Key Facts

Acute leukaemia is the most common malignancy of childhood. ALL and AML differ in cell lineage, treatment approach, and prognosis. Modern risk-stratified treatment protocols have transformed ALL from a uniformly fatal disease to one with excellent cure rates.

Epidemiology

ALL incidence is approximately 3-4 per 100,000 children per year in the UK, with peak at 2-5 years. AML incidence is approximately 0.7 per 100,000 with a bimodal distribution (peaks in <2 years and adolescence). Slight male predominance in ALL (1.2:1). ALL is more common in Caucasian and Hispanic populations.

Aetiology

ALL: Multistep process — initiating genetic event (often prenatal, e.g., ETV6-RUNX1 translocation) followed by additional postnatal 'hits'. Delayed infection hypothesis (Greaves): Abnormal immune response to common infections in children with limited early infectious exposure.

AML: Chromosomal translocations disrupting haematopoietic transcription factors (e.g., t(8;21) RUNX1-RUNX1T1, PML-RARA in APML).

Predisposition: Down syndrome (ALL and AMKL), Li-Fraumeni syndrome, ataxia telangiectasia, Bloom syndrome, Fanconi anaemia.

Pathophysiology

Clonal proliferation of immature lymphoid (ALL) or myeloid (AML) progenitors in the bone marrow → marrow failure (anaemia, neutropenia, thrombocytopenia) → extramedullary spread (liver, spleen, lymph nodes, CNS, testes). In ALL, leukaemic blasts accumulate due to arrested differentiation and impaired apoptosis. In AML, differentiation arrest at the myeloid progenitor stage.

Common Presenting Features

• Bone marrow failure: Pallor/fatigue (anaemia), recurrent infections/fever (neutropenia), bruising/petechiae/bleeding (thrombocytopenia)
• Organ infiltration: Hepatosplenomegaly (~60%), lymphadenopathy (~50%), bone/joint pain (~25%)
• CNS involvement: Headache, vomiting, cranial nerve palsies (more common in AML, T-cell ALL)
• Testicular involvement: Painless testicular enlargement (ALL)

Specific to ALL

• Bone pain (may mimic JIA)
• Mediastinal mass (T-cell ALL → SVC obstruction, stridor)
• Symptoms often subacute over weeks

Specific to AML

• Gum hypertrophy, skin infiltration (leukaemia cutis)
• DIC (especially APML — acute promyelocytic leukaemia)
• Chloroma (myeloid sarcoma — solid collection of myeloid blasts)

Red Flags

• Pancytopenia or blast cells on blood film — immediate haematology referral
• Mediastinal mass with respiratory compromise — oncological emergency
• DIC (bruising, bleeding, oozing) — APML must be excluded urgently (treat empirically with ATRA)
• Tumour lysis syndrome: Hyperkalaemia, hyperuricaemia, hyperphosphataemia, hypocalcaemia — can be fatal

Bedside

• Full examination: Lymphadenopathy, hepatosplenomegaly, skin/mucosal bleeding, testicular examination
• Observations: Temperature (infection/neutropenic fever), HR, BP

Bloods

• FBC and blood film: Anaemia, thrombocytopenia, WCC variable (may be low, normal, or very high); blast cells on film (diagnostic clue)
• LDH: Elevated (cell turnover)
• Uric acid: Elevated (tumour lysis risk)
• U&Es, calcium, phosphate: Tumour lysis syndrome screening
• Coagulation screen: DIC screening (especially if AML/APML suspected)
• LFTs: Baseline; hepatic infiltration
• Blood group and crossmatch: Anticipate transfusion needs

Imaging

• CXR: Mediastinal mass (T-cell ALL), pulmonary infiltrates
• USS abdomen: Hepatosplenomegaly, renal infiltration

Special Tests

• Bone marrow aspirate and trephine (ESSENTIAL): ≥25% blasts = leukaemia diagnosis
  • Morphology: L1/L2 (ALL), M0-M7 (AML FAB classification)
  • Immunophenotyping (flow cytometry): B-cell ALL (CD19+, CD10+), T-cell ALL (CD3+, CD7+), AML (CD13+, CD33+, MPO+)
  • Cytogenetics: Karyotype, FISH — ETV6-RUNX1 (good prognosis), BCR-ABL1 (poor prognosis), KMT2A rearrangement
  • Molecular genetics: PCR for fusion genes, minimal residual disease (MRD) markers
• Lumbar puncture: CSF cytology for CNS involvement — performed at diagnosis with intrathecal methotrexate
• MRD assessment: Day 29 bone marrow — key prognostic factor; <0.01% MRD = good response

Non-pharmacological

• Specialist PTC management: All childhood leukaemia treated in or through a Principal Treatment Centre
• Supportive care: Blood product support (RBC, platelet transfusions), infection prevention, nutritional support
• Central venous access: Hickman line or port-a-cath insertion
• Tumour lysis syndrome prevention: IV hydration, rasburicase (0.2mg/kg IV) for high uric acid
• Fertility preservation: Discuss prior to treatment in post-pubertal patients

Pharmacological

• ALL treatment phases (e.g., UKALL2011/ALLTogether protocol):
  • Induction (4-5 weeks): Vincristine, dexamethasone, PEG-asparaginase, ± daunorubicin — aim for remission
  • Consolidation/Intensification: Cyclophosphamide, cytarabine, 6-mercaptopurine, methotrexate
  • CNS-directed therapy: Intrathecal methotrexate (all patients); cranial radiotherapy only for CNS disease (now minimised)
  • Maintenance (to total 2 years from diagnosis in girls, 3 years in boys): Daily 6-mercaptopurine, weekly methotrexate, monthly vincristine/dexamethasone pulses
• AML treatment: Intensive chemotherapy (cytarabine + daunorubicin/idarubicin), typically 4-5 cycles over 6-9 months; stem cell transplant for high-risk patients
• APML: All-trans retinoic acid (ATRA) 25mg/m² BD + arsenic trioxide (ATO) — excellent prognosis (~95% cure)
• Ph+ ALL: Imatinib 340mg/m² OD added to chemotherapy backbone

Surgical/Interventional

• Stem cell transplant: For high-risk ALL (poor MRD response, Ph+, KMT2A rearranged, relapsed), high-risk/relapsed AML
• CAR-T cell therapy: Tisagenlecleucel (Kymriah) — NICE TA554 approved for relapsed/refractory B-cell ALL in patients up to age 25

Referral Criteria

• Suspected leukaemia — immediate referral to paediatric haematology/oncology (same day)
• Blast cells on blood film — emergency discussion with PTC

• ALL 5-year survival: ~90% overall; >95% for standard-risk; ~70-80% for high-risk
• AML 5-year survival: ~65-70% overall; APML >95% with ATRA/ATO
• Relapse: Occurs in ~15-20% of ALL; prognosis worse (50-60% salvage depending on timing — late relapse better than early)
• MRD: The single most important prognostic factor — MRD negative at end of induction confers excellent prognosis
• Late effects of treatment: Cardiotoxicity (anthracyclines), neurocognitive (methotrexate, cranial RT), endocrine (GH deficiency, gonadal failure), secondary malignancy (~5% at 30 years), metabolic syndrome, psychosocial
• Infant ALL (KMT2A-rearranged): Poor prognosis — ~50% 5-year survival

ALL Risk Stratification

Key Chromosomal Abnormalities in Childhood Leukaemia