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:

1. How to classify leukaemias (WHO Haematolymphoid Tumours, 5th edition)
2. How to manage acute and chronic leukaemias (supportive + specific)
3. Haematological emergencies that can kill before you even make a diagnosis
4. Haematopoietic stem cell transplantation (HSCT) — how and why it cures leukaemia
5. 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

The WHO 5th-edition framework (released online in 2022; print volume 2024) prioritises defining genetic abnormalities over morphology. The hierarchy is:

1. AML with defining genetic abnormalities (specific translocations/mutations define distinct entities) ^[1]
   • APL with PML::RARA fusion — t(15;17)
   • AML with RUNX1::RUNX1T1 fusion — t(8;21)
   • AML with CBFB::MYH11 fusion — inv(16)
   • AML with DEK::NUP214 fusion
   • AML with RBM15::MRTFA fusion
   • AML with BCR::ABL1 fusion
   • AML with KMT2A rearrangement
   • AML with MECOM rearrangement
   • AML with NPM1 mutation
   • AML with NUP98 rearrangement
   • AML with CEBPA mutation
   • AML, myelodysplasia-related
2. AML, defined by differentiation (when no defining genetic abnormality is found) ^[1]
   • AML with minimal differentiation
   • AML without maturation
   • AML with maturation
   • Acute myelomonocytic leukaemia
   • Acute monocytic leukaemia
   • Acute erythroid leukaemia
   • Acute megakaryoblastic leukaemia
3. Step 2 — Diagnostic qualifier appended to any of the above diagnoses ^[1]:
   • Post cytotoxic therapy / therapy-related
   • Post-MDS or MDS/MPN
   • Associated with germline gene variant or genetic predisposition

How to read the dense classification slide: the myeloid table moves genetics-defined AML entities ahead of morphology-defined categories; the lymphoid diagram similarly combines morphology, immunophenotype and defining genomic lesions. The practical message is to preserve material for cytogenetics and molecular testing. The conventional 20% blast threshold is not absolute for every genetics-defined AML entity, so do not let a single blast percentage overrule a defining abnormality. ^[9][10]

Why does this matter? The integrated diagnosis determines risk, targeted therapy and transplant planning. In suspected APL, however, life-saving ATRA begins before genetic confirmation rather than waiting for the final classification.

Use the local protocol definition; a common high-risk definition is a single oral temperature ≥38.3°C or ≥38.0°C sustained for ≥1 hour, with ANC < 0.5 × 10⁹/L or expected to fall below it. A clinically septic patient is treated immediately even if the latest ANC has not yet crossed a numeric threshold.

Why is this an emergency? Without neutrophils, infection may progress rapidly while pus, erythema and other inflammatory signs remain muted.

The first case slide is already an emergency: WBC 86.5 × 10⁹/L with approximately 91% blasts, platelets 27 × 10⁹/L and ANC about 0.9 × 10⁹/L, together with fever, petechiae and hypotension, shows blast-dominant AML with thrombocytopenia and evolving neutropenic sepsis/shock. The blood film is dominated by large immature cells; morphology raises AML, while flow/genetics complete the diagnosis.

Management:

1. Assess ABC, lactate and organ perfusion; activate the local neutropenic-sepsis pathway.
2. Draw peripheral and line blood cultures (plus targeted cultures/imaging) without delaying antibiotics.
3. Give an empirical IV antipseudomonal regimen immediately; in a systemically compromised patient, aim for delivery within 1 hour. Add agents only for specific clinical/epidemiologic indications.
4. Give careful fluid resuscitation and vasopressors when indicated, with early critical-care input. ^[11][12]

TLS is metabolic injury from rapid malignant-cell breakdown; it may be spontaneous or treatment-induced.

Cell lysis releases K⁺ and phosphate and supplies nucleic acids for urate production: hyperkalaemia causes arrhythmia; phosphate binds calcium, producing hypocalcaemia and calcium-phosphate precipitation; and urate plus calcium phosphate injure the kidney. LDH reflects cell turnover but is not itself a Cairo–Bishop criterion.

Clinical case and images: WBC 540.95 × 10⁹/L, Hb 6.5 g/dL, platelets 62 × 10⁹/L and circulating blasts 423.74 × 10⁹/L indicate extreme hyperleukocytosis with marrow failure. The film shows large lymphoblasts with high nuclear-to-cytoplasmic ratios and scant agranular basophilic cytoplasm; flow establishes T lineage. Paired chest radiographs show a large mediastinal mass that markedly regresses after treatment, fitting thymic T-ALL. Before or around treatment, K 5.5 mmol/L, creatinine 369 µmol/L, phosphate 1.73 mmol/L, urate 1161 µmol/L and LDH 729 U/L indicate spontaneous/established clinical TLS with acute kidney injury, not merely “risk of TLS.”

