Acute Leukaemia Flashcards
What is acute leukaemia?
Cancer of the blood cells, it is the result of accumulation of early myeloid or lymphoid precursors in the bone marrow, blood and other tissues
Why does acute leukaemia normally occur?
As a result of a somatic mutation within a population of early progenitor cells, may arise de novo (first presenting event) or be the terminal event of a pre-existing blood disorder (eg. CML)
What are the 4 basic types of leukaemia, how is each classified?
Depending on whether it occurs from a progenitor of the myeloid line or lymphoid line:
1) Myeloid leukaemia
2) Lymphoblastic leukaemia
Whether it is acute or chronic
What are therefore the 2 main sub groups of acute leukaemia?
1) AML = acute myeloid leukaemia
2) ALL = acute lymphoblastic leukaemia
How can ALL and AML be further subdivided?
On morphological grounds into various subcategories
What is the name given to the immature cells which appear in the blood in acute leukaemia?
Blast cells - immature neoplastic cells which cannot perform their function
Do the appearance of blast cells vary between ALL and AML how can the appearance be used?
Yes - the morphology is important in determining the subtype but other tests must be performed to confirm the sub type before any therapy is started
What are the 4 main clinical features of leukaemia?
Presents with the features of bone marrow failure:
1) Anaemia
2) Infections
3) Easy bruising and haemorrhage
Organ infiltration by leukaemia cells may also occur eg. spleen, liver, meninges, testes and skin
Why are unusual severe infections common in leukmaemia?
Because as a result of the leukaemia the immune system is incompetent
Give 3 unusual infections which could occur in leukaemia?
1) Staph aureus infection of orbit
2) Severe oral candida infection
3) E Coli and Strep faecalis causing perianal infection
Morphology is the cornerstone of diagnosis of sub-type of acute leukaemia, however what second modality is used to confirm diagnosis and look at prognosis?
Looking at immunological markers
How are immunological markers identified and thus a diagnosis made in leukaemia?
Immunofluorescence and fluorescence activated cell sorting (FACS) which now allows rapid leukaemia diagnosis
Use a monoclonal Abs which are designed to attach to cell surface Ag which differ depending on the type of blast cell. These Ab are fluorescently labelled and those which are bound can be identified, to determine the cell surface Ag and thus the form of leukaemia
What are the 2 classification systems for AML and what is each based on?
FAB classification - based on morphology )
Has been supersceeded by
WHO classification - more risk adapted and based on prognosis
What does the M6 FAB classification refer to?
Leukaemia of erythroblasts which is rare
What are the 5 modalities used in diagnosis of leukaemia?
1) Morphology
2) Cytochemistry - still sometimes done
3) Immunological markers
4) Cytogenetics, FISH - required in diagnosis of certain subtypes
5) Molecular Techniques - PCR
What do cytogenetic abnormalities refer to?
Changes to the structure/ number of whole chromosomes not individual genes
How can cytogenetics aid diagnosis of leukaemia?
1) May help to confirm diagnosis and indicate subtype
2) Can enable you to identify certain cytogenetic abnormalities which correlate with prognosis
Give 2 cytogenetic abnormalities that confer good prognosis in AML?
1) t(8,21)
2) t(15,17)
Give 1 cytogenetic abnormality in AML and one in ALL which confer bad prognosis?
1) Monosomy 7 in AML
2) t(9,22) in ALL
Which cytogenetic abnormality is famously found in CML and is also found in AML?
t(9,22) - the Philadelphia chromosome
ABL-BCR fusion gene = increased tyrosine kinase activity
What is meant by molecular abnormalities?
Changes at the individual gene level
For what 2 reasons are molecular abnormalities important in acute leukaemia?
1) Chr translocations cause molecular changes which may be important in aetiology eg. AML-ETO gene fusion product in t(8,21) - ie can monitor levels of this product in the blood and marrow to check responses to treatment and also catch relapses early
2) Molecular changes may be important in developing treatment strategies eg. use all trans retinoic acid (ATRA) to treat APML (a type of leukaemia) because it targets the PML-RARalpha fusion gene in t(15,17) translocation present in APML
Give 3 mutations found in AML which lead to abnormal cell proliferation?
1) FLT3 mutations - associated with bad prognosis
2) Ras mutations
3) c-KIT mutations
Give 3 molecular abnormalities found in AML which are associated with a block in differentiation?
1) CBF AML (t(8,21) and inv(16))
2) PML-RAR alpha (t(15,17))
3) MLL translocations (11q23)
Give a molecular abnormality found in AML associated with tumour suppression?
NPM1
Which of FLT3 and NPM1 is associated with a good and poor prognosis?
Good = mutations in NPM1 Bad = mutations in FLT3
What is the significance of molecular markers in current management of AML?
1) Risk assessment is complex as more than one abnormality may be present
2) Current interest is development of molecular signature using micro-array analysis (assess each individuals leukaemia genetic profile with an assay of common molecular abnormalities)
3) Minimal residual disease monitoring (MRD) using PCR may allow detection of early relapse and allow earlier treatment of some subtypes eg. APML
4) Some may be the target for therapy eg. FLT3 inhibitors
Give 6 factors which confer poor prognosis in ALL?
1) Increasing age
2) High WCC
3) Male sex
4) Certain cytogenetic abnormalities
5) Poor response to treatment
6) T-ALL and null ALL
What is the treatment for AML? 2
1) Induction treatment to obtain remission, then consolidation with further courses of combination chemo
2) In younger patients consider and bone marrow transplant (sibling or MUD - matched unrelated donor)
What is the treatment for ALL? 4
1) All patients receive induction chemotherapy followed by consolidation therapy
2) All patients receive prophylaxis of meningeal leukaemia with intra-thecal methotrexate (and cranial radiation)
3) Following this maintenance chemotherapy is given or:
4) Bone marrow transplantation in bad risk patients
Why are patients given prophylaxis for meningeal leukaemia?
Brain is a sanctuary sight for leukaemia cells and often chemo doesnt reach there (the same is true for testes) so need to prevent meningeal leukaemia
How are high risk patients with ALL identified for bone marrow transplantation?
Patients with factors conferring poor prognosis such as poor response to treatment and certain cytogenetic abnormalities
How is bone marrow transplant carried out? 2
1) Traditionally a large bore needle to the posterior ilium
2) Now peripheral blood stem cell transplantation can be carried out - now give patients GCSF (granulocyte colony stimulating factor) which stimulates production of stem cells so they spill out into peripheral blood and can be harvested
Why is sepsis such a significant complication of leukaemia therapy?
Neutropenic sepsis occurs
All pts receiving intensive chemo will become neutropenic for 10-21 days - frequently the neutrophil count will fall to levels below 0.2 or be unrecordable
How is neutropenic fever defined?
Pyrexia in the presence of a neutrophil count of less than 0.1 x 10^9/L
What is the cornerstone of management of neutropenic sepsis?
Immediate administration of broad spectrum IV Abx (often Tazocin and Gentamicin) given empirically before the results of cultures are available
In addition to the administration of immediate Abx at the first sign of fever, what 5 other methods are used in prevention of neutropenic sepsis?
1) Protective isolation
2) Prophylactic Abx eg. levofloxacin
3) Use of GCSF (granulocyte colony stimulating factors)
4) Strict hand hygiene
5) Patient education - pt will be going home with neutropenia and thus still at high risk of sepsis
What is one of the main risks of intensive chemotherapy for leukaemia?
Neutropenic sepsis
