormality is found
Why does this matter? Because the specific genetic abnormality dictates treatment and prognosis. For instance, APL with PML-RARA is treated with ATRA + arsenic trioxide (not conventional chemo), and has an excellent prognosis if recognised early.
Treatment of Acute Leukaemia [1]
Treatment is divided into Supportive and Specific.
Watch out for haematological emergencies:
| Emergency | Key action |
|---|---|
| Septic shock | Resuscitation |
| Neutropenic sepsis | Immediate empirical broad-spectrum IV antibiotics |
| Tumour lysis syndrome | Hydration + urate-lowering agents (allopurinol, febuxostat, rasburicase) |
| Leukostasis | Urgent leukapheresis + chemotherapy |
| DIC in APL | Urgent ATRA + supportive transfusion |
Additional supportive measures:
- RBC and platelet transfusions
- Antifungal prophylaxis in patients with prolonged/profound neutropenia (invasive aspergillosis is a major killer in AML)
- Proper nursing care — reverse isolation, face masks, hand hygiene, low-bacteria diet [1]
| Phase | Regimen | Notes |
|---|---|---|
| Induction | Daunorubicin + Cytarabine ("3+7") | Aims to achieve complete remission |
| + Targeted therapy | Midostaurin (for FLT3-ITD mutated cases) | FLT3 mutations confer poor prognosis; midostaurin is a multi-kinase inhibitor |
| Gemtuzumab ozogamicin (for non-transplant favourable risk AML) | Anti-CD33 antibody-drug conjugate | |
| Consolidation | High-dose cytarabine | Prevents relapse by eliminating residual leukaemia cells |
| Allogeneic HSCT | For high-risk cases based on cytogenetics/molecular profile, or at relapse | Curative intent |
| Phase | Regimen | Notes |
|---|---|---|
| Induction | Multi-agent: Cyclophosphamide, Daunorubicin, Vincristine, Prednisolone, L-asparaginase, Methotrexate, Cytarabine | Adapted from paediatric protocols (higher CR rates) |
| CNS prophylaxis | Intrathecal methotrexate, cranial irradiation, high-dose IV methotrexate | ALL has high CNS relapse risk — MUST give prophylaxis |
| Maintenance | Prolonged oral chemo (usually 2–3 years) | Lower-intensity but extended treatment |
| Allogeneic HSCT | For high-risk cases or at relapse |
Why CNS Prophylaxis in ALL?
The blood-brain barrier prevents most systemically administered chemotherapy from reaching the CNS. ALL blasts can hide there and cause relapse. Intrathecal methotrexate delivers drug directly into the CSF. This concept does not apply to AML (except some subtypes with high WBC or monocytic morphology).
HAEMATOLOGICAL EMERGENCIES (The Killer Slides)
These are extremely high-yield for exams. The lecture dedicates a clinical case to each emergency.
Defined as fever in a patient with ANC < 1 × 10⁹/L. [1]
More specifically (from senior notes [3]):
- Neutropenia: ANC ≤ 1.5 × 10⁹/L
- Severe neutropenia: ANC ≤ 0.5 × 10⁹/L
- Profound neutropenia: ANC ≤ 0.1 × 10⁹/L
- Fever: single oral temp ≥ 38.3°C OR sustained ≥ 38.0°C for ≥ 1 hour
Why is this an emergency? Without neutrophils, the patient cannot mount an inflammatory response. Infections progress rapidly from bacteraemia to septic shock and death within hours. The classic signs of infection (pus, erythema, fluctuance) may be ABSENT because these require neutrophils.
