Leukamia - Part 1 Blood Cell Abnormalities

Question 1

What disease is Leukamia

Answer 1

Disease of the bone marrow

Question 2

How does the cancer arise and what are the two different types?

Answer 2

It is caused by mutation in the precursor cells.
Myeloid and lymphoid

Note that myeloid may include precursors of granulocytes and monocytes but also erythroid and megakaryocytic

Question 3

Why does it differ from other cancer?

Answer 3

Cells circulate in the blood and migrate (cant apply concept of metastasis)
Can form localised tumours, which in fact are not inevitable from early stages of disease either

Question 4

What are the two terms to describe leukamias and what do they mean instead of acute and chronic?

Answer 4

Acute - if untreated profound pathological effects and leads to death in a matter of days, weeks or months.
Chronic leukaemia - less impairment of function of normal tissue but eventually will lead to death

So to finalise - will get acute, chronic, lymphoid, myeloid

Question 5

How does leukamia occur?

Answer 5

Mutations in primitive cell, has growth or survival advantage over normal cells undergone mutation.
Gives rise to clones
Which slowly replace normal cells
Mutations in proto oncogenes and sometime tumour suppressor genes.

Question 6

Causes of acute lymphoblastic

Answer 6

Usually unknown 
Sometimes mutagenic agents 
Exposure to irradiation 
Chemicals in utero 
Delayed exposure to common pathogen or pathogens

Question 7

Acute myeloid

Answer 7

Usually unknown
Sometimes irriadiation
Mutanogenic chemicals
Chemicals (benzene, cigarette smoke)

Question 8

Chronic myeloid

Answer 8

Usually unknown

Rarely irradiation or mutanogenic drugs

Question 9

Chronic lymphoid

Answer 9

Unknown but some families are predisposed

Question 10

What behaviour can a leukaemic clone induce

Answer 10

Growth that occurs without dependence on growth factors
Continued proliferation without maturation
Failure to undergo normal cell death (apoptosis)

Question 11

Say some clinical features of AML

Answer 11

• middle to old age
• demonstrated as a result of multiple mutations
• onset effect is usually acute but there is a smouldering or preleukaemic phase in about 15%
• survival for adults between 25-45 years old

Question 12

Differences in blood film and blood count in AML

Haematological results

Answer 12

Anaemia present
Thrombocytopenia
Increased blast cells in peripheral blood
These cells might be myeloblasts, monoblasts, or both
Neutropenia and they might show dysplasia
Anisocytosis and poikilocytosis is common
Bone marrow is hypercellular and aspiration may be difficult.

Note that AML can be classified according to differentiation in myeloblasts, monoblasts, erythroblasts, megakaryoblasts

Question 13

Some clinical features

Answer 13

From proliferation of leukaemic cells
- splenomegaly and hepatomegaly and often lymphadomegaly
-leukaemic cells can infiltrate the skin and gums when in monocytic differentiation
- in high white blood counts can lead to obstruction of blood vessels known as leucostasis
- can lead to stroke or resp impairment
Often promyelocytic is associated with DIC and prominent bleeding bruising

See common features for others

Question 14

Treatment if AML

Answer 14

Intensive chemotherapy with drugs such as - daunorubicin and cytarabine which would make the initial leukaemic cells to disappear. This is them followed by consolidation therapy to eliminate any residual cells and prevent relapse. Usually several courses. And then maintained therapy, less toxic drugs given for one to two years

Note the patient always needs support with red cell, platelet transfusion, antibiotics, antivirals, antifungals.

Immunotherapy using a a myeloid antigen

Haemopoetic stem cell transplant

Question 15

Prognosis in AML

Answer 15

70% of adults achieve remission but over half relapse within 2 years. Long term survival is 25%.

Long term results in children are better

Question 16

How can blasts be recognised 4

Answer 16

Large size
High nuclei/ cytoplasm ration
Open chromatic pattern of nuclei
Prominent nucleoli

Question 17

Some difference between chronic and acute

Answer 17

Acute - mutation in transcription factors which means inability to mature. Cells can still proliferate but there is an inability to mature. So this continued proliferation without maturation, they replace normal bone marrow cells and failure occurs

Chronic - mutation involves activation of signalling pathways within the cell. Cells can still proliferate without needing growth factors. Abnormal interaction with stroma and cell survival prolonged to steady expansion of the leukaemic clone and I the case of myeloid mature stem cells can still function. But in lymphocytic we get a steady expansion of the clones so functionally useless and impaired tissue function as more clones replace actual cells.

Question 18

Prevalence of chronic myeloid leukaemia

Answer 18

Uncommon type with about 1-2 between 100000 per year

It is more common in adults than children

Question 19

Haematological features of CML 4

Answer 19

Increase in white blood cells - leucocytosis
Particularly in granulocytes - eosinophils, basophils, neutrophils and monocytes
Platelet count is usually normal or high, may be anaemia which is usually severe.
Bone marrow is hypercellular because of increase in granulocytic and megakaryocytes

Question 20

What causes CML ?