Do not routinely alkalinise urine: it lacks clear benefit and can promote calcium-phosphate deposition. Treat hyperkalaemia immediately; avoid treating asymptomatic hypocalcaemia unless necessary. ^[13]

Reading the purine diagram: hypoxanthine → xanthine → uric acid is catalysed by xanthine oxidase, so allopurinol/febuxostat prevent new urate formation. Rasburicase acts downstream on urate already present. That is why allopurinol alone is inadequate for Ms B's urate of 1161 µmol/L.

Leukostasis is a clinical syndrome of end-organ dysfunction from hyperleukocytosis, most often affecting lungs and brain. No WBC threshold by itself diagnoses it.

Hyperleukocytosis is often defined as WBC > 100 × 10⁹/L, but symptoms can occur below this in AML and be absent above it in lymphoid disease. Large, poorly deformable and adhesive blasts impair the microcirculation; this is why lineage and cell biology matter as much as the count.

Clinical features: pulmonary leukostasis causes dyspnoea, hypoxia and diffuse infiltrates; cerebral disease causes headache, lethargy, confusion or focal/visual symptoms. Retinal vascular compromise and priapism may occur.

Reading Ms B's emergency images: new desaturation and mental dullness with bilateral diffuse pulmonary infiltrates and no intracranial haemorrhage on CT is clinical leukostasis involving lung ± brain. Infection, pulmonary oedema, haemorrhage and TLS can coexist and must be assessed in parallel.

Treatment:

1. Urgent haematology/critical-care review, oxygen/airway support and cautious IV hydration.
2. Immediate cytoreduction (often hydroxyurea while arranging lineage-directed definitive therapy); treat TLS and DIC concurrently.
3. Leukapheresis is selective and adjunctive for symptomatic leukostasis. Evidence does not support routine use for asymptomatic hyperleukocytosis, and it must not delay definitive therapy; it is generally avoided in APL.
4. RBC transfusion can increase viscosity. If anaemia is not immediately life-threatening, defer until cytoreduction; if essential, use cautious aliquots with haematology/transfusion input rather than an absolute “never transfuse” rule.

t(15;17) creates PML::RARA, producing a differentiation block at the promyelocyte stage.

APL coagulopathy combines procoagulant activity, hyperfibrinolysis and endothelial/proteolytic effects; it is more complex than simple release of “granule tissue factor.” Expect bleeding, thrombocytopenia, raised D-dimer and low fibrinogen, with abnormal heavily granulated promyelocytes and bundles of Auer rods on film.

WBC is often low/normal but is variable; WBC > 10 × 10⁹/L defines high-risk APL in the classic risk model.

Treatment — do not wait to start ATRA:

• Start ATRA immediately when APL is suspected, then urgently confirm PML::RARA. Risk-adapted arsenic-trioxide-based therapy follows confirmation, with anthracycline or gemtuzumab added for high-risk disease according to protocol.
• Maintain fibrinogen > 100–150 mg/dL, platelets > 30–50 × 10⁹/L and INR < 1.5 with cryoprecipitate/fibrinogen, platelets and FFP as needed; recheck coagulation at least daily and more often while unstable.
• Avoid non-essential invasive procedures. Routine heparin or antifibrinolytic therapy is not recommended. ^[16]

Clinical Presentation (Ms. C case): ^[1]

• F/58, fatigue, weight loss, early satiety, LUQ fullness
• Splenomegaly 7 cm below costal margin
• CBC: WBC 254.56 × 10⁹/L, Hb 7.9 g/dL and platelets 608 × 10⁹/L, with neutrophilia, myelocytes and basophilia; peripheral-blood blasts are only about 1%
• PB image: a continuous granulocytic maturation spectrum with increased basophils, not a blast-dominant acute-leukaemia film
• BM image: marked hypercellularity with granulocytic proliferation and small hypolobated (“dwarf”) megakaryocytes — a classic CML pattern, confirmed by BCR::ABL1

Natural history and current classification: ^[1][17]

The lecture's three-arrow diagram reflects the historical chronic → accelerated → blast-phase model. WHO HAEM5 uses a biphasic chronic/blast-phase model, while ICC/ELN retain accelerated-phase or warning features for clinical risk assessment; always state which framework you are using. ^[9][17]

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]

Monitoring: ^[1]

Monitor molecular response with quantitative RT-PCR for BCR::ABL1 transcript levels.

