Acute Leukaemia Flashcards
Definition
Clonal haematopoietic neoplasm characterised by accumulation of malignant white cells in the bone marrow and blood
> 20% blasts in PB or BM
Aggressive clinical course
Aetiology and Epidemiology
De novo
- genetic predisposition e.g. Down’s syndrome, fanconi’s anaemia, bloom syndrome
- previous chemotherapy/ radiation
Secondary to MDS or MPN
Epidemiology
- ALL is common form in children (highest incidence at 3-7 yrs)
- AML at all ages but increasing incidence with age
Clinical presentation of acute leukaemia
BM failure (blasts interfere with normal development)
- anaemia
- thrombocytopenia (bleeding tendency)
- neutropenia (infection)
Hyperleucocytosis (>100)
–> hyperviscosity syndrome –> reduced tissue perfusion and hypoxia
Organ infiltration
- bone pain (ALL)
- lymphadenopathy (ALL)
- testicular swelling (ALL)
- CNS symptoms e.g. headache, blurred vision, SOB (ALL)
- mediastinal mass (T-ALL)
- gum hypertrophy (AML-M5)
Classical presentations of APL
Bleeding tendency!
- Extensive ecchymoses due to DIC, fibrinolysis and thrombocytopenia
- intracranial bleeding
Classification of leukaemia
Myeloid vs Lymphoid
Acute vs Chronic
- acute = accumulation of precursors (blasts
- chronic = accumulation of mature/differentiated cells
Classification of AML
Risk stratification, predict prognosis and formulate management
Classify based on cytogenetic abnormalities, gene mutations, dysplasia, history of therapy
- AML with recurrent genetic abnormalities e.g. inv(16), t(8;21), APL with t(15;17), NPM1 mutation etc
- AML with myelodysplasia related changes e.g. hx of MDS
- therapy related myeloid neoplasms e.g. hx of chemotherapy
- AML not otherwise specified
Classification of ALL
B lymphoblastic vs T lymphoblastic vs ambiguous lineage
for B-ALL
- with recurrent genetic abnormalities e.g. t(9;22), hyperdiploidy
- not otherwise specified
Investigation of acute leukaemia
- CBC, Blood film, BM immunophenotyping –> confirm diagnosis and define Myeloblast vs Lymphoblast
- Cytogenetics (karyotyping, FISH) and genetic analysis –> subtyping, identify markers useful for therapy and monitoring
- Plan appropriate treatment e.g. chemotherapy with ATRA and arsenic trioxide in APL, allogeneic SCT in poor risk groups, molecular targeted therapies
- Look for complications
- profound DIC in APL – PT, APTT, D-dimer, Fibrinogen
- septicaemia – blood culture
- tumour lysis syndrome – RFT, uric acid, Ca, PO4, LDH
- extra-medullary involvement – lumbar puncture (ALL) - Rule out other diseases that may mimic acute leukaemia e.g. AA, marrow infiltration by CA causing B< failure
B-ALL prognostic subgroups
Unfavourable
- <1 yrs old or >10 yrs old
- hypodiploidy, t(9;22)
- MRD >0.01% on day 29
Favourable
- 1-10 yrs old
- hyperdiploidy, t(12;21)
AML prognostic subgroups
Favourable
- APL
- t(8;21), inv(16)
- NPM1/CEBPA mutant
Unfavourable
- inv(3), monosomy 7
- FLT3 mutant
CBC, Blood film and BM in acute leukaemia
CBC
- pancytopenia
- leucocytosis (variable)
Blood film
- circulating blasts (myelo-/lympho-)
- circulating promyelocytes – APL (bi-lobated nuclei, heavily granulated, auer rods; Faggot cells)
- Auer rods
- leucoerythroblastic blood picture
- dysplastic neutrophils (hyposegmented, hypogranular cytoplasm)
BM
- blasts
- hypercellular with diffuse infiltration
- abnormal promyelocytes with auer rods
Myeloblast vs Lymphoblast morphology
Myeloblast
- abundant cytoplasm, fine granules, Auer rods, fine chromatin, prominent nucleoli
Lymphoblast
- very high N:C ratio, agranular cytoplasm, clumped chromatin, indistinct nucleoli
Immunophenotyping - function, method, differentiating markers
Confirm diagnosis and lineage by identification of lineage specific antigens
Fluorochrome labelled Ab specific to cell surface markers –> process by flow cytometry –> scatter plots
B-lymphoblasts: CD10, 19, 22, 34, Tdt (rarely express CD20 which is mature Ag)
T lymphoblasts: CD3, 7, 34, Tdt (early); CD2, 5, 4, 8 (on further differentiation)
- negative for surface CD3 which is expressed late in maturation
Myeloid:
- myeloblast, monoblast: CD34, 117, 13, 33
- erythroblast: CD235a, HbA (and 34, 117)
- megakaryoblast: CD31, 41, 42, 61
Genetic analysis in acute leukaemia - purpose
DNA changes at chromosome level or nucleotide level which can be visualised in cytogenetic analysis or detected by PCR
==> prognostic implication and risk stratification
==> molecular targeted therapy feasibility
==> MRD monitoring
Genetic analysis: cytogenetics - method, example of abnormality
Direct morphological analysis of chromosomes
- tumour cells cultured and arrested at metaphase the condensed
- each chromosome has own specific banding pattern
Look for gain/loss of chromosome
Deletion, duplication, inversion, translocation
e.g. t(15;17) in APL - PML-RARA