Answer 20

From specific chromosomal translocation in the chromosome 9 and 22
In a single haemopoetic stem cell
So turns form a ABL1 gene which codes for tyrosine kinase enzyme which has a tighly regulated activity
But the new mutation is BCR- ABL1 (oncogene) which leads to uncontrolled tyrosine kinase and gives rise to a leukaemic clone
This results to an abnormally short chromosome 22 which is called the Philadelphia chromosome (first chromosome found to link to malignancy)

The mutation gives the cells growth and survival advantage which gives rise to the leukaemic clone

All the haemoatological results above could be due reactive neutrophilia. So the cytogenic analysis is needed for for confirmation of the diagnosis

Question 21

Some clinical features or CML not the general ones

Answer 21

• splenomegaly
• tyrosine kinase - phosphorylate the tyrosine residues. Key in cell proliferation. When growth factor attaches to the cell then tyrosine kinase start signal and proliferation occurs

Question 22

Treatment for CML

Answer 22

Most successful treatment is the tyrosine kinase inhibitors

Question 23

Key features for acute lymphoblastic leukaemia

Answer 23

Childhood disease peak age 2-5 years old
85% cured, much worse in adults than children this is because Philadelphia translocation is rare in children
Heterogeneous group of disorders, 75-80% are of the B lineage and the rest of the T lineage

Question 24

Describe briefly about ALL

Answer 24

Increase of lymphoblastic with failure to develop into mature lymphocytes
= results to impaired haemopoisis and the lymphoblastic circulate peripheral blood

Question 25

Clinical features of ALL

Answer 25

• effects can result from direct effects of proliferation of leukaemic cells or from bone marrow impairement or over crowding of haemopoetic stem cells

Common infiltrations-
But also testicular infiltration, renal infiltration or CNS one
So with high WBC you can have renal failure and other metabolic disturbances, as a result of tumour lysis syndrome.

Paleness and bruising
If in T cell lineage then there is enlargement of the thymus which can be seen in a chest x ray.

Question 26

Haematological features of ALL

Answer 26

• anaemia normocytic, normochromic
• leukocytosis with lymphoblasts in the blood
• thrombocytopenia
• replacement of normal bone marrow cells by lymphoblasts

Question 27

Why is cytogenetic and molecular genetic analysis done in ALL and what does it show

Answer 27

Useful because it gives us information about the prognosis and give us more targeted development targeted treatment
Hyper diploidy is a good prognosis
With translocation in chromosomes 12 and 21
But a bad prognosis is associated with some other translocations such as 4, 11. Chromosomes and the others such as the 9 and 22 one which is the Philadelphia chromosome.

Question 28

Treatment for ALL

Answer 28

Two fold so supportive therapy and then a combo of chemotherapy and attack to leukaemia.

So first supportive- red cells, platelets and antibiotics if infection occurs.
Careful fluid management is key.

Chemotherapy has a few different stages — remission/induction, consolidation, maintenance.
Systemic chemotherapy, can give drugs to cerebrospinal fluid, by a lumbar puncture and drugs that can cross the blood brain barrier.
Cranial irridiation can sometimes occur and if Philadelphia chromosome is present then there is a chance of tyrosine kinase inhibitors used. And for poor prognosis then there is a chance is a allogeneic stem cell transplantation offer the only chance of a cure.

Chemo is tailored to the translocation and genetics in general.

Can have both long term and short term toxicity. Short term is reversible to normal tissue and bone marrow suppression.
But long term can result to infertility, mild cognitive impairment. And a slight risk of developing AML by damage to normal haemopoietic stem cells by chemotherapy. So it is really important to balance the good and the bad of this illness.

Question 29

Key features of chronic lymphocytic leukamia

Answer 29

Early middle age and to elderly
Median age is 70s. Commonest leukaemia in Western Europe and Northern America
And more common in men than in women.

Question 30

What can we see in CLL, haematological features

Answer 30

mature but abnormal T B and NK cells.
Lymphocytosis
With more advanced disease there is more bone marrow infiltration.

See 4 mature CLL lymphocytes
And a smear or smudge characteristic.
So small mature lymphocytes with clamped chromatin and scanty (small and insufficient quantity) cytoplasm these are small and fragile cells and result to smear cells.

(Seeing the profile of the cell surface markers expressed at lymphocytes helps determine the cause of lymphocytosis, or to cytometry to see a specific pattern)

Question 31

Treatment for CLL

Answer 31

Most don’t need treatment but the ones that do may be given cyclophosphamide, fludarabine, rituximab which is immunotherapy and gives good results overall.

Vaccinate against influenza and meningococcus

Question 32

What are the direct effects of proliferation of leukaemic cells 4

Answer 32

Bone pain
Hepatomegaly
Splenomegaly
Lymphadenomegaly

Question 33

What are the indirect effects of leukaemia of cell proliferation

Answer 33

This leads to replacement of normal bone marrow cells by leukaemic cells causing anaemia, thrombocytopenia, neutropenia

Question 34

Clinical features include 6 sub parts with symptoms

Answer 34

• fatigue, lethargy, pallor (anaemia)
• fever and infections (neutropenia)
• bruising and petechiae (thrombocytopenia)
• bone pain (bone marrow expansion)
• abdominal enlargement (hepatomegaly, splenomegaly)
• lumps and swelling (lymphadenomegaly)

Question 35

What are some key investigations needed?

Answer 35

• full blood count
• blood film
• characterise cell surface markers by a technique known as flow cytometry
• bone marrow sample, to perform a cytogenetic/molecular analysis on blood markers such as the Philadelphia chromosomes
  This gives information about prognosis and how to approach treatment.

Question 36

Can mutations happen in pluripotent lymphoid myeloid stem cells?

Answer 36

Yes they can and include both myeloid and lymphoid cells.

Question 37

Where do lymphomas occur? And what are the two different types?

Answer 37

They develop in other tissues
Non Hodgkin lymphoma - may be B T or NK lineage. Divided to lymphoblastic lymphomas which are similar to lymphoblastic leukaemia. And then of each different lineage of B or T or NK
Hodgkin - the neoplastic cell of B lineage which lacks some B cell features