Acute Leukaemia Flashcards
What is acute leukaemia?
A neoplastic condition characterised by: Rapid onset Early death if untreated Immature cells (blast cells) Bone marrow failure
What symptoms can occur due to bone marrow failure in acute leukaemia?
Anaemia: fatigue, pallor, breathlessness
Neutropenia: infections
Thrombocytopenia: bleeding
How would you differentiate acute myeloid leukaemia on blood film under microscope?
Fine granules
What is the epidemiology of AML?
Increases with age
Prognosis worse with increasing age
40% of adults cured
What are the risk factors for AML?
Irradiation
Certain drugs
Benzene exposure
Mostly unknown
What chromosome features may be found in AML?
Many AMLs have aberrations in chromosome count or structure
Such abberations are recurrent and may be directly involved in the development of the leukaemia
List the types of chromosomal abnormalities
Duplication Loss Translocation (new chromosome is called a derivative) Inversion Deletion
What do chromosomal translocations and inversions in leukaemia lead to?
Altered DNA sequence
creation of new fusion genes (AML and ALL)
Abnormal regulation of genes (mainly ALL)
What is the relationship between chromosomal duplication and leukaemia?
Common in AML
Disease hotspts: +8, +21 gives predisposition
What is the relationship between chromosomal loss or deletion and leukaemia?
Common in AML
Disease hotspots - deletion and loss of 5/5q & 7/7q
What happens in most acute myeloid leukaemia?
Block in maturation, blast cells accumulate
Why do people get AML?
Familial or constitutional predisposition Irradiation Anticancer drugs Cigarette smoking Unknown
How does leukaemogeneis occur in AML?
Multiple genetic hits - at least 2 interacting molecular defects, synergise to give leukaemic phenotype
What are the types of abnormalities leading to leukaemogenesis in AML?
Type 1 abnormalities: promote proliferation and survival
Type 2 abnormalities: block differentiation (which would normally be followed by apoptosis)
What is required for differentiation?
Transcription factors: bind to DNA, alter structure to favour transcription, regulate gene expression
What is the gene abnormality in acute promyelocytic leukaemia?
t(15;17)
What are features of acute promyelocytic leukaemia?
Molecular mechanisms understood so molecular treatment can be applied
An excess of abnormal promyelocytes
Disseminated intravascular coagulation
Auer rods
How do we distinguish between AML and ALL?
Cytological features: myeloid - granules and auer rods
(Cytochemistry)
Immunophenotyping: cell surface and cytoplasmic antigens
What are the features of AML on blood film?
Granules
Auer rods
What clinical features occur due to bone marrow failure in AML?
Anaemia: pallor, fatigue
Neutropenia: infection, may be severe and life threatening (septic shock, renal failure, DIC)
Thrombocytopenia: bleeding
What clinical features occur due to local infiltration failure in AML?
Splenomegaly Hepatomegaly Gum infiltration (if monocytic) Lymphadenopathy occasionally Skin, CNS, other sites
What are the steps in diagnosis of AML?
Clinical history Physical examination Blood count and film Bone marrow aspirate (morphology) Cytogenetic studies Immunophenotypic Molecular studies and FISH in selected patient
What are the important features of clinical history in AML?
Past drug/irradiation exposure
What can occur as result of a high white cell count in AML?
Hyperviscosity: retinal haemorrhage, retinal exudates
Why is blood count and film important in diagnosis of AML?
Usually diagnostic: circulating blasts
Auer rods - proves myeloid
What are the treatments available for AML?
Supportive care Chemotherapy Combination chemotherapy Targeted molecular therapy Possibly immunotherapy Transplantation (haematopoietic stem cell transplantation)
What supportive care is given in AML?
Correct the effects of inadequate bone marrow function:
Red cells
Platelets
FFP/Cryoprecipitate if DIC
Antibiotics
Long line
Allopurinol, fluid and electrolyte balance
How does the chemotherapy affect the bone marrow?
Damages DNA
Normal stem cells: often quiescent, checkpoints allow repair of DNA damage
Leukaemia cells: continuously dividing, lack of cell cycle checkpoint control
What is combination chemotherapy?
Use two or more chemotherapy drugs
Different mechanisms of action
Synergy
Non-overlapping toxicity
What determines the prognosis for AML?
Patient characteristics: age, fitness Morphology Immunophenotyping Cytogenetics Genetics Response to treatment
What is the epidemiology of ALL?
Peak incidence in childhood
Most common childhood malignancy
85% of children cured
Prognosis worse with increasing age
What are the clinical features of ALL?
Lymphadenopathy: more common in T-lineage, infiltration of thymus, CNS and testes much more common than AML
Bone marrow failure: anaemia, neutropenia, thrombocytopenia
Local infiltration: lymphadenopathy, splenomegaly, hepatomegaly, kidney, bone
What are the peripheral blood pathological features of ALL?
Anaemia
Neutrophenia
Thrombocytopenia
Usually lymphoblasts
What are the bone marrow and other tissue pathological features of AML?
Lymphoblast infiltration
Lymphoblasts may be B or T lineage
B-lineage - starts in bone marrow
T-lineage - starts in thymus
What are the leukaemogenic mechanisms of ALL?
Proto-oncogene dysregulation: chromosomal translocation - fusion genes, wrong gene promoter, dysregulation by proximity to T cell receptor
What is required for the diagnosis of ALL?
Clinical suspicion Blood count and film Bone marrow aspirate Immunophenotyping Cytogenetic/molecular genetic analysis Blood group, LFTs, creatinine, electrolytes, calcium, phosphate, uric acid, coagulation screen
What are the principles of specific therapy in ALL?
Systemic chemotherapy
CNS-directed therapy
Molecularly targeted treatment
Transplantation
What symptoms in children should make you consider leukaemia as a diagnosis?
Bone pain Limping Pallor Bruising Organomegaly
What symptoms in adults would make you consider leukaemia?
Pallor Bruising Bleeding Infection Organomegaly