Can be due to both gram-positive (especially in patients with central catheters) and gram-negative organisms. [1]
Management:
- Septic workup (blood cultures × 2 sets from different sites including central line, urine culture, CXR)
- Start IV antibiotics ASAP — do NOT wait for culture results
- Fluid resuscitation and/or inotropes if haemodynamically unstable [1]
The most common organism currently identified is S. epidermidis (coagulase-negative staph — from indwelling catheters). P. aeruginosa remains the most serious/feared gram-negative. [3]
A set of metabolic complications resulting from a rapidly proliferating and drug-sensitive neoplasm. Can also be spontaneous. [1]
Pathophysiology (from first principles):
When tumour cells lyse (either from chemo or spontaneously), they release their intracellular contents into the bloodstream:
- K⁺ (intracellular cation) → hyperkalaemia → arrhythmia, cardiac arrest
- Phosphate (from nucleic acids/ATP) → hyperphosphataemia → binds calcium → hypocalcaemia → seizures, tetany
- Nucleic acids → metabolised to purines → xanthine → uric acid → hyperuricaemia → crystallises in renal tubules → acute kidney injury
- LDH released from lysed cells → raised LDH (marker of cell turnover)
Hyperuricaemia, hyperkalaemia, hyperphosphataemia, hypocalcaemia, raised LDH [1] Acute renal failure, arrhythmia, seizure, confusion [1]
Clinical Case (Ms. B): [1]
- T-ALL with marked leukocytosis
- Labs: hyperkalaemia, acute renal failure, hyperphosphataemia, hyperuricaemia, raised LDH
- Diagnosis: Tumour Lysis Syndrome
Prevention & Treatment: [1]
| Strategy | Agent | Mechanism | Caveats |
|---|---|---|---|
| Hydration | Aggressive IV fluids | Dilute metabolites, maintain renal perfusion | Monitor fluid status |
| Allopurinol | Xanthine oxidase inhibitor | Blocks conversion of xanthine → uric acid | Check HLA-B5801* (risk of severe drug hypersensitivity, especially in SE Asian / Chinese populations) |
| Febuxostat | Xanthine oxidase inhibitor (non-purine) | Same pathway | Expensive; does not require renal dose adjustment (unlike allopurinol); C/I in IHD |
| Rasburicase | Recombinant urate oxidase | Directly breaks down uric acid to allantoin (soluble) | Contraindicated in G6PD deficiency (produces H₂O₂ → oxidative haemolysis) |
| Haemodialysis | Renal replacement therapy | Remove K⁺, PO₄, urate when medical therapy fails | For severe refractory cases |
Monitor: WBC or tumour size, fluid status, urine output, electrolytes, RFT, LDH, pH [1]
Classic Exam Trap: Rasburicase and G6PD
Rasburicase is the most effective urate-lowering agent for TLS, BUT it is absolutely contraindicated in G6PD-deficient patients because its enzymatic reaction generates hydrogen peroxide, which cannot be neutralised in G6PD-deficient red cells → massive oxidative haemolysis. Always check G6PD before giving rasburicase.
Impaired tissue oxygenation due to sludging of leukocytes in the microcirculation of a patient with high WBC. [1]
Pathophysiology:
- When WBC count is very high (typically > 100 × 10⁹/L in AML or > 200 × 10⁹/L in ALL), the large, sticky blast cells physically clog small blood vessels.
- Unlike mature cells, blasts are large and rigid — they do not deform easily.
- This depends on cell pliability — AML blasts are larger/stickier than ALL blasts, so leukostasis occurs at lower WBC counts in AML. [1]
Clinical features:
- Pulmonary leukostasis: progressive dyspnoea, hypoxia, diffuse interstitial infiltrates on CXR
- Cerebral leukostasis: lethargy, headache, impaired mental state, visual/hearing impairment
- Central retinal vein thrombosis, priapism [1]
BEWARE: Anaemia may protect a patient with marked leukostasis from the effect of high whole blood viscosity. Red cell transfusion before cytoreduction may precipitate leukostasis. [1]
Why? Whole blood viscosity = f(RBC mass + WBC mass + plasma viscosity). If Hb is low, viscosity is partially offset. Transfusing RBCs increases viscosity suddenly → tips patient into symptomatic leukostasis. Cytoreduction FIRST, then transfuse cautiously.
Treatment: [1]
- Adequate hydration
- Urgent leukapheresis (physical removal of WBCs)
- Chemotherapy (cytoreduction — e.g., hydroxyurea)
- TLS prophylaxis (because rapid cell lysis will follow)
APL is characterised by t(15;17)(q22;q21). The resultant PML-RARA fusion protein blocks RAR-mediated induction of promyelocyte differentiation. [1]
Why DIC specifically in APL?
