Acute Lymphoblastic Leukaemia
Malignant proliferation of lymphoid blast cells in bone marrow and blood. Most common childhood cancer (peak age 2–5 years). Highly curable in children (~90% survival) but carries a poorer prognosis in adults.
Key Facts
Most common childhood cancer: peak incidence 2–5 years; ~85% are B-cell ALL Bone marrow failure: anaemia (pallor, fatigue), neutropenia (infections), thrombocytopenia (bleeding, bruising) Lymphoblasts ≥20% in bone marrow (WHO definition) Philadelphia chromosome t(9;22): BCR-ABL1 fusion; present in ~25% of adult ALL (poor prognosis; add TKI — imatinib) CNS involvement: prophylactic intrathecal methotrexate + cranial radiation (children) to prevent CNS relapse Treatment (children): induction (dexamethasone, vincristine, asparaginase, daunorubicin) → consolidation → maintenance (2–3 years) Child survival: ~90% cure rate; adult ALL ~40–50% 5-year survival Tumour lysis syndrome: major risk during initial chemotherapy; prevent with allopurinol/rasburicase, aggressive hydration
Overview
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%)
Clinical Presentation
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
Differential Diagnosis
| Diagnosis | Key Features | Investigation |
|---|---|---|
| AML | Myeloid blasts, Auer rods, MPO positive | Bone marrow, flow cytometry |
| Aplastic anaemia | Pancytopenia, hypocellular marrow, no blasts | Bone marrow |
| Infectious mononucleosis | Reactive lymphocytes, pharyngitis, hepatosplenomegaly | Monospot, EBV serology |
| JIA (systemic) | Fever, rash, arthritis, no blasts on marrow | FBC, bone marrow |
| Neuroblastoma | Young child, abdominal mass, raised catecholamines | Imaging, urine catecholamines |
Diagnosis / Investigation
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)
Management
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)
Prognosis
- 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
Other Relevant Information
Prognostic Factors
| Factor | Good | Poor |
|---|---|---|
| Age | 1–9 years | <1 or >10 years |
| WCC | <50 × 10⁹/L | >50 × 10⁹/L |
| Cytogenetics | Hyperdiploidy, t(12;21) | Hypodiploidy, t(9;22), MLL |
| Immunophenotype | Precursor B-cell | T-cell (variable) |
| MRD (day 29) | Negative | Positive |