ALL Flashcards
What
Malignant transformation of a clone of cells from lymphoid progenitor cells
Majority are of B-cell origin, but can also arise from T-cell precursors.
Lymphoid precursors proliferate and replace normal cells of bone marrow -> blasts spill into peripheral circulation
Distinguished from other lymphoid malignancies by immunophenotype of cells
Types
Common (75%): CD10 present, pre-B phenotype
T-cell (20%)
B-cell (5%)
Epidemiology/Risk factors
Most common childhood malignancy, 80% of childhood leukaemias
Peak age 2-4 years, rare in adults (small peak >50yo)
Few causal links established. Complex disease and may need several ‘hits’ for malignant transformation.
Genetics: concordance in twin studies; trisomy 21 have 10-20x risk; other disorders with chromosomal fragility have higher risk (eg Fanconi’s anaemia); many pts have cytogenetic abnormalities at diagnosis; prenatal chromosomal translocations -> fusion genes are important but not sufficient alone.
Environmental: Difficult to investigate; radiation important (high-dose in adults, potentially even low-dose background IONISING (not non-ionising such as phone mast/power lines) in children); other (weakly) suggested include hydrocarbons, pesticides, alcohol, cigarettes, drugs.
Infection: Insulation from common infections early may predispose to abnormal reactions later -> higher risk; babies who attend daycare have decreased risk; ?seasonal variation in birthdate/diagnosis; ?viruses; increased ALL with ‘outbreaks’ in rural immunologically naïve communities -> Kinlen’s population mixing theory.
Presentation
Typically deteriorate rapidly
Initially generalised fatigue and malaise, quickly progress to BM failure
Anaemia: lethargy, pallor, dizziness, palpitations, dyspnoea, tachycardia + flow murmur
Neutropenia: frequent/severe infections (oral, throat, skin, perianal), fever without obvious infection
Thrombocytopenia: bruising, petechiae (purpura/ecchymoses), nosebleeds
DIC: thrombosis
BM infiltration: Bone pain (severe/unusual)
Splenomegaly: LUQ fullness and early satiety; abdominal distention
Testicular enlargement
Lymphadenopathy
Gum hypertrophy
Leukaemia cutis
CNS involvement: headache, irritability, neck stiffness, altered mental state
Large mediastinal mass in T-cell tumours: dypsnoea
Mature B-cell ALL: cranial nerve palsy (III, IV, VI)
Investigations - bloods
FBC: anaemia, may be severe; thrombocytopenia; WCC high, normal or low but with neutropenia. If FBC normal leukaemia unlikely (but some patients may not yet have marrow suppression)
Blood film: blast cells (but may be normal if blast cells confined to BM)
Clotting: DIC -> raised PT, reduced fibrinogen, presence of fibrin degredation products
LDH: raised
Urate: raised
LFTs, U+Es: prior to chemo
If fever, identify and treat infection (eg blood cultures)
Investigations - imaging
CXR: pneumonia, mediastinal mass, lytic bone lesions
Testicular US: if testes enlarged
ECG, ECHO and/or MUGA: cytotoxic chemo
Haematology, immunology and genetic tests
BM aspiration (and biopsy): >20% blasts in BM or blood
Immunophenotyping: to confirm lymphoid (Tcells, Bcells, NKcells), not myeloid (all the others) and reveal subtype - important for therapy
Cytogenetics (of BM): Hyperdiploidy common, several balanced translocations identified including t(12;21) -> TEL-AML fusion gene -> common phenotype. Phildalphia chr (t(9;22)) in some adults - very poor prognosis. Others too.
Negative myeloperoxidase stain
BCR-ABL PCR - identify those who came to ALL as blastic phase of CML
Management - general and supportive
Exact protocols vary by age
Typically remission induction, consolidation (intestification) and maintenance (continuation) therapies.
Replacement of blood cells - deficiency due to ALL aggravated by chemo
Growth factors for profound myelosuppression
Antibiotics and antifungals for opportunistic infections.
Allopurinol during induction to control urate levels.
Central venous catheter is usual.
Management - induction of remission
Goals:
1) Eliminate >99% of initial burden of leukaemic cells
2) Restore normal haematopoiesis
3) Restore previous performance status
Treatment should start immediately.
Steroids +/- another drug
Lots of supportive therapy. Severe neutropenia often seen.
Complete remission rates are good.
Management - maintenance
Once normal haematopoiesis achieved.
Usually daily 6-mercaptopurine and weekly methotrexate.
Sometimes repeated more intensive chemo cycles given.
Treatment duration usually 2.5-3 years
Management - CNS prophylaxis
Meningeal leukaemia common esp at relapse
Effective prophylaxis essential part of ALL therapy.
Lots of ways of doing it, can reduce CNS relapse rate.
Cranial irradiation can cause acute and late complications (secondary cancers, neurocognitive deficits, endocrinopathy) so largely no longer used.
Management - SCT
Allows more intensive chemo
Exact benefit unclear
Benefits most those with Philadelphia chr and poor response to treatment
Management - relapse
Very poor prognosis
Trial ‘salvage’ therapies - better prognosis if young and short duration of first remission
Chemo
Biologic therapies coming through
Complications - acute
Most complications due to therapy Haemorrhage, anaemia, infection, even with blood replacement. Fever in neutropenic patient = emergency Hair loss, rashes GI effects (all of them) Electrolyte disturbances Nephrotoxicity, hepatotoxicity Peripheral neuropathy Psychological disturbances Tumour lysis syndrome (esp children): Raised urate, phosphate and postassium, low calcium - treat with alkaline IV fluids to aid renal excretion. Closely monitor U+Es Sinus venous thrombosis -> stroke Acute GvHD
Complications - longer-term
Cardiomyopathy, arrhythmias Lung fibrosis Growth delary Hypothryoidism Infertility Secondary malignancies Pyschosocial effects - education and occupation