- The abnormal promyelocytes contain heavy granulation. When they lyse (or even while alive), they release procoagulants (tissue factor, cancer procoagulant) from the leukaemic blasts → triggers the coagulation cascade → consumption of clotting factors and platelets → simultaneous thrombosis and bleeding = DIC. [1]
Key clinical features distinguishing APL from other AML: [1]
- Pancytopenia rather than high WBC — APL often presents with LOW WBC
- Prominent bleeding symptoms (mucosal bleeding, ecchymoses, life-threatening haemorrhage)
- Abnormal promyelocytes in circulation (bilobed nuclei, heavy azurophilic granulation, Auer rods in bundles — "faggot cells")
- Check: Platelet count, PT, APTT, D-dimer, fibrinogen
Treatment — DO NOT WAIT for cytogenetics: [1]
- Urgent ATRA (all-trans-retinoic acid) + arsenic trioxide
- ATRA forces the blocked promyelocytes to differentiate → resolves DIC
- This is one of the greatest success stories in targeted cancer therapy
- Supportive transfusion: platelets, FFP (fresh frozen plasma), cryoprecipitate (to replenish fibrinogen)
High Yield: APL Is Different From All Other AML
APL (t(15;17)/PML-RARA) presents with LOW WBC + DIC + bleeding. It is a medical emergency. Treatment is ATRA + arsenic trioxide (NOT standard "3+7" chemo). If recognised and treated early, cure rate > 90%. If missed, patients die of haemorrhage within hours.
CHRONIC LEUKAEMIA
Clinical Presentation (Ms. C case): [1]
- F/58, fatigue, weight loss, early satiety, LUQ fullness
- Splenomegaly 7 cm below costal margin
- CBC: Marked leukocytosis, predominantly neutrophils and myelocytes, thrombocytosis
- PB: blasts only 1%
- BM: markedly hypercellular, bimodal distribution of myelocytes and neutrophils, basophilia, increased megakaryopoiesis
Natural History — Three Phases: [1]
| Phase | Features |
|---|---|
| Chronic phase (CP) | Leukocytosis with full maturation, basophilia, splenomegaly. Often asymptomatic or mild symptoms. Blasts < 10%. |
| Accelerated phase (AP) | Rising blast count (10–19%), increasing basophilia, refractory cytopenias, additional cytogenetic abnormalities |
| Blast crisis (BC) | ≥ 20% blasts — behaves like acute leukaemia (myeloid or lymphoid). Fatal without treatment. |
The Philadelphia Chromosome: [1]
CML is defined by the Philadelphia chromosome: t(9;22)(q34.1;q11.2). The resultant BCR::ABL fusion gene product is a constitutively active tyrosine kinase. [1]
From first principles:
- Chromosome 9 carries the ABL gene (a tyrosine kinase normally under tight regulation)
- Chromosome 22 carries the BCR gene
- The reciprocal translocation fuses BCR to ABL → a chimeric protein with constitutive (always-on) tyrosine kinase activity
- This phosphorylates multiple downstream substrates → drives uncontrolled proliferation + survival of myeloid progenitors
Targeted Therapy — Tyrosine Kinase Inhibitors (TKIs): [1]
| Generation | Drug(s) |
|---|---|
| 1st | Imatinib (revolutionary — turned CML from fatal to chronic disease) |
| 2nd | Nilotinib, Dasatinib |
| 3rd | Ponatinib (specifically active against T315I "gatekeeper" mutation) |
| Newer | Asciminib (STAMP inhibitor — different binding site) |
Monitoring: [1]
Monitor molecular response with quantitative RT-PCR (for BCR-ABL transcript levels).
This is the concept of molecular remission — even when no leukaemia cells are visible on microscopy, RT-PCR can detect residual BCR-ABL transcripts. Deepening molecular response allows consideration of treatment-free remission in selected patients.
HSCT in CML: [1]
Reserved for patients not responding to TKI treatment, or in blast transformation. Specifically: T315I mutation (resistant to all TKIs except ponatinib/asciminib), or progression to AP/BC.
