HaematologyTier 1Disease (DEADMAN)

Acute lymphoblastic leukaemia

Description

Malignant clonal proliferation of lymphoid precursors (lymphoblasts) in marrow/blood +/- extramedullary sites
B-cell ALL (~85%) vs T-cell ALL (~15%)
Bimodal age distribution - childhood peak, second rise in older adults

Commonest childhood malignancy - peak age 2-5yrs
Second peak >50yrs (biologically different, worse prognosis)
Children: cure rates now >85-90%
Adults: historically much worse outcomes than children, though paediatric-inspired protocols have narrowed the gap in young adults

Acquired genetic lesions in lymphoid progenitors -> maturation arrest + uncontrolled proliferation
Key cytogenetic/molecular subgroups (drive risk stratification):
- Philadelphia chromosome t(9;22) BCR-ABL1 - inc frequency with age (~25% adults, ~3-5% children), historically poor prognosis, transformed by TKIs
- Hyperdiploidy, ETV6-RUNX1 - favourable, mostly paediatric
- Ph-like ALL - genomically resembles Ph+ without the fusion, poor prognosis unless targetable kinase lesion identified
- KMT2A (MLL) rearrangement - infants, poor prognosis
Associated with Down syndrome (both inc ALL risk and inc treatment-related toxicity), NF1, Li-Fraumeni, ataxia-telangiectasia

FBE - anaemia, thrombocytopenia, variable WCC (may be low, normal or very high); blasts on film
Bone marrow aspirate/biopsy - >=20% lymphoblasts confirms diagnosis (WHO)
Immunophenotyping (flow cytometry) - lineage assignment (B vs T), maturation stage
Cytogenetics/FISH + molecular (BCR-ABL1, KMT2A, Ph-like panel) - essential for risk stratification and targeted therapy selection
CNS assessment - lumbar puncture with cytospin at diagnosis (CNS is a sanctuary site)
Distinguish from AML - myeloperoxidase negative, lymphoid markers positive

Risk-stratified, multi-phase chemo-immunotherapy

Induction -> consolidation/intensification -> maintenance (long, 1.5-3 yrs, distinctive to ALL vs AML)
CNS-directed therapy in all patients - intrathecal chemotherapy +/- cranial irradiation in high-risk - prevents/treats sanctuary-site relapse
Philadelphia-positive ALL - TKI (imatinib/dasatinib) added to chemotherapy backbone - transformed outcomes, now near-standard even for older/frail patients
Immunotherapy for relapsed/refractory or MRD-positive B-ALL:
- Blinatumomab (CD19 bispecific T-cell engager)
- Inotuzumab ozogamicin (CD22 antibody-drug conjugate)
- CAR-T cell therapy (tisagenlecleucel) - relapsed/refractory B-ALL, esp. paediatric/young adult
Allogeneic stem cell transplant - high-risk cytogenetics, poor MRD response, relapsed disease
MRD (measurable residual disease) monitoring - central to modern risk stratification and treatment intensity decisions

Down syndrome (inc incidence, inc treatment toxicity/mortality)
Li-Fraumeni syndrome, NF1, ataxia-telangiectasia, constitutional mismatch repair deficiency
Tumour lysis syndrome risk at induction (high proliferative burden) - prophylaxis mandatory
Testicular relapse - a recognised extramedullary sanctuary site (esp. boys)

Children: >85-90% long-term cure with modern protocols
Adults: less favourable overall, but Ph+ outcomes now approach paediatric-like results with TKI era; older/comorbid patients still have worse outcomes
Relapse - marrow, CNS, or testis; salvage options include blinatumomab, inotuzumab, CAR-T, transplant
Long-term survivors (esp. childhood) - late effects surveillance: cardiotoxicity (anthracyclines), secondary malignancy, neurocognitive effects (esp. if cranial irradiation used), infertility

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