Acute Lymphoblastic Leukemia

Acute lymphoblastic leukaemia (ALL) is malignant proliferation of lymphoid precursors (B or T lineage), commonest in childhood.

• Incidence 1.5 per 100,000; peak 2 to 5 years, second peak in older adults; survival over 90% in children, 40 to 50% in adults.
• B ALL (85%): subtypes with ETV6::RUNX1, hyperdiploidy (favourable), BCR::ABL1 (Philadelphia), KMT2A rearranged, hypodiploidy, TCF3::HLF (poor), Ph-like (CRLF2).
• T ALL: NOTCH1 mutations, mediastinal mass.
• Associations: Down syndrome, ataxia telangiectasia, ionising radiation.
• Complications: infection, bleeding, tumour lysis, CNS and testicular involvement, asparaginase toxicity.

• Fatigue, pallor, fever, bleeding, bone pain, limp, hepatosplenomegaly, lymphadenopathy.
• T ALL: mediastinal mass with airway compromise, high white count.
• CNS: cranial nerve palsy, headache; testicular enlargement.
• Superior vena cava syndrome.

• Blood film (lymphoblasts), count, LDH, uric acid, electrolytes, coagulation.
• Bone marrow: 20% or more lymphoblasts, immunophenotype (TdT, CD19, CD10, CD3), cytogenetics and FISH, RT-PCR for BCR::ABL1, next generation sequencing (IKZF1, TP53).
• Lumbar puncture with cytology (CNS status), chest radiograph for mediastinal mass, echocardiogram.
• Minimal residual disease (flow or PCR) at end of induction.

• Multi-agent chemotherapy over 2 to 3 years: induction (vincristine 1.5 mg/m2 weekly, daunorubicin 25 to 30 mg/m2 weekly, prednisolone 40 to 60 mg/m2 or dexamethasone 6 to 10 mg/m2, pegaspargase 2500 units/m2, intrathecal methotrexate 12 mg), consolidation (cyclophosphamide, cytarabine, 6 mercaptopurine 60 mg/m2), high dose methotrexate 3 to 5 g/m2 with leucovorin rescue, delayed intensification, maintenance (6 MP 50 to 75 mg/m2 daily, methotrexate 20 mg/m2 weekly, vincristine-steroid pulses) to 2 years (3 years in boys historically).
• Philadelphia positive ALL: add imatinib 400 to 600 mg daily or dasatinib 100 mg daily (ponatinib 45 mg), with reduced intensity chemotherapy; blinatumomab.
• Relapsed or refractory: blinatumomab 9 then 28 micrograms/day continuous for 4 weeks, inotuzumab ozogamicin, CAR T cell therapy (tisagenlecleucel, brexucabtagene), allogeneic transplant.
• Adolescents and young adults benefit from paediatric inspired regimens.
• T-ALL: nelarabine 1500 mg/m2 days 1, 3, 5 for relapsed disease.
• CNS prophylaxis with intrathecal triple therapy; cranial irradiation limited.
• Supportive: tumour lysis prophylaxis, Pneumocystis prophylaxis (co-trimoxazole 960 mg three times weekly), antiemetics, monitoring for asparaginase pancreatitis, thrombosis, hepatotoxicity.
• Late effects follow up (cardiac, endocrine, neurocognitive).