Clinical Presentation (Mr. D case): [1]
- M/78, SOB on exertion, fatigue, weight loss
- Cervical and groin lymphadenopathy, splenomegaly 2 cm below costal margin
- CBC: Rising lymphocyte count over 6 months, smear cells (smudge cells — fragile CLL lymphocytes rupture during smear preparation)
- Hb and platelets initially normal
Key Features: [1]
- Usually occurs in older patients
- Often an incidental finding of lymphocytosis
- Constitutional symptoms: fatigue, weight loss
- Lymphadenopathy, hepatosplenomegaly
- May transform to aggressive large cell lymphoma → Richter transformation [1]
Why "smear cells"? CLL cells are mature small lymphocytes, but they are fragile and rupture when the blood film is being made → characteristic artefact.
Treatment: [1]
| Situation | Approach |
|---|---|
| Early stage, asymptomatic | Watch and Wait (W&W) — no survival benefit from early treatment |
| Young and fit | Fludarabine + Cyclophosphamide + Rituximab (FCR) |
| Old and frail | Chlorambucil (alkylating agent, well-tolerated) |
| Novel targeted agents | Ibrutinib, Acalabrutinib (BTK inhibitors); Idelalisib (PI3K inhibitor); Venetoclax (BCL2 inhibitor) |
Treatment decision is based on clinical staging and symptoms. No treatment in early stages. [1]
Staging (Rai/Binet systems) — while not detailed on slides, the principle is that treatment is initiated for progressive or symptomatic disease (cytopenias, bulky lymphadenopathy, constitutional symptoms, doubling time < 6 months).
BONE MARROW TRANSPLANTATION / HSCT
BMT = bone marrow transplantation; PBSCT = peripheral blood stem cell transplantation; HSCT = haematopoietic stem cell transplantation (umbrella term). [1]
Stem cells can be harvested from:
- Bone marrow (iliac crest aspiration under GA)
- Peripheral blood (after mobilisation with G-CSF → leukapheresis)
- Umbilical cord blood
| Category | Specific indications |
|---|---|
| Leukaemia | AML/ALL — high risk at first remission or at relapse; CML (T315I, AP/BC); MDS (high risk); Transformed MPN |
| Lymphoma | Relapsed lymphoma |
| Bone marrow failure | Aplastic anaemia |
| Haemoglobinopathy | Thalassaemia major; Sickle cell anaemia |
| Inherited BM failure | Fanconi's anaemia; Blackfan-Diamond syndrome |
| Immunodeficiency | SCID; Wiskott-Aldrich syndrome |
| Metabolic | Inborn errors of metabolism |
1. High-dose chemotherapy/radiotherapy eradicates the leukaemia 2. A healthy donor marrow replaces the diseased marrow 3. Graft-versus-Leukaemia (GVL) effect → lower relapse rate [1]
GVL effect explained: The donor's immune cells (especially T-cells) recognise residual recipient leukaemia cells as "foreign" and destroy them. This is why allogeneic HSCT has a lower relapse rate than autologous — you get an immune attack on the leukaemia.
ABO incompatibility is NOT an exclusion in HSCT. [1]
Why? ABO antigens are on red cells; HLA antigens are on all nucleated cells. HSCT success depends on HLA matching, not ABO matching. ABO-mismatched transplants are managed with plasma/RBC depletion of the graft and careful transfusion support.
Timeline:
- Day −6 to −1: Conditioning regimen — high-dose chemo ± total body irradiation (TBI)
- Purpose: Eradicate residual leukaemia + suppress patient's immune system to prevent graft rejection
- Day 0: Stem cell infusion — donor graft (BM or PBSC) infused IV
- Day +1 to +14-21: Cytopenic phase — pancytopenia; high risk of infection and bleeding
- Engraftment — recovery of neutrophils and platelets (typically day +14 to +21 for PBSC)
- Post-engraftment: Immunosuppression for GVHD prophylaxis [1]
| Donor type | Description |
|---|---|
| Autologous | Self (patient's own stem cells, collected in remission) |
| Syngeneic | Monozygotic (identical) twin — genetically identical |
| Allogeneic — HLA-matched sibling | First choice |
| Allogeneic — Matched unrelated donor (MUD) | From local/overseas donor registries |
| Cord blood | Uncommon in adults because of dose (fewer stem cells in a cord unit) |
| Haploidentical | Mismatched family donor (parent, child, half-matched sibling) — increasingly used |
IMMUNOGENETICS — THE HLA SYSTEM [1]
HLA antigens are encoded by the MHC gene complex on the short arm of chromosome 6. HLA antigens are expressed on cell surfaces and are involved in recognition of "self" (tolerate) and "non-self" (eliminate). [1]
| Class | Loci | Expression | Function |
|---|---|---|---|
| Class I | HLA-A, B, C | All nucleated cells | Present intracellular peptides to CD8⁺ T cells |
| Class II | HLA-DR, DQ, DP | Immune cells (APCs: macrophages, dendritic cells, B cells) | Present extracellular peptides to CD4⁺ T cells |
HLA matching is crucial in HSCT to avoid graft rejection and graft-versus-host disease. [1]
Why?
