Define Acute Lymphoblastic Leukaemia. Describe its clinical features, investigations, management and prognosis.

Definition

• Acute lymphoblastic leukaemia (all) is a malignant proliferation of immature lymphoid precursor cells (lymphoblasts) in the bone marrow, which replace normal haematopoiesis.
• It is the commonest childhood malignancy, with a peak incidence at 2–5 years.

Clinical Features

Symptoms arise from bone-marrow failure and tissue infiltration:

• Anaemia — pallor, fatigue, breathlessness.
• Thrombocytopenia — bruising, petechiae, bleeding.
• Neutropenia — fever and recurrent/severe infections.
• Infiltration — bone pain (limp, refusal to walk), generalised lymphadenopathy, hepatosplenomegaly, a mediastinal mass (T-cell all), and CNS or testicular involvement.

Investigations

• Haemogram — anaemia, thrombocytopenia, and a variable white-cell count with circulating blasts.
• Peripheral smear — lymphoblasts.
• Bone-marrow examination — diagnostic (> 20–25% blasts); with immunophenotyping (flow cytometry) and cytogenetics/molecular studies for classification and risk.
• CSF examination (CNS involvement); raised LDH and uric acid; baseline biochemistry and imaging.

Management

• Multi-agent chemotherapy in phases — induction (to achieve remission), consolidation/intensification, CNS-directed therapy (intrathecal chemotherapy ± cranial radiation), and maintenance for a total of ~2–3 years.
• Risk stratification (age, WBC count, immunophenotype, cytogenetics, treatment response/MRD) guides intensity.
• Supportive care — transfusions, management of febrile neutropenia (prompt broad-spectrum antibiotics), and prevention/treatment of tumour lysis syndrome (hydration, allopurinol/rasburicase).
• Stem-cell transplant for high-risk/relapsed disease.

Prognosis

• The prognosis is very good in children — with modern risk-adapted therapy, long-term cure rates exceed 85%.
• Favourable factors include age 1–10 years, a low presenting white-cell count, B-cell lineage, favourable cytogenetics and a rapid response to treatment.

Classification

• B-cell precursor all — the commonest, generally more favourable.
• T-cell all — often older boys, high WBC count and a mediastinal mass.
• Sub-classified further by cytogenetics/molecular markers for risk.

Differential Diagnosis

• Aplastic anaemia (pancytopenia, no organomegaly), ITP (isolated thrombocytopenia).
• Infections (EBV, whooping cough with lymphocytosis), juvenile arthritis (bone/joint pain), other malignancies (neuroblastoma marrow infiltration).

Tumour Lysis Syndrome

• Massive tumour breakdown at the start of therapy → hyperkalaemia, hyperphosphataemia, hyperuricaemia, hypocalcaemia and acute kidney injury.
• Prevent with hydration and allopurinol/rasburicase and close biochemical monitoring.

Late Effects of Therapy

• Neurocognitive effects (CNS therapy), endocrine/growth effects, cardiotoxicity (anthracyclines), second malignancies and infertility.
• Long-term survivorship follow-up is important.

Prognostic Factors

Sanctuary Sites & Relapse

The CNS and testes are 'sanctuary sites' where chemotherapy penetrates poorly — hence dedicated CNS-directed therapy; relapse at these sites (or in the marrow) is treated with intensified therapy or transplant.

Supportive Care

• Transfusion support; prompt management of febrile neutropenia; infection prophylaxis.
• Nutritional and psychological support; management of chemotherapy side-effects.

Emergencies in a Child with Leukaemia

• Febrile neutropenia — urgent broad-spectrum antibiotics.
• Tumour lysis syndrome — hydration + allopurinol/rasburicase.
• Hyperleukocytosis (very high WBC) — risk of leukostasis; mediastinal mass — airway/SVC compression.

WHY a Limping Child May Have Leukaemia

• A clinical pattern worth knowing is understanding why a child with acute lymphoblastic leukaemia may present not with pallor or bleeding but with bone pain — refusing to walk, or limping, or waking at night crying.
• The leukaemic blasts do not stay in the blood: they proliferate massively within the marrow cavity, expanding it and stretching the richly-innervated periosteum, and they also infiltrate the bone directly.
• The result is deep, persistent bone pain — characteristically in the long bones of the legs, often worse at night, and not relieved by rest.
• A small child cannot describe this: they simply limp, refuse to weight-bear, or become irritable and stop walking — and they are frequently misdiagnosed as having 'growing pains', a viral arthritis, juvenile idiopathic arthritis or trauma, and treated with analgesics for weeks.
• The clues that should prompt a full blood count and film are: bone pain that is persistent, nocturnal and out of proportion; associated pallor, fever, bruising or petechiae; lymphadenopathy or hepatosplenomegaly; or any unexplained cytopenia.
• Hence the rule: in any child with unexplained bone pain or a limp, DO A blood count and look AT the film.

WHY the CNS Must Be Treated Even Though It Looks Clear

• One of the most instructive principles in oncology is understanding why every child with all receives treatment directed at the brain and spinal cord — even when there is no evidence whatever of disease there.
• The reason is the blood-brain barrier.
• Most systemic chemotherapy penetrates the CNS poorly — so the central nervous system acts as a 'sanctuary site': any leukaemic cells that seeded there early are shielded from the drugs that are clearing the marrow and the blood.
• The child therefore goes into apparent complete remission — while a small population of blasts survives, protected, in the meninges.
• Weeks or months later, they multiply and cause a CNS relapse, which then re-seeds the marrow and is far harder to cure.
• Before CNS-directed therapy became routine, this was the commonest cause of treatment failure.
• The solution is to deliver the drug where the blood cannot: intrathecal methotrexate, given directly into the CSF, together with high-dose systemic methotrexate (and cranial irradiation in selected high-risk cases) — given prophylactically to every child.
• This single strategy is a major reason why childhood all is now cured in over 80%.