22.1 Acute Leukaemias

Haematological malignancies encompass a heterogeneous spectrum of clonal neoplastic proliferations arising from myeloid or lymphoid lineages. In the MRCP(UK) Part 1 examination, success requires rapid recall of signature chromosomal translocations, immunophenotypic cell-surface clusters of differentiation (CD markers), characteristic peripheral blood film and histological findings, and urgent management protocols for acute oncological presentations.

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1. Acute Leukaemias: AML & ALL

Acute leukaemias represent rapid, uncontrolled clonal expansions of immature haematopoietic progenitor cells (blasts) that arrest normal haematopoietic differentiation, rapidly leading to bone marrow failure.

Acute Myeloid Leukaemia (AML)

• Epidemiology: Predominantly a disease of older adults (median age at diagnosis ~68 years).
• Diagnostic Threshold: World Health Organization (WHO) diagnostic criteria define AML by the presence of >=20% blasts in the bone marrow or peripheral blood (or the presence of AML-defining recurrent cytogenetic abnormalities—such as t(8;21), inv(16), or t(15;17)—regardless of blast percentage).
• Morphology & Cytochemistry: Myeloblasts are large cells with delicate, lacy chromatin, prominent nucleoli, and moderate basophilic cytoplasm containing Auer rods (fused, crystallized primary azurophilic granules containing peroxidase; pathognomonic of myeloid lineage). Blasts stain strongly positive for myeloperoxidase (MPO) and Sudan black B.
• Immunophenotyping: Expression of myeloid surface antigens: CD13+, CD33+, CD34+, and CD117+ (c-kit).

Acute Promyelocytic Leukaemia (APML / AML M3 Subtype)

• Cytogenetics & Molecular Mechanism: Balanced reciprocal translocation t(15;17)(q24;q21), fusing the promyelocytic leukaemia (PML) gene on chromosome 15 to the retinoic acid receptor-alpha (RARA) gene on chromosome 17. The resulting PML-RARA oncoprotein represses transcription, causing absolute maturation arrest at the promyelocyte stage.
• Clinical Emergency: Promyelocytes contain dense, abnormal azurophilic granules rich in tissue factor and annexin II. Cell breakdown releases massive procoagulant and fibrinolytic proteases, precipitating fulminant Disseminated Intravascular Coagulation (DIC) with widespread microvascular thrombosis and life-threatening haemorrhage (catastrophic intracranial or pulmonary bleeding).
• Morphology: Promyelocytes packed with abundant azurophilic granules and stacked clusters/bundles of Auer rods within the cytoplasm, termed "faggot cells".
• MANDATORY EXAM RULE: If APML is clinically or morphologically suspected, EMERGENCY ORAL ALL-TRANS RETINOIC ACID (ATRA / tretinoin) MUST BE INITIATED IMMEDIATELY, without waiting for cytogenetic or molecular confirmation! ATRA binds to the mutated RARA receptor, forcing malignant promyelocytes to overcome the maturation block and differentiate into mature neutrophils. It is combined with arsenic trioxide (ATO), producing cure rates >90% without conventional cytotoxic chemotherapy.
• Differentiation Syndrome: Complication of ATRA/ATO therapy occurring 7–14 days after initiation; presents with fever, dyspnoea, bilateral pulmonary infiltrates, pleural/pericardial effusions, and acute renal failure. Managed by prompt initiation of high-dose intravenous dexamethasone (10 mg twice daily).

Acute Lymphoblastic Leukaemia (ALL)

• Epidemiology: The most common childhood malignancy (peak incidence 2–5 years); secondary smaller incidence peak in adults >60 years.
• Morphology & Cytochemistry: Lymphoblasts have a high nuclear-to-cytoplasmic ratio, condensed chromatin, and inconspicuous nucleoli; MPO negative, but characteristically positive for terminal deoxynucleotidyl transferase (TdT), a specialized DNA polymerase expressed exclusively in immature pre-B and pre-T lymphoblasts.
• Immunophenotypic Subtypes:
  • B-cell ALL (85%): CD10+ (Common ALL Antigen / CALLA), CD19+, CD22+, CD79a+.
  • T-cell ALL (15%): CD2+, CD3+ (cytoplasmic and surface), CD5+, CD7+. Frequently presents in adolescent males as an anterior mediastinal mass causing superior vena cava (SVC) obstruction, stridor, and large pleural effusions.
• Cytogenetic Stratification:
  • t(12;21)(p13;q22) ETV6-RUNX1: Most common in children (~25%); carries an exceptionally favourable prognosis.
  • t(9;22)(q34;q11) BCR-ABL1 (Philadelphia chromosome): Occurs in 25–30% of adult ALL; historically confers an extremely poor prognosis, but outcome is dramatically improved by incorporating BCR-ABL tyrosine kinase inhibitors (imatinib, dasatinib) into chemotherapy.
• Central Nervous System (CNS) Prophylaxis: Lymphoblasts cross the blood-brain barrier and colonize the leptomeninges (meningeal leukaemia: headache, cranial nerve palsies). Intrathecal chemotherapy (methotrexate and cytarabine) is a mandatory component of all curative ALL regimens.

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Presentation and Emergency Complications

Acute leukaemia presents through marrow failure: anaemia causing fatigue and breathlessness, thrombocytopenia causing purpura, epistaxis and gum bleeding, and neutropenia causing fever and infection. Superimposed on this are complications of the leukaemic burden itself.

Leukostasis is far more common in AML than ALL at any given white cell count, because myeloblasts are larger and less deformable. Avoid red cell transfusion before cytoreduction where leukostasis is suspected, since raising the haematocrit worsens hyperviscosity.

Distinguishing AML from ALL

Prognostic Genetics

Cytogenetics dominate prognosis and therefore treatment intensity. In AML, t(15;17) PML-RARA, t(8;21) and inv(16) are favourable, NPM1 mutation without FLT3-ITD is favourable, while FLT3-ITD, complex karyotype and monosomy 7 or 5q deletion are adverse and push toward allogeneic transplantation in first remission. In ALL, the Philadelphia chromosome t(9;22) is the key adverse marker in adults and is now treated with a tyrosine kinase inhibitor added to chemotherapy; hyperdiploidy is favourable.

Acute promyelocytic leukaemia is the one subtype where treatment precedes confirmation. Suspicion alone — a young patient with pancytopenia, bleeding out of proportion to the platelet count, and hypergranular promyelocytes — justifies starting all-trans retinoic acid immediately, because early haemorrhagic death is the main cause of mortality and ATRA is rapidly effective. Differentiation syndrome (fever, dyspnoea, pulmonary infiltrates, weight gain, hypotension) is the principal complication of ATRA and is treated with dexamethasone.