The slide's response pyramid is historically useful but its printed percentages are not the current International Scale. Report BCR::ABL1IS:

“Undetectable” is not synonymous with zero disease: report assay sensitivity and control-transcript adequacy rather than “complete molecular response.” Milestones at approximately 3, 6 and 12 months guide whether to continue, investigate adherence/interactions, mutate-test or switch therapy. Treatment-free remission is considered only in carefully selected patients with sustained deep molecular response and access to frequent PCR monitoring. ^[17][18]

HSCT in CML: ^[1]

Reserved mainly for advanced-phase disease or resistant/intolerant CML with inadequate TKI options. T315I alone is no longer an automatic transplant indication because ponatinib and asciminib may be active; the whole mutation, response and risk trajectory matters. ^[17]

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

The serial CBC rises from an absolute lymphocyte count of about 6.3 to 17.9 × 10⁹/L in 6 months. The film shows many small mature lymphocytes with clumped chromatin and red-arrowed smudge debris; occasional larger cells should prompt attention but do not by themselves prove transformation. Persistent clonal B-cell lymphocytosis ≥5 × 10⁹/L for ≥3 months, confirmed by flow cytometry, establishes CLL rather than morphology alone. ^[19]

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]

Treatment starts for iwCLL-defined active disease (for example progressive marrow failure, symptomatic/progressive bulky nodes or spleen, rapid progression, refractory autoimmune cytopenia or constitutional symptoms), not for stage or lymphocyte count alone. TP53 status, IGHV, renal/cardiac risk, drug interactions and patient preference shape regimen selection. FCR, chlorambucil monotherapy and idelalisib are lecture-era options, not default modern first-line choices. ^[19][20]

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).

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

1. Conditioning suppresses host immunity and reduces disease burden 2. Donor haematopoietic stem cells engraft and reconstitute marrow/immune function 3. Graft-versus-leukaemia (GVL) immunity attacks residual malignant cells ^[1]

Conditioning may be myeloablative or reduced-intensity; cure is not simply “more chemotherapy plus replacement marrow.” Donor immune effect is central, especially with reduced-intensity conditioning. GVL and GVHD are related alloimmune phenomena, so the aim is disease control without harmful host-tissue attack.

ABO incompatibility is NOT an exclusion in HSCT. ^[1]

Why? HLA compatibility is the dominant immunogenetic issue. ABO-mismatched grafts remain feasible but can cause haemolysis, delayed erythroid engraftment or pure red-cell aplasia and may require graft processing/transfusion planning; “not an exclusion” does not mean “irrelevant.”

Timeline:

1. Pre-graft conditioning (illustrated as day −6 to −1) — chemotherapy ± TBI; intensity and duration vary
   • Purpose: reduce disease, create marrow/immune space and prevent rejection
2. Day 0: Stem cell infusion — donor graft (BM or PBSC) infused IV
3. Post-graft aplastic phase — cytopenias with infection and bleeding risk; duration varies by source/regimen
4. Engraftment — recovery of donor-derived neutrophils, followed later by platelets/immune reconstitution
5. GVHD prophylaxis and surveillance begin around transplantation and continue after engraftment according to regimen ^[1]

Reading the procedure images: marrow harvest is performed under anaesthesia from the posterior iliac crests; peripheral-blood stem cells are collected by apheresis after mobilisation. The transplant itself is an intravenous infusion resembling a blood transfusion, not an operation to implant marrow into bone.

Donor choice is now integrated rather than a fixed ladder: HLA match and donor-specific antibodies, donor age/health, graft source, disease urgency, CMV status, sex/pregnancy history, ABO compatibility and the planned GVHD-prophylaxis platform all matter. Modern post-transplant cyclophosphamide has improved outcomes with haploidentical and mismatched unrelated donors. ^[21][22]

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]

High-resolution HLA matching reduces — but does not eliminate — graft failure and GVHD. Minor histocompatibility antigens and non-HLA donor/recipient factors still matter. ^[21][22]

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 linked HLA alleles on one chromosome 6. Each full sibling has an independent 25% chance of inheriting both of the same parental haplotypes, 50% of sharing one, and 25% of sharing neither. The pedigree slide's wording should read “one haplotype from each parent,” not “patient.”

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).

Donor availability in practice: ^[1][21][22]

• A given full sibling has a 25% chance of being HLA-identical; family size determines whether a patient actually has one.
• Search and procurement times vary greatly, so high-resolution patient/family typing and unrelated-donor search should begin early when HCT is plausible.
• Haploidentical, mismatched unrelated and cord-blood grafts widen access; each has distinct donor-specific-antibody, graft-dose, engraftment and GVHD considerations.
• The local 2017–2023 activity graph shows increased haploidentical use at one centre. It is an institutional snapshot, not proof that one donor type is universally superior.

Expanding access — Reduced-Intensity Conditioning (RIC): ^[1]

• Introduction of less-toxic reduced-intensity conditioning regimens, improved supportive care, and better antimicrobial agents have expanded HSCT eligibility to older patients previously considered ineligible
• Eligibility is based on disease benefit, frailty/comorbidity and patient goals rather than chronological age alone.