Acute Lymphoblastic Leukaemia (ALL)

See Leukaemias — Overview for the cross-subtype comparison table.

A malignancy of B or T lymphoblasts. A series of acquired genetic aberrations produces abnormal proliferation, aberrant differentiation and diminished apoptosis, so malignant cells replace normal marrow elements. Blasts may be B-lymphoblasts or T-lymphoblasts, giving B-ALL and T-ALL.

Leukaemic infiltration of the central nervous system and testes is characteristic — sanctuary sites that shape treatment.

Demographics: the most common cancer in children, and it also strikes adults of all ages. Peak incidence age 2–5, with a second peak after 50. Sixty percent of all ALL cases occur in children. Average lifetime risk about 1 in 1000.

Pattern: malaise + pallor + bone pain.

History

Symptoms and signs may be present for only days to weeks before diagnosis. Some patients are asymptomatic and picked up incidentally on a blood count. The presentation is usually a complication of disrupted haematopoiesis, or of tissue infiltration.

• Anaemia: fatigue, weakness, pallor, malaise, exertional dyspnoea, tachycardia, exertional chest pain.
• Thrombocytopenia: mucosal bleeding, easy bruising, petechiae and purpura, epistaxis, bleeding gums, heavy menstrual bleeding. Spontaneous intracranial or intra-abdominal haemorrhage occurs.
• Neutropenia: fever with severe or recurrent bacterial, fungal or viral infection.
• Infiltration: bone and joint pain (especially in children); enlarged liver, spleen, lymph nodes or testicles; cranial nerve palsies, headache, visual or auditory symptoms, seizures, dizziness, TIA or stroke.

Constitutional symptoms — fevers, fatigue, sweats — are common but may be mild.

Over half of children with leukaemia have at least one of five features at presentation: palpable liver, palpable spleen, pallor, fever, or bruising.

Examination

Hepatomegaly, splenomegaly and lymphadenopathy are seen in up to half of adults at presentation. Check the testes. A mediastinal mass or superior vena cava syndrome can be the presenting problem in T-ALL.

Investigations in general practice

Focused history and thorough clinical assessment, plus full blood examination and film. Add electrolytes, renal function and LDH.

Repeat the film if suspicion persists and the first is unremarkable — features can evolve quickly.

• FBC and film — pancytopenia with peripheral blasts suggests acute leukaemia. Blasts in the peripheral smear may approach 90% of the white cell count.
• Auer rods are never present in ALL, unlike acute myeloid leukaemia.
• Consider aplastic anaemia, viral infection (including EBV), and B12 or folate deficiency in the differential of severe pancytopenia.

Specialist investigations that follow: bone marrow aspirate and biopsy (diagnostic at 20% or more lymphoblasts), immunophenotyping, cytogenetics, and lumbar puncture for CNS involvement.

Referral — this is time-critical

Given the potential for rapid progression, a patient with signs, symptoms or laboratory suspicion of ALL should be promptly assessed and referred to a specialised cancer centre immediately.

• Sepsis, bleeding or severe symptoms — a medical emergency. Refer the same day to an emergency facility, without waiting for laboratory results. Symptomatic anaemia and hyperviscosity symptoms belong in this group too.
• Laboratory diagnosis of possible ALL, patient well — urgent haematology assessment within 24 hours.
• Make direct contact with the emergency and haematology departments to say a patient is on their way with suspected ALL.
• Most initial referrals for ALL will be to an emergency department.

Include psychosocial and medical history, family history, current symptoms, medications and allergies, and all investigation results, so the referral can be triaged for urgency.

Management

Treatment is haematology-led. The GP-relevant shape of it:

• Induction — for children, an anthracycline, vincristine, asparaginase and a corticosteroid. Tyrosine kinase inhibitors are added for Philadelphia-chromosome-positive disease (imatinib, dasatinib, nilotinib, ponatinib).
• Consolidation, then maintenance with oral 6-mercaptopurine or methotrexate.
• CNS prophylaxis by the intrathecal route — often 8 to 16 intrathecal treatments.
• Most protocols take two to three years to complete.
• Stem cell transplantation where indicated, though its role is declining as chemotherapy improves.
• CAR-T therapy (tisagenlecleucel, PBS-listed for relapsed/refractory paediatric and young-adult B-ALL) and blinatumomab for relapsed, refractory or MRD-positive disease.

All blood products must be irradiated before transfusion to prevent transfusion-associated graft-versus-host disease.

Complications seen in primary care

• Febrile neutropenia — fever in a patient on treatment is an emergency, not a wait-and-see.
• Tumour lysis syndrome — hyperuricaemia, high potassium and phosphate, low calcium, renal failure. Occurs on starting chemotherapy; prevented with fluids, and treated with aggressive fluid therapy.
• CAR-T toxicity — cytokine release syndrome and cerebral oedema, both potentially fatal.
• Coagulation problems and infection risk persist throughout treatment.

Prognosis

• Children: five-year overall survival now above 85%.
• Adults: only about 30% can be cured with current therapy.

Good prognostic features: age under 30, normal cytogenetics, white cell count under 30,000, remission within 4 weeks, and in children high hyperdiploidy or t(12;21).

Poor prognostic features: age over 60, t(9;22) or t(4;11), failure to achieve remission within 4 weeks, and precursor B-cell count above 100,000.

Follow-up — the shared-care part

The highest risk of relapse is within the first three years of starting therapy, but later relapse occurs — relapses have been reported as far out as 21 years. Follow-up of asymptomatic patients includes regular full blood count and chemistry plus history and examination.

Usual surveillance schedule in first remission:

• Years 2–3 after treatment: FBC and clinical assessment every 3 months.
• Years 3–5: FBC and clinical review every 3 to 6 months.
• After 5 years: annual FBC and clinical review indefinitely.

Evidence comparing shared follow-up care with specialised care shows equivalence in recurrence rate, survival and quality of life — so a GP-shared schedule is a legitimate model, not a compromise.

Watch for late effects, which may appear months or years later and depend on the treatment given: fatigue, cognitive change, fear of recurrence, anxiety and depression, sleep problems, return-to-work and financial difficulty, and fertility, contraception and pregnancy issues needing specialist input. Cancer survivors are also more likely than the general population to develop comorbidities.