- If the donor and recipient have different HLA antigens, the donor T-cells will see the recipient's tissues as "foreign" → GVHD (graft attacks host)
- Conversely, any residual host T-cells can see the donor graft as foreign → graft rejection (host attacks graft)
HLA genes are inherited in a simple Mendelian co-dominant fashion. Each sibling inherits one haplotype from each parent. Each sibling has a 1 in 4 chance of being HLA-identical to the patient. [1]
What is a haplotype? The set of HLA genes on one chromosome 6. Since we have two copies of chromosome 6, we have two haplotypes. A sibling can inherit the same two haplotypes as the patient (1/4 chance), one matching haplotype (2/4 = haploidentical), or neither (1/4).
1. Matched unrelated donor from registries 2. Cord blood (uncommon in adults due to cell dose) 3. Haploidentical donor (mismatched family member) [1]
Haploidentical transplants have become increasingly feasible with modern GVHD prophylaxis regimens (e.g., post-transplant cyclophosphamide).
| Timing | Complication | Mechanism |
|---|---|---|
| Early (related to conditioning) | Infection | Pancytopenia during cytopenic phase |
| Haemorrhage | Thrombocytopenia | |
| Veno-occlusive disease (VOD) of liver | Sinusoidal endothelial damage from conditioning → hepatic venous outflow obstruction (jaundice, RUQ pain, ascites, weight gain) | |
| Allogeneic-specific | Graft-versus-host disease (GVHD) | Donor T-cells attack recipient tissues (skin, GI, liver) |
| Graft rejection (host-versus-graft) | Residual host T-cells reject donor cells | |
| Late effects | Cataract | Mainly due to TBI |
| Immunodeficiency | Slow immune reconstitution | |
| Endocrine dysfunction & infertility | Alkylating agents + TBI damage gonads, thyroid | |
| Secondary malignancy | Late consequence of prior chemo/TBI | |
| Relapse of disease | Despite everything, leukaemia can recur |
GVHD [1]
Acute GVHD (classically < 100 days post-HSCT):
- Skin (maculopapular rash — as shown on lecture slide), GI tract (diarrhoea, abdominal pain), Liver (jaundice, elevated LFTs)
- Graded I–IV
Chronic GVHD (> 100 days):
- Resembles autoimmune disease — scleroderma-like skin changes, sicca syndrome, bronchiolitis obliterans, oral lichen planus, fascial fibrosis
- A major cause of long-term morbidity
Reactive causes of high WBC are common in clinical practice. Ascertainment of the abnormal cell type is key. Leukaemia treatment depends on specific diagnosis, disease risk, and patient comorbidities. Look out for haematological emergencies. Allogeneic HSCT for high-risk cases and at relapse. HLA-matching is essential in allogeneic HSCT.
| Related lecture | Connection |
|---|---|
| GC 086 Splenomegaly | CML causes massive splenomegaly; CLL causes moderate splenomegaly. Myeloproliferative neoplasms overlap. [2] |
| GC 076 Pallor/Anaemia | Leukaemia causes anaemia via marrow failure (anaemia of marrow infiltration). Leukoerythroblastic blood film. |
| GC 102 Fever after chemo | Neutropenic sepsis management in detail — antibiotics, antifungals, viral prophylaxis. |
| GC 155 Blood transfusion | Platelet and RBC transfusion support; irradiation of blood products for HSCT patients (to prevent transfusion-associated GVHD). |
| Flow cytometry seminar | Immunophenotyping for leukaemia sub-classification (CD markers). |
Exam Intelligence
| Pattern in vignette | Most likely diagnosis | Key discriminator |
|---|---|---|
| WBC 150 × 10⁹/L, neutrophils + myelocytes, basophilia, splenomegaly, thrombocytosis | CML | Philadelphia chromosome t(9;22), BCR-ABL, TKI |
| WBC 70 × 10⁹/L, 90% small lymphocytes, smear cells, elderly, lymphadenopathy, asymptomatic | CLL | Watch and Wait if early stage |
| Young patient, circulating blasts 90%, pancytopenia, gum hypertrophy | AML (monocytic subtype) | MPO+, bone marrow exam |
| Young patient, mediastinal mass, lymphadenopathy, hepatosplenomegaly, blasts | T-ALL | Flow cytometry for T-cell markers |
| Pancytopenia + DIC + abnormal promyelocytes, bleeding | APL | t(15;17), PML-RARA, ATRA + arsenic trioxide |
| Post-chemo fever, ANC < 0.5 | Neutropenic sepsis | Empirical IV antibiotics ASAP |
| Rising K⁺, PO₄, urate, LDH, falling Ca²⁺, AKI post-chemo | Tumour lysis syndrome | Hydration + rasburicase (check G6PD) |
| WBC > 100, desaturation, confusion, diffuse CXR infiltrates | Leukostasis | Leukapheresis + cytoreduction; do NOT transfuse RBCs first |
Traps to Avoid
- APL presents with LOW WBC, not HIGH — do not assume all AML has high WBC.
- Rasburicase is C/I in G6PD deficiency — always check G6PD.
- Do NOT transfuse RBCs in leukostasis before cytoreduction — it worsens viscosity.
- ABO incompatibility does NOT exclude HSCT — HLA matching is what matters.
- CLL: do NOT treat early-stage asymptomatic disease — Watch and Wait.
- Each sibling has a 1 in 4 (25%) chance of being HLA-identical — not 50%.
- Allopurinol prevents TLS but does NOT treat established hyperuricaemia — use rasburicase for treatment. [5]
| Feature | AML | ALL | CML | CLL |
|---|---|---|---|---|
| Age peak | Adults (median ~65) | Children + young adults | Middle-aged adults | Elderly (> 65) |
| Cell type | Myeloid blasts | Lymphoid blasts | Mature myeloid cells (neutrophils, myelocytes) | Mature small lymphocytes |
| WBC | Variable (can be low in APL) | Often very high | Very high (often > 100) | Moderate–high lymphocytosis |
| Key finding on film | Blasts, Auer rods | Blasts | Left shift, basophilia, no hiatus | Smear/smudge cells |
| Cytochemistry | MPO+, SBB+ | MPO−, SBB− | N/A | N/A |
| Characteristic genetics | t(15;17) in APL; t(8;21); inv(16) | Ph+ ALL [t(9;22)] in adults | t(9;22) BCR-ABL (100%) | del(17p), del(11q), TP53 |
| Hallmark treatment | Daunorubicin + Cytarabine; ATRA for APL | Multi-agent chemo + CNS prophylaxis | TKIs (imatinib, etc.) | W&W → FCR / BTK inhibitors |
| HSCT role | High risk or relapse | High risk or relapse | TKI failure / blast crisis | Rarely |
| Emergency | DIC (APL), TLS, leukostasis | TLS, leukostasis | Blast crisis | Richter transformation |
Q1 (SAQ/Minicase style): A 52-year-old woman presents with fatigue and early satiety. Examination shows massive splenomegaly. WBC 150 × 10⁹/L with predominance of neutrophils and myelocytes, basophilia, Hb 10 g/dL, platelets 510 × 10⁹/L. (a) What is the most likely diagnosis? (b) Name the diagnostic cytogenetic abnormality. (c) Name TWO first-line specific treatments. (d) How is treatment response monitored?
