12- Introduction to Leukemia

Question 1

what is leukaemia?

Answer 1

a group of malignant disorders of haemopoietic stem cells

associated with a clonal increase of white cells in bone marrow and/or peripheral blood from a single mutant cell

Question 2

concept/ causes of leukaemia?

Answer 2

• clonal disease = all the malignant cells originate from a single mutant stem cell
• mutations can occur in HSCs or progenitor cells
• give rise to leukemic stem cells which can self-renew and divide indefinitely, and overproduce abnormal blood cells

Question 3

list diagnostic tests for leukaemia

Answer 3

peripheral blood blast tests
bone marrow test/biopsy
lumbar puncture

Question 4

describe different diagnostic tests for leukaemia

Answer 4

peripheral blood blast tests = examining peripheral blood film to identify presence of abnormal blast cells

bone marrow test/ biopsy = identify leukemic white cells

lumbar puncture = collecting CSF to check for leukaemia involvement in the CNS

Question 5

clinical presentation of leukaemia

Answer 5

varies between different types of leukaemia

• abnormal bruising
• repeating abnormal infections
• sometimes anaemia

caused by loss of normal blood cell production and increased WBCs

Question 6

list different methods for molecular and pathophysiological characterisation of leukemic cells

Answer 6

immunophenotyping
cytomorphology
FISH
NGS
flow cytometry

Question 7

describe the different methods for molecular and pathophysiological characterisation of leukemic cells

Answer 7

cytomorphology = microscopic examination of cell morphology to identify abnormal cells

immunophenotyping = identifying cell surface markers using antibodies to classify cell types, can identify type of leukaemia

NGS = identifies specific DNA mutations, information of leukaemia gene profile

flow cytometry = identifies specific cell populations, analyses physical and chemical characteristics

FISH = detect chromosomal abnormalities in bone marrow sample cells/ leukemic cells

Question 8

different types of causes for leukaemia

Answer 8

exact cause is unclear, believed to be a combination of predisposing factors

1. genetic risk factors
2. environmental risk factors
3. lifestyle-related risk factors
4. uncertain, unproven/ controversial factors

Question 9

describe the genetic risk factors for leukaemia

Answer 9

it isn’t a hereditary disease but there are genetic risk factors that increase susceptibility:

• chromosomal abnormalities
  = rearranging genetic material between different chromosomes can activate oncogenes or inactivate TS genes, produce fusion oncogenes
• gene mutations
  = oncogenes activated - promote uncontrolled cell growth
  = TS genes inactivated - loss of cell growth and proliferation regulation
• rare genetic diseases
  = e.g. Fanconi’s anaemia, Down’s syndrome, inherited immune problems
• familial chronic lymphocytic leukaemia
  = family history - genetic predisposition

Question 10

describe environmental risk factors for leukaemia

Answer 10

radiation exposure
chemical exposure or past chemotherapy
immune system suppression

Question 11

describe lifestyle-related risk factors for leukaemia

Answer 11

smoking
drinking
excessive sun exposure
overweight

Question 12

describe the more controversial risk factors

Answer 12

exposure to electromagnetic fields
infections in early life
mother’s age when child was born
nuclear power stations
parent’s smoking history
foetal exposure to hormones

Question 13

what are the two main divisions for leukaemia? compare their differences

Answer 13

acute and chronic

acute
- mainly in children, sudden onset of symptoms, lasts weeks/ months
- variable WBC count
- acute lymphoid & acute myeloid leukaemias

chronic
- mainly in the elderly, slow onset of symptoms, lasts years
- high WBC count
- chronic lymphoid & myeloid leukaemias

Question 14

describe acute leukaemia

Answer 14

includes acute lymphoid (ALL) and acute myeloid (AML)

• sudden onset of symptoms
• most common type of leukaemia in children = 75% ALL, 20% AML
• type of blast can’t be identified based on morphology

mechanism:
- uncontrolled clonal proliferation and accumulation of immature WBCs/ blasts in bone marrow and blood
- blast cell pool doesn’t develop into mature cells = no cell death = increased accumulation of lymphoblasts/ myeloblasts
- type of blast can’t be identified based on morphology

Question 15

symptoms of acute leukaemia (ALL/AML)

Answer 15

low platelets/ thrombocytopenia causes - bruising/ purpura, nosebleeds and gum bleeding

neutropenia - prone to recurrent infections

anaemia - weakness, fatigue, shortness of breath

Question 16

describe acute lymphoid leukaemia - prevalence, origin, classification, treatment and treatment outcome

Answer 16

prevalence - commonest cancer in children

origin - cancer of accumulated immature lymphocytes/ lymphoblasts

classification - B - and T cell-leukaemia

treatment - chemotherapy, bone marrow transplant

treatment outcome - 5-year event free survival, 1 in 10 patients relapse
= adults have a poorer prognosis
= remission in 50% of patients after second chemo treatment following a bone marrow transplant

Question 17

describe acute myeloid leukaemia - prevalence, origin, classification, treatment and treatment outcome

Answer 17

prevalence - rarer, 20% of leukaemia cases in children

origin - cancer of immature myeloid WBCs

classification - M0-M7

treatment - chemotherapy, or monoclonal antibodies for immunotherapy, or allogenic bone marrow transplant

treatment outcome - 5-year event-free survival of 50/60%

Question 18

describe chronic leukaemia

Answer 18

differentiated leukaemia

characterised by uncontrolled clonal proliferation and accumulation of mature WBCs - generally the one’s before final differentiation

CLL.(lymphoid) or CML (myeloid)

Question 19

describe chronic lymphoid leukaemia - prevalence, origin, symptoms, treatment and treatment outcome

Answer 19

prevalence - more common than CML

origin - large numbers of mature clonal lymphocytes in bone marrow and peripheral blood

symptoms
- recurrent infections from neutropenia and suppressed lymphocyte function
- anaemia
- thrombocytopenia
- lymph node enlargement
- hepatosplenomegaly

treatment - regular chemotherapy

outcome - 5-year event free survival of 83%
- many patients survive more than 12 years

Question 20

describe chronic myeloid leukaemia - prevalence, origin, symptoms, treatment and treatment outcome

Answer 20

prevalence - less common than CLL

origin - large numbers of mature myeloid WBCs

symptoms/ features
- often asymptomatic, diagnosed through routine blood tests
- high white cell count/ neutrophilia
- presence of Philadelphia chromosome = causes 95% of cases

treatment - targeted therapy by imatinib

outcome - 5-year event-free survival of 90%
- if it progresses to a blast crisis = allogenic bone marrow transplant is needed

Question 21

what are the effects of the Philadelphia chromosome oncogene that contribute to leukaemia?

Answer 21

BCR-ABL gene induces:

• proliferation of progenitor cells in the absence of growth factors
• decreased apoptosis
• decreased adhesion to bone marrow stroma

Question 22

how can the Philadelphia chromosome be used in diagnosis and treatment of CML?

Answer 22

diagnosis
- FISH can identify fusion BCR-ABL oncogene on translocated chromosome 22 through differential labelling of the two genes

treatment
- imatinib = targets inhibition of ABL
= has fewer side effects though some patients become drug resistant

Question 23

what is imatinib?

Answer 23

drug used to treat CML through targeted therapy - targets inhibition of ABL gene

prevents proliferation of myeloid progenitor cells without growth factors, increases apoptosis and adhesion to bone marrow stroma = prevents cancer development and progression