Markscheme: (a) CML. (b) Philadelphia chromosome t(9;22) / BCR-ABL. (c) TKIs — imatinib, nilotinib, or dasatinib. (d) Quantitative RT-PCR for BCR-ABL transcript levels. [6][7]
Q2: A 28-year-old woman with T-ALL and WBC 200 × 10⁹/L develops progressive dyspnoea, hypoxia, and confusion. CXR shows diffuse infiltrates. CT brain normal. What is the diagnosis and immediate management?
Markscheme: Leukostasis. Management: (1) Urgent leukapheresis, (2) Cytoreduction with chemotherapy, (3) TLS prophylaxis (hydration + allopurinol). Do NOT transfuse RBCs before cytoreduction. [1]
Q3: List the metabolic abnormalities in tumour lysis syndrome and the mechanism for each.
Markscheme: Hyperkalaemia (intracellular K⁺ release), hyperphosphataemia (nucleic acid breakdown), hyperuricaemia (purine catabolism), hypocalcaemia (calcium-phosphate precipitation), raised LDH (cell lysis marker), AKI (uric acid/calcium phosphate crystal deposition in renal tubules). [1]
Q4: What is the chance that a sibling is HLA-identical to the patient? Explain why.
Markscheme: 1 in 4 (25%). HLA genes are inherited as haplotypes in Mendelian co-dominant fashion. Each parent contributes one haplotype. A sibling may inherit the same or different haplotype from each parent → 4 possible combinations → 1/4 probability of inheriting both identical haplotypes. [1]
Q5: Name THREE complications of HSCT that are specific to allogeneic transplantation (not seen in autologous).
Markscheme: (1) Graft-versus-host disease (GVHD), (2) Graft rejection (host-versus-graft), (3) GVL effect (beneficial but unique to allogeneic). Also acceptable: more severe immunodeficiency, need for prolonged immunosuppression. [1]
High Yield Summary
1. Leukaemia = clonal malignancy of haematopoiesis; classified by lineage (myeloid/lymphoid) and maturity (acute/chronic).
2. Acute leukaemia presents with bone marrow failure (anaemia, infection, bleeding) ± extramedullary infiltration. Diagnose with bone marrow exam (morphology + cytochemistry + flow cytometry + cytogenetics + molecular).
3. Four haematological emergencies: Neutropenic fever (empirical IV antibiotics ASAP), TLS (hydration + urate-lowering; rasburicase C/I in G6PD), Leukostasis (leukapheresis + chemo; do NOT transfuse RBCs first), DIC in APL (urgent ATRA + arsenic trioxide).
4. CML = Philadelphia chromosome t(9;22) BCR-ABL → constitutively active tyrosine kinase → treat with TKIs (imatinib etc.); monitor with RT-PCR.
5. CLL = elderly, lymphocytosis, smear cells, lymphadenopathy. Watch & Wait if early. Treat with FCR or targeted agents (BTK/BCL2 inhibitors) if symptomatic.
6. Allogeneic HSCT cures via conditioning + healthy donor marrow + GVL effect. HLA matching is essential (Class I on all nucleated cells, Class II on immune cells). Each sibling has 25% chance of HLA match. ABO mismatch is NOT a contraindication.
7. HSCT complications: infection, haemorrhage, VOD, GVHD (acute = skin/GI/liver; chronic = autoimmune-like), graft rejection, cataracts, endocrine dysfunction, secondary malignancy, relapse.
Active Recall - High White Cell Count
[1] Lecture slides: GC 060. High white cell count.pdf (all pages) [2] Lecture slides: GC 086. Splenomegaly.pdf (p3 — take-home message recap) [3] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf (Neutropenic fever section, p1329) [4] Senior notes: Block A - High white cell count_ acute and chronic leukaemia; bone marrow transplantation; immunogenetics.pdf [5] Senior notes: Maksim Medicine Notes.pdf (Tumour lysis syndrome section, p50) [6] Past papers: 2018 Fourth Summative MCQ.pdf (Questions 4-6, p3) [7] Past papers: 2021 Fourth Summative SAQ.pdf (Question 4, p5) [8] Past papers: 2023 Fourth Summative MCQ.pdf (Haematopoietic neoplasms EMQ